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Entry
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- *600163 - SODIUM VOLTAGE-GATED CHANNEL, ALPHA SUBUNIT 5; SCN5A
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*600163</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<a href="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/600163">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</div>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000183873;t=ENST00000423572" class="mim-tip-hint" title="Genome databases for vertebrates and other eukaryotic species." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/genome/gdv/browser/gene/?id=6331" class="mim-tip-hint" title="Detailed views of the complete genomes of selected organisms from vertebrates to protozoa." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Genome Viewer', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Genome Viewer</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&hgFind=omimGeneAcc&position=600163" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000183873;t=ENST00000423572" class="mim-tip-hint" title="Transcript-based views for coding and noncoding DNA." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl (MANE Select)</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_000335,NM_001099404,NM_001099405,NM_001160160,NM_001160161,NM_001354701,NM_001407185,NM_001407186,NM_001407187,NM_198056,NR_176299,XM_011533991" class="mim-tip-hint" title="A collection of genome, gene, and transcript sequence data from several sources, including GenBank, RefSeq." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI RefSeq', 'domain': 'ncbi.nlm.nih'})">NCBI RefSeq</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_000335" class="mim-tip-hint" title="A collection of genome, gene, and transcript sequence data from several sources, including GenBank, RefSeq." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI RefSeq (MANE)', 'domain': 'ncbi.nlm.nih'})">NCBI RefSeq (MANE Select)</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&hgFind=omimGeneAcc&position=600163" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimProtein">
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<span class="panel-title">
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<span class="small">
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<a href="#mimProteinLinksFold" id="mimProteinLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimProteinLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Protein
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</a>
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</span>
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</span>
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</div>
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<div id="mimProteinLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://hprd.org/summary?hprd_id=02543&isoform_id=02543_1&isoform_name=Isoform_1" class="mim-tip-hint" title="The Human Protein Reference Database; manually extracted and visually depicted information on human proteins." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HPRD', 'domain': 'hprd.org'})">HPRD</a></div>
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<div><a href="https://www.proteinatlas.org/search/SCN5A" class="mim-tip-hint" title="The Human Protein Atlas contains information for a large majority of all human protein-coding genes regarding the expression and localization of the corresponding proteins based on both RNA and protein data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HumanProteinAtlas', 'domain': 'proteinatlas.org'})">Human Protein Atlas</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/protein/184039,15072487,18073677,18073679,18073681,18073683,18073685,18073687,18073689,18073691,18073695,24559815,29569618,30089970,30410900,37622907,44886082,44886084,62087312,70673315,119584944,119584945,119584946,124302208,125662134,125662136,125662138,125662140,129714326,146048457,148888458,148888460,150417967,150417969,187954621,215273881,219521582,237512980,237512982,289470054,526131777,767923970,1237938032,1471157318,1471157346,2245789868,2245789928,2245789948,2462591806" class="mim-tip-hint" title="NCBI protein data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Protein', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Protein</a></div>
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<div><a href="https://www.uniprot.org/uniprotkb/Q14524" class="mim-tip-hint" title="Comprehensive protein sequence and functional information, including supporting data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UniProt', 'domain': 'uniprot.org'})">UniProt</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGeneInfo">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGeneInfoLinksFold" id="mimGeneInfoLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimGeneInfoLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Gene Info</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimGeneInfoLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="http://biogps.org/#goto=genereport&id=6331" class="mim-tip-hint" title="The Gene Portal Hub; customizable portal of gene and protein function information." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'BioGPS', 'domain': 'biogps.org'})">BioGPS</a></div>
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<div><a href="https://www.ensembl.org/Homo_sapiens/Gene/Summary?db=core;g=ENSG00000183873;t=ENST00000423572" class="mim-tip-hint" title="Orthologs, paralogs, regulatory regions, and splice variants." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl</a></div>
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<div><a href="https://www.genecards.org/cgi-bin/carddisp.pl?gene=SCN5A" class="mim-tip-hint" title="The Human Genome Compendium; web-based cards integrating automatically mined information on human genes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GeneCards', 'domain': 'genecards.org'})">GeneCards</a></div>
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<div><a href="http://amigo.geneontology.org/amigo/search/annotation?q=SCN5A" class="mim-tip-hint" title="Terms, defined using controlled vocabulary, representing gene product properties (biologic process, cellular component, molecular function) across species." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GeneOntology', 'domain': 'amigo.geneontology.org'})">Gene Ontology</a></div>
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<div><a href="https://www.genome.jp/dbget-bin/www_bget?hsa+6331" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<dd><a href="http://v1.marrvel.org/search/gene/SCN5A" class="mim-tip-hint" title="Model organism Aggregated Resources for Rare Variant ExpLoration." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MARRVEL', 'domain': 'marrvel.org'})">MARRVEL</a></dd>
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<dd><a href="https://monarchinitiative.org/NCBIGene:6331" class="mim-tip-hint" title="Monarch Initiative." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Monarch', 'domain': 'monarchinitiative.org'})">Monarch</a></dd>
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<div><a href="https://www.ncbi.nlm.nih.gov/gene/6331" class="mim-tip-hint" title="Gene-specific map, sequence, expression, structure, function, citation, and homology data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Gene', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Gene</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chr3&hgg_gene=ENST00000423572.7&hgg_start=38548062&hgg_end=38649687&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:10593" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:10593" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=600163[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimVariation">
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<span class="panel-title">
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<span class="small">
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<a href="#mimVariationLinksFold" id="mimVariationLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimVariationLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">▼</span> Variation
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</a>
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</span>
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</span>
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</div>
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<div id="mimVariationLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ncbi.nlm.nih.gov/clinvar?term=600163[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://www.deciphergenomics.org/gene/SCN5A/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000183873" class="mim-tip-hint" title="The Genome Aggregation Database (gnomAD), Broad Institute." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'gnomAD', 'domain': 'gnomad.broadinstitute.org'})">gnomAD</a></div>
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<div><a href="https://www.ebi.ac.uk/gwas/search?query=SCN5A" class="mim-tip-hint" title="GWAS Catalog; NHGRI-EBI Catalog of published genome-wide association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Catalog', 'domain': 'gwascatalog.org'})">GWAS Catalog </a></div>
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<div><a href="https://www.gwascentral.org/search?q=SCN5A" class="mim-tip-hint" title="GWAS Central; summary level genotype-to-phenotype information from genetic association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Central', 'domain': 'gwascentral.org'})">GWAS Central </a></div>
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<div><a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=SCN5A" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="#mimLocusSpecificDBsFold" id="mimLocusSpecificDBsToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="A gene-specific database of variation."><span id="mimLocusSpecificDBsToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Locus Specific DBs</div>
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<div id="mimLocusSpecificDBsFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="http://databases.lovd.nl/genomed/home.php?select_db=SCN5A" title="Zhejiang University-Adinovo Center SCN5A Database" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Zhejiang University-Adinov…</a></div><div style="margin-left: 0.5em;"><a href="http://www.fsm.it/cardmoc/" title="Gene Connection for the Heart" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Gene Connection for the He…</a></div><div style="margin-left: 0.5em;"><a href="http://www.ssi.dk/graphics/html/lqtsdb/lqtsdb.htm" title="Long QT Syndrome mutation database" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Long QT Syndrome mutation …</a></div>
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</div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=SCN5A&upstreamSize=0&downstreamSize=0&x=0&y=0" class="mim-tip-hint" title="National Heart, Lung, and Blood Institute Exome Variant Server." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NHLBI EVS', 'domain': 'evs.gs.washington.edu'})">NHLBI EVS</a></div>
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<div><a href="https://www.pharmgkb.org/gene/PA304" class="mim-tip-hint" title="Pharmacogenomics Knowledge Base; curated and annotated information regarding the effects of human genetic variations on drug response." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PharmGKB', 'domain': 'pharmgkb.org'})">PharmGKB</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
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<span class="panel-title">
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<span class="small">
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<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Animal Models</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.alliancegenome.org/gene/HGNC:10593" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://flybase.org/reports/FBgn0285944.html" class="mim-tip-hint" title="A Database of Drosophila Genes and Genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'FlyBase', 'domain': 'flybase.org'})">FlyBase</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:98251" class="mim-tip-hint" title="International Mouse Phenotyping Consortium." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'IMPC', 'domain': 'knockoutmouse.org'})">IMPC</a></div>
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<div><a href="http://v1.marrvel.org/search/gene/SCN5A#HomologGenesPanel" class="mim-tip-hint" title="Model organism Aggregated Resources for Rare Variant ExpLoration." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MARRVEL', 'domain': 'marrvel.org'})">MARRVEL</a></div>
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<div><a href="http://www.informatics.jax.org/marker/MGI:98251" class="mim-tip-hint" title="Mouse Genome Informatics; international database resource for the laboratory mouse, including integrated genetic, genomic, and biological data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Gene', 'domain': 'informatics.jax.org'})">MGI Mouse Gene</a></div>
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<div><a href="https://www.mmrrc.org/catalog/StrainCatalogSearchForm.php?search_query=" class="mim-tip-hint" title="Mutant Mouse Resource & Research Centers." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MMRRC', 'domain': 'mmrrc.org'})">MMRRC</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gene/6331/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=6331" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellLines">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cell Lines</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellLinesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://catalog.coriell.org/Search?q=OmimNum:600163" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:6331" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<div><a href="https://reactome.org/content/query?q=SCN5A&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 283645003, 51178009, 60423000, 698249005<br />
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<strong>ICD10CM:</strong> I49.8<br />
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<strong>ICD9CM:</strong> 427.81, 798.0<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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600163
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</span>
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</span>
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</div>
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</div>
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<div>
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<a id="preferredTitle" class="mim-anchor"></a>
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<h3>
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<span class="mim-font">
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SODIUM VOLTAGE-GATED CHANNEL, ALPHA SUBUNIT 5; SCN5A
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</span>
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</h3>
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</div>
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<div>
|
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
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SODIUM CHANNEL, VOLTAGE-GATED, TYPE V, ALPHA SUBUNIT<br />
|
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NAV1.5
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=SCN5A" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">SCN5A</a></em></strong>
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</span>
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</p>
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</div>
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<div>
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<a id="cytogeneticLocation" class="mim-anchor"></a>
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<p>
|
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<span class="mim-text-font">
|
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<strong>
|
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<em>
|
|
Cytogenetic location: <a href="/geneMap/3/181?start=-3&limit=10&highlight=181">3p22.2</a>
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|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr3:38548062-38649687&dgv=pack&knownGene=pack&omimGene=pack" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">3:38,548,062-38,649,687</a> </span>
|
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</em>
|
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</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
|
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<a id="geneMap" class="mim-anchor"></a>
|
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<div style="margin-bottom: 10px;">
|
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<span class="h4 mim-font">
|
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<strong>Gene-Phenotype Relationships</strong>
|
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</span>
|
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</div>
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<div>
|
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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<span class="hidden-sm hidden-xs pull-right">
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<a href="/clinicalSynopsis/table?mimNumber=272120,614022,601144,601154,113900,113900,603830,608567,603829" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
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View Clinical Synopses
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</a>
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<th>
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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<td rowspan="9">
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<span class="mim-font">
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<a href="/geneMap/3/181?start=-3&limit=10&highlight=181">
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3p22.2
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</a>
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</td>
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<td>
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<span class="mim-font">
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{Sudden infant death syndrome, susceptibility to}
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<span class="mim-font">
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<a href="/entry/272120"> 272120 </a>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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<span class="mim-font">
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Atrial fibrillation, familial, 10
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/614022"> 614022 </a>
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</span>
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</td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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<span class="mim-font">
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Brugada syndrome 1
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</span>
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<td>
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<span class="mim-font">
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<a href="/entry/601144"> 601144 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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<tr>
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<span class="mim-font">
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Cardiomyopathy, dilated, 1E
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/601154"> 601154 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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<tr>
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<td>
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<span class="mim-font">
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Heart block, nonprogressive
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/113900"> 113900 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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</span>
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</td>
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<tr>
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<td>
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<span class="mim-font">
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Heart block, progressive, type IA
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/113900"> 113900 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Long QT syndrome 3
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/603830"> 603830 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Sick sinus syndrome 1
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/608567"> 608567 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Ventricular fibrillation, familial, 1
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/603829"> 603829 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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<div class="btn-group">
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
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PheneGene Graphics <span class="caret"></span>
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</button>
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<ul class="dropdown-menu" style="width: 17em;">
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<li><a href="/graph/linear/600163" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<li><a href="/graph/radial/600163" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
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</ul>
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</div>
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<a id="text" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<strong>TEXT</strong>
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<div>
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<a id="cloning" class="mim-anchor"></a>
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<h4 href="#mimCloningFold" id="mimCloningToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimCloningToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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<div id="mimCloningFold" class="collapse in mimTextToggleFold">
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<p><a href="#20" class="mim-tip-reference" title="Gellens, M. E., George, A. L., Jr., Chen, L., Chahine, M., Horn, R., Barchi, R. L., Kallen, R. G. <strong>Primary structure and functional expression of the human cardiac tetrodotoxin-insensitive voltage-dependent sodium channel.</strong> Proc. Nat. Acad. Sci. 89: 554-558, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1309946/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1309946</a>] [<a href="https://doi.org/10.1073/pnas.89.2.554" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1309946">Gellens et al. (1992)</a> cloned and characterized the cardiac sodium channel gene SCN5A. The deduced 2,016-amino acid protein has a structure similar to that of previously characterized sodium channels (see <a href="/entry/182392">182392</a>) and contains 4 homologous domains, each of which has 6 putative membrane-spanning regions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1309946" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#19" class="mim-tip-reference" title="Freyermuth, F., Rau, F., Kokunai, Y., Linke, T., Sellier, C., Nakamori, M., Kino, Y., Arandel, L., Jollet, A., Thibault, C., Philipps, M., Vicaire, S., and 31 others. <strong>Splicing misregulation of SCN5A contributes to cardiac-conduction delay and heart arrhythmia in myotonic dystrophy.</strong> Nature Commun. 7: 11067, 2016. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27063795/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27063795</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27063795[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ncomms11067" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27063795">Freyermuth et al. (2016)</a> stated that alternative splicing creates fetal and adult isoforms of SCN5A that differ in inclusion of alternative exons 6a or 6b, respectively. Both exons 6 have 92 bp, but encode 7 different amino acids in the voltage-sensor region of SCN5A domain I. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27063795" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<br />
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<a id="geneStructure" class="mim-anchor"></a>
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<h4 href="#mimGeneStructureFold" id="mimGeneStructureToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimGeneStructureToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<strong>Gene Structure</strong>
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</h4>
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<p><a href="#69" class="mim-tip-reference" title="Wang, Q., Li, Z., Shen, J., Keating, M. T. <strong>Genomic organization of the human SCN5A gene encoding the cardiac sodium channel.</strong> Genomics 34: 9-16, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8661019/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8661019</a>] [<a href="https://doi.org/10.1006/geno.1996.0236" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8661019">Wang et al. (1996)</a> found that SCN5A consists of 28 exons spanning approximately 80 kb. They described the sequences of all intron/exon boundaries and a dinucleotide repeat polymorphism in intron 16. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8661019" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<br />
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<a id="mapping" class="mim-anchor"></a>
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<h4 href="#mimMappingFold" id="mimMappingToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimMappingToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><a href="#21" class="mim-tip-reference" title="George, A. L., Jr., Varkony, T. A., Drabkin, H. A., Han, J., Knops, J. F., Finley, W. H., Brown, G. B., Ward, D. C., Haas, M. <strong>Assignment of the human heart tetrodotoxin-resistant voltage-gated Na(+) channel alpha-subunit gene (SCN5A) to band 3p21.</strong> Cytogenet. Cell Genet. 68: 67-70, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7956363/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7956363</a>] [<a href="https://doi.org/10.1159/000133892" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7956363">George et al. (1995)</a> mapped the SCN5A gene to chromosome 3p21 by fluorescence in situ hybridization, thus making it an important candidate gene for long QT syndrome-3 (LQT3; <a href="/entry/603830">603830</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7956363" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#25" class="mim-tip-reference" title="Gross, M. B. <strong>Personal Communication.</strong> Baltimore, Md. 4/23/2019."None>Gross (2019)</a> mapped the SCN5A gene to chromosome 3p22.2 based on an alignment of the SCN5A sequence (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=BC051374" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">BC051374</a>) with the genomic sequence (GRCh38).</p>
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<strong>Gene Function</strong>
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<p>By immunoprecipitation and nano-liquid chromatography-mass spectroscopy/mass spectroscopy of transgenic mouse bone marrow macrophages expressing the human macrophage splice variant of SCN5A, followed by Western blot analysis, <a href="#28" class="mim-tip-reference" title="Jones, A., Kainz, D., Khan, F., Lee, C., Carrithers, M. D. <strong>Human macrophage SCN5A activates an innate immune signaling pathway for antiviral host defense.</strong> J. Biol. Chem. 289: 35326-35340, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25368329/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25368329</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25368329[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1074/jbc.M114.611962" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25368329">Jones et al. (2014)</a> identified interaction of SCN5A with activating transcription factor-2 (ATF2; <a href="/entry/123811">123811</a>). Microarray analysis of SCN5A-positive macrophages revealed increased expression of Sp100 (<a href="/entry/604585">604585</a>), an Atf2-regulated gene. Knockdown of Adcy8 (<a href="/entry/103070">103070</a>), the calcium-dependent isoform of adenylate cyclase, inhibited channel agonist-induced expression of Sp100-related genes. Activation of SCN5A increased expression of cAMP in macrophages. Treatment of macrophages with poly(I:C), a mimic of viral double-stranded RNA, activated the Adcy8 signaling pathway to regulate expression of Sp100-related genes and Ifnb (<a href="/entry/147640">147640</a>). Electrophysiologic analysis showed that the SCN5A variant mediated nonselective outward currents, as well as a small yet detectable inward current. <a href="#28" class="mim-tip-reference" title="Jones, A., Kainz, D., Khan, F., Lee, C., Carrithers, M. D. <strong>Human macrophage SCN5A activates an innate immune signaling pathway for antiviral host defense.</strong> J. Biol. Chem. 289: 35326-35340, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25368329/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25368329</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25368329[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1074/jbc.M114.611962" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25368329">Jones et al. (2014)</a> proposed that human macrophage SCN5A initiates signaling in an innate immune pathway relevant to antiviral host defense, and that SCN5A is a pathogen sensor. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25368329" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Myotonic dystrophy (see DM1, <a href="/entry/160900">160900</a>) is caused by expression of mutant RNAs containing expanded CUG repeats. These repeats sequester muscleblind-like (MBNL; see MBNL1, <a href="/entry/606516">606516</a>) splicing factors in nuclear RNA foci, resulting in changes in pre-mRNA splicing. <a href="#19" class="mim-tip-reference" title="Freyermuth, F., Rau, F., Kokunai, Y., Linke, T., Sellier, C., Nakamori, M., Kino, Y., Arandel, L., Jollet, A., Thibault, C., Philipps, M., Vicaire, S., and 31 others. <strong>Splicing misregulation of SCN5A contributes to cardiac-conduction delay and heart arrhythmia in myotonic dystrophy.</strong> Nature Commun. 7: 11067, 2016. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27063795/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27063795</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27063795[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ncomms11067" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27063795">Freyermuth et al. (2016)</a> showed that MBNL1 specifically promoted inclusion of exon 6b in SCN5A pre-mRNA and expression of the adult SCN5A isoform. <a href="#19" class="mim-tip-reference" title="Freyermuth, F., Rau, F., Kokunai, Y., Linke, T., Sellier, C., Nakamori, M., Kino, Y., Arandel, L., Jollet, A., Thibault, C., Philipps, M., Vicaire, S., and 31 others. <strong>Splicing misregulation of SCN5A contributes to cardiac-conduction delay and heart arrhythmia in myotonic dystrophy.</strong> Nature Commun. 7: 11067, 2016. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27063795/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27063795</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27063795[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ncomms11067" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27063795">Freyermuth et al. (2016)</a> found that left ventricle samples of 3 adult DM1 patients showed alternative splicing in a number of genes, including SCN5A. A portion of the SCN5A mRNA in these samples was the fetal isoform. When expressed in Xenopus oocytes, the fetal isoform of SCN5A showed reduced excitability compared with the adult SCN5A isoform. In mice, expression of fetal Scn5a promoted heart arrhythmia and cardiac-conduction delay, which are 2 predominant features of myotonic dystrophy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27063795" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>Missense mutations in the skeletal muscle sodium channel gene, SCN4A (<a href="/entry/603967">603967</a>), cause myotonia. Physiologic data show that these mutations affect sodium channel inactivation and lead to repetitive depolarizations, consistent with the myotonic phenotype. By analogy, similar mutations in the cardiac sodium channel gene might be expected to cause a phenotype like LQT. Indeed, <a href="#71" class="mim-tip-reference" title="Wang, Q., Shen, J., Splawski, I., Atkinson, D., Li, Z., Robinson, J. L., Moss, A. J., Towbin, J. A., Keating, M. T. <strong>SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome.</strong> Cell 80: 805-811, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7889574/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7889574</a>] [<a href="https://doi.org/10.1016/0092-8674(95)90359-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7889574">Wang et al. (1995)</a> found a mutation in the SCN5A gene in families with chromosome 3-linked LQT (see <a href="#0001">600163.0001</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7889574" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Bennett, P. B., Yazawa, K., Makita, N., George, A. L., Jr. <strong>Molecular mechanism for an inherited cardiac arrhythmia.</strong> Nature 376: 683-685, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7651517/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7651517</a>] [<a href="https://doi.org/10.1038/376683a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7651517">Bennett et al. (1995)</a> determined the functional defect resulting from the 3-amino acid (KPQ) deletion (<a href="#0001">600163.0001</a>) in the SCN5A protein. By expression of recombinant human heart sodium channels in Xenopus laevis oocytes, mutant channels showed a sustained inward current during membrane depolarization. Single-channel recordings indicated that mutant channels fluctuate between normal and noninactivating gating modes. Persistent inward sodium current explains prolongation of cardiac action potentials and provides a molecular mechanism for the chromosome 3-linked form of long QT syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7651517" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#70" class="mim-tip-reference" title="Wang, Q., Shen, J., Li, Z., Timothy, K., Vincent, G. M., Priori, S. G., Schwartz, P. J., Keating, M. T. <strong>Cardiac sodium channel mutations in patients with long QT syndrome, an inherited cardiac arrhythmia.</strong> Hum. Molec. Genet. 4: 1603-1607, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8541846/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8541846</a>] [<a href="https://doi.org/10.1093/hmg/4.9.1603" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8541846">Wang et al. (1995)</a> identified SCN5A mutations in affected members of 4 additional families with chromosome 3-linked LQT. Two of the families had the same 9-bp deletion found earlier; the other families were found to have missense mutations affecting highly conserved amino acid residues (<a href="#0002">600163.0002</a> and <a href="#0003">600163.0003</a>). The location and character of the mutation suggested to the authors that this form of LQT results from a delay in cardiac sodium channel fast inactivation or altered voltage-dependence of inactivation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8541846" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#66" class="mim-tip-reference" title="Wang, D. W., Yazawa, K., George, A. L., Jr., Bennett, P. B. <strong>Characterization of human cardiac Na(+) channel mutations in the congenital long QT syndrome.</strong> Proc. Nat. Acad. Sci. 93: 13200-13205, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8917568/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8917568</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=8917568[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.93.23.13200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8917568">Wang et al. (1996)</a> determined the biophysical and functional characteristics of each of the 3 distinct mutations that had been identified in the cardiac sodium channel gene in patients with LQT3 to that time. For this they used heterologous expression of a recombinant human heart sodium channel in a mammalian cell line. Each mutation caused a sustained, noninactivating sodium current amounting to a few percent of the peak inward sodium current, observable during long (more than 50 msec) depolarizations. The voltage dependence and rate of inactivation were altered and the rate of recovery from inactivation was changed compared with wildtype channels. These mutations in diverse regions of the ion channel protein all produced a common defect in channel gating that can cause the long QT phenotype. The sustained inward current caused by these mutations would prolong the action potential. Furthermore, they might create conditions that promote arrhythmias due to prolonged depolarization and the altered recovery from inactivation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8917568" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#67" class="mim-tip-reference" title="Wang, D. W., Yazawa, K., Makita, N., George, A. L., Jr., Bennett, P. B. <strong>Pharmacological targeting of long QT mutant sodium channels.</strong> J. Clin. Invest. 99: 1714-1720, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9120016/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9120016</a>] [<a href="https://doi.org/10.1172/JCI119335" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9120016">Wang et al. (1997)</a> explored the potential for targeted suppression of the defect in LQT3 by heterologous expression of mutant channels in cultured human cells. Channel behavior and inhibition by mexiletine were investigated by whole-cell patch-clamp methods. The investigators showed that late-opening LQT3 mutant channels were much more sensitive to inhibition by mexiletine than were wildtype sodium channels. The defective late openings were selectively suppressed more than the peak sodium current and these late openings could be suppressed by concentrations at the lower end of the therapeutic range. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9120016" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using a candidate gene approach, <a href="#9" class="mim-tip-reference" title="Chen, Q., Kirsch, G. E., Zhang, D., Brugada, R., Brugada, J., Brugada, P., Potenza, D., Moya, A., Borggrefe, M., Breithardt, G., Ortiz-Lopez, R., Wang, Z., Antzelevitch, C., O'Brien, R. E., Schulze-Bahr, E., Keating, M. T., Towbin, J. A., Wang, Q. <strong>Genetic basis and molecular mechanism for idiopathic ventricular fibrillation.</strong> Nature 392: 293-295, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9521325/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9521325</a>] [<a href="https://doi.org/10.1038/32675" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9521325">Chen et al. (1998)</a> studied 6 small families and 2 sporadic patients with idiopathic ventricular fibrillation (IVF; <a href="/entry/603829">603829</a>) using SSCP and DNA sequence analyses to identify mutations in known ion channel genes, including the cardiac sodium channel gene SCN5A. They identified several mutations in families with a distinct form of IVF known as Brugada syndrome (BRGDA1; <a href="/entry/601144">601144</a>). In 1 family all affected members had 2 mutations: an arg1232-to-trp mutation in exon 21 of the gene in the extracellular loop between transmembrane segments S1 and S2 of domain III of the protein, and a thr1620-to-met mutation in exon 28 of the gene in the extracellular loop between S3 and S4 of domain IV of the protein (<a href="#0004">600163.0004</a>). Additional SCN5A mutations were found in 2 IVF families: insertion of 2 nucleotides (AA) in the splice-donor sequence of intron 7 (<a href="#0005">600163.0005</a>); and deletion of a single nucleotide (A) at codon 1397, resulting in an in-frame stop codon (<a href="#0006">600163.0006</a>). The frameshift mutation caused the sodium channel to be nonfunctional. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9521325" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#54" class="mim-tip-reference" title="Schott, J.-J., Alshinawi, C., Kyndt, F., Probst, V., Hoorntje, T. M., Hulsbeek, M., Wilde, A. A. M., Escande, D., Mannens, M. M. A. M., Le Marec, H. <strong>Cardiac conduction defects associate with mutations in SCN5A. (Letter)</strong> Nature Genet. 23: 20-21, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10471492/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10471492</a>] [<a href="https://doi.org/10.1038/12618" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10471492">Schott et al. (1999)</a> reported a mutation in the SCN5A gene that segregated with progressive familial heart block (PFHB1A; <a href="/entry/113900">113900</a>) in an autosomal dominant manner in a large French family. In a smaller Dutch family, another SCN5A mutation cosegregated with familial nonprogressive conduction defect (see <a href="/entry/113900">113900</a>). The French family with PFHB1A was identified through a member with right bundle branch block (RBBB) and syncope; a brother had RBBB, and a sister had complete atrioventricular (AV) block and syncope. Clinical and electrocardiographic abnormalities were found in 15 members of the family; mean QRS duration was 135 +/- 7 ms. RBBB was present in 5, left bundle branch block (LBBB) in 2, left anterior or posterior hemiblock in 3, and long PR interval (more than 210 ms) in 8. None had a structural heart disease. Four members of earlier generations had received a pacemaker implantation because of syncope or complete AV block. Long-term follow-up of several affected members demonstrated that their conduction defect increased in severity with age. In the Dutch family, the proband presented after birth with an asymptomatic first-degree AV block associated with RBBB (PR interval and QRS duration, 200 and 120 ms, respectively). In the French family, <a href="#54" class="mim-tip-reference" title="Schott, J.-J., Alshinawi, C., Kyndt, F., Probst, V., Hoorntje, T. M., Hulsbeek, M., Wilde, A. A. M., Escande, D., Mannens, M. M. A. M., Le Marec, H. <strong>Cardiac conduction defects associate with mutations in SCN5A. (Letter)</strong> Nature Genet. 23: 20-21, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10471492/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10471492</a>] [<a href="https://doi.org/10.1038/12618" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10471492">Schott et al. (1999)</a> excluded the chromosome 19 locus for this disorder (<a href="/entry/604559">604559</a>) by linkage studies, as well as other loci for inherited cardiac disorders associated with conduction defects. SCN5A was considered a candidate locus, and using markers flanking SCN5A, the authors demonstrated segregation of the disease with D3S1260 in every affected individual (maximum lod score of 6.03 at theta of 0.0). A donor splice site mutation in SCN5A was found in the French family (<a href="#0009">600163.0009</a>), and a frameshift mutation was identified in the Dutch family (<a href="#0010">600163.0010</a>). Clinical data and family histories indicated that none of the affected individuals in these 2 families had LQT3 or idiopathic ventricular fibrillation (Brugada syndrome). Therefore, PFHB1 represents a third cardiac disease linked to SCN5A. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10471492" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#57" class="mim-tip-reference" title="Splawski, I., Shen, J., Timothy, K. W., Lehmann, M. H., Priori, S., Robinson, J. L., Moss, A. J., Schwartz, P. J., Towbin, J. A., Vincent, G. M., Keating, M. T. <strong>Spectrum of mutations in long-QT syndrome genes: KVLQT1, HERG, SCN5A, KCNE1, and KCNE2.</strong> Circulation 102: 1178-1185, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10973849/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10973849</a>] [<a href="https://doi.org/10.1161/01.cir.102.10.1178" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10973849">Splawski et al. (2000)</a> screened 262 unrelated individuals with LQT syndrome for mutations in the 5 defined genes (KCNQ1, <a href="/entry/607542">607542</a>; KCNH2, <a href="/entry/152427">152427</a>; SCN5A; KCNE1, <a href="/entry/176261">176261</a>; and KCNE2, <a href="/entry/603796">603796</a>) and identified mutations in 177 individuals (68%). KCNQ1 and KCNH2 accounted for 87% of mutations (42% and 45%, respectively), and SCN5A, KCNE1, and KCNE2 for the remaining 13% (8%, 3%, and 2%, respectively). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10973849" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#60" class="mim-tip-reference" title="Tan, H. L., Kupershmidt, S., Zhang, R., Stepanovic, S., Roden, D. M., Wilde, A. A. M., Anderson, M. E., Balser, J. R. <strong>A calcium sensor in the sodium channel modulates cardiac excitability.</strong> Nature 415: 442-447, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11807557/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11807557</a>] [<a href="https://doi.org/10.1038/415442a" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11807557">Tan et al. (2002)</a> demonstrated that calmodulin (<a href="/entry/114180">114180</a>) binds to the carboxy terminal 'IQ' domain of the SCN5A in a calcium-dependent manner. This binding interaction significantly enhances slow inactivation, a channel-gating process linked to life-threatening idiopathic ventricular arrhythmias. Mutations targeted to the IQ domain disrupted calmodulin binding and eliminated calcium/calmodulin-dependent slow inactivation, whereas the gating effects of calcium/calmodulin were restored by intracellular application of a peptide modeled after the IQ domain. A naturally occurring mutation (A1924T; <a href="#0012">600163.0012</a>) in the IQ domain altered SCN5A function in a manner characteristic of the Brugada syndrome, but at the same time inhibited slow inactivation induced by calcium/calmodulin, yielding a clinically benign (arrhythmia-free) phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11807557" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#58" class="mim-tip-reference" title="Splawski, I., Timothy, K. W., Tateyama, M., Clancy, C. E., Malhotra, A., Beggs, A. H., Cappuccio, F. P., Sagnella, G. A., Kass, R. S., Keating, M. T. <strong>Variant of SCN5A sodium channel implicated in risk of cardiac arrhythmia.</strong> Science 297: 1333-1336, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12193783/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12193783</a>] [<a href="https://doi.org/10.1126/science.1073569" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12193783">Splawski et al. (2002)</a> identified a common variant of the SCN5A gene, ser1103 to tyr (S1103Y; <a href="#0024">600163.0024</a>), which is present in 13.2% of African Americans and is associated with accelerated channel activation, increasing the likelihood of abnormal cardiac repolarization and arrhythmia. <a href="#58" class="mim-tip-reference" title="Splawski, I., Timothy, K. W., Tateyama, M., Clancy, C. E., Malhotra, A., Beggs, A. H., Cappuccio, F. P., Sagnella, G. A., Kass, R. S., Keating, M. T. <strong>Variant of SCN5A sodium channel implicated in risk of cardiac arrhythmia.</strong> Science 297: 1333-1336, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12193783/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12193783</a>] [<a href="https://doi.org/10.1126/science.1073569" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12193783">Splawski et al. (2002)</a> suggested that the S1103Y mutation in the African American population may be a useful molecular marker for the prediction of arrhythmia susceptibility in the context of additional acquired risk factors such as the use of certain medications or the presence of hypokalemia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12193783" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#52" class="mim-tip-reference" title="Rivolta, I., Abriel, H., Tateyama, M., Liu, H., Memmi, M., Vardas, P., Napolitano, C., Priori, S. G., Kass, R. S. <strong>Inherited Brugada and long QT-3 syndrome mutations of a single channel residue of the cardiac sodium channel confer distinct channel and clinical phenotypes.</strong> J. Biol. Chem. 276: 30623-30630, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11410597/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11410597</a>] [<a href="https://doi.org/10.1074/jbc.M104471200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11410597">Rivolta et al. (2001)</a> identified 2 mutations at the same codon of the SCN5A gene: a tyr1795-to-cys mutation (Y1795C; <a href="#0029">600163.0029</a>) in a patient with LQT3, and a Y1795H (<a href="#0030">600163.0030</a>) mutation in a patient with Brugada syndrome. Functional analysis revealed marked and opposing effects on channel gating consistent with activity associated with the cellular basis of each clinical disorder: Y1795H accelerated and Y1795C slowed the onset of activation; Y1795H, but not Y1795C, caused a marked negative shift in the voltage dependence of inactivation; and neither affected the kinetics of the recovery from inactivation. However, both mutations increased the expression of sustained Na(+) channel activity compared with wildtype channels, although this effect was most pronounced for the Y1795C mutation, and both promoted entrance into an intermediate or slowly developing inactivated state. <a href="#52" class="mim-tip-reference" title="Rivolta, I., Abriel, H., Tateyama, M., Liu, H., Memmi, M., Vardas, P., Napolitano, C., Priori, S. G., Kass, R. S. <strong>Inherited Brugada and long QT-3 syndrome mutations of a single channel residue of the cardiac sodium channel confer distinct channel and clinical phenotypes.</strong> J. Biol. Chem. 276: 30623-30630, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11410597/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11410597</a>] [<a href="https://doi.org/10.1074/jbc.M104471200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11410597">Rivolta et al. (2001)</a> concluded that these data confirmed the key role of the C-terminal tail of the cardiac Na(+) channel in the control of channel gating and provided further evidence of the close interrelationship between Brugada syndrome and LQT3 at the molecular level. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11410597" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#14" class="mim-tip-reference" title="Clancy, C. E., Tateyama, M., Kass, R. S. <strong>Insights into the molecular mechanisms of bradycardia-triggered arrhythmias in long QT-3 syndrome.</strong> J. Clin. Invest. 110: 1251-1262, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12417563/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12417563</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12417563[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI15928" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12417563">Clancy et al. (2002)</a> performed detailed kinetic analyses of the Y1795C mutant described by <a href="#52" class="mim-tip-reference" title="Rivolta, I., Abriel, H., Tateyama, M., Liu, H., Memmi, M., Vardas, P., Napolitano, C., Priori, S. G., Kass, R. S. <strong>Inherited Brugada and long QT-3 syndrome mutations of a single channel residue of the cardiac sodium channel confer distinct channel and clinical phenotypes.</strong> J. Biol. Chem. 276: 30623-30630, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11410597/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11410597</a>] [<a href="https://doi.org/10.1074/jbc.M104471200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11410597">Rivolta et al. (2001)</a>. Theoretical entry and exit rates from the bursting mode of gating were derived from single channels. Computational analysis suggested that the amount of time mutant channels spend bursting (burst mode dwell time) is primarily responsible for rate-dependent changes in single-channel bursting and macroscopic inward sodium channel (I-sus), hence delaying repolarization and prolonging the QT interval. This prediction was experimentally confirmed by analysis of delta-KPQ mutant channels (<a href="#0001">600163.0001</a>) for which the burst mode exit rate (determined by the burst mode dwell time) was found to be very similar to the derived rate for Y1795C channels. These results provided an explanation of the molecular mechanism for bradycardia-induced QT prolongation in patients carrying LQT3 mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11410597+12417563" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#63" class="mim-tip-reference" title="Veldkamp, M. W., Wilders, R., Baartscheer, A., Zegers, J. G., Bezzina, C. R., Wilde, A. A. M. <strong>Contribution of sodium channel mutations to bradycardia and sinus node dysfunction in LQT3 families.</strong> Circ. Res. 92: 976-983, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12676817/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12676817</a>] [<a href="https://doi.org/10.1161/01.RES.0000069689.09869.A8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12676817">Veldkamp et al. (2003)</a> studied the effect of the 1795insD SCN5A mutation (<a href="#0013">600163.0013</a>), which causes LQT3 or Brugada syndrome, on sinoatrial (SA) pacemaking. Activity of 1795insD channels during SA node pacemaking was confirmed by action potential (AP) clamp experiments, and the previously characterized persistent inward current (I-pst) and negative shift were implemented into SA node (AP) models. The -10 mV shift decreased the sinus rate by decreasing the diastolic depolarization rate, whereas the I-pst decreased the sinus rate by AP prolongation, despite a concomitant increase in the diastolic depolarization rate. In combination, a moderate I-pst (1 to 2%) and the shift reduced the sinus rate by about 10%. <a href="#63" class="mim-tip-reference" title="Veldkamp, M. W., Wilders, R., Baartscheer, A., Zegers, J. G., Bezzina, C. R., Wilde, A. A. M. <strong>Contribution of sodium channel mutations to bradycardia and sinus node dysfunction in LQT3 families.</strong> Circ. Res. 92: 976-983, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12676817/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12676817</a>] [<a href="https://doi.org/10.1161/01.RES.0000069689.09869.A8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12676817">Veldkamp et al. (2003)</a> concluded that sodium channel mutations displaying an I-pst or a negative shift in inactivation may account for the bradycardia seen in LQT3 patients, whereas SA node pauses or arrest may result from failure of SA node cells to repolarize under conditions of extra net inward current. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12676817" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Based on prior associations with disorders of cardiac rhythm and conduction, <a href="#7" class="mim-tip-reference" title="Benson, D. W., Wang, D. W., Dyment, M., Knilans, T. K., Fish, F. A., Strieper, M. J., Rhodes, T. H., George, A. L., Jr. <strong>Congenital sick sinus syndrome caused by recessive mutations in the cardiac sodium channel gene (SCN5A).</strong> J. Clin. Invest. 112: 1019-1028, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14523039/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14523039</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14523039[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI18062" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14523039">Benson et al. (2003)</a> screened the SCN5A gene as a candidate gene in 10 pediatric patients from 7 families who were diagnosed with autosomal recessive congenital sick sinus syndrome (SSS1; <a href="/entry/608567">608567</a>) during the first decade of life. Probands from 3 kindreds exhibited compound heterozygosity for 6 distinct SCN5A alleles (e.g., <a href="#0025">600163.0025</a>), 2 of which had previously been associated with dominant disorders of cardiac excitability. Biophysical characterization of the mutants using heterologously expressed recombinant human heart sodium channels demonstrated loss of function or significant impairment in channel gating that predicted reduced myocardial excitability. Thus <a href="#7" class="mim-tip-reference" title="Benson, D. W., Wang, D. W., Dyment, M., Knilans, T. K., Fish, F. A., Strieper, M. J., Rhodes, T. H., George, A. L., Jr. <strong>Congenital sick sinus syndrome caused by recessive mutations in the cardiac sodium channel gene (SCN5A).</strong> J. Clin. Invest. 112: 1019-1028, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14523039/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14523039</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14523039[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI18062" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14523039">Benson et al. (2003)</a> provided a molecular basis for some forms of congenital SSS and defined a recessive disorder of a human heart voltage-gated sodium channel. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14523039" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a patient with Brugada syndrome, <a href="#43" class="mim-tip-reference" title="Mohler, P. J., Rivolta, I., Napolitano, C., LeMaillet, G., Lambert, S., Priori, S. G., Bennett, V. <strong>Na(v)1.5 E1053K mutation causing Brugada syndrome blocks binding to ankyrin-G and expression of Na(v)1.5 on the surface of cardiomyocytes.</strong> Proc. Nat. Acad. Sci. 101: 17533-17538, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15579534/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15579534</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15579534[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0403711101" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15579534">Mohler et al. (2004)</a> identified an E1053K mutation (<a href="#0033">600163.0033</a>) in the ankyrin-binding motif of Na(v)1.5. The mutation abolished binding of Na(v)1.5 to ankyrin-G (ANK3; <a href="/entry/600465">600465</a>), and also prevented accumulation of Na(v)1.5 at cell surface sites in ventricular cardiomyocytes. Both ankyrin-G and Na(v)1.5 localized at intercalated disc and T-tubule membranes in cardiomyocytes, and Na(v)1.5 coimmunoprecipitated with the 190-kD ankyrin-G isoform from detergent-soluble lysates from rat heart. These data suggested that Na(v)1.5 associates with ankyrin-G and that ankyrin-G is required for Na(v)1.5 localization at excitable membranes in cardiomyocytes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15579534" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#42" class="mim-tip-reference" title="Miller, T. E., Estrella, E., Myerburg, R. J., Garcia de Viera, J., Moreno, N., Rusconi, P., Ahearn, M. E., Baumbach, L., Kurlansky, P., Wolff, G., Bishopric, N. H. <strong>Recurrent third-trimester fetal loss and maternal mosaicism for long-QT syndrome.</strong> Circulation 109: 3029-3034, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15184283/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15184283</a>] [<a href="https://doi.org/10.1161/01.CIR.0000130666.81539.9E" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15184283">Miller et al. (2004)</a> reported a case of repeated germline transmission of a severe form of LQT syndrome from an asymptomatic mother with somatic mosaicism for a mutation in the SCN5A gene (<a href="#0007">600163.0007</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15184283" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#33" class="mim-tip-reference" title="Maekawa, K., Saito, Y., Ozawa, S., Adachi-Akahane, S., Kawamoto, M., Komamura, K., Shimizu, W., Ueno, K., Kamakura, S., Kamatani, N., Kitakaze, M., Sawada, J. <strong>Genetic polymorphisms and haplotypes of the human cardiac sodium channel alpha subunit gene (SCN5A) in Japanese and their association with arrhythmia.</strong> Ann. Hum. Genet. 69: 413-428, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15996170/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15996170</a>] [<a href="https://doi.org/10.1046/j.1529-8817.2005.00167.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15996170">Maekawa et al. (2005)</a> sequenced the SCN5A gene in 166 Japanese patients with arrhythmia who were not diagnosed with LQT or Brugada syndrome and in 232 healthy controls, identifying 69 genetic variations including 66 SNPs. The frequency of a 703+130G-A SNP was significantly higher in patients than in controls (OR, 1.70), suggesting an association with an unknown risk factor for arrhythmia. Haplotype analysis revealed that the so-called GG haplotype with both the leu1988-to-arg and his558-to-arg (<a href="#0031">600163.0031</a>) SNPs was significantly less frequent in patients than in controls (p = 0.018), suggesting a possible protective effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15996170" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#61" class="mim-tip-reference" title="Tester, D. J., Will, M. L., Haglund, C. M., Ackerman, M. J. <strong>Compendium of cardiac channel mutations in 541 consecutive unrelated patients referred for long QT syndrome genetic testing.</strong> Heart Rhythm 2: 507-517, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15840476/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15840476</a>] [<a href="https://doi.org/10.1016/j.hrthm.2005.01.020" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15840476">Tester et al. (2005)</a> analyzed 5 LQTS-associated cardiac channel genes in 541 consecutive unrelated patients with LQT syndrome (average QTc, 482 ms). In 272 (50%) patients, they identified 211 different pathogenic mutations, including 88 in KCNQ1, 89 in KCNH2, 32 in SCN5A, and 1 each in KCNE1 and KCNE2. Mutations considered pathogenic were absent in more than 1,400 reference alleles. Among the mutation-positive patients, 29 (11%) had 2 LQTS-causing mutations, of which 16 (8%) were in 2 different LQTS genes (biallelic digenic). <a href="#61" class="mim-tip-reference" title="Tester, D. J., Will, M. L., Haglund, C. M., Ackerman, M. J. <strong>Compendium of cardiac channel mutations in 541 consecutive unrelated patients referred for long QT syndrome genetic testing.</strong> Heart Rhythm 2: 507-517, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15840476/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15840476</a>] [<a href="https://doi.org/10.1016/j.hrthm.2005.01.020" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15840476">Tester et al. (2005)</a> noted that patients with multiple mutations were younger at diagnosis, but they did not discern any genotype/phenotype correlations associated with location or type of mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15840476" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 44 unrelated patients with LQT syndrome, <a href="#41" class="mim-tip-reference" title="Millat, G., Chevalier, P., Restier-Miron, L., Da Costa, A., Bouvagnet, P., Kugener, B., Fayol, L., Gonzalez Armengod, C., Oddou, B., Chanavat, V., Froidefond, E., Perraudin, R., Rousson, R., Rodriguez-Lafrasse, C. <strong>Spectrum of pathogenic mutations and associated polymorphisms in a cohort of 44 unrelated patients with long QT syndrome.</strong> Clin. Genet. 70: 214-227, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16922724/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16922724</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2006.00671.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16922724">Millat et al. (2006)</a> used DHLP chromatography to analyze the KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 genes for mutations and SNPs. Most of the patients (84%) showed a complex molecular pattern, with an identified mutation associated with 1 or more SNPs located in several LQTS genes; 4 of the patients also had a second mutation in a different LQTS gene (biallelic digenic inheritance; see, e.g., <a href="#0007">600163.0007</a> and <a href="/entry/603796#0005">603796.0005</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16922724" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In affected members of the family reported by <a href="#22" class="mim-tip-reference" title="Greenlee, P. R., Anderson, J. L., Lutz, J. R., Lindsay, A. E., Hagan, A. D. <strong>Familial automaticity-conduction disorder with associated cardiomyopathy.</strong> West. J. Med. 144: 33-41, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3953067/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3953067</a>]" pmid="3953067">Greenlee et al. (1986)</a> with a form of dilated cardiomyopathy (CMD1E; <a href="/entry/601154">601154</a>), <a href="#39" class="mim-tip-reference" title="McNair, W. P., Ku, L., Taylor, M. R. G., Fain, P. R., Dao, D., Wolfel, E., Mestroni, L., Familial Cardiomyopathy Registry Research Group. <strong>SCN5A mutation associated with dilated cardiomyopathy, conduction disorder, and arrhythmia.</strong> Circulation 110: 2163-2167, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15466643/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15466643</a>] [<a href="https://doi.org/10.1161/01.CIR.0000144458.58660.BB" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15466643">McNair et al. (2004)</a> identified heterozygosity for a missense mutation (D1765N; <a href="#0001">600163.0001</a>) in the SCN5A gene. In affected members of a family with atrial standstill (ATRST1; <a href="/entry/108770">108770</a>), <a href="#23" class="mim-tip-reference" title="Groenewegen, W. A., Firouzi, M., Bezzina, C. R., Vliex, S., van Langen, I. M., Sandkuijl, L., Smits, J. P. P., Hulsbeek, M., Rook, M. B., Jongsma, H. J., Wilde, A. A. M. <strong>A cardiac sodium channel mutation cosegregates with a rare connexin40 genotype in familial atrial standstill.</strong> Circ. Res. 92: 14-22, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12522116/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12522116</a>] [<a href="https://doi.org/10.1161/01.res.0000050585.07097.d7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12522116">Groenewegen et al. (2003)</a> had identified coinheritance of the D1275N mutation in the SCN5A gene with polymorphisms in the atria-specific junction channel protein connexin-40 (GJA5; <a href="/entry/121013">121013</a>). None of the patients with atrial standstill had dilated cardiomyopathy, leading <a href="#24" class="mim-tip-reference" title="Groenewegen, W. A., Wilde, A. A. M. <strong>Letter regarding article by McNair et al, 'SCN5A mutation associated with dilated cardiomyopathy, conduction disorder, and arrhythmia'. (Letter)</strong> Circulation 112: e9, 2005. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15998690/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15998690</a>] [<a href="https://doi.org/10.1161/CIRCULATIONAHA.104.531475" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15998690">Groenewegen and Wilde (2005)</a> to question the relationship of the SCN5A mutation to dilated cardiomyopathy in the family reported by <a href="#39" class="mim-tip-reference" title="McNair, W. P., Ku, L., Taylor, M. R. G., Fain, P. R., Dao, D., Wolfel, E., Mestroni, L., Familial Cardiomyopathy Registry Research Group. <strong>SCN5A mutation associated with dilated cardiomyopathy, conduction disorder, and arrhythmia.</strong> Circulation 110: 2163-2167, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15466643/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15466643</a>] [<a href="https://doi.org/10.1161/01.CIR.0000144458.58660.BB" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15466643">McNair et al. (2004)</a>. <a href="#40" class="mim-tip-reference" title="McNair, W. P., Ku, L., Taylor, M. R. G., Fain, P. R., Wolfel, E., Mestroni, L. <strong>Response to letter regarding article by McNair et al., 'SCN5A mutation associated with dilated cardiomyopathy, conduction disorder, and arrhythmia'. (Letter)</strong> Circulation 112: e9, 2005. Note: Electronic Article."None>McNair et al. (2005)</a> responded that the younger age of the affected members studied by <a href="#23" class="mim-tip-reference" title="Groenewegen, W. A., Firouzi, M., Bezzina, C. R., Vliex, S., van Langen, I. M., Sandkuijl, L., Smits, J. P. P., Hulsbeek, M., Rook, M. B., Jongsma, H. J., Wilde, A. A. M. <strong>A cardiac sodium channel mutation cosegregates with a rare connexin40 genotype in familial atrial standstill.</strong> Circ. Res. 92: 14-22, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12522116/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12522116</a>] [<a href="https://doi.org/10.1161/01.res.0000050585.07097.d7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12522116">Groenewegen et al. (2003)</a> as well as additional or genetic environmental factors may account for the difference between the 2 families. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3953067+12522116+15466643+15998690" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a Japanese family in which an 11-year-old boy had sick sinus syndrome that progressed to atrial standstill, <a href="#35" class="mim-tip-reference" title="Makita, N., Sasaki, K., Groenewegen, W. A., Yokota, T., Yokoshiki, H., Murakami, T., Tsutsui, H. <strong>Congenital atrial standstill associated with coinheritance of a novel SCN5A mutation and connexin 40 polymorphisms.</strong> Heart Rhythm 2: 1128-1134, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16188595/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16188595</a>] [<a href="https://doi.org/10.1016/j.hrthm.2005.06.032" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16188595">Makita et al. (2005)</a> analyzed 3 cardiac ion channel genes previously associated with atrial standstill, atrial fibrillation, or sick sinus syndrome: SCN5A, HCN4 (<a href="/entry/605206">605206</a>), and GJA5. No mutations were found in HCN4, but the proband and his asymptomatic father were heterozygous for a missense mutation in SCN5A (L212P; <a href="#0048">600163.0048</a>). In addition, the proband and his unaffected mother and maternal grandmother were all heterozygous for the same 2 rare GJA5 polymorphisms identified by <a href="#23" class="mim-tip-reference" title="Groenewegen, W. A., Firouzi, M., Bezzina, C. R., Vliex, S., van Langen, I. M., Sandkuijl, L., Smits, J. P. P., Hulsbeek, M., Rook, M. B., Jongsma, H. J., Wilde, A. A. M. <strong>A cardiac sodium channel mutation cosegregates with a rare connexin40 genotype in familial atrial standstill.</strong> Circ. Res. 92: 14-22, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12522116/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12522116</a>] [<a href="https://doi.org/10.1161/01.res.0000050585.07097.d7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12522116">Groenewegen et al. (2003)</a> in atrial standstill patients, -44A/+71G. Functional analysis with the L212P mutant channels demonstrated large hyperpolarizing shifts in both the voltage dependence of activation and inactivation and delayed recovery from inactivation compared to wildtype. <a href="#35" class="mim-tip-reference" title="Makita, N., Sasaki, K., Groenewegen, W. A., Yokota, T., Yokoshiki, H., Murakami, T., Tsutsui, H. <strong>Congenital atrial standstill associated with coinheritance of a novel SCN5A mutation and connexin 40 polymorphisms.</strong> Heart Rhythm 2: 1128-1134, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16188595/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16188595</a>] [<a href="https://doi.org/10.1016/j.hrthm.2005.06.032" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16188595">Makita et al. (2005)</a> suggested that defects in SCN5A underlie atrial standstill, and that coinheritance of GJA5 polymorphisms represents a possible genetic modifier of the clinical manifestations. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16188595+12522116" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#49" class="mim-tip-reference" title="Olson, T. M., Michels, V. V., Ballew, J. D., Reyna, S. P., Karst, M. L., Herron, K. I., Horton, S. C., Rodeheffer, R. J., Anderson, J. L. <strong>Sodium channel mutations and susceptibility of heart failure and atrial fibrillation.</strong> JAMA 293: 447-454, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15671429/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15671429</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15671429[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1001/jama.293.4.447" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15671429">Olson et al. (2005)</a> analyzed the SCN5A gene in 156 unrelated patients with dilated cardiomyopathy who were negative for mutations in the known CMD genes encoding cardiac actin (<a href="/entry/102540">102540</a>), alpha-tropomyosin (<a href="/entry/191010">191010</a>), and metavinculin (see <a href="/entry/193065">193065</a>), and identified 5 heterozygous mutations in 5 probands, respectively (see, e.g., <a href="#0027">600163.0027</a>, <a href="#0038">600163.0038</a>-<a href="#0039">600163.0039</a>). All of the mutations altered highly conserved residues in the transmembrane domains of SCN5A. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15671429" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Albert, C. M., Nam, E. G., Rimm, E. B., Jin, H. W., Hajjar, R. J., Hunter, D. J., MacRae, C. A., Ellinor, P. T. <strong>Cardiac sodium channel gene variants and sudden cardiac death in women.</strong> Circulation 117: 16-23, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18071069/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18071069</a>] [<a href="https://doi.org/10.1161/CIRCULATIONAHA.107.736330" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18071069">Albert et al. (2008)</a> analyzed 5 cardiac ion channel genes, SCN5A, KCNQ1, KCNH2, KCNE1, and KCNE2, in 113 cases of sudden cardiac death. No mutations or rare variants were identified in any of the 53 male subjects, but in 6 (10%) of 60 female subjects, 5 rare missense variants in SCN5A were identified, 2 previously associated with long QT syndrome, 1 with sudden infant death syndrome, and 2 not previously reported in control populations. Functional studies showed that all of the variants resulted in significantly shorter recovery times from inactivation. <a href="#4" class="mim-tip-reference" title="Albert, C. M., Nam, E. G., Rimm, E. B., Jin, H. W., Hajjar, R. J., Hunter, D. J., MacRae, C. A., Ellinor, P. T. <strong>Cardiac sodium channel gene variants and sudden cardiac death in women.</strong> Circulation 117: 16-23, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18071069/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18071069</a>] [<a href="https://doi.org/10.1161/CIRCULATIONAHA.107.736330" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18071069">Albert et al. (2008)</a> concluded that functionally significant mutations and rare variants in the SCN5A gene may contribute to the risk of sudden cardiac death in women. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18071069" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#34" class="mim-tip-reference" title="Makita, N., Behr, E., Shimizu, W., Horie, M., Sunami, A., Crotti, L., Schulze-Bahr, E., Fukuhara, S., Mochizuki, N., Makiyama, T., Itoh, H., Christiansen, M., McKeown, P., Miyamoto, K., Kamakura, S., Tsutsui, H., Schwartz, P. J., George, A. L., Jr., Roden, D. M. <strong>The E1784K mutation in SCN5A is associated with mixed clinical phenotype of type 3 long QT syndrome.</strong> J. Clin. Invest. 118: 2219-2229, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18451998/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18451998</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18451998[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI34057" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18451998">Makita et al. (2008)</a> genotyped 66 members of 44 LQT3 families of multiple ethnicities and identified the E1784K mutation (<a href="#0008">600163.0008</a>) in 41 individuals from 15 (34%) of the kindreds; the diagnoses in these individuals included LQT3 syndrome, Brugada syndrome, and/or sinus node dysfunction (see <a href="/entry/608567">608567</a>). In vitro functional characterization of E1784K channels compared to properties reported for other LQT3 variants suggested that a negative shift of steady-state Na channel inactivation and enhanced tonic block in response to Na channel blockers confer an additional Brugada syndrome/sinus node dysfunction phenotype, and further indicated that class IC drugs should be avoided in patients with Na channels displaying these behaviors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18451998" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a large Finnish family with atrial fibrillation (AF) and conduction defects (ATFB10; <a href="/entry/614022">614022</a>), <a href="#31" class="mim-tip-reference" title="Laitinen-Forsblom, P. J., Makynen, P., Makynen, H., Yli-Mayry, S., Virtanen, V., Kontula, K., Aalto-Setala, K. <strong>SCN5A mutation associated with cardiac conduction defect and atrial arrhythmias.</strong> J. Cardiovasc. Electrophysiol. 17: 480-485, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16684018/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16684018</a>] [<a href="https://doi.org/10.1111/j.1540-8167.2006.00411.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16684018">Laitinen-Forsblom et al. (2006)</a> analyzed the SCN5A gene and identified a heterozygous missense mutation (<a href="#0034">600163.0034</a>) that segregated with disease and was not found in more than 370 control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16684018" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#18" class="mim-tip-reference" title="Ellinor, P. T., Nam, E. G., Shea, M. A., Milan, D. J., Ruskin, J. N., MacRae, C. A. <strong>Cardiac sodium channel mutation in atrial fibrillation.</strong> Heart Rhythm 5: 99-105, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18088563/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18088563</a>] [<a href="https://doi.org/10.1016/j.hrthm.2007.09.015" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18088563">Ellinor et al. (2008)</a> analyzed the SCN5A gene in 57 probands with a familial history of isolated or 'lone' atrial fibrillation and identified heterozygosity for a missense mutation (<a href="#0041">600163.0041</a>) in a 45-year-old male proband and his affected father. The authors concluded that SCN5A gene was not a major cause of familial AF. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18088563" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Darbar, D., Kannankeril, P. J., Donahue, B. S., Kucera, G., Stubblefield, T., Haines, J. L., George, A. L., Jr., Roden, D. M. <strong>Cardiac sodium channel (SCN5A) variants associated with atrial fibrillation.</strong> Circulation 117: 1927-1935, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18378609/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18378609</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18378609[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1161/CIRCULATIONAHA.107.757955" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18378609">Darbar et al. (2008)</a> analyzed the SCN5A gene in 375 probands with AF, including 118 with lone AF, which was defined as AF occurring in individuals less than 65 years of age who did not have hypertension, overt structural heart disease, or thyroid dysfunction. The authors identified 8 heterozygous variants in 10 probands that were not found in 360 age-, sex-, and ethnicity-matched controls (see, e.g., <a href="#0042">600163.0042</a>-<a href="#0045">600163.0045</a>). In addition, 11 previously reported rare nonsynonymous coding region variants were identified in 12 probands (see, e.g., <a href="#0033">600163.0033</a>), and 3 known common nonsynonymous SCN5A polymorphisms were also identified in the AF cohort (see, e.g., <a href="#0024">600163.0024</a> and <a href="#0031">600163.0031</a>). <a href="#15" class="mim-tip-reference" title="Darbar, D., Kannankeril, P. J., Donahue, B. S., Kucera, G., Stubblefield, T., Haines, J. L., George, A. L., Jr., Roden, D. M. <strong>Cardiac sodium channel (SCN5A) variants associated with atrial fibrillation.</strong> Circulation 117: 1927-1935, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18378609/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18378609</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18378609[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1161/CIRCULATIONAHA.107.757955" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18378609">Darbar et al. (2008)</a> stated that in their study, nearly 6% of AF probands carried heterozygous mutations or rare variants in the SCN5A gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18378609" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In affected members of 2 unrelated families with CMD and conduction system disease, <a href="#26" class="mim-tip-reference" title="Hershberger, R. E., Parks, S. B., Kushner, J. D., Li, D., Ludwigsen, S., Jakobs, P., Nauman, D., Burgess, D., Partain, J., Litt, M. <strong>Coding sequence mutations identified in MYH7, TNNT2, SCN5A, CSRP3, LBD3 (sic), and TCAP from 313 patients with familial or idiopathic dilated cardiomyopathy.</strong> Clin. Transl. Sci. 1: 21-26, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19412328/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19412328</a>] [<a href="https://doi.org/10.1111/j.1752-8062.2008.00017.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19412328">Hershberger et al. (2008)</a> identified heterozygosity for 2 different missense mutations in the SCN5A gene, R222Q (<a href="#0046">600163.0046</a>) and I1835T (<a href="#0047">600163.0047</a>), respectively. <a href="#11" class="mim-tip-reference" title="Cheng, J., Morales, A., Siegfried, J. D., Li, D., Norton, N., Song, J., Gonzalez-Quintana, J., Makielski, J. C., Hershberger, R. E. <strong>SCN5A rare variants in familial dilated cardiomyopathy decrease peak sodium current depending on the common polymorphism H558R and common splice variant Q1077del.</strong> Clin. Transl. Sci. 3: 287-294, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21167004/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21167004</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21167004[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1111/j.1752-8062.2010.00249.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21167004">Cheng et al. (2010)</a> restudied the 2 families, noting that all affected individuals were also either homozygous or heterozygous for the SCN5A common polymorphism, H558R (<a href="#0031">600163.0031</a>). Whole-cell voltage clamp studies in HEK293 cells using the Q1077del background, which is the more abundant alternatively spliced SCN5A transcript present in human hearts (65%), showed that sodium current densities of the R222Q and I1835T mutants were not different from wildtype, but the combined variants R222Q/H558R and I1835T/H558R caused approximately 35% and 30% reduction, respectively, and each showed slower recovery from inactivation than wildtype. With the Q1077del background, R222Q and R222Q/H558R variants also exhibited a significant negative shift in both activation and inactivation, whereas I1835T/H558R showed a significant negative shift in inactivation that tended to decrease window current. In contrast, expression in the Q1077 background showed no changes in peak sodium current densities, decay, or recovery from inactivation for R222Q/H558R or I1835T/H558R. <a href="#11" class="mim-tip-reference" title="Cheng, J., Morales, A., Siegfried, J. D., Li, D., Norton, N., Song, J., Gonzalez-Quintana, J., Makielski, J. C., Hershberger, R. E. <strong>SCN5A rare variants in familial dilated cardiomyopathy decrease peak sodium current depending on the common polymorphism H558R and common splice variant Q1077del.</strong> Clin. Transl. Sci. 3: 287-294, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21167004/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21167004</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21167004[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1111/j.1752-8062.2010.00249.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21167004">Cheng et al. (2010)</a> concluded that CMD-associated SCN5A rare variants perturb the SCN5A biophysical phenotype that is modulated by SCN5A common variants. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=21167004+19412328" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 3 unrelated families with multifocal ectopic Purkinje-related premature contractions and dilated cardiomyopathy, <a href="#32" class="mim-tip-reference" title="Laurent, G., Saal, S., Amarouch, M. Y., Beziau, D. M., Marsman, R. F. J., Faivre, L., Barc, J., Dina, C., Bertaux, G., Barthez, O., Thauvin-Robinet, C., Charron, P., and 15 others. <strong>Multifocal ectopic Purkinje-related premature contractions.</strong> J. Am. Coll. Cardiol. 60: 144-156, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22766342/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22766342</a>] [<a href="https://doi.org/10.1016/j.jacc.2012.02.052" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22766342">Laurent et al. (2012)</a> identified heterozygosity for the R222Q mutation in the SCN5A gene, which was fully penetrant and strictly segregated with the cardiac phenotype in each family. <a href="#32" class="mim-tip-reference" title="Laurent, G., Saal, S., Amarouch, M. Y., Beziau, D. M., Marsman, R. F. J., Faivre, L., Barc, J., Dina, C., Bertaux, G., Barthez, O., Thauvin-Robinet, C., Charron, P., and 15 others. <strong>Multifocal ectopic Purkinje-related premature contractions.</strong> J. Am. Coll. Cardiol. 60: 144-156, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22766342/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22766342</a>] [<a href="https://doi.org/10.1016/j.jacc.2012.02.052" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22766342">Laurent et al. (2012)</a> stated that the R222Q effects that they observed on channel parameters were similar to those measured by <a href="#11" class="mim-tip-reference" title="Cheng, J., Morales, A., Siegfried, J. D., Li, D., Norton, N., Song, J., Gonzalez-Quintana, J., Makielski, J. C., Hershberger, R. E. <strong>SCN5A rare variants in familial dilated cardiomyopathy decrease peak sodium current depending on the common polymorphism H558R and common splice variant Q1077del.</strong> Clin. Transl. Sci. 3: 287-294, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21167004/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21167004</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21167004[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1111/j.1752-8062.2010.00249.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21167004">Cheng et al. (2010)</a>; in addition, they noted that the effects were intermediate in the heterozygous state and also impaired the window current, which is crucial during the plateau phase of the action potential. In vitro studies recapitulated the normalization of the ventricular action potentials in the presence of quinidine. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=21167004+22766342" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In affected members of a 3-generation Canadian family with CMD and junctional escape ventricular capture bigeminy, <a href="#44" class="mim-tip-reference" title="Nair, K., Pekhletski, R., Harris, L., Care, M., Morel, C., Farid, T., Backx, P. H., Szabo, E., Nanthakumar, K. <strong>Escape capture bigeminy: phenotypic marker of cardiac sodium channel voltage sensor mutation R222Q.</strong> Heart Rhythm 9: 1681-1688, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22710484/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22710484</a>] [<a href="https://doi.org/10.1016/j.hrthm.2012.06.029" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22710484">Nair et al. (2012)</a> identified the R222Q mutation in the SCN5A gene. Heterologous expression studies revealed a unique biophysical phenotype of R222Q channels in which an approximately 10-mV leftward shift in the sodium current steady-state activation curve occurs without corresponding shifts in steady-state inactivation at cardiomyocyte resting membrane-potential voltages. <a href="#44" class="mim-tip-reference" title="Nair, K., Pekhletski, R., Harris, L., Care, M., Morel, C., Farid, T., Backx, P. H., Szabo, E., Nanthakumar, K. <strong>Escape capture bigeminy: phenotypic marker of cardiac sodium channel voltage sensor mutation R222Q.</strong> Heart Rhythm 9: 1681-1688, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22710484/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22710484</a>] [<a href="https://doi.org/10.1016/j.hrthm.2012.06.029" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22710484">Nair et al. (2012)</a> noted that the absence of H558R in these patients established that the H558R polymorphism is not required for the induction of cardiomyopathy in patients carrying the R222Q mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22710484" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 16 affected members over 3 generations of a large kindred with CMD and multiple arrhythmias, including premature ventricular complexes (PVCs) of variable morphologies, <a href="#38" class="mim-tip-reference" title="Mann, S. A., Castro, M. L., Ohanian, M., Guo, G., Zodgekar, P., Sheu, A., Stockhammer, K., Thompson, T., Playford, D., Subbiah, R., Kuchar, D., Aggarwal, A., Vandenberg, J. I., Fatkin, D. <strong>R222Q SCN5A mutation is associated with reversible ventricular ectopy and dilated cardiomyopathy.</strong> J. Am. Coll. Cardiol. 60: 1566-1573, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22999724/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22999724</a>] [<a href="https://doi.org/10.1016/j.jacc.2012.05.050" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22999724">Mann et al. (2012)</a> identified heterozygosity for the R222Q mutation in the SCN5A gene. The mutation was also identified in 1 clinically unaffected family member, a 56-year-old man with a normal EKG and echocardiogram. None of the R222Q carriers had the common SCN5A variant, H558R. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22999724" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#48" class="mim-tip-reference" title="O'Neill, M. J., Muhammad, A., Li, B., Wada, Y., Hall, L., Solus, J. F., Short, L., Roden, D. M., Glazer, A. M. <strong>Dominant negative effects of SCN5A missense variants.</strong> Genet. Med. 24: 1238-1248, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35305865/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35305865</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=35305865[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.gim.2022.02.010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35305865">O'Neill et al. (2022)</a> studied the effects of 50 previously published, functionally characterized missense variants in the SCN5A gene. Based on their effects on peak currents, variants were divided into loss-of-function (less than 10% of wildtype peak current, 35 variants) and partial loss-of-function (10-50% of wildtype peak current, 15 variants). Using cell lines created to study the effects of the variants in heterozygous coexpression with wildtype SCN5A, the authors found that 32 of 35 loss-of-function variants and 6 of 15 partial loss-of-function variants showed a reduction to less than 75% of wildtype-alone peak current, demonstrating evidence of dominant-negative effects. Using data from a published consortia and gnomAD, they found that patients with dominant-negative variants were 2.7 times more likely to present with Brugada syndrome than individuals with putative haploinsufficient variants (p = 0.019). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35305865" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
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For discussion of a possible association between variants in the SCN5A, SCN10A (<a href="/entry/604427">604427</a>), and HEY2 (<a href="/entry/604674">604674</a>) genes and Brugada syndrome, see <a href="/entry/601144">601144</a>.</p>
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<p><a href="#74" class="mim-tip-reference" title="Westenskow, P., Splawski, I., Timothy, K. W., Keating, M. T., Sanguinetti, M. C. <strong>Compound mutations: a common cause of severe long-QT syndrome.</strong> Circulation 109: 1834-1841, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15051636/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15051636</a>] [<a href="https://doi.org/10.1161/01.CIR.0000125524.34234.13" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15051636">Westenskow et al. (2004)</a> analyzed the KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 genes in 252 probands with long QT syndrome and identified 19 with biallelic mutations in LQTS genes, of whom 18 were either compound (monogenic) or double (digenic) heterozygotes and 1 was a homozygote. They also identified 1 patient who had triallelic digenic mutations (see <a href="/entry/152427#0021">152427.0021</a>). Compared with probands who had 1 or no identified mutation, probands with 2 mutations had longer QTc intervals (p less than 0.001) and were 3.5-fold more likely to undergo cardiac arrest (p less than 0.01). All 20 probands with 2 mutations had experienced cardiac events. <a href="#74" class="mim-tip-reference" title="Westenskow, P., Splawski, I., Timothy, K. W., Keating, M. T., Sanguinetti, M. C. <strong>Compound mutations: a common cause of severe long-QT syndrome.</strong> Circulation 109: 1834-1841, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15051636/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15051636</a>] [<a href="https://doi.org/10.1161/01.CIR.0000125524.34234.13" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15051636">Westenskow et al. (2004)</a> concluded that biallelic mono- or digenic mutations (which the authors termed 'compound mutations') cause a severe phenotype and are relatively common in long QT syndrome. The authors noted that these findings support the concept of arrhythmia risk as a multi-hit process and suggested that genotype can be used to predict risk. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15051636" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#45" class="mim-tip-reference" title="Niu, D.-M., Hwang, B., Hwang, H.-W., Wang, N. H., Wu, J.-Y., Lee, P.-C., Chien, J.-C., Shieh, R.-C., Chen, Y.-T. <strong>A common SCN5A polymorphism attenuates a severe cardiac phenotype caused by a nonsense SCN5A mutation in a Chinese family with an inherited cardiac conduction defect.</strong> J. Med. Genet. 43: 817-821, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16707561/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16707561</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16707561[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1136/jmg.2006.042192" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16707561">Niu et al. (2006)</a> analyzed the SCN5A gene in 17 members of a 4-generation Han Chinese family with apparent autosomal dominant inheritance of cardiac arrhythmias and sudden death. All affected individuals were heterozygous for a nonsense mutation in the SCN5A gene (W1421X; <a href="#0036">600163.0036</a>), and 1 unaffected individual was compound heterozygous for the W1421X mutation and R1193Q (<a href="#0023">600163.0023</a>). <a href="#45" class="mim-tip-reference" title="Niu, D.-M., Hwang, B., Hwang, H.-W., Wang, N. H., Wu, J.-Y., Lee, P.-C., Chien, J.-C., Shieh, R.-C., Chen, Y.-T. <strong>A common SCN5A polymorphism attenuates a severe cardiac phenotype caused by a nonsense SCN5A mutation in a Chinese family with an inherited cardiac conduction defect.</strong> J. Med. Genet. 43: 817-821, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16707561/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16707561</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16707561[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1136/jmg.2006.042192" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16707561">Niu et al. (2006)</a> suggested that the R1193Q mutation, which results in a gain of sodium channel function, may compensate for the deleterious effects of W1421X. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16707561" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#47" class="mim-tip-reference" title="Nuyens, D., Stengl, M., Dugarmaa, S., Rossenbacker, T., Compernolle, V., Rudy, Y., Smits, J. F., Flameng, W., Clancy, C. E., Moons, L., Vos, M. A., Dewerchin, M., Benndorf, K., Collen, D., Carmeliet, E., Carmeliet, P. <strong>Abrupt rate accelerations or premature beats cause life-threatening arrhythmias in mice with long-QT3 syndrome.</strong> Nature Med. 7: 1021-1027, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11533705/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11533705</a>] [<a href="https://doi.org/10.1038/nm0901-1021" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11533705">Nuyens et al. (2001)</a> reported that mice heterozygous for a knockin KPQ deletion (<a href="#0001">600163.0001</a>) of the Scn5a gene showed the essential features of LQT3 and spontaneously developed life-threatening polymorphous ventricular arrhythmias. Sudden accelerations in heart rate or premature beats caused lengthening of the action potential with early after-depolarization and triggered arrhythmias in mice heterozygous for the deletion. Adrenergic agonists normalized the response to rate acceleration in vitro and suppressed arrhythmias upon premature stimulation in vivo. These results showed the possible risk of sudden heart rate accelerations. The heterozygous knockin mouse with its predisposition for pacing-induced arrhythmia might be a useful model for the development of new treatments for the LQT3 syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11533705" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#50" class="mim-tip-reference" title="Papadatos, G. A., Wallerstein, P. M. R., Head, C. E. G., Ratcliff, R., Brady, P. A., Benndorf, K., Saumarez, R. C., Trezise, A. E. O., Huang, C. L.-H., Vandenberg, J. I., Colledge, W. H., Grace, A. A. <strong>Slowed conduction and ventricular tachycardia after targeted disruption of the cardiac sodium channel gene Scn5a.</strong> Proc. Nat. Acad. Sci. 99: 6210-6215, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11972032/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11972032</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11972032[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.082121299" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11972032">Papadatos et al. (2002)</a> showed that disruption of the mouse Scn5a gene caused intrauterine lethality in homozygotes with severe defects in ventricular morphogenesis, whereas heterozygotes showed normal survival. Whole-cell patch-clamp analyses of isolated ventricular myocytes from adult Scn5a +/- mice demonstrated a reduction of approximately 50% in sodium conductance. Scn5a +/- hearts had several defects, including impaired atrioventricular conduction, delayed intramyocardial conduction, increased ventricular refractoriness, and ventricular tachycardia with characteristics of reentrant excitation. These findings reconciled reduced activity of the cardiac sodium channel leading to slowed conduction with several apparently diverse clinical phenotypes, providing a model for the detailed analysis of the pathophysiology of arrhythmias. <a href="#46" class="mim-tip-reference" title="Noble, D. <strong>Unraveling the genetics and mechanisms of cardiac arrhythmia. (Commentary)</strong> Proc. Nat. Acad. Sci. 99: 5755-5756, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11983875/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11983875</a>] [<a href="https://doi.org/10.1073/pnas.102171699" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11983875">Noble (2002)</a> commented that detailed understanding of the mechanisms of cardiac arrhythmia at all relevant levels is important to the design of therapeutic programs, and cited the work of <a href="#50" class="mim-tip-reference" title="Papadatos, G. A., Wallerstein, P. M. R., Head, C. E. G., Ratcliff, R., Brady, P. A., Benndorf, K., Saumarez, R. C., Trezise, A. E. O., Huang, C. L.-H., Vandenberg, J. I., Colledge, W. H., Grace, A. A. <strong>Slowed conduction and ventricular tachycardia after targeted disruption of the cardiac sodium channel gene Scn5a.</strong> Proc. Nat. Acad. Sci. 99: 6210-6215, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11972032/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11972032</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11972032[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.082121299" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11972032">Papadatos et al. (2002)</a> as an important step. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11983875+11972032" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<span id="mimAllelicVariantsToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<strong>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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<strong>48 Selected Examples</a>):</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=600163[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs397514251 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397514251;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs397514251" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs397514251" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000009962 OR RCV000183165 OR RCV002336463 OR RCV003318368 OR RCV004804804" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009962, RCV000183165, RCV002336463, RCV003318368, RCV004804804" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009962...</a>
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<p>In 2 apparently unrelated kindreds with chromosome 3-linked LQT syndrome (LQT3; <a href="/entry/603830">603830</a>), <a href="#71" class="mim-tip-reference" title="Wang, Q., Shen, J., Splawski, I., Atkinson, D., Li, Z., Robinson, J. L., Moss, A. J., Towbin, J. A., Keating, M. T. <strong>SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome.</strong> Cell 80: 805-811, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7889574/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7889574</a>] [<a href="https://doi.org/10.1016/0092-8674(95)90359-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7889574">Wang et al. (1995)</a> found deletion of 9 basepairs beginning at nucleotide 4661 of their cDNA for SCN5A. The deletion, which was detected by sequencing an aberrant SSCP conformer, resulted in deletion of lys-pro-gln (KPQ), which are 3 conserved amino acids in the cytoplasmic linker between domains III and IV of the channel protein. The 3 amino acids involved in the in-frame deletion are lys1505, pro1506, and gln1507. The effect of this mutation on membrane depolarization was studied by <a href="#6" class="mim-tip-reference" title="Bennett, P. B., Yazawa, K., Makita, N., George, A. L., Jr. <strong>Molecular mechanism for an inherited cardiac arrhythmia.</strong> Nature 376: 683-685, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7651517/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7651517</a>] [<a href="https://doi.org/10.1038/376683a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7651517">Bennett et al. (1995)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7889574+7651517" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#12" class="mim-tip-reference" title="Clancy, C. E., Rudy, Y. <strong>Linking a genetic defect to its cellular phenotype in a cardiac arrhythmia.</strong> Nature 400: 566-569, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10448858/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10448858</a>] [<a href="https://doi.org/10.1038/23034" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10448858">Clancy and Rudy (1999)</a> developed a model representative of the behavior of the sodium channel in heart muscle cells using a single-channel-based Markov model approach. They showed that the delta-KPQ mutant form of the sodium channel stays open for too long, causing an overlarge inward current of sodium which gives rise to arrhythmia. This model view was corroborated by experiments recording actual sodium currents in cardiac muscle cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10448858" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs28937316 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28937316;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs28937316?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs28937316" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs28937316" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000009963 OR RCV000058726 OR RCV000183090 OR RCV000246905 OR RCV002307360 OR RCV003591624 OR RCV004545721" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009963, RCV000058726, RCV000183090, RCV000246905, RCV002307360, RCV003591624, RCV004545721" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009963...</a>
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<p>In a mother and son with the long QT syndrome (LQT3; <a href="/entry/603830">603830</a>), <a href="#70" class="mim-tip-reference" title="Wang, Q., Shen, J., Li, Z., Timothy, K., Vincent, G. M., Priori, S. G., Schwartz, P. J., Keating, M. T. <strong>Cardiac sodium channel mutations in patients with long QT syndrome, an inherited cardiac arrhythmia.</strong> Hum. Molec. Genet. 4: 1603-1607, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8541846/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8541846</a>] [<a href="https://doi.org/10.1093/hmg/4.9.1603" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8541846">Wang et al. (1995)</a> demonstrated a CGC-to-CAC mutation in codon 1644, resulting in the substitution of a highly conserved arginine residue by histidine. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8541846" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs28937317 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28937317;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs28937317" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs28937317" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000009964 OR RCV000058618 OR RCV002354154 OR RCV003234898" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009964, RCV000058618, RCV002354154, RCV003234898" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009964...</a>
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<p>In a family in which members of 4 generations had been affected by the long QT syndrome (LQT3; <a href="/entry/603830">603830</a>), <a href="#70" class="mim-tip-reference" title="Wang, Q., Shen, J., Li, Z., Timothy, K., Vincent, G. M., Priori, S. G., Schwartz, P. J., Keating, M. T. <strong>Cardiac sodium channel mutations in patients with long QT syndrome, an inherited cardiac arrhythmia.</strong> Hum. Molec. Genet. 4: 1603-1607, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8541846/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8541846</a>] [<a href="https://doi.org/10.1093/hmg/4.9.1603" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8541846">Wang et al. (1995)</a> found an AAT-to-AGT transition in codon 1325, predicted to cause substitution of a highly conserved asparagine residue by a serine residue. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8541846" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs199473207 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199473207;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs199473207" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs199473207" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div> <div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs199473282 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199473282;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs199473282?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs199473282" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs199473282" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000009965 OR RCV000058588 OR RCV000058715 OR RCV000144030 OR RCV000144031 OR RCV000183042 OR RCV001836727 OR RCV001842342 OR RCV001842371 OR RCV002345369 OR RCV002477202" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009965, RCV000058588, RCV000058715, RCV000144030, RCV000144031, RCV000183042, RCV001836727, RCV001842342, RCV001842371, RCV002345369, RCV002477202" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009965...</a>
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<p>In affected members of a family with Brugada syndrome (BRGDA1; <a href="/entry/601144">601144</a>), a distinct form of idiopathic ventricular fibrillation, <a href="#9" class="mim-tip-reference" title="Chen, Q., Kirsch, G. E., Zhang, D., Brugada, R., Brugada, J., Brugada, P., Potenza, D., Moya, A., Borggrefe, M., Breithardt, G., Ortiz-Lopez, R., Wang, Z., Antzelevitch, C., O'Brien, R. E., Schulze-Bahr, E., Keating, M. T., Towbin, J. A., Wang, Q. <strong>Genetic basis and molecular mechanism for idiopathic ventricular fibrillation.</strong> Nature 392: 293-295, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9521325/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9521325</a>] [<a href="https://doi.org/10.1038/32675" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9521325">Chen et al. (1998)</a> found an arg1232-to-trp (R1232W) and a thr1620-to-met (T1620M) mutation on the same chromosome with no mutation in the other chromosome, suggesting to them that IVF in this family was inherited as an autosomal dominant trait. The presence of both normal and mutated sodium channels in the same tissue would promote heterogeneity of the refractory period, a well established mechanism in arrhythmogenesis, and therefore may be the underlying molecular defect that causes re-entrant arrhythmia in this family. The potential contribution of R1232W and T1620M mutations to the mechanism of IVF was determined by heterologous expression in Xenopus oocytes. They found that sodium channels with the missense mutation recovered from inactivation more rapidly than normal, indicating that IVF with right bundle branch block (RBBB) and ST segment elevation is a defect distinct from long QT syndrome. When studied alone, the R1232W mutant behaved most like normal channels, whereas the T1620M mutant closely followed the kinetic pattern of the double mutant. This indicated that T1620M is the mutation probably responsible for the IVF phenotype in this kindred and that R1232W could be a rare polymorphism. In summary, biophysical analysis of the 2 missense mutations in SCN5A showed a shift in the voltage dependence of steady-state inactivation toward more positive potentials associated with a 25 to 30% acceleration in recovery time from inactivation at potentials near -80mV. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9521325" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Commenting that studies of the thr1620-to-met mutant by <a href="#9" class="mim-tip-reference" title="Chen, Q., Kirsch, G. E., Zhang, D., Brugada, R., Brugada, J., Brugada, P., Potenza, D., Moya, A., Borggrefe, M., Breithardt, G., Ortiz-Lopez, R., Wang, Z., Antzelevitch, C., O'Brien, R. E., Schulze-Bahr, E., Keating, M. T., Towbin, J. A., Wang, Q. <strong>Genetic basis and molecular mechanism for idiopathic ventricular fibrillation.</strong> Nature 392: 293-295, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9521325/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9521325</a>] [<a href="https://doi.org/10.1038/32675" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9521325">Chen et al. (1998)</a> revealed an abnormal electrophysiologic profile at room temperature that did not adequately explain the ECG signature of Brugada syndrome, <a href="#16" class="mim-tip-reference" title="Dumaine, R., Towbin, J. A., Brugada, P., Vatta, M., Nesterenko, D. V., Nesterenko, V. V., Brugada, J., Brugada, R., Antzelevitch, C. <strong>Ionic mechanisms responsible for the electrocardiographic phenotype of the Brugada syndrome are temperature dependent.</strong> Circ. Res. 85: 803-809, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10532948/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10532948</a>] [<a href="https://doi.org/10.1161/01.res.85.9.803" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10532948">Dumaine et al. (1999)</a> undertook a more detailed electrophysiologic study of the thr1620-to-met mutant protein. <a href="#16" class="mim-tip-reference" title="Dumaine, R., Towbin, J. A., Brugada, P., Vatta, M., Nesterenko, D. V., Nesterenko, V. V., Brugada, J., Brugada, R., Antzelevitch, C. <strong>Ionic mechanisms responsible for the electrocardiographic phenotype of the Brugada syndrome are temperature dependent.</strong> Circ. Res. 85: 803-809, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10532948/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10532948</a>] [<a href="https://doi.org/10.1161/01.res.85.9.803" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10532948">Dumaine et al. (1999)</a> expressed the mutant protein in a mammalian cell line and employed a patch-clamp technique to study current kinetics at 32 degrees C. The results indicated that current decay kinetics were faster in mutant than in wildtype channels at this temperature and that recovery from inactivation was slower, with a significant shift in steady-state activation. These findings provided an explanation for the ECG features of Brugada syndrome and represented the first illustration of a cardiac sodium channel mutation in which arrhythmogenicity is revealed only at temperatures approaching the physiologic range. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10532948+9521325" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Voltage-gated sodium channels are multimeric structures consisting of a large, heavily glycosylated alpha subunit and 1 or 2 smaller beta subunits. The beta subunits are thought necessary for normal gating function. In brain and skeletal muscle, the beta-1 subunit (<a href="/entry/600235">600235</a>) accelerates sodium channel inactivation. <a href="#37" class="mim-tip-reference" title="Makita, N., Shirai, N., Wang, D. W., Sasaki, K., George, A. L., Kanno, M., Kitabatake, A. <strong>Cardiac Na+ channel dysfunction in Brugada syndrome is aggravated by beta(1)-subunit.</strong> Circulation 101: 54-60, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10618304/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10618304</a>] [<a href="https://doi.org/10.1161/01.cir.101.1.54" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10618304">Makita et al. (2000)</a> characterized the functional roles of the auxiliary beta subunit by coexpression of the beta subunit with either wildtype SCN5A or SCN5A carrying the heterologously expressed T1620M mutation in Xenopus oocytes. The midpoint of steady-state inactivation was significantly shifted to positive potentials in the T1620M alpha/beta-1 channel, with an acceleration in recovery from inactivation when compared to other channels. <a href="#37" class="mim-tip-reference" title="Makita, N., Shirai, N., Wang, D. W., Sasaki, K., George, A. L., Kanno, M., Kitabatake, A. <strong>Cardiac Na+ channel dysfunction in Brugada syndrome is aggravated by beta(1)-subunit.</strong> Circulation 101: 54-60, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10618304/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10618304</a>] [<a href="https://doi.org/10.1161/01.cir.101.1.54" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10618304">Makita et al. (2000)</a> therefore suggested that coexpression of T1620M alpha/beta-1 subunits exposed a significant electrophysiologic deficit that may predispose to ventricular fibrillation. Expression of both normal and mutant channels, as in the hearts of patients with Brugada syndrome, would promote heterogeneity of the refractory period in their myocardium, which serves as an ideal electrical substrate for reentrant arrhythmia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10618304" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs397514252 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397514252;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs397514252" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs397514252" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In affected members of a family with idiopathic ventricular fibrillation with right bundle branch block (RBBB) and elevated ST segments, a disorder known as Brugada syndrome (BRGDA1; <a href="/entry/601144">601144</a>), <a href="#9" class="mim-tip-reference" title="Chen, Q., Kirsch, G. E., Zhang, D., Brugada, R., Brugada, J., Brugada, P., Potenza, D., Moya, A., Borggrefe, M., Breithardt, G., Ortiz-Lopez, R., Wang, Z., Antzelevitch, C., O'Brien, R. E., Schulze-Bahr, E., Keating, M. T., Towbin, J. A., Wang, Q. <strong>Genetic basis and molecular mechanism for idiopathic ventricular fibrillation.</strong> Nature 392: 293-295, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9521325/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9521325</a>] [<a href="https://doi.org/10.1038/32675" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9521325">Chen et al. (1998)</a> found an insertion of 2 nucleotides, AA, after the first 4 nucleotides (gtaa) in the splice donor sequence of intron 7 of the SCN5A gene. The functional consequences of this splicing mutation were not established. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9521325" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs397514446 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397514446;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs397514446" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs397514446" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In affected members of a family with idiopathic ventricular fibrillation characterized by RBBB and elevated ST segments, a disorder known as Brugada syndrome (BRGDA1; <a href="/entry/601144">601144</a>), <a href="#9" class="mim-tip-reference" title="Chen, Q., Kirsch, G. E., Zhang, D., Brugada, R., Brugada, J., Brugada, P., Potenza, D., Moya, A., Borggrefe, M., Breithardt, G., Ortiz-Lopez, R., Wang, Z., Antzelevitch, C., O'Brien, R. E., Schulze-Bahr, E., Keating, M. T., Towbin, J. A., Wang, Q. <strong>Genetic basis and molecular mechanism for idiopathic ventricular fibrillation.</strong> Nature 392: 293-295, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9521325/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9521325</a>] [<a href="https://doi.org/10.1038/32675" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9521325">Chen et al. (1998)</a> found a deletion of a single nucleotide (A) from codon 1397 of the SCN5A gene. This deletion resulted in an in-frame stop at codon 1398 (normally val). The resulting truncation eliminated DIII/S6, DIV/S1-S6, and the C-terminal portion of the cardiac sodium channel. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9521325" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs137854600 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137854600;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs137854600" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs137854600" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In an infant Japanese girl with a severe form of long QT syndrome (LQT3; <a href="/entry/603830">603830</a>), <a href="#36" class="mim-tip-reference" title="Makita, N., Shirai, N., Nagashima, M., Matsuoka, R., Yamada, Y., Tohse, N., Kitabatake, A. <strong>A de novo missense mutation of human cardiac Na(+) channel exhibiting novel molecular mechanisms of long QT syndrome.</strong> FEBS Lett. 423: 5-9, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9506831/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9506831</a>] [<a href="https://doi.org/10.1016/s0014-5793(98)00033-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9506831">Makita et al. (1998)</a> identified a de novo missense mutation, arg1623 to gln (R1623Q), in the S4 segment of domain 4 of the SCN5A gene. When expressed in oocytes, mutant sodium channels exhibited only minor abnormalities in channel activation, but in contrast to 3 previously characterized LQT3 mutations, had significantly delayed macroscopic inactivation. Single channel analysis revealed that R1623Q channels had significantly prolonged open times with bursting behavior, suggesting a novel mechanism of pathophysiology in Na(+) channel-linked long QT syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9506831" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#29" class="mim-tip-reference" title="Kambouris, N. G., Nuss, H. B., Johns, D. C., Marban, E., Tomaselli, G. F., Balser, J. R. <strong>A revised view of cardiac sodium channel 'blockade' in the long-QT syndrome.</strong> J. Clin. Invest. 105: 1133-1140, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10772658/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10772658</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10772658[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI9212" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10772658">Kambouris et al. (2000)</a> reported that the R1623Q mutation imparts unusual lidocaine sensitivity to the sodium channel that is attributable to its altered functional behavior. Studies of lidocaine on individual R1623Q single-channel openings indicated that the open-time distribution was not changed, indicating the drug does not block the open pore as proposed previously. Rather, the mutant channels have a propensity to inactivate without ever opening ('closed-state inactivation'), and lidocaine augments this gating behavior. An allosteric gating model incorporating closed-state inactivation recapitulated the effects of lidocaine on the pathologic sodium current. These findings explained the unusual drug sensitivity of R1623Q and provided a general and unanticipated mechanism for understanding how sodium channel-blocking agents may suppress the pathologic, sustained sodium current induced by LQT3 mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10772658" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a male infant diagnosed with ventricular arrhythmias and cardiac decompensation in utero at 28 weeks' gestation and with long QT syndrome at birth, <a href="#42" class="mim-tip-reference" title="Miller, T. E., Estrella, E., Myerburg, R. J., Garcia de Viera, J., Moreno, N., Rusconi, P., Ahearn, M. E., Baumbach, L., Kurlansky, P., Wolff, G., Bishopric, N. H. <strong>Recurrent third-trimester fetal loss and maternal mosaicism for long-QT syndrome.</strong> Circulation 109: 3029-3034, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15184283/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15184283</a>] [<a href="https://doi.org/10.1161/01.CIR.0000130666.81539.9E" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15184283">Miller et al. (2004)</a> identified heterozygosity for the R1623Q mutation. The mother had no ECG abnormalities, but a previous and a subsequent pregnancy both ended in stillbirth at 7 months. Initial studies detected no genetic abnormality, but a sensitive restriction enzyme-based assay revealed a small percentage (8 to 10%) of cells harboring the mutation in the mother's blood, skin, and buccal mucosa; R1623Q was also identified in cord blood from the third fetus. <a href="#42" class="mim-tip-reference" title="Miller, T. E., Estrella, E., Myerburg, R. J., Garcia de Viera, J., Moreno, N., Rusconi, P., Ahearn, M. E., Baumbach, L., Kurlansky, P., Wolff, G., Bishopric, N. H. <strong>Recurrent third-trimester fetal loss and maternal mosaicism for long-QT syndrome.</strong> Circulation 109: 3029-3034, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15184283/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15184283</a>] [<a href="https://doi.org/10.1161/01.CIR.0000130666.81539.9E" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15184283">Miller et al. (2004)</a> concluded that recurrent late-term fetal loss or sudden infant death can result from unsuspected parental mosaicism for LQT-associated mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15184283" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a 1-month-old male infant who had syncope, torsade de pointes, cardiac arrest, and a QTc of 460 ms, <a href="#41" class="mim-tip-reference" title="Millat, G., Chevalier, P., Restier-Miron, L., Da Costa, A., Bouvagnet, P., Kugener, B., Fayol, L., Gonzalez Armengod, C., Oddou, B., Chanavat, V., Froidefond, E., Perraudin, R., Rousson, R., Rodriguez-Lafrasse, C. <strong>Spectrum of pathogenic mutations and associated polymorphisms in a cohort of 44 unrelated patients with long QT syndrome.</strong> Clin. Genet. 70: 214-227, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16922724/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16922724</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2006.00671.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16922724">Millat et al. (2006)</a> identified biallelic digenic mutations: a 4868G-A transition in exon 28 of the SCN5A gene resulting in the R1623Q substitution; and a missense mutation in the KCNE2 gene (F60L; <a href="/entry/603796#0005">603796.0005</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16922724" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs137854601 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137854601;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs137854601?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs137854601" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs137854601" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000009972 OR RCV000009973 OR RCV000009974 OR RCV000058773 OR RCV000183117 OR RCV000208193 OR RCV000245905 OR RCV000588022 OR RCV000824758 OR RCV003591625 OR RCV004545722 OR RCV004795388" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009972, RCV000009973, RCV000009974, RCV000058773, RCV000183117, RCV000208193, RCV000245905, RCV000588022, RCV000824758, RCV003591625, RCV004545722, RCV004795388" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009972...</a>
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<p><a href="#73" class="mim-tip-reference" title="Wei, J., Wang, D. W., Alings, M., Fish, F., Wathen, M., Roden, D. M., George, A. L., Jr. <strong>Congenital long-QT syndrome caused by a novel mutation in a conserved acidic domain of the cardiac Na(+) channel.</strong> Circulation 99: 3165-3171, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10377081/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10377081</a>] [<a href="https://doi.org/10.1161/01.cir.99.24.3165" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10377081">Wei et al. (1999)</a> described a family in which the 13-year-old proband died suddenly at rest with no antecedent illness and no significant findings at postmortem. Her father had sinus bradycardia with occasional sinus pauses and ventricular ectopy together with profound prolongation of his QT interval (QTc = 527 ms) (see LQT3; <a href="/entry/603830">603830</a>). He experienced only occasional light-headedness. Other family members experienced occasional syncope and had sinus bradycardia and prolonged QT intervals on their ECGs. In those individuals with prolonged QT intervals, SSCP analysis detected an aberrant conformer in the coding region of the SCN5A gene corresponding to the C terminus. Nucleotide sequencing revealed a G-to-A transition at codon 1784, resulting in a glu-to-lys substitution. This mutation occurs at a highly conserved residue in most voltage-gated sodium channels in most animals, including invertebrates. When the mutation was expressed in Xenopus oocytes, a defect in channel inactivation was demonstrated in the form of a small residual steady state current throughout prolonged depolarization. <a href="#73" class="mim-tip-reference" title="Wei, J., Wang, D. W., Alings, M., Fish, F., Wathen, M., Roden, D. M., George, A. L., Jr. <strong>Congenital long-QT syndrome caused by a novel mutation in a conserved acidic domain of the cardiac Na(+) channel.</strong> Circulation 99: 3165-3171, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10377081/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10377081</a>] [<a href="https://doi.org/10.1161/01.cir.99.24.3165" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10377081">Wei et al. (1999)</a> explored this further by engineering SCN5A constructs with amino acid substitutions at other positions in the C terminus. All exhibited similar electrophysiologic phenotypes, suggesting that heterozygous charge-neutralizing amino acid substitution at this site causes an allosteric effect on sodium channel gating, resulting in delayed myocardial repolarization. This provided a novel mechanism for LQT3. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10377081" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#34" class="mim-tip-reference" title="Makita, N., Behr, E., Shimizu, W., Horie, M., Sunami, A., Crotti, L., Schulze-Bahr, E., Fukuhara, S., Mochizuki, N., Makiyama, T., Itoh, H., Christiansen, M., McKeown, P., Miyamoto, K., Kamakura, S., Tsutsui, H., Schwartz, P. J., George, A. L., Jr., Roden, D. M. <strong>The E1784K mutation in SCN5A is associated with mixed clinical phenotype of type 3 long QT syndrome.</strong> J. Clin. Invest. 118: 2219-2229, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18451998/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18451998</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18451998[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI34057" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18451998">Makita et al. (2008)</a> genotyped 66 members of 44 LQT3 families of multiple ethnicities and identified the E1784K mutation in 41 individuals from 15 (34%) of the kindreds, including the family previously reported by <a href="#73" class="mim-tip-reference" title="Wei, J., Wang, D. W., Alings, M., Fish, F., Wathen, M., Roden, D. M., George, A. L., Jr. <strong>Congenital long-QT syndrome caused by a novel mutation in a conserved acidic domain of the cardiac Na(+) channel.</strong> Circulation 99: 3165-3171, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10377081/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10377081</a>] [<a href="https://doi.org/10.1161/01.cir.99.24.3165" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10377081">Wei et al. (1999)</a>; the diagnoses in these individuals included LQT3 syndrome, Brugada syndrome (BRGDA1; <a href="/entry/601144">601144</a>), and/or sinus node disease (see <a href="/entry/608567">608567</a>). Heterologously expressed E1784K channels showed a 15.0-mV negative shift in the voltage dependence of Na channel inactivation and a 7.5-fold increase in flecainide affinity for resting-state channels, properties also seen with other LQT3 mutations associated with a mixed clinical phenotype. Furthermore, these properties were absent in Na channels harboring the T1304M mutation, which is associated with LQT3 without a mixed clinical phenotype. <a href="#34" class="mim-tip-reference" title="Makita, N., Behr, E., Shimizu, W., Horie, M., Sunami, A., Crotti, L., Schulze-Bahr, E., Fukuhara, S., Mochizuki, N., Makiyama, T., Itoh, H., Christiansen, M., McKeown, P., Miyamoto, K., Kamakura, S., Tsutsui, H., Schwartz, P. J., George, A. L., Jr., Roden, D. M. <strong>The E1784K mutation in SCN5A is associated with mixed clinical phenotype of type 3 long QT syndrome.</strong> J. Clin. Invest. 118: 2219-2229, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18451998/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18451998</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18451998[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI34057" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18451998">Makita et al. (2008)</a> suggested that a negative shift of steady-state Na channel inactivation and enhanced tonic block by class IC drugs represent common biophysical mechanisms underlying the phenotypic overlap of LQT3 and Brugada syndromes, and further indicated that class IC drugs should be avoided in patients with Na channels displaying these behaviors. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10377081+18451998" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0009 PROGRESSIVE FAMILIAL HEART BLOCK, TYPE IA</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs397514447 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397514447;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs397514447" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs397514447" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000009975 OR RCV003541536" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009975, RCV003541536" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009975...</a>
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<p>In a large French family with progressive heart block (PFHB1A; <a href="/entry/113900">113900</a>), <a href="#54" class="mim-tip-reference" title="Schott, J.-J., Alshinawi, C., Kyndt, F., Probst, V., Hoorntje, T. M., Hulsbeek, M., Wilde, A. A. M., Escande, D., Mannens, M. M. A. M., Le Marec, H. <strong>Cardiac conduction defects associate with mutations in SCN5A. (Letter)</strong> Nature Genet. 23: 20-21, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10471492/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10471492</a>] [<a href="https://doi.org/10.1038/12618" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10471492">Schott et al. (1999)</a> identified a T-to-C transition in the highly conserved +2 donor splice site of intron 22 of the SCN5A gene. The abnormal transcript predicted in-frame skipping of exon 22 and an impaired gene product lacking the voltage-sensitive DIIIS4 segment. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10471492" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs397514448 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397514448;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs397514448" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs397514448" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000009976" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009976" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009976</a>
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<p>In a Dutch family with asymptomatic first-degree atrioventricular block associated with right bundle branch block from birth, without apparent progression (see <a href="/entry/113900">113900</a>), <a href="#54" class="mim-tip-reference" title="Schott, J.-J., Alshinawi, C., Kyndt, F., Probst, V., Hoorntje, T. M., Hulsbeek, M., Wilde, A. A. M., Escande, D., Mannens, M. M. A. M., Le Marec, H. <strong>Cardiac conduction defects associate with mutations in SCN5A. (Letter)</strong> Nature Genet. 23: 20-21, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10471492/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10471492</a>] [<a href="https://doi.org/10.1038/12618" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10471492">Schott et al. (1999)</a> identified a 1-bp deletion (G) at nucleotide 5280 of the SCN5A gene, resulting in a frameshift predicted to cause a premature stop codon. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10471492" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0011 BRUGADA SYNDROME 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs137854602 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137854602;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs137854602?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs137854602" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs137854602" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000009977 OR RCV000058688 OR RCV000157490 OR RCV000222521 OR RCV001841232 OR RCV004018610" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009977, RCV000058688, RCV000157490, RCV000222521, RCV001841232, RCV004018610" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009977...</a>
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<p>In the screening of SCN5A in 6 individuals with Brugada syndrome (BRGDA1; <a href="/entry/601144">601144</a>), <a href="#53" class="mim-tip-reference" title="Rook, M. B., Alshinawi, C. B., Groenewegen, W. A., van Gelder, I. C., van Ginneken, A. C. G., Jongsma, H. J., Mannens, M. M. A. M., Wilde, A. A. M. <strong>Human SCN5A gene mutations alter cardiac sodium channel kinetics and are associated with the Brugada syndrome.</strong> Cardiovasc. Res. 44: 507-517, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10690282/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10690282</a>] [<a href="https://doi.org/10.1016/s0008-6363(99)00350-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10690282">Rook et al. (1999)</a> found missense mutations in the coding region of the gene in 2: arg1512 to trp (R1512W) in the DIII-DIV cytoplasmic linker, and ala1924 to thr (A1924T; <a href="#0012">600163.0012</a>) in the C-terminal cytoplasmic domain. In 2 other patients mutations were detected near intron/exon junctions. To assess the functional consequences of the R1512W and A1924T mutations, wildtype and mutant sodium channel proteins were expressed in Xenopus oocytes. Both missense mutations affected channel function and seemed to be associated with an increase in inward sodium current during the action potential upstroke. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10690282" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0012 BRUGADA SYNDROME 1</strong>
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SCN5A, ALA1924THR
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs137854603 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137854603;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs137854603?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs137854603" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs137854603" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000009978 OR RCV000058806 OR RCV000420298 OR RCV001841233 OR RCV002251424 OR RCV004017231" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009978, RCV000058806, RCV000420298, RCV001841233, RCV002251424, RCV004017231" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009978...</a>
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<p>For discussion of the ala1924-to-thr (A1924T) substitution in the SCN5A gene that was found in compound heterozygous state in 2 patients with Brugada syndrome (BRGDA1; <a href="/entry/601144">601144</a>) by <a href="#53" class="mim-tip-reference" title="Rook, M. B., Alshinawi, C. B., Groenewegen, W. A., van Gelder, I. C., van Ginneken, A. C. G., Jongsma, H. J., Mannens, M. M. A. M., Wilde, A. A. M. <strong>Human SCN5A gene mutations alter cardiac sodium channel kinetics and are associated with the Brugada syndrome.</strong> Cardiovasc. Res. 44: 507-517, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10690282/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10690282</a>] [<a href="https://doi.org/10.1016/s0008-6363(99)00350-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10690282">Rook et al. (1999)</a>, see <a href="#0011">600163.0011</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10690282" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0013 LONG QT SYNDROME 3</strong>
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BRUGADA SYNDROME 1, INCLUDED
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SCN5A, 3-BP INS, 5537TGA
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs397514449 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397514449;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs397514449" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs397514449" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000009979 OR RCV000009980 OR RCV001530164" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009979, RCV000009980, RCV001530164" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009979...</a>
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<p>In a large Dutch family with electrocardiographic features both of long QT syndrome (LQT3; <a href="/entry/603830">603830</a>) and Brugada syndrome (BRGDA1; <a href="/entry/601144">601144</a>), <a href="#8" class="mim-tip-reference" title="Bezzina, C., Veldkamp, M. W., van den Berg, M. P., Postma, A. V., Rook, M. B., Viersma, J.-W., van Langen, I. M., Tan-Sindhunata, G., Bink-Boelkens, M. T. E., van der Hout, A. H., Mannens, M. M. A. M., Wilde, A. A. M. <strong>A single Na+ channel mutation causing both long-QT and Brugada syndromes.</strong> Circ. Res. 85: 1206-1213, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10590249/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10590249</a>] [<a href="https://doi.org/10.1161/01.res.85.12.1206" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10590249">Bezzina et al. (1999)</a> demonstrated a 3-bp insertion at nucleotide position 5537 of the SCN5A gene, predicted to cause insertion of an aspartic acid residue at amino acid position 1795 (1795insD) in the C-terminal domain of the protein. Expression of this mutant channel protein in Xenopus oocytes permitted characterization of defects in channel activation and inactivation when compared to a wildtype control. These defects were predicted to cause a reduction in sodium flux during the upstroke of the cardiac action potential. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10590249" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The co-occurrence of Brugada syndrome and long QT syndrome in this family was paradoxical, since LQT3 is associated with activating SCN5A mutations and Brugada syndrome with inactivating mutations. <a href="#13" class="mim-tip-reference" title="Clancy, C. E., Rudy, Y. <strong>Na+ channel mutation that causes both Brugada and long-QT syndrome phenotypes: a simulation study of mechanism.</strong> Circulation 105: 1208-1213, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11889015/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11889015</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11889015[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1161/hc1002.105183" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11889015">Clancy and Rudy (2002)</a> modeled the cellular effects of the 1795insD mutation in a virtual transgenic cell. Since ion channel proteins are expressed nonuniformly throughout the myocardium, there is an intrinsic electrophysiologic heterogeneity. The authors demonstrated that the interplay between this underlying myocardial electrophysiologic heterogeneity and the mutation-induced changes in cardiac sodium channel function provided the substrate for both ST segment elevation (in Brugada syndrome) and QT prolongation (LQT3) in a rate-dependent manner. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11889015" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0014" class="mim-anchor"></a>
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<strong>.0014 VENTRICULAR FIBRILLATION, PAROXYSMAL FAMILIAL, 1 (1 patient)</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs137854604 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137854604;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs137854604?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs137854604" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs137854604" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000009981 OR RCV000058743 OR RCV000183102 OR RCV000197520 OR RCV000246596 OR RCV001841234 OR RCV002504774 OR RCV004017232 OR RCV004554591" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009981, RCV000058743, RCV000183102, RCV000197520, RCV000246596, RCV001841234, RCV002504774, RCV004017232, RCV004554591" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009981...</a>
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<p><a href="#3" class="mim-tip-reference" title="Akai, J., Makita, N., Sakurada, H., Shirai, N., Ueda, K., Kitabatake, A., Nakazawa, K., Kimura, A., Hiraoka, M. <strong>A novel SCN5A mutation associated with idiopathic ventricular fibrillation without typical ECG findings of Brugada syndrome.</strong> FEBS Lett. 479: 29-34, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10940383/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10940383</a>] [<a href="https://doi.org/10.1016/s0014-5793(00)01875-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10940383">Akai et al. (2000)</a> screened 25 Japanese patients with idiopathic ventricular fibrillation (VF1; <a href="/entry/603829">603829</a>). The diagnosis was based on the occurrence of at least one episode of syncope and/or cardiac arrest and documentation of ventricular fibrillation. Structural heart disorders were excluded. Eighteen patients were diagnosed as Brugada syndrome. The authors identified a heterozygous ser1710-to-leu missense mutation of the SCN5A gene in a 39-year-old man who was admitted to the hospital for recurrent syncope and suffered an episode of spontaneous ventricular fibrillation while hospitalized. An implanted cardiac defibrillator was successful in preventing further attacks of palpitation or syncope. Brugada syndrome was not present. The paternal grandfather and a paternal uncle had died suddenly in their sixth decade of unknown cause; the parents and sibs were asymptomatic. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10940383" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs137854605 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137854605;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs137854605" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs137854605" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000009982 OR RCV003542271 OR RCV004018611" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009982, RCV003542271, RCV004018611" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009982...</a>
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<p><a href="#55" class="mim-tip-reference" title="Schwartz, P. J., Priori, S. G., Dumaine, R., Napolitano, C., Antzelevitch, C., Stramba-Badiale, M., Richard, T. A., Berti, M. R., Bloise, R. <strong>A molecular link between the sudden infant death syndrome and the long-QT syndrome.</strong> New Eng. J. Med. 343: 262-267, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10911008/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10911008</a>] [<a href="https://doi.org/10.1056/NEJM200007273430405" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10911008">Schwartz et al. (2000)</a> described an infant who nearly died of SIDS (<a href="/entry/272120">272120</a>), whose parents had normal QT intervals and in whom the long QT syndrome (LQT3; <a href="/entry/603830">603830</a>) was diagnosed with identification of a spontaneous mutation of the SCN5A gene: a change of codon 941 from TCC (serine) to AAC (asparagine). The patient had all the classic features of near-SIDS. Before the episode, the infant appeared to be in perfect health. His age at the time of the episode (7 weeks) was within the age range of 5 to 12 weeks during which the incidence of SIDS peaks. The parents found him cyanotic, apneic, and pulseless. Ventricular fibrillation was documented in an emergency room; this point is important given the frequent statements that ventricular arrhythmias have not been recorded in infants at risk for SIDS. Had the infant died--an outcome that was almost a certainty in the absence of cardioversion--the absence of an electrocardiogram and the normal QT intervals of both parents would have eliminated suspicion of the long QT syndrome and would have prompted a diagnosis of SIDS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10911008" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0016 CARDIAC CONDUCTION DEFECT, NONPROGRESSIVE</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs137854606 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137854606;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs137854606" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs137854606" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000009984 OR RCV000058427" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009984, RCV000058427" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009984...</a>
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<p><a href="#59" class="mim-tip-reference" title="Tan, H. L., Bink-Boelkens, M. T. E., Bezzina, C. R., Viswanathan, P. C., Beaufort-Krol, G. C. M., van Tintelen, P. J., van den Berg, M. P., Wilde, A. A. M., Balser, J. R. <strong>A sodium-channel mutation causes isolated cardiac conduction disease.</strong> Nature 409: 1043-1047, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11234013/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11234013</a>] [<a href="https://doi.org/10.1038/35059090" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11234013">Tan et al. (2001)</a> studied a family who came to medical attention when the proband, a 3-year-old girl, experienced episodes of fainting during a febrile illness. Her 12-lead ECG showed characteristics of slow conduction throughout the atria and ventricles, including broad P waves, PR interval prolongation, and a wide QRS complex (see <a href="/entry/113900">113900</a>). Continuous monitoring revealed episodes of severe bradycardia (25 beats/minute). During these slow periods the cardiac rhythm was maintained by infrequent atrioventricular nodal 'escape' impulses. Conduction disturbance persisted after the febrile illness, but there was no evidence of structural heart disease or systemic diseases associated with conduction defects in children. Therapeutic intervention with a dual-chamber pacemaker was initially limited by inability to pace the atrium (maximal stimulus: 10 V, 1 ms); however, this difficulty resolved with 1 week of empiric steroid treatment. During the 4 years following diagnosis, the patient continuously required dual-chamber pacing. The proband's 6-year-old sister was similarly affected and required pacemaker implantation, with episodes of noncapture that reproducibly resolved with corticosteroid therapy. Three other family members with no structural heart disease had ECG evidence of conduction slowing (prolonged PR and QRS intervals), but did not experience bradycardia or require pacemaker implantation. All affected family members had a G-to-T transition in the first nucleotide of codon 514 in exon 12 of the SCN5A gene resulting in the replacement of glycine by cysteine (G514C). Biophysical characterization of the mutant channel showed that there were abnormalities in voltage-dependent gating behavior that could be partially corrected by dexamethasone, consistent with the salutary effects of glucocorticoids on the clinical phenotype. Computational analysis predicts that the gating defects of G514C selectively slow myocardial conduction, but do not provoke the rapid cardiac arrhythmias associated previously with SCN5A mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11234013" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0017 PROGRESSIVE FAMILIAL HEART BLOCK, TYPE IA</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs137854607 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137854607;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs137854607" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs137854607" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000009983 OR RCV000058705 OR RCV000183084 OR RCV001329632 OR RCV004528098" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009983, RCV000058705, RCV000183084, RCV001329632, RCV004528098" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009983...</a>
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<p><a href="#65" class="mim-tip-reference" title="Wang, D. W., Viswanathan, P. C., Balser, J. R., George, A. L., Jr., Benson, W. <strong>Clinical, genetic and biophysical characterisation of SCN5A mutations associated with atrioventricular block.</strong> Circulation 105: 341-346, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11804990/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11804990</a>] [<a href="https://doi.org/10.1161/hc0302.102592" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11804990">Wang et al. (2002)</a> reported a family in which the proband had presented with first-degree atrioventricular block at the age of 9, progressing to complete AV block by the age of 20 (PFHB1A; <a href="/entry/113900">113900</a>). The proband's sister and father had electrocardiographic evidence of right bundle branch block and left axis deviation with normal PR intervals. The corrected QT interval was normal (less than 420 ms) in all 3 individuals. Sequencing of the coding region of SCN5A revealed a G-to-A mutation at nucleotide position 4783, which replaced an aspartic acid residue at amino acid position 1595 with asparagine (D1595N). The G4783A mutation was engineered into a recombinant human heart sodium channel and transiently coexpressed with human sodium channel beta-1 subunit (<a href="/entry/600760">600760</a>) in a cultured mammalian cell line (tsA201). Functional characterization using a patch-clamp technique revealed a significant defect in the kinetics of fast-channel inactivation distinct from those of SCN5A mutations reported in LQT3 (<a href="/entry/603830">603830</a>). The authors considered this a plausible mechanism for the observed conduction system disease in this family. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11804990" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs137854608 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137854608;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs137854608?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs137854608" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs137854608" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000009985 OR RCV000058858 OR RCV000151803 OR RCV000415287 OR RCV001149035 OR RCV001149036 OR RCV001149037 OR RCV001149038 OR RCV001149039 OR RCV001841235 OR RCV002482852 OR RCV003137510 OR RCV004018612" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009985, RCV000058858, RCV000151803, RCV000415287, RCV001149035, RCV001149036, RCV001149037, RCV001149038, RCV001149039, RCV001841235, RCV002482852, RCV003137510, RCV004018612" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009985...</a>
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<p><a href="#65" class="mim-tip-reference" title="Wang, D. W., Viswanathan, P. C., Balser, J. R., George, A. L., Jr., Benson, W. <strong>Clinical, genetic and biophysical characterisation of SCN5A mutations associated with atrioventricular block.</strong> Circulation 105: 341-346, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11804990/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11804990</a>] [<a href="https://doi.org/10.1161/hc0302.102592" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11804990">Wang et al. (2002)</a> reported a child in whom second-degree atrioventricular block had been diagnosed at the age of 6, progressing to complete atrioventricular block by the age of 12 (PFHB1A; <a href="/entry/113900">113900</a>). The child's mother had a normal electrocardiogram and the father declined testing. There was no family history of sudden death. Sequencing of the coding region of SCN5A revealed a G-to-A mutation at nucleotide position 892 that replaced a glycine residue at amino acid position 298 with serine (G298S). The G892A mutation was engineered into a recombinant human heart sodium channel and transiently coexpressed with human sodium channel beta-1 subunit (<a href="/entry/600760">600760</a>) in a cultured mammalian cell line (tsA201). Functional characterization using a patch-clamp technique revealed a significant defect in the kinetics of fast-channel inactivation distinct from those of SCN5A mutations reported in LQT3 (<a href="/entry/603830">603830</a>). The authors considered this a plausible mechanism for the observed conduction system disease in this family. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11804990" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs137854609 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137854609;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs137854609?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs137854609" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs137854609" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000009986 OR RCV000058542 OR RCV000183020 OR RCV002504775 OR RCV003591626 OR RCV004532320 OR RCV005051733" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009986, RCV000058542, RCV000183020, RCV002504775, RCV003591626, RCV004532320, RCV005051733" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009986...</a>
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<p>In a 6-week-old male infant who died of SIDS (<a href="/entry/272120">272120</a>), <a href="#1" class="mim-tip-reference" title="Ackerman, M. J., Siu, B. L., Sturner, W. Q., Tester, D. J., Valdivia, C. R., Makielski, J. C., Towbin, J. A. <strong>Postmortem molecular analysis of SCN5A defects in sudden infant death syndrome.</strong> JAMA 286: 2264-2269, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11710892/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11710892</a>] [<a href="https://doi.org/10.1001/jama.286.18.2264" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11710892">Ackerman et al. (2001)</a> identified a heterozygous G-to-T transversion in the SCN5A gene, resulting in an ala997-to-ser substitution. The mutation was not detected in 800 control alleles. <a href="#1" class="mim-tip-reference" title="Ackerman, M. J., Siu, B. L., Sturner, W. Q., Tester, D. J., Valdivia, C. R., Makielski, J. C., Towbin, J. A. <strong>Postmortem molecular analysis of SCN5A defects in sudden infant death syndrome.</strong> JAMA 286: 2264-2269, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11710892/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11710892</a>] [<a href="https://doi.org/10.1001/jama.286.18.2264" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11710892">Ackerman et al. (2001)</a> determined that amino acid 997 is located in the cytoplasmic connector between the second and third domains of the sodium channel and is highly conserved across species. They demonstrated that the mutant SCN5A channel expressed a sodium current characterized by slower decay and a 2- to 3-fold increase in late sodium current. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11710892" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0020 LONG QT SYNDROME 3</strong>
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SCN5A, ARG1826HIS
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs137854610 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137854610;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs137854610?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs137854610" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs137854610" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000009987 OR RCV000058786 OR RCV000148848 OR RCV000154827 OR RCV000619902 OR RCV000766811 OR RCV001841236 OR RCV002476953" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009987, RCV000058786, RCV000148848, RCV000154827, RCV000619902, RCV000766811, RCV001841236, RCV002476953" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009987...</a>
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<p>In a 42-day-old male infant who died of possible SIDS (<a href="/entry/272120">272120</a>), <a href="#1" class="mim-tip-reference" title="Ackerman, M. J., Siu, B. L., Sturner, W. Q., Tester, D. J., Valdivia, C. R., Makielski, J. C., Towbin, J. A. <strong>Postmortem molecular analysis of SCN5A defects in sudden infant death syndrome.</strong> JAMA 286: 2264-2269, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11710892/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11710892</a>] [<a href="https://doi.org/10.1001/jama.286.18.2264" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11710892">Ackerman et al. (2001)</a> identified a heterozygous G-to-A replacement in the SCN5A gene, resulting in an arg1826-to-his substitution. The mutation was not detected in 800 control alleles. <a href="#1" class="mim-tip-reference" title="Ackerman, M. J., Siu, B. L., Sturner, W. Q., Tester, D. J., Valdivia, C. R., Makielski, J. C., Towbin, J. A. <strong>Postmortem molecular analysis of SCN5A defects in sudden infant death syndrome.</strong> JAMA 286: 2264-2269, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11710892/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11710892</a>] [<a href="https://doi.org/10.1001/jama.286.18.2264" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11710892">Ackerman et al. (2001)</a> determined that amino acid 1826 is located in the cytoplasmic C-terminal region of the sodium channel and is highly conserved. They demonstrated that the SCN5A mutant channel expressed a sodium current characterized by slower decay and a 2- to 3-fold increase in late sodium current. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11710892" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0021 BRUGADA SYNDROME 1</strong>
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SCN5A, ARG367HIS
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs28937318 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28937318;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs28937318" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs28937318" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000009988 OR RCV000058390 OR RCV001841237 OR RCV002426498 OR RCV003654174 OR RCV004734509" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009988, RCV000058390, RCV001841237, RCV002426498, RCV003654174, RCV004734509" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009988...</a>
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<p>Sudden unexplained nocturnal death syndrome (SUNDS), a disorder found in southeast Asia, is characterized by an abnormal electrocardiogram with ST segment elevation in leads V1 to V3 and sudden death due to ventricular fibrillation, identical to that seen in Brugada syndrome (BRGDA1; <a href="/entry/601144">601144</a>). <a href="#62" class="mim-tip-reference" title="Vatta, M., Dumaine, R., Varghese, G., Richard, T. A., Shimizu, W., Aihara, N., Nademanee, K., Brugada, R., Brugada, J., Veerakul, G., Li, H., Bowles, N. E., Brugada, P., Antzelevitch, C., Towbin, J. A. <strong>Genetic and biophysical basis of sudden unexplained nocturnal death syndrome (SUNDS), a disease allelic to Brugada syndrome.</strong> Hum. Molec. Genet. 11: 337-345, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11823453/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11823453</a>] [<a href="https://doi.org/10.1093/hmg/11.3.337" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11823453">Vatta et al. (2002)</a> found mutations in the SCN5A gene in 3 of 10 Asian SUNDS patients. In a sporadic Asian SUNDS patient, the authors identified a 1100G-A transition in SCN5A. The mutation is predicted to result in an arg367-to-his (R367H) substitution, which lies in the first P segment of the pore-lining region between the DIS5 and DIS6 transmembrane segments. In transfected Xenopus oocytes, the R367H mutant channel did not express any current. The authors hypothesized that the likely effect of this mutation is to depress peak current due to the loss of one functional allele. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11823453" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0022 BRUGADA SYNDROME 1</strong>
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SCN5A, ALA735VAL
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs137854611 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137854611;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs137854611?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs137854611" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs137854611" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000009989 OR RCV000058488 OR RCV003591627 OR RCV003654175 OR RCV003996084" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009989, RCV000058488, RCV003591627, RCV003654175, RCV003996084" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009989...</a>
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<p>In a family with SUNDS, a disorder identical to Brugada syndrome (BRGDA1; <a href="/entry/601144">601144</a>), that exhibited autosomal dominant inheritance, <a href="#62" class="mim-tip-reference" title="Vatta, M., Dumaine, R., Varghese, G., Richard, T. A., Shimizu, W., Aihara, N., Nademanee, K., Brugada, R., Brugada, J., Veerakul, G., Li, H., Bowles, N. E., Brugada, P., Antzelevitch, C., Towbin, J. A. <strong>Genetic and biophysical basis of sudden unexplained nocturnal death syndrome (SUNDS), a disease allelic to Brugada syndrome.</strong> Hum. Molec. Genet. 11: 337-345, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11823453/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11823453</a>] [<a href="https://doi.org/10.1093/hmg/11.3.337" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11823453">Vatta et al. (2002)</a> identified among affected members a 2204C-T transition, which is predicted to result in an ala735-to-val (A735V) substitution. The mutation lies in the first transmembrane segment of domain II, (DIIS1), close to the first extracellular loop between DIIS1 and DIIS2. In transfected Xenopus oocytes, the A735V mutant expressed currents with steady-state activation voltage shifted to more positive potentials and exhibited reduced sodium channel current at the end of phase I of the action potential. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11823453" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0023 BRUGADA SYNDROME 1</strong>
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LONG QT SYNDROME 3, ACQUIRED, SUSCEPTIBILITY TO, INCLUDED
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SCN5A, ARG1193GLN
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs41261344 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs41261344;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs41261344?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs41261344" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs41261344" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000009990 OR RCV000009991 OR RCV000058578 OR RCV000154828 OR RCV000157488 OR RCV000171819 OR RCV000252422 OR RCV000755697 OR RCV001147624 OR RCV001147625 OR RCV001147626 OR RCV001147627 OR RCV001841238 OR RCV002476954 OR RCV003149566" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009990, RCV000009991, RCV000058578, RCV000154828, RCV000157488, RCV000171819, RCV000252422, RCV000755697, RCV001147624, RCV001147625, RCV001147626, RCV001147627, RCV001841238, RCV002476954, RCV003149566" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009990...</a>
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<p>In a pair of Japanese dizygotic twins, one of whom died at 4 months of SUNDS, a disorder identical to Brugada syndrome (BRGDA1; <a href="/entry/601144">601144</a>), <a href="#62" class="mim-tip-reference" title="Vatta, M., Dumaine, R., Varghese, G., Richard, T. A., Shimizu, W., Aihara, N., Nademanee, K., Brugada, R., Brugada, J., Veerakul, G., Li, H., Bowles, N. E., Brugada, P., Antzelevitch, C., Towbin, J. A. <strong>Genetic and biophysical basis of sudden unexplained nocturnal death syndrome (SUNDS), a disease allelic to Brugada syndrome.</strong> Hum. Molec. Genet. 11: 337-345, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11823453/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11823453</a>] [<a href="https://doi.org/10.1093/hmg/11.3.337" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11823453">Vatta et al. (2002)</a> identified a 3575G-A transition in exon 20 of the SCN5A gene, predicted to result in an arg1192-to-gln (R1192Q) substitution in Domain III. In transfected Xenopus oocytes, the mutation accelerated the inactivation of the sodium channel current and exhibited reduced sodium channel current at the end of phase I of the action potential. <a href="#72" class="mim-tip-reference" title="Wang, Q. <strong>Author's reply: link of SCN5A SNP R1193Q to long QT syndrome. (Letter)</strong> J. Med. Genet. 42: e8, 2005. Note: Electronic Article."None>Wang (2005)</a> stated that this variant was mislabeled in the <a href="#62" class="mim-tip-reference" title="Vatta, M., Dumaine, R., Varghese, G., Richard, T. A., Shimizu, W., Aihara, N., Nademanee, K., Brugada, R., Brugada, J., Veerakul, G., Li, H., Bowles, N. E., Brugada, P., Antzelevitch, C., Towbin, J. A. <strong>Genetic and biophysical basis of sudden unexplained nocturnal death syndrome (SUNDS), a disease allelic to Brugada syndrome.</strong> Hum. Molec. Genet. 11: 337-345, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11823453/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11823453</a>] [<a href="https://doi.org/10.1093/hmg/11.3.337" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11823453">Vatta et al. (2002)</a> report and should be designated R1993Q. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11823453" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In an 82-year-old Caucasian male who developed long QT syndrome after the administration of D-sotolol or quinidine (see LQT3, <a href="/entry/603830">603830</a>), <a href="#68" class="mim-tip-reference" title="Wang, Q., Chen, S., Chen, Q., Wan, X., Shen, J., Hoeltge, G. A., Timur, A. A., Keating, M. T., Kirsch, G. E. <strong>The common SCN5A mutation R1193Q causes LQTS-type electrophysiological alterations of the cardiac sodium channel.</strong> J. Med. Genet. 41: e66, 2004. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15121794/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15121794</a>] [<a href="https://doi.org/10.1136/jmg.2003.013300" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15121794">Wang et al. (2004)</a> identified heterozygosity for the R1993Q mutation in the SCN5A gene. The mutation was found in 4 of 2,087 predominantly Caucasian controls (0.2%). Electrophysiologic studies showed that mutant R1193Q channels destabilize inactivation gating and generate a persistent, nonactivating current that is expected to prolong the cardiac action potential duration, leading to LQT syndrome; single channel recording revealed the molecular mechanism to be frequent, dispersed reopening of the channels. The patient also carried the H558R SCN5A variant (<a href="#0031">600163.0031</a>), but due to a lack of family members, it could not be determined whether H558R was in cis or trans with R1993Q. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15121794" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#27" class="mim-tip-reference" title="Hwang, H. W., Chen, J. J., Lin, Y. J., Shieh, R. C., Lee, M. T., Hung, S. I., Wu, J. Y., Chen, Y. T., Niu, D. M., Hwang, B. T., Chen, Y. T. <strong>R1193Q of SCN5A, a Brugada and long QT mutation, is a common polymorphism in Han Chinese. (Letter)</strong> J. Med. Genet. 42: e7, 2005. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15689442/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15689442</a>] [<a href="https://doi.org/10.1136/jmg.2004.027995" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15689442">Hwang et al. (2005)</a> found the R1993Q mutation in 11 of 94 (12%) randomly selected Han Chinese individuals and concluded that the variant is a common polymorphism in this population. None of the carriers had electrocardiographic signs of Brugada syndrome, although 1 had a prolonged QTc interval (472 ms) and another, who was homozygous for the mutation, had a borderline long QTc (437 ms). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15689442" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In an asymptomatic 73-year-old male member of a 4-generation Han Chinese family with autosomal dominant cardiac arrhythmias and sudden death, <a href="#45" class="mim-tip-reference" title="Niu, D.-M., Hwang, B., Hwang, H.-W., Wang, N. H., Wu, J.-Y., Lee, P.-C., Chien, J.-C., Shieh, R.-C., Chen, Y.-T. <strong>A common SCN5A polymorphism attenuates a severe cardiac phenotype caused by a nonsense SCN5A mutation in a Chinese family with an inherited cardiac conduction defect.</strong> J. Med. Genet. 43: 817-821, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16707561/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16707561</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16707561[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1136/jmg.2006.042192" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16707561">Niu et al. (2006)</a> identified compound heterozygosity for R1193Q and a nonsense mutation in the SCN5A gene (W1421X; <a href="#0036">600163.0036</a>). <a href="#45" class="mim-tip-reference" title="Niu, D.-M., Hwang, B., Hwang, H.-W., Wang, N. H., Wu, J.-Y., Lee, P.-C., Chien, J.-C., Shieh, R.-C., Chen, Y.-T. <strong>A common SCN5A polymorphism attenuates a severe cardiac phenotype caused by a nonsense SCN5A mutation in a Chinese family with an inherited cardiac conduction defect.</strong> J. Med. Genet. 43: 817-821, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16707561/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16707561</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16707561[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1136/jmg.2006.042192" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16707561">Niu et al. (2006)</a> suggested that the R1193Q mutation, which results in a gain of sodium channel function, may compensate for the deleterious effects of W1421X. Haplotype analysis of an asymptomatic daughter-in-law and 2 asymptomatic grandchildren who also carried the R1193Q mutation revealed that the children inherited the mutation from their mother rather than their grandfather. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16707561" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs7626962 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs7626962;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs7626962?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs7626962" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs7626962" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000009992 OR RCV000009993 OR RCV000041615 OR RCV000058563 OR RCV000204216 OR RCV000274325 OR RCV000304064 OR RCV000363449 OR RCV000368908 OR RCV000396768 OR RCV000621429 OR RCV000755696 OR RCV001094834 OR RCV001841239 OR RCV002504776 OR RCV003125829 OR RCV003149567" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009992, RCV000009993, RCV000041615, RCV000058563, RCV000204216, RCV000274325, RCV000304064, RCV000363449, RCV000368908, RCV000396768, RCV000621429, RCV000755696, RCV001094834, RCV001841239, RCV002504776, RCV003125829, RCV003149567" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009992...</a>
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<p><a href="#58" class="mim-tip-reference" title="Splawski, I., Timothy, K. W., Tateyama, M., Clancy, C. E., Malhotra, A., Beggs, A. H., Cappuccio, F. P., Sagnella, G. A., Kass, R. S., Keating, M. T. <strong>Variant of SCN5A sodium channel implicated in risk of cardiac arrhythmia.</strong> Science 297: 1333-1336, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12193783/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12193783</a>] [<a href="https://doi.org/10.1126/science.1073569" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12193783">Splawski et al. (2002)</a> screened DNA samples from individuals with nonfamilial cardiac arrhythmias and identified a C-to-A transversion in the SCN5A gene leading to a ser1103-to-tyr (S1103Y) substitution 1 patient. <a href="#2" class="mim-tip-reference" title="Ackerman, M. J., Splawski, I., Makielski, J. C., Tester, D. J., Will, M. L., Timothy, K. W., Keating, M. T., Jones, G., Chadha, M., Burrow, C. R., Stephens, J. C., Xu, C., Judson, R., Curran, M. E. <strong>Spectrum and prevalence of cardiac sodium channel variants among black, white, Asian, and Hispanic individuals: implications for arrhythmogenic susceptibility and Brugada/long QT syndrome genetic testing.</strong> Heart Rhythm 1: 600-607, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15851227/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15851227</a>] [<a href="https://doi.org/10.1016/j.hrthm.2004.07.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15851227">Ackerman et al. (2004)</a> noted that the variant was originally published as SER1102TYR from numbering based on the 2,015 amino acid alternatively spliced transcript. Subsequently, numbering was revised to account for the full-length 2,016 amino acid transcript. Serine-1103 is a conserved residue located in the intracellular sequences that link domains II and III of the channel. The proband had idiopathic dilated cardiomyopathy and hypokalemia and developed prolonged QT and torsade de pointes ventricular tachycardia while on amiodarone. <a href="#58" class="mim-tip-reference" title="Splawski, I., Timothy, K. W., Tateyama, M., Clancy, C. E., Malhotra, A., Beggs, A. H., Cappuccio, F. P., Sagnella, G. A., Kass, R. S., Keating, M. T. <strong>Variant of SCN5A sodium channel implicated in risk of cardiac arrhythmia.</strong> Science 297: 1333-1336, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12193783/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12193783</a>] [<a href="https://doi.org/10.1126/science.1073569" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12193783">Splawski et al. (2002)</a> determined that the Y1103 allele is present in 19.2% of West Africans and Caribbeans and in 13.2% of African Americans. The Y1103 allele was not found in 511 Caucasians or 578 Asians. <a href="#58" class="mim-tip-reference" title="Splawski, I., Timothy, K. W., Tateyama, M., Clancy, C. E., Malhotra, A., Beggs, A. H., Cappuccio, F. P., Sagnella, G. A., Kass, R. S., Keating, M. T. <strong>Variant of SCN5A sodium channel implicated in risk of cardiac arrhythmia.</strong> Science 297: 1333-1336, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12193783/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12193783</a>] [<a href="https://doi.org/10.1126/science.1073569" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12193783">Splawski et al. (2002)</a> studied 22 African Americans with acquired arrhythmia and 100 population-matched controls. The Y1103 allele was overrepresented among arrhythmia patients, being found in 56.5% of cases and among 13% of controls. The likelihood of displaying signs of arrhythmia in a Y1103 carrier heterozygote or homozygote yielded an odds ratio of 8.7 (95% CI 3.2 to 23.9). The odds ratio was not significantly altered after controlling for age or gender. To determine whether this mutation is an inherited risk factor for arrhythmias, <a href="#58" class="mim-tip-reference" title="Splawski, I., Timothy, K. W., Tateyama, M., Clancy, C. E., Malhotra, A., Beggs, A. H., Cappuccio, F. P., Sagnella, G. A., Kass, R. S., Keating, M. T. <strong>Variant of SCN5A sodium channel implicated in risk of cardiac arrhythmia.</strong> Science 297: 1333-1336, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12193783/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12193783</a>] [<a href="https://doi.org/10.1126/science.1073569" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12193783">Splawski et al. (2002)</a> examined the extended family of 1 proband. They ascertained and phenotypically characterized 23 members of this kindred. Phenotypic analysis revealed that 11 members of the family had prolonged QT and/or a history of syncope. All 11 phenotypically affected members of this family carried the Y1103 allele (6 were homozygotes and 5 were heterozygotes). Physiologic analysis of the effect of this mutation recorded a small but significant negative shift in the voltage dependence of activation. <a href="#58" class="mim-tip-reference" title="Splawski, I., Timothy, K. W., Tateyama, M., Clancy, C. E., Malhotra, A., Beggs, A. H., Cappuccio, F. P., Sagnella, G. A., Kass, R. S., Keating, M. T. <strong>Variant of SCN5A sodium channel implicated in risk of cardiac arrhythmia.</strong> Science 297: 1333-1336, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12193783/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12193783</a>] [<a href="https://doi.org/10.1126/science.1073569" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12193783">Splawski et al. (2002)</a> concluded that the Y1103 allele is a common SCN5A variant in Africans and African Americans and causes a small but inherent chronic risk of acquired arrhythmia. In the setting of additional acquired risk factors, including medications, hypokalemia, or structural heart disease, individuals carrying this allele are at increased risk of arrhythmia. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12193783+15851227" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 3 white sisters and their father, <a href="#10" class="mim-tip-reference" title="Chen, S., Chung, M. K., Martin, D., Rozich, R., Tchou, P. J., Wang, Q. <strong>SNP S1103Y in the cardiac sodium channel gene SCN5A is associated with cardiac arrhythmias and sudden death in a white family.</strong> J. Med. Genet. 39: 913-915, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12471205/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12471205</a>] [<a href="https://doi.org/10.1136/jmg.39.12.913" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12471205">Chen et al. (2002)</a> identified the S1103Y mutation, thus demonstrating that this mutation does exist in the white population. The mutation was associated with a considerable risk of syncope, ventricular arrhythmia, ventricular fibrillation, and sudden death, Each of the 3 sibs was genotyped for 31 'ancestry informative markers' to provide an estimation of biogeographic ancestry on 3 axes: Native American, West African, and European. The maximum likelihood point estimates for each of the sibs were 100% European, 0.0% African, and 0.0% Native American. The proband had a baseline QTc of 520 ms, and developed 2 episodes of syncope at age 49 years. The first episode was triggered by emotion and excitement. The second episode occurred in the setting of amiodarone and low serum potassium, and progressed to ventricular fibrillation and cardiac arrest. She was resuscitated by cardioversion. The second sister had a QTc of 431 ms, and died suddenly at age 44 years when awakening from sleep. The third sister had a QTc of 452 ms, developed 1 episode of syncope at the age of 33 years, and had complained of palpitations all her life. The father died suddenly in his sleep at age 50 years. Family members without S1103Y had a normal QTc. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12471205" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#51" class="mim-tip-reference" title="Plant, L. D., Bowers, P. N., Liu, Q., Morgan, T., Zhang, T., State, M. W., Chen, W., Kittles, R. A., Goldstein, S. A. N. <strong>A common cardiac sodium channel variant associated with sudden infant death in African Americans, SCN5A S1103Y.</strong> J. Clin. Invest. 116: 430-435, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16453024/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16453024</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16453024[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI25618" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16453024">Plant et al. (2006)</a> screened DNA samples from 133 African American autopsy-confirmed cases of sudden infant death syndrome (SIDS; <a href="/entry/272120">272120</a>) and identified 3 that were homozygous for the S1103Y variant. Among 1,056 African American controls, 120 were carriers of the heterozygous genotype, suggesting that infants with 2 copies of S1103Y have a 24-fold increased risk for SIDS. Variant Y1103 channels were found to operate normally under baseline conditions in vitro. Because risk factors for SIDS include apnea and respiratory acidosis, Y1103 and wildtype channels were subjected to lowered intracellular pH; only Y1103 channels developed abnormal function, with late reopenings suppressible by the drug mexiletine. <a href="#51" class="mim-tip-reference" title="Plant, L. D., Bowers, P. N., Liu, Q., Morgan, T., Zhang, T., State, M. W., Chen, W., Kittles, R. A., Goldstein, S. A. N. <strong>A common cardiac sodium channel variant associated with sudden infant death in African Americans, SCN5A S1103Y.</strong> J. Clin. Invest. 116: 430-435, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16453024/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16453024</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16453024[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI25618" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16453024">Plant et al. (2006)</a> suggested that the Y1103 variant confers susceptibility to acidosis-induced arrhythmia, a gene-environment interaction. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16453024" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Darbar, D., Kannankeril, P. J., Donahue, B. S., Kucera, G., Stubblefield, T., Haines, J. L., George, A. L., Jr., Roden, D. M. <strong>Cardiac sodium channel (SCN5A) variants associated with atrial fibrillation.</strong> Circulation 117: 1927-1935, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18378609/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18378609</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18378609[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1161/CIRCULATIONAHA.107.757955" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18378609">Darbar et al. (2008)</a> stated that the S1103Y variant was a known common nonsynonymous polymorphism in the SCN5A gene; they detected S1103Y in 1 patient with lone atrial fibrillation and in 5 patients with atrial fibrillation associated with other heart disease, as well as in 15 of 720 control chromosomes, for a minor allele frequency of 0.7%. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18378609" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs28937319 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28937319;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs28937319" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs28937319" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 3 sibs with congenital sick sinus syndrome (SSS1; <a href="/entry/608567">608567</a>), <a href="#7" class="mim-tip-reference" title="Benson, D. W., Wang, D. W., Dyment, M., Knilans, T. K., Fish, F. A., Strieper, M. J., Rhodes, T. H., George, A. L., Jr. <strong>Congenital sick sinus syndrome caused by recessive mutations in the cardiac sodium channel gene (SCN5A).</strong> J. Clin. Invest. 112: 1019-1028, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14523039/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14523039</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14523039[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI18062" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14523039">Benson et al. (2003)</a> identified compound heterozygosity for 2 mutations in the SCN5A gene. The maternal allele carried a 3893C-T transition, resulting in a pro1298-to-leu (P1298L) change; the paternal allele carried a gly1408-to-arg substitution (<a href="#0026">600163.0026</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14523039" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000009995 OR RCV000009996 OR RCV000009997 OR RCV000058649 OR RCV000183190 OR RCV002326672 OR RCV002496318 OR RCV003996085" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009995, RCV000009996, RCV000009997, RCV000058649, RCV000183190, RCV002326672, RCV002496318, RCV003996085" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009995...</a>
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<p>In 3 sibs with congenital sick sinus syndrome (SSS1; <a href="/entry/608567">608567</a>) with compound heterozygosity for mutation in the SCN5A gene, <a href="#7" class="mim-tip-reference" title="Benson, D. W., Wang, D. W., Dyment, M., Knilans, T. K., Fish, F. A., Strieper, M. J., Rhodes, T. H., George, A. L., Jr. <strong>Congenital sick sinus syndrome caused by recessive mutations in the cardiac sodium channel gene (SCN5A).</strong> J. Clin. Invest. 112: 1019-1028, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14523039/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14523039</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14523039[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI18062" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14523039">Benson et al. (2003)</a> found on the paternal allele a 4222G-A transition, resulting in a gly1408-to-arg substitution (G1408R). The maternal allele carried a pro1298-to-leu substitution (<a href="#0025">600163.0025</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14523039" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#30" class="mim-tip-reference" title="Kyndt, F., Probst, V., Potet, F., Demolombe, S., Chevallier, J.-C., Baro, I., Moisan, J.-P., Boisseau, P., Schott, J.-J., Escande, D., Le Marec, H. <strong>Novel SCN5A mutation leading either to isolated cardiac conduction defect or Brugada syndrome in a large French family.</strong> Circulation 104: 3081-3086, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11748104/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11748104</a>] [<a href="https://doi.org/10.1161/hc5001.100834" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11748104">Kyndt et al. (2001)</a> reported the G1408R mutation, which they designated GLY1406ARG, in heterozygous state in a large French family segregating both isolated cardiac conduction defect (see <a href="/entry/601144">601144</a>) and Brugada syndrome (BRGDA1; <a href="/entry/601144">601144</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11748104" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs45620037 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs45620037;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs45620037?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs45620037" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs45620037" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000009998 OR RCV000058832 OR RCV000148857 OR RCV000151804 OR RCV000251727 OR RCV000258831 OR RCV000586618 OR RCV000622951 OR RCV000678935 OR RCV001841241 OR RCV004528099" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009998, RCV000058832, RCV000148857, RCV000151804, RCV000251727, RCV000258831, RCV000586618, RCV000622951, RCV000678935, RCV001841241, RCV004528099" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009998...</a>
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<p>In a child with congenital sick sinus syndrome (SSS1; <a href="/entry/608567">608567</a>), <a href="#7" class="mim-tip-reference" title="Benson, D. W., Wang, D. W., Dyment, M., Knilans, T. K., Fish, F. A., Strieper, M. J., Rhodes, T. H., George, A. L., Jr. <strong>Congenital sick sinus syndrome caused by recessive mutations in the cardiac sodium channel gene (SCN5A).</strong> J. Clin. Invest. 112: 1019-1028, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14523039/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14523039</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14523039[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI18062" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14523039">Benson et al. (2003)</a> identified compound heterozygosity for 2 mutations in the SCN5A gene: the paternal allele carried a 659C-T transition, resulting in a thr220-to-ile (T220I) mutation, and the maternal allele carried a 4867C-T transition, resulting in an arg1623-to-ter mutation (R1623X; <a href="#0028">600163.0028</a>). The authors noted that an R1623Q mutation (<a href="#0007">600163.0007</a>) resulting in congenital long QT syndrome-3 (<a href="/entry/603830">603830</a>) had previously been described. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14523039" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a 54-year-old man with dilated cardiomyopathy (CMD1E; <a href="/entry/601154">601154</a>), atrial fibrillation, and heart block, <a href="#49" class="mim-tip-reference" title="Olson, T. M., Michels, V. V., Ballew, J. D., Reyna, S. P., Karst, M. L., Herron, K. I., Horton, S. C., Rodeheffer, R. J., Anderson, J. L. <strong>Sodium channel mutations and susceptibility of heart failure and atrial fibrillation.</strong> JAMA 293: 447-454, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15671429/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15671429</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15671429[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1001/jama.293.4.447" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15671429">Olson et al. (2005)</a> identified heterozygosity for a 659C-T transition in exon 6 of the SCN5A gene, resulting in a thr220-to-ile (T220I) substitution at a highly conserved residue in the transmembrane domain. Coronary artery disease was excluded by angiography; cardiac biopsy showed moderate myocyte hypertrophy and marked interstitial fibrosis. He died 13 years later in severe congestive heart failure. A female first cousin once removed who also carried the mutation was diagnosed at 55 years of age with dilated cardiomyopathy (ejection fraction, 10%) and incomplete bundle branch block; she died 2 years later, also in severe congestive heart failure. Other relatives were reported to have enlarged hearts, but were unavailable for evaluation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15671429" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0028 SICK SINUS SYNDROME 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs137854613 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137854613;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs137854613?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs137854613" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs137854613" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000009968 OR RCV000183087 OR RCV000465149 OR RCV000477950 OR RCV000622049 OR RCV001841231 OR RCV002496317 OR RCV003996083 OR RCV004528097" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009968, RCV000183087, RCV000465149, RCV000477950, RCV000622049, RCV001841231, RCV002496317, RCV003996083, RCV004528097" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009968...</a>
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<p>For discussion of the arg1623-to-ter (R1623X) mutation that was found in compound heterozygous state in a child with congenital sick sinus syndrome (SSS1; <a href="/entry/608567">608567</a>) by <a href="#7" class="mim-tip-reference" title="Benson, D. W., Wang, D. W., Dyment, M., Knilans, T. K., Fish, F. A., Strieper, M. J., Rhodes, T. H., George, A. L., Jr. <strong>Congenital sick sinus syndrome caused by recessive mutations in the cardiac sodium channel gene (SCN5A).</strong> J. Clin. Invest. 112: 1019-1028, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14523039/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14523039</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14523039[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI18062" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14523039">Benson et al. (2003)</a>, see <a href="#0027">600163.0027</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14523039" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs137854614 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137854614;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs137854614" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs137854614" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000009969 OR RCV000058778 OR RCV001561910 OR RCV002345237" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009969, RCV000058778, RCV001561910, RCV002345237" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009969...</a>
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<p>In a patient with long QT syndrome-3 (LQT3; <a href="/entry/603830">603830</a>), <a href="#52" class="mim-tip-reference" title="Rivolta, I., Abriel, H., Tateyama, M., Liu, H., Memmi, M., Vardas, P., Napolitano, C., Priori, S. G., Kass, R. S. <strong>Inherited Brugada and long QT-3 syndrome mutations of a single channel residue of the cardiac sodium channel confer distinct channel and clinical phenotypes.</strong> J. Biol. Chem. 276: 30623-30630, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11410597/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11410597</a>] [<a href="https://doi.org/10.1074/jbc.M104471200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11410597">Rivolta et al. (2001)</a> identified a tyr1795-to-cys (Y1795C) mutation in the SCN5A gene. The mutation slowed the onset of activation, but did not cause a marked negative shift in the voltage dependence of inactivation or affect the kinetics of the recovery from inactivation. The mutation increased the expression of sustained Na(+) channel activity compared with wildtype channels and promoted entrance into an intermediate or slowly developing inactivated state. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11410597" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0030 BRUGADA SYNDROME 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs137854615 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137854615;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs137854615" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs137854615" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000009999 OR RCV000058777" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009999, RCV000058777" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009999...</a>
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<p>In a patient with Brugada syndrome (BRGDA1; <a href="/entry/601144">601144</a>), <a href="#52" class="mim-tip-reference" title="Rivolta, I., Abriel, H., Tateyama, M., Liu, H., Memmi, M., Vardas, P., Napolitano, C., Priori, S. G., Kass, R. S. <strong>Inherited Brugada and long QT-3 syndrome mutations of a single channel residue of the cardiac sodium channel confer distinct channel and clinical phenotypes.</strong> J. Biol. Chem. 276: 30623-30630, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11410597/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11410597</a>] [<a href="https://doi.org/10.1074/jbc.M104471200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11410597">Rivolta et al. (2001)</a> identified a tyr1795-to-his (Y1795H) mutation in the SCN5A gene. The mutation accelerated the onset of activation and caused a marked negative shift in the voltage dependence of inactivation. It did not affect the kinetics of the recovery from inactivation. The mutation increased the expression of sustained Na(+) channel activity compared with wildtype channels and promoted entrance into an intermediate or slowly developing inactivated state. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11410597" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0031 PROGRESSIVE FAMILIAL HEART BLOCK, TYPE IA</strong>
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SCN5A, THR512ILE AND HIS558ARG
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs1805124 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1805124;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs1805124?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1805124" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs1805124" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div> <div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs199473118 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199473118;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs199473118?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs199473118" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs199473118" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000010000 OR RCV000041604 OR RCV000058426 OR RCV000058440 OR RCV000144029 OR RCV000251327 OR RCV000300603 OR RCV000304709 OR RCV000339196 OR RCV000361696 OR RCV000405409 OR RCV000406777 OR RCV000588264 OR RCV000987225 OR RCV001841593 OR RCV002496658 OR RCV002498340 OR RCV003125879 OR RCV003996525" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010000, RCV000041604, RCV000058426, RCV000058440, RCV000144029, RCV000251327, RCV000300603, RCV000304709, RCV000339196, RCV000361696, RCV000405409, RCV000406777, RCV000588264, RCV000987225, RCV001841593, RCV002496658, RCV002498340, RCV003125879, RCV003996525" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010000...</a>
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<p>In a 2-year-old boy with second-degree atrioventricular conduction block (PFHB1A; <a href="/entry/113900">113900</a>) necessitating a pacemaker, <a href="#64" class="mim-tip-reference" title="Viswanathan, P. C., Benson, D. W., Balser, J. R. <strong>A common SCN5A polymorphism modulates the biophysical effects of an SCN5A mutation.</strong> J. Clin. Invest. 111: 341-346, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12569159/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12569159</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12569159[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI16879" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12569159">Viswanathan et al. (2003)</a> identified a heterozygous 1535C-T transition in the SCN5A gene, resulting in a thr512-to-ile (T512I) substitution. In addition, there was a homozygous 1673A-G transition, resulting in a his558-to-arg (H558R) substitution. H558R (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1805124;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs1805124</a>) is a polymorphism present in 20% of the population (<a href="#75" class="mim-tip-reference" title="Yang, P., Kanki, H., Drolet, B., Yang, T., Wei, J., Viswanathan, P. C., Hohnloser, S. H., Shimizu, W., Schwartz, P. J., Stanton, M., Murray, K. T., Norris, K., George, A. L., Jr., Roden, D. M. <strong>Allelic variants in long-QT disease genes in patients with drug-associated torsades de pointes.</strong> Circulation 105: 1943-1948, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11997281/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11997281</a>] [<a href="https://doi.org/10.1161/01.cir.0000014448.19052.4c" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11997281">Yang et al., 2002</a>). One of the patient's alleles contained both T512I and H558R. The patient's father was heterozygous for the H558R substitution, the asymptomatic mother was compound heterozygous for the T512I and H558R substitutions, and 2 sibs were heterozygous for the H558R substitution. Functional expression studies showed that activation and inactivation of wildtype and H558R channels were similar. By contrast, voltage-dependent activation and inactivation of the T512I channel was shifted negatively by 8 to 9 mV and had enhanced slow activation and slower recovery from inactivation compared to the wildtype channel. Studies of the double H558R/T512I channel showed that H558R eliminated the negative shift induced by T512I, but only partially restored the kinetic abnormalities. <a href="#64" class="mim-tip-reference" title="Viswanathan, P. C., Benson, D. W., Balser, J. R. <strong>A common SCN5A polymorphism modulates the biophysical effects of an SCN5A mutation.</strong> J. Clin. Invest. 111: 341-346, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12569159/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12569159</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12569159[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI16879" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12569159">Viswanathan et al. (2003)</a> suggested that enhanced slow inactivation disproportionately affected Purkinje cells, which have a longer action potential duration and smaller diastolic interval, resulting in slowed atrioventricular conduction. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12569159+11997281" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Darbar, D., Kannankeril, P. J., Donahue, B. S., Kucera, G., Stubblefield, T., Haines, J. L., George, A. L., Jr., Roden, D. M. <strong>Cardiac sodium channel (SCN5A) variants associated with atrial fibrillation.</strong> Circulation 117: 1927-1935, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18378609/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18378609</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18378609[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1161/CIRCULATIONAHA.107.757955" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18378609">Darbar et al. (2008)</a> stated that the H558R variant was a known common nonsynonymous polymorphism in the SCN5A gene; they detected H558R in 59 patients with lone atrial fibrillation and in 130 patients with atrial fibrillation associated with other heart disease, as well as in 128 of 720 control chromosomes, for a minor allele frequency of approximately 25%. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18378609" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0032" class="mim-anchor"></a>
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<strong>.0032 BRUGADA SYNDROME 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs137854616 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137854616;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs137854616?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs137854616" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs137854616" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000010001 OR RCV000058602 OR RCV000755698 OR RCV001146725 OR RCV001146726 OR RCV001146727 OR RCV001753410 OR RCV003996086 OR RCV004018613 OR RCV004528100" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010001, RCV000058602, RCV000755698, RCV001146725, RCV001146726, RCV001146727, RCV001753410, RCV003996086, RCV004018613, RCV004528100" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010001...</a>
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<p><a href="#56" class="mim-tip-reference" title="Shin, D.-J., Jang, Y., Park, H.-Y., Lee, J. E., Yang, K., Kim, E., Bae, Y., Kim, J., Kim, J., Kim, S. S., Lee, M. H., Chahine, M., Yoon, S. K. <strong>Genetic analysis of the cardiac sodium channel gene SCN5A in Koreans with Brugada syndrome.</strong> J. Hum. Genet. 49: 573-578, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15338453/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15338453</a>] [<a href="https://doi.org/10.1007/s10038-004-0182-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15338453">Shin et al. (2004)</a> studied a family with 9 members as well as 12 unrelated sporadic cases, all Koreans, diagnosed with Brugada syndrome (BRGDA1; <a href="/entry/601144">601144</a>). They identified a novel missense mutation associated with Brugada syndrome in the family: a single-nucleotide substitution of G to A at nucleotide position 3934 in exon 21 of the SCN5A gene that changed glycine-1262 to serine (G1262S) in segment 2 of domain III of the SCN5A protein. Four individuals in the family carried the identical mutation, but none of the 12 sporadic patients did. The mutation was not found in 150 unrelated normal individuals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15338453" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs137854617 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137854617;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs137854617?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs137854617" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs137854617" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000010002 OR RCV000022945 OR RCV000058552 OR RCV000755695 OR RCV001528558 OR RCV001841242 OR RCV002321478 OR RCV004526592" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010002, RCV000022945, RCV000058552, RCV000755695, RCV001528558, RCV001841242, RCV002321478, RCV004526592" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010002...</a>
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<p>In a patient with Brugada syndrome (BRGDA1; <a href="/entry/601144">601144</a>), <a href="#43" class="mim-tip-reference" title="Mohler, P. J., Rivolta, I., Napolitano, C., LeMaillet, G., Lambert, S., Priori, S. G., Bennett, V. <strong>Na(v)1.5 E1053K mutation causing Brugada syndrome blocks binding to ankyrin-G and expression of Na(v)1.5 on the surface of cardiomyocytes.</strong> Proc. Nat. Acad. Sci. 101: 17533-17538, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15579534/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15579534</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15579534[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0403711101" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15579534">Mohler et al. (2004)</a> identified a 3157G-A transition in the SCN5A gene resulting in a glu1053-to-lys (E1053K) mutation in the ankyrin-binding motif of the cardiac sodium channel. The mutation abolished binding of Na(v)1.5 to ankyrin-G (<a href="/entry/600465">600465</a>) and also prevented accumulation of Na(v)1.5 at cell surface sites in ventricular cardiomyocytes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15579534" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a patient with lone atrial fibrillation (ATFB10; <a href="/entry/614022">614022</a>), <a href="#15" class="mim-tip-reference" title="Darbar, D., Kannankeril, P. J., Donahue, B. S., Kucera, G., Stubblefield, T., Haines, J. L., George, A. L., Jr., Roden, D. M. <strong>Cardiac sodium channel (SCN5A) variants associated with atrial fibrillation.</strong> Circulation 117: 1927-1935, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18378609/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18378609</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18378609[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1161/CIRCULATIONAHA.107.757955" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18378609">Darbar et al. (2008)</a> identified heterozygosity for the E1053K mutation in the SCN5A gene. The mutation was not found in 720 control alleles. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18378609" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs137854618 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137854618;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs137854618?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs137854618" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs137854618" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000010003 OR RCV000022946 OR RCV000058604 OR RCV000114992 OR RCV000183045 OR RCV000617238 OR RCV000656563 OR RCV002222347 OR RCV004532321" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010003, RCV000022946, RCV000058604, RCV000114992, RCV000183045, RCV000617238, RCV000656563, RCV002222347, RCV004532321" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010003...</a>
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<p>In a large family reported by <a href="#22" class="mim-tip-reference" title="Greenlee, P. R., Anderson, J. L., Lutz, J. R., Lindsay, A. E., Hagan, A. D. <strong>Familial automaticity-conduction disorder with associated cardiomyopathy.</strong> West. J. Med. 144: 33-41, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3953067/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3953067</a>]" pmid="3953067">Greenlee et al. (1986)</a> with dilated cardiomyopathy with conduction disorder and arrhythmia (CMD1E; <a href="/entry/601154">601154</a>), <a href="#39" class="mim-tip-reference" title="McNair, W. P., Ku, L., Taylor, M. R. G., Fain, P. R., Dao, D., Wolfel, E., Mestroni, L., Familial Cardiomyopathy Registry Research Group. <strong>SCN5A mutation associated with dilated cardiomyopathy, conduction disorder, and arrhythmia.</strong> Circulation 110: 2163-2167, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15466643/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15466643</a>] [<a href="https://doi.org/10.1161/01.CIR.0000144458.58660.BB" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15466643">McNair et al. (2004)</a> identified heterozygosity for a 3823G-A mutation in exon 21 of the SCN5A gene, resulting in an asp1275-to-asn (D1275N) substitution and predicting a change of charge within the S2 segment of domain III. The mutation was present in 22 affected family members and was not found in 300 control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3953067+15466643" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#23" class="mim-tip-reference" title="Groenewegen, W. A., Firouzi, M., Bezzina, C. R., Vliex, S., van Langen, I. M., Sandkuijl, L., Smits, J. P. P., Hulsbeek, M., Rook, M. B., Jongsma, H. J., Wilde, A. A. M. <strong>A cardiac sodium channel mutation cosegregates with a rare connexin40 genotype in familial atrial standstill.</strong> Circ. Res. 92: 14-22, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12522116/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12522116</a>] [<a href="https://doi.org/10.1161/01.res.0000050585.07097.d7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12522116">Groenewegen et al. (2003)</a> reported the D1275N mutation, coinherited with polymorphisms in the atrial-specific gap junction channel protein connexin-40 (GJA5; <a href="/entry/121013">121013</a>), in affected members of a family with atrial standstill (ATRST1; <a href="/entry/108770">108770</a>). No member of this family had dilated cardiomyopathy, leading <a href="#24" class="mim-tip-reference" title="Groenewegen, W. A., Wilde, A. A. M. <strong>Letter regarding article by McNair et al, 'SCN5A mutation associated with dilated cardiomyopathy, conduction disorder, and arrhythmia'. (Letter)</strong> Circulation 112: e9, 2005. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15998690/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15998690</a>] [<a href="https://doi.org/10.1161/CIRCULATIONAHA.104.531475" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15998690">Groenewegen and Wilde (2005)</a> to question whether the D1275N mutation was the primary cause of dilated cardiomyopathy as reported by <a href="#39" class="mim-tip-reference" title="McNair, W. P., Ku, L., Taylor, M. R. G., Fain, P. R., Dao, D., Wolfel, E., Mestroni, L., Familial Cardiomyopathy Registry Research Group. <strong>SCN5A mutation associated with dilated cardiomyopathy, conduction disorder, and arrhythmia.</strong> Circulation 110: 2163-2167, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15466643/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15466643</a>] [<a href="https://doi.org/10.1161/01.CIR.0000144458.58660.BB" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15466643">McNair et al. (2004)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12522116+15466643+15998690" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In affected members of a large Finnish family with atrial fibrillation and conduction defects (ATFB10; <a href="/entry/614022">614022</a>), <a href="#31" class="mim-tip-reference" title="Laitinen-Forsblom, P. J., Makynen, P., Makynen, H., Yli-Mayry, S., Virtanen, V., Kontula, K., Aalto-Setala, K. <strong>SCN5A mutation associated with cardiac conduction defect and atrial arrhythmias.</strong> J. Cardiovasc. Electrophysiol. 17: 480-485, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16684018/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16684018</a>] [<a href="https://doi.org/10.1111/j.1540-8167.2006.00411.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16684018">Laitinen-Forsblom et al. (2006)</a> identified heterozygosity for the D1275N mutation in the SCN5A gene. The mutation was not found in more than 370 control chromosomes. Echocardiography revealed an enlarged left ventricle with an increased end-diastolic left ventricular diameter in 1 affected individual, and the right ventricle was slightly enlarged in 3 other affected individuals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16684018" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs137854619 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137854619;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs137854619?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs137854619" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs137854619" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000010005 OR RCV000058782 OR RCV000171695 OR RCV000183199 OR RCV000987198 OR RCV001507624 OR RCV001841243 OR RCV002345238 OR RCV004772829" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010005, RCV000058782, RCV000171695, RCV000183199, RCV000987198, RCV001507624, RCV001841243, RCV002345238, RCV004772829" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010005...</a>
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<p>In a 41-year-old female who had cardiac arrest due to torsade de pointes triggered by exercise and leading to ventricular fibrillation, and a QTc of 520 ms (see <a href="/entry/603830">603830</a>), <a href="#41" class="mim-tip-reference" title="Millat, G., Chevalier, P., Restier-Miron, L., Da Costa, A., Bouvagnet, P., Kugener, B., Fayol, L., Gonzalez Armengod, C., Oddou, B., Chanavat, V., Froidefond, E., Perraudin, R., Rousson, R., Rodriguez-Lafrasse, C. <strong>Spectrum of pathogenic mutations and associated polymorphisms in a cohort of 44 unrelated patients with long QT syndrome.</strong> Clin. Genet. 70: 214-227, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16922724/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16922724</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2006.00671.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16922724">Millat et al. (2006)</a> identified biallelic digenic mutations: a 5455G-A transition in exon 28 of the SCN5A gene, resulting in an asp1819-to-asn (D1819N) substitution; and a missense mutation in the KCNH2 gene (R100G; <a href="/entry/152427#0023">152427.0023</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16922724" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs137854620 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137854620;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs137854620" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs137854620" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000010006" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010006" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010006</a>
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<p>In affected members of a 4-generation Han Chinese family with autosomal dominant cardiac arrhythmias and sudden death (BRGDA1; <a href="/entry/601144">601144</a>), <a href="#45" class="mim-tip-reference" title="Niu, D.-M., Hwang, B., Hwang, H.-W., Wang, N. H., Wu, J.-Y., Lee, P.-C., Chien, J.-C., Shieh, R.-C., Chen, Y.-T. <strong>A common SCN5A polymorphism attenuates a severe cardiac phenotype caused by a nonsense SCN5A mutation in a Chinese family with an inherited cardiac conduction defect.</strong> J. Med. Genet. 43: 817-821, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16707561/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16707561</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16707561[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1136/jmg.2006.042192" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16707561">Niu et al. (2006)</a> identified heterozygosity for a G-A transition in exon 24 of the SCN5A gene, resulting in a trp1421-to-ter (W1421X) substitution. The mutation was not found in 95 control subjects. An asymptomatic 73-year-old male family member was found to be compound heterozygous for W1421X and the R1993Q mutation (<a href="#0023">600163.0023</a>). <a href="#45" class="mim-tip-reference" title="Niu, D.-M., Hwang, B., Hwang, H.-W., Wang, N. H., Wu, J.-Y., Lee, P.-C., Chien, J.-C., Shieh, R.-C., Chen, Y.-T. <strong>A common SCN5A polymorphism attenuates a severe cardiac phenotype caused by a nonsense SCN5A mutation in a Chinese family with an inherited cardiac conduction defect.</strong> J. Med. Genet. 43: 817-821, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16707561/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16707561</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16707561[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1136/jmg.2006.042192" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16707561">Niu et al. (2006)</a> suggested that R1193Q, which results in a gain of sodium channel function, may compensate for the deleterious effects of W1421X. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16707561" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0038 CARDIOMYOPATHY, DILATED, 1E</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs397514450 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397514450;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs397514450" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs397514450" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000010008 OR RCV000183154 OR RCV001842933 OR RCV002433811 OR RCV002500544 OR RCV003996817" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010008, RCV000183154, RCV001842933, RCV002433811, RCV002500544, RCV003996817" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010008...</a>
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<p>In a man with dilated cardiomyopathy (CMD1E; <a href="/entry/601154">601154</a>) and monomorphic ventricular tachycardia who later developed third-degree heart block requiring pacemaker implantation, <a href="#49" class="mim-tip-reference" title="Olson, T. M., Michels, V. V., Ballew, J. D., Reyna, S. P., Karst, M. L., Herron, K. I., Horton, S. C., Rodeheffer, R. J., Anderson, J. L. <strong>Sodium channel mutations and susceptibility of heart failure and atrial fibrillation.</strong> JAMA 293: 447-454, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15671429/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15671429</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15671429[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1001/jama.293.4.447" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15671429">Olson et al. (2005)</a> identified heterozygosity for a 2-bp insertion (2550insTG) in exon 17 of the SCN5A gene, resulting in a premature stop codon and a truncated protein. Cardiac biopsy was normal. His father, who carried the mutation, was diagnosed with CMD (ejection fraction, 30%), left bundle branch block, and monomorphic ventricular tachycardia at age 67 years. The mutation was also present in a paternal uncle who had sinus bradycardia, first-degree heart block, and complete left bundle branch block; his paternal grandfather developed congestive heart failure at 50 years of age and died 6 years later, but DNA was unavailable for evaluation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15671429" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0039 CARDIOMYOPATHY, DILATED, 1E</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs137854607 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137854607;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs137854607" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs137854607" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000010009 OR RCV000058706 OR RCV001258074 OR RCV003156212 OR RCV005031434" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010009, RCV000058706, RCV001258074, RCV003156212, RCV005031434" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010009...</a>
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<p>In a 7-year-old boy with early manifestations of dilated cardiomyopathy (CMD1E; <a href="/entry/601154">601154</a>) including sinus bradycardia, left ventricular dilation, and normal contractile function, <a href="#49" class="mim-tip-reference" title="Olson, T. M., Michels, V. V., Ballew, J. D., Reyna, S. P., Karst, M. L., Herron, K. I., Horton, S. C., Rodeheffer, R. J., Anderson, J. L. <strong>Sodium channel mutations and susceptibility of heart failure and atrial fibrillation.</strong> JAMA 293: 447-454, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15671429/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15671429</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15671429[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1001/jama.293.4.447" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15671429">Olson et al. (2005)</a> identified heterozygosity for a 4783G-C transversion in exon 27 of the SCN5A gene, resulting in an asp1595-to-his (D1595H) substitution at a highly conserved residue in the transmembrane domain. The mutation was found in DNA from postmortem tissue of a brother who died at 34 years of age with an autopsy diagnosis of cardiomyopathy and only mild coronary artery disease. The mutation was also identified in 2 sibs and a paternal uncle, all of whom had sinus bradycardia, and a paternal aunt with borderline left atrial enlargement. His father, an obligate mutation carrier, had atrial fibrillation and died at 49 years of age from pulmonary embolism; his paternal grandfather, a presumed mutation carrier, developed congestive heart failure at 70 years of age. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15671429" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs41313031 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs41313031;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs41313031?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs41313031" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs41313031" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div> <div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs45471994 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs45471994;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs45471994?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs45471994" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs45471994" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000010010 OR RCV000058614 OR RCV000058840 OR RCV000148841 OR RCV000148856 OR RCV000176338 OR RCV000243761 OR RCV000246365 OR RCV000724673 OR RCV000987205 OR RCV000987235 OR RCV001842355 OR RCV001842410" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010010, RCV000058614, RCV000058840, RCV000148841, RCV000148856, RCV000176338, RCV000243761, RCV000246365, RCV000724673, RCV000987205, RCV000987235, RCV001842355, RCV001842410" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010010...</a>
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<p>In a 45-year-old black man with no history of cardiac disease who developed monomorphic wide-complex ventricular tachycardia with right precordial ST segment elevation consistent with Brugada syndrome (BRGDA1; <a href="/entry/601144">601144</a>) after the administration of lidocaine, <a href="#5" class="mim-tip-reference" title="Barajas-Martinez, H. M., Hu, D., Cordeiro, J. M., Wu, Y., Kovacs, R. J., Meltser, H., Kui, H., Elena, B., Brugada, R., Antzelevitch, C., Dumaine, R. <strong>Lidocaine-induced Brugada syndrome phenotype linked to a novel double mutation in the cardiac sodium channel.</strong> Circ. Res. 103: 396-404, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18599870/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18599870</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18599870[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1161/CIRCRESAHA.108.172619" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18599870">Barajas-Martinez et al. (2008)</a> identified 2 mutations in the SCN5A gene, a G-to-A transition in exon 6 of the SCN5A gene, resulting in a val232-to-ile (V232I) substitution in the C terminus of the transmembrane segment S4 of domain I, and a C-to-T transition in exon 22, resulting in a leu1308-to-phe (L1308F) substitution, in the C terminus of transmembrane segment S4 of domain III. Although L1308F had previously been identified as a polymorphism found mostly in Americans of African descent (<a href="#2" class="mim-tip-reference" title="Ackerman, M. J., Splawski, I., Makielski, J. C., Tester, D. J., Will, M. L., Timothy, K. W., Keating, M. T., Jones, G., Chadha, M., Burrow, C. R., Stephens, J. C., Xu, C., Judson, R., Curran, M. E. <strong>Spectrum and prevalence of cardiac sodium channel variants among black, white, Asian, and Hispanic individuals: implications for arrhythmogenic susceptibility and Brugada/long QT syndrome genetic testing.</strong> Heart Rhythm 1: 600-607, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15851227/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15851227</a>] [<a href="https://doi.org/10.1016/j.hrthm.2004.07.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15851227">Ackerman et al., 2004</a>), <a href="#5" class="mim-tip-reference" title="Barajas-Martinez, H. M., Hu, D., Cordeiro, J. M., Wu, Y., Kovacs, R. J., Meltser, H., Kui, H., Elena, B., Brugada, R., Antzelevitch, C., Dumaine, R. <strong>Lidocaine-induced Brugada syndrome phenotype linked to a novel double mutation in the cardiac sodium channel.</strong> Circ. Res. 103: 396-404, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18599870/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18599870</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18599870[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1161/CIRCRESAHA.108.172619" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18599870">Barajas-Martinez et al. (2008)</a> did not find either mutation in over 400 alleles from 200 ethnically matched controls. The patient's parents were unavailable for study, but given the severity of his clinical manifestations, the authors strongly suspected that both mutations were on the same allele (<a href="#17" class="mim-tip-reference" title="Dumaine, R. <strong>Personal Communication.</strong> Quebec, Canada 6/2009."None>Dumaine, 2009</a>). Using patch-clamp techniques in mammalian TSA201 cells, <a href="#5" class="mim-tip-reference" title="Barajas-Martinez, H. M., Hu, D., Cordeiro, J. M., Wu, Y., Kovacs, R. J., Meltser, H., Kui, H., Elena, B., Brugada, R., Antzelevitch, C., Dumaine, R. <strong>Lidocaine-induced Brugada syndrome phenotype linked to a novel double mutation in the cardiac sodium channel.</strong> Circ. Res. 103: 396-404, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18599870/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18599870</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18599870[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1161/CIRCRESAHA.108.172619" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18599870">Barajas-Martinez et al. (2008)</a> observed use-dependent inhibition of I(Na) by lidocaine that was more pronounced in double-mutant channels than in wildtype; the individual mutations produced a much less accentuated effect. The authors concluded that the double mutation in SCN5A alters the affinity of the cardiac sodium channel for lidocaine such that the drug assumes class IC characteristics with potent use-dependent block of the sodium channel. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=18599870+15851227" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs199473335 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199473335;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs199473335?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs199473335" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs199473335" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000022947 OR RCV000148858 OR RCV000154830 OR RCV000756620 OR RCV001841252 OR RCV004018664" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000022947, RCV000148858, RCV000154830, RCV000756620, RCV001841252, RCV004018664" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000022947...</a>
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<p>In a father and son with atrial fibrillation (ATFB10; <a href="/entry/614022">614022</a>), <a href="#18" class="mim-tip-reference" title="Ellinor, P. T., Nam, E. G., Shea, M. A., Milan, D. J., Ruskin, J. N., MacRae, C. A. <strong>Cardiac sodium channel mutation in atrial fibrillation.</strong> Heart Rhythm 5: 99-105, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18088563/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18088563</a>] [<a href="https://doi.org/10.1016/j.hrthm.2007.09.015" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18088563">Ellinor et al. (2008)</a> identified heterozygosity for a 5958C-A transversion in the SCN5A gene, resulting in an asn1986-to-lys (N1986K) substitution in the C-terminal region of the protein. The mutation was not found in more than 600 ethnically and racially matched control chromosomes. Expression of the N1986K mutant in Xenopus oocytes revealed a hyperpolarizing shift in channel steady-state inactivation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18088563" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0042 ATRIAL FIBRILLATION, FAMILIAL, 10</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs199473112 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199473112;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs199473112?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs199473112" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs199473112" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000022948 OR RCV000058414 OR RCV000418451 OR RCV000991041 OR RCV001841253 OR RCV002381260 OR RCV002504819" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000022948, RCV000058414, RCV000418451, RCV000991041, RCV001841253, RCV002381260, RCV002504819" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000022948...</a>
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<p>In white male proband who was diagnosed with paroxysmal lone atrial fibrillation (ATFB10; <a href="/entry/614022">614022</a>) at 39 years of age, <a href="#15" class="mim-tip-reference" title="Darbar, D., Kannankeril, P. J., Donahue, B. S., Kucera, G., Stubblefield, T., Haines, J. L., George, A. L., Jr., Roden, D. M. <strong>Cardiac sodium channel (SCN5A) variants associated with atrial fibrillation.</strong> Circulation 117: 1927-1935, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18378609/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18378609</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18378609[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1161/CIRCULATIONAHA.107.757955" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18378609">Darbar et al. (2008)</a> identified heterozygosity for a G-to-C transversion in the SCN5A gene, resulting in a his445-to-asp (H445D) substitution at a highly conserved residue that was predicted to perturb cardiac sodium channel function. The proband had left atrial enlargement and an ejection fraction of 60% by transthoracic echocardiography. The mutation was also detected in his affected father and brother, but was not found in an unaffected sister or in 720 control alleles. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18378609" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs199473115 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199473115;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs199473115?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs199473115" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs199473115" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000022949 OR RCV000058421 OR RCV002482899 OR RCV003541160 OR RCV003996114" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000022949, RCV000058421, RCV002482899, RCV003541160, RCV003996114" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000022949...</a>
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<p>In a black male proband who was diagnosed with paroxysmal lone atrial fibrillation (ATFB10; <a href="/entry/614022">614022</a>) at 17 years of age, <a href="#15" class="mim-tip-reference" title="Darbar, D., Kannankeril, P. J., Donahue, B. S., Kucera, G., Stubblefield, T., Haines, J. L., George, A. L., Jr., Roden, D. M. <strong>Cardiac sodium channel (SCN5A) variants associated with atrial fibrillation.</strong> Circulation 117: 1927-1935, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18378609/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18378609</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18378609[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1161/CIRCULATIONAHA.107.757955" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18378609">Darbar et al. (2008)</a> identified heterozygosity for a G-to-C transversion in the SCN5A gene, resulting in an asn470-to-lys (N470K) substitution at a highly conserved residue and predicted to perturb cardiac sodium channel function. The proband had left atrial enlargement with an ejection fraction of 60% by transthoracic echocardiography. The mutation was also detected in his affected mother and maternal grandmother, but was not found in an unaffected maternal aunt or in 720 control alleles. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18378609" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs199473111 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199473111;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs199473111?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs199473111" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs199473111" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a white male proband who was diagnosed with paroxysmal lone atrial fibrillation (ATFB10; <a href="/entry/614022">614022</a>) at 52 years of age, <a href="#15" class="mim-tip-reference" title="Darbar, D., Kannankeril, P. J., Donahue, B. S., Kucera, G., Stubblefield, T., Haines, J. L., George, A. L., Jr., Roden, D. M. <strong>Cardiac sodium channel (SCN5A) variants associated with atrial fibrillation.</strong> Circulation 117: 1927-1935, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18378609/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18378609</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18378609[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1161/CIRCULATIONAHA.107.757955" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18378609">Darbar et al. (2008)</a> identified heterozygosity for a A-to-G transition in the SCN5A gene, resulting in an glu428-to-lys (E428K) substitution at a highly conserved residue and predicted to perturb cardiac sodium channel function. The proband had left atrial enlargement with an ejection fraction of 58% by transthoracic echocardiography. The mutation was also detected in his affected daughter and granddaughter, but was not found in an unaffected daughter and granddaughter or in 720 control alleles. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18378609" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs199473579 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199473579;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs199473579?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs199473579" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs199473579" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a white female proband who was diagnosed with paroxysmal lone atrial fibrillation (ATFB10; <a href="/entry/614022">614022</a>) at 37 years of age, <a href="#15" class="mim-tip-reference" title="Darbar, D., Kannankeril, P. J., Donahue, B. S., Kucera, G., Stubblefield, T., Haines, J. L., George, A. L., Jr., Roden, D. M. <strong>Cardiac sodium channel (SCN5A) variants associated with atrial fibrillation.</strong> Circulation 117: 1927-1935, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18378609/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18378609</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18378609[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1161/CIRCULATIONAHA.107.757955" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18378609">Darbar et al. (2008)</a> identified heterozygosity for an A-to-G transition in the SCN5A gene, resulting in a glu655-to-lys (E655K) substitution at a highly conserved residue that was predicted to perturb cardiac sodium channel function. The proband had a normal-sized left atrium and ventricle with an ejection fraction of 55% by transthoracic echocardiography. The mutation was also detected in her affected daughter and maternal grandmother, but was not found in 720 control alleles. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18378609" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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SCN5A, ARG222GLN (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs45546039;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs45546039</a>)
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs45546039 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs45546039;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs45546039?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs45546039" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs45546039" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000032639 OR RCV000058833 OR RCV000182941 OR RCV000211852 OR RCV000678965 OR RCV000763109" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000032639, RCV000058833, RCV000182941, RCV000211852, RCV000678965, RCV000763109" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000032639...</a>
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<p>In 6 affected members over 3 generations of a non-Hispanic white family with cardiomyopathy and conduction system disease (CMD1E; <a href="/entry/601154">601154</a>), <a href="#26" class="mim-tip-reference" title="Hershberger, R. E., Parks, S. B., Kushner, J. D., Li, D., Ludwigsen, S., Jakobs, P., Nauman, D., Burgess, D., Partain, J., Litt, M. <strong>Coding sequence mutations identified in MYH7, TNNT2, SCN5A, CSRP3, LBD3 (sic), and TCAP from 313 patients with familial or idiopathic dilated cardiomyopathy.</strong> Clin. Transl. Sci. 1: 21-26, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19412328/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19412328</a>] [<a href="https://doi.org/10.1111/j.1752-8062.2008.00017.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19412328">Hershberger et al. (2008)</a> identified heterozygosity for a 36683G-A (numbering per SeattleSNP) transition in exon 6 of the SCN5A gene, resulting in an arg222-to-gln (R222Q) substitution at a conserved residue. The mutation was not found in unaffected family members or in 253 controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19412328" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 19 affected individuals from 3 unrelated 3-generation families with multifocal ectopic Purkinje-related premature contractions and dilated cardiomyopathy, <a href="#32" class="mim-tip-reference" title="Laurent, G., Saal, S., Amarouch, M. Y., Beziau, D. M., Marsman, R. F. J., Faivre, L., Barc, J., Dina, C., Bertaux, G., Barthez, O., Thauvin-Robinet, C., Charron, P., and 15 others. <strong>Multifocal ectopic Purkinje-related premature contractions.</strong> J. Am. Coll. Cardiol. 60: 144-156, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22766342/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22766342</a>] [<a href="https://doi.org/10.1016/j.jacc.2012.02.052" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22766342">Laurent et al. (2012)</a> identified heterozygosity for the 665G-A (R222Q) mutation in the SCN5A gene, located in the voltage-sensing S4 segment of domain I. The mutation, which was fully penetrant and strictly segregated with the cardiac phenotype in each family, was not found in 600 control chromosomes; haplotype analysis showed that a founder effect for these 3 families was very unlikely. In vitro studies recapitulated the normalization of the ventricular action potentials in the presence of quinidine. Because only 6 of the 19 patients carrying the R222Q mutation had CMD, and the cardiomyopathy recovered at least partially with antiarrhythmia treatment and a reduction in the number of premature ventricular contractions, <a href="#32" class="mim-tip-reference" title="Laurent, G., Saal, S., Amarouch, M. Y., Beziau, D. M., Marsman, R. F. J., Faivre, L., Barc, J., Dina, C., Bertaux, G., Barthez, O., Thauvin-Robinet, C., Charron, P., and 15 others. <strong>Multifocal ectopic Purkinje-related premature contractions.</strong> J. Am. Coll. Cardiol. 60: 144-156, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22766342/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22766342</a>] [<a href="https://doi.org/10.1016/j.jacc.2012.02.052" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22766342">Laurent et al. (2012)</a> suggested that CMD might be a consequence of the arrhythmia and not directly linked to the mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22766342" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In affected members of a 3-generation Canadian family with CMD and junctional escape ventricular capture bigeminy, <a href="#44" class="mim-tip-reference" title="Nair, K., Pekhletski, R., Harris, L., Care, M., Morel, C., Farid, T., Backx, P. H., Szabo, E., Nanthakumar, K. <strong>Escape capture bigeminy: phenotypic marker of cardiac sodium channel voltage sensor mutation R222Q.</strong> Heart Rhythm 9: 1681-1688, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22710484/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22710484</a>] [<a href="https://doi.org/10.1016/j.hrthm.2012.06.029" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22710484">Nair et al. (2012)</a> identified the R222Q mutation in the SCN5A gene. Heterologous expression studies in Chinese hamster ovary K1 cells revealed a unique biophysical phenotype of R222Q channels in which an approximately 10-mV leftward shift in the sodium current steady-state activation curve occurs without corresponding shifts in steady-state inactivation at cardiomyocyte resting membrane-potential voltages. The activation and inactivation of cells expressing equimolar combinations of wildtype and R222Q channels showed properties intermediate between those seen in cells expressing either wildtype or mutant channels alone. The changes in mutant channel properties were predicted to produce hyperexcitability of R222Q sodium channels. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22710484" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 16 affected members over 3 generations of a large kindred with CMD and multiple arrhythmias, including premature ventricular complexes (PVCs) of variable morphology, <a href="#38" class="mim-tip-reference" title="Mann, S. A., Castro, M. L., Ohanian, M., Guo, G., Zodgekar, P., Sheu, A., Stockhammer, K., Thompson, T., Playford, D., Subbiah, R., Kuchar, D., Aggarwal, A., Vandenberg, J. I., Fatkin, D. <strong>R222Q SCN5A mutation is associated with reversible ventricular ectopy and dilated cardiomyopathy.</strong> J. Am. Coll. Cardiol. 60: 1566-1573, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22999724/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22999724</a>] [<a href="https://doi.org/10.1016/j.jacc.2012.05.050" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22999724">Mann et al. (2012)</a> identified heterozygosity for the R222Q mutation in the SCN5A gene. The mutation was also identified in 1 clinically unaffected family member, a 56-year-old man with a normal EKG and echocardiogram, but was not found in 200 control chromosomes. Patch-clamp studies showed that the R222Q mutation did not alter sodium channel current density, but did shift steady-state parameters of activation and inactivation to the left. Using a voltage ramp protocol, normalized current responses of mutant channels were of earlier onset and greater magnitude than wildtype. Action potential modeling using Purkinje fiber and ventricular cell models suggested that rate-dependent ectopy of Purkinje fiber origin is the predominant ventricular effect of the R222Q variant; this was supported by the clinical observation that PVC frequency increased during periods of low heart rate at rest and at night, and was reduced by high heart rates during exercise. Patients responded to sodium-channel blocking drugs with early and substantial reductions in PVCs followed by normalization of CMD over time. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22999724" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs45563942 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs45563942;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs45563942?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs45563942" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs45563942" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 3 affected members over 2 generations of an African American family with cardiomyopathy and conduction system disease (CMD1E; <a href="/entry/601154">601154</a>), <a href="#26" class="mim-tip-reference" title="Hershberger, R. E., Parks, S. B., Kushner, J. D., Li, D., Ludwigsen, S., Jakobs, P., Nauman, D., Burgess, D., Partain, J., Litt, M. <strong>Coding sequence mutations identified in MYH7, TNNT2, SCN5A, CSRP3, LBD3 (sic), and TCAP from 313 patients with familial or idiopathic dilated cardiomyopathy.</strong> Clin. Transl. Sci. 1: 21-26, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19412328/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19412328</a>] [<a href="https://doi.org/10.1111/j.1752-8062.2008.00017.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19412328">Hershberger et al. (2008)</a> identified heterozygosity for a 99599T-C transition (numbering per SeattleSNP) in exon 28 of the SCN5A gene, resulting in an ile1835-to-thr (I1835T) substitution at a conserved residue. The mutation was not found in unaffected family members or in 253 controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19412328" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs199473070 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199473070;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs199473070" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs199473070" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000058830 OR RCV000114993 OR RCV003539788" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000058830, RCV000114993, RCV003539788" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000058830...</a>
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<p>In a Japanese boy with atrial standstill (ATRST1; <a href="/entry/108770">108770</a>), <a href="#35" class="mim-tip-reference" title="Makita, N., Sasaki, K., Groenewegen, W. A., Yokota, T., Yokoshiki, H., Murakami, T., Tsutsui, H. <strong>Congenital atrial standstill associated with coinheritance of a novel SCN5A mutation and connexin 40 polymorphisms.</strong> Heart Rhythm 2: 1128-1134, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16188595/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16188595</a>] [<a href="https://doi.org/10.1016/j.hrthm.2005.06.032" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16188595">Makita et al. (2005)</a> identified coinheritance of a heterozygous c.635C-T transition in exon 6 of the SCN5A gene, resulting in a leu212-to-pro (L212P) substitution in the extracellular loop connecting transmembrane segments 3 and 4 of domain 1 of the Nav1.5 cardiac sodium channel, and heterozygous rare polymorphisms in the GJA5 gene (<a href="/entry/121013">121013</a>). The L212P mutation, which was also present in the proband's asymptomatic father, was not found in 400 control chromosomes. Functional analysis with the L212P mutant channels demonstrated large hyperpolarizing shifts in both the voltage dependence of activation and inactivation and delayed recovery from inactivation compared to wildtype. The asymptomatic father did not carry the rare polymorphisms in the GJA5 gene; the GJA5 polymorphisms were, however, present in heterozygosity in the proband's unaffected mother and maternal grandmother, who did not carry the L212P mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16188595" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<h4 href="#mimReferencesFold" id="mimReferencesToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span class="mim-font">
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<strong>REFERENCES</strong>
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<a id="Ackerman2001" class="mim-anchor"></a>
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Ackerman, M. J., Siu, B. L., Sturner, W. Q., Tester, D. J., Valdivia, C. R., Makielski, J. C., Towbin, J. A.
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<strong>Postmortem molecular analysis of SCN5A defects in sudden infant death syndrome.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11710892/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11710892</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11710892" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1001/jama.286.18.2264" target="_blank">Full Text</a>]
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<a id="Ackerman2004" class="mim-anchor"></a>
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Ackerman, M. J., Splawski, I., Makielski, J. C., Tester, D. J., Will, M. L., Timothy, K. W., Keating, M. T., Jones, G., Chadha, M., Burrow, C. R., Stephens, J. C., Xu, C., Judson, R., Curran, M. E.
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<strong>Spectrum and prevalence of cardiac sodium channel variants among black, white, Asian, and Hispanic individuals: implications for arrhythmogenic susceptibility and Brugada/long QT syndrome genetic testing.</strong>
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Heart Rhythm 1: 600-607, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15851227/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15851227</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15851227" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.hrthm.2004.07.013" target="_blank">Full Text</a>]
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<a id="Akai2000" class="mim-anchor"></a>
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<p class="mim-text-font">
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Akai, J., Makita, N., Sakurada, H., Shirai, N., Ueda, K., Kitabatake, A., Nakazawa, K., Kimura, A., Hiraoka, M.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10940383/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10940383</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10940383" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/s0014-5793(00)01875-5" target="_blank">Full Text</a>]
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<a id="Albert2008" class="mim-anchor"></a>
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Albert, C. M., Nam, E. G., Rimm, E. B., Jin, H. W., Hajjar, R. J., Hunter, D. J., MacRae, C. A., Ellinor, P. T.
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<strong>Cardiac sodium channel gene variants and sudden cardiac death in women.</strong>
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Circulation 117: 16-23, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18071069/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18071069</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18071069" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1161/CIRCULATIONAHA.107.736330" target="_blank">Full Text</a>]
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<a id="Barajas-Martinez2008" class="mim-anchor"></a>
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Barajas-Martinez, H. M., Hu, D., Cordeiro, J. M., Wu, Y., Kovacs, R. J., Meltser, H., Kui, H., Elena, B., Brugada, R., Antzelevitch, C., Dumaine, R.
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<strong>Lidocaine-induced Brugada syndrome phenotype linked to a novel double mutation in the cardiac sodium channel.</strong>
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Circ. Res. 103: 396-404, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18599870/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18599870</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18599870[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18599870" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1161/CIRCRESAHA.108.172619" target="_blank">Full Text</a>]
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<a id="6" class="mim-anchor"></a>
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<a id="Bennett1995" class="mim-anchor"></a>
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<p class="mim-text-font">
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Bennett, P. B., Yazawa, K., Makita, N., George, A. L., Jr.
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<strong>Molecular mechanism for an inherited cardiac arrhythmia.</strong>
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Nature 376: 683-685, 1995.
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[<a href="https://doi.org/10.1038/376683a0" target="_blank">Full Text</a>]
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<a id="Benson2003" class="mim-anchor"></a>
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<div class="">
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Benson, D. W., Wang, D. W., Dyment, M., Knilans, T. K., Fish, F. A., Strieper, M. J., Rhodes, T. H., George, A. L., Jr.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14523039/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14523039</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14523039[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14523039" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1172/JCI18062" target="_blank">Full Text</a>]
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<a id="Bezzina1999" class="mim-anchor"></a>
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<div class="">
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Bezzina, C., Veldkamp, M. W., van den Berg, M. P., Postma, A. V., Rook, M. B., Viersma, J.-W., van Langen, I. M., Tan-Sindhunata, G., Bink-Boelkens, M. T. E., van der Hout, A. H., Mannens, M. M. A. M., Wilde, A. A. M.
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[<a href="https://doi.org/10.1161/01.res.85.12.1206" target="_blank">Full Text</a>]
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<a id="Chen1998" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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[<a href="https://doi.org/10.1038/32675" target="_blank">Full Text</a>]
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<a id="Chen2002" class="mim-anchor"></a>
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Chen, S., Chung, M. K., Martin, D., Rozich, R., Tchou, P. J., Wang, Q.
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[<a href="https://doi.org/10.1136/jmg.39.12.913" target="_blank">Full Text</a>]
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<a id="Cheng2010" class="mim-anchor"></a>
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Cheng, J., Morales, A., Siegfried, J. D., Li, D., Norton, N., Song, J., Gonzalez-Quintana, J., Makielski, J. C., Hershberger, R. E.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21167004/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21167004</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21167004[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21167004" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1111/j.1752-8062.2010.00249.x" target="_blank">Full Text</a>]
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<a id="Clancy1999" class="mim-anchor"></a>
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Clancy, C. E., Rudy, Y.
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<strong>Linking a genetic defect to its cellular phenotype in a cardiac arrhythmia.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10448858/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10448858</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10448858" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/23034" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1161/hc1002.105183" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1172/JCI15928" target="_blank">Full Text</a>]
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<strong>Novel SCN5A mutation leading either to isolated cardiac conduction defect or Brugada syndrome in a large French family.</strong>
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[<a href="https://doi.org/10.1161/hc5001.100834" target="_blank">Full Text</a>]
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<strong>SCN5A mutation associated with cardiac conduction defect and atrial arrhythmias.</strong>
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[<a href="https://doi.org/10.1111/j.1540-8167.2006.00411.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.jacc.2012.02.052" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1046/j.1529-8817.2005.00167.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1172/JCI34057" target="_blank">Full Text</a>]
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<strong>Congenital atrial standstill associated with coinheritance of a novel SCN5A mutation and connexin 40 polymorphisms.</strong>
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[<a href="https://doi.org/10.1016/j.hrthm.2005.06.032" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0014-5793(98)00033-7" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1161/01.cir.101.1.54" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.jacc.2012.05.050" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15466643/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15466643</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15466643" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1161/01.CIR.0000144458.58660.BB" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1111/j.1399-0004.2006.00671.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1161/01.CIR.0000130666.81539.9E" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.0403711101" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22710484/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22710484</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22710484" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.hrthm.2012.06.029" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.2006.042192" target="_blank">Full Text</a>]
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<a id="Noble2002" class="mim-anchor"></a>
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[<a href="https://doi.org/10.1073/pnas.102171699" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/11.3.337" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1161/01.RES.0000069689.09869.A8" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1172/JCI16879" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1161/hc0302.102592" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.93.23.13200" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1172/JCI119335" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.2003.013300" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1006/geno.1996.0236" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/4.9.1603" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/0092-8674(95)90359-3" target="_blank">Full Text</a>]
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<strong>Congenital long-QT syndrome caused by a novel mutation in a conserved acidic domain of the cardiac Na(+) channel.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10377081/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10377081</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10377081" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1161/01.cir.99.24.3165" target="_blank">Full Text</a>]
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Westenskow, P., Splawski, I., Timothy, K. W., Keating, M. T., Sanguinetti, M. C.
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<strong>Compound mutations: a common cause of severe long-QT syndrome.</strong>
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[<a href="https://doi.org/10.1161/01.CIR.0000125524.34234.13" target="_blank">Full Text</a>]
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Yang, P., Kanki, H., Drolet, B., Yang, T., Wei, J., Viswanathan, P. C., Hohnloser, S. H., Shimizu, W., Schwartz, P. J., Stanton, M., Murray, K. T., Norris, K., George, A. L., Jr., Roden, D. M.
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<strong>Allelic variants in long-QT disease genes in patients with drug-associated torsades de pointes.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11997281/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11997281</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11997281" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1161/01.cir.0000014448.19052.4c" target="_blank">Full Text</a>]
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<span class="mim-text-font">
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Sonja A. Rasmussen - updated : 09/12/2022
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Matthew B. Gross - updated : 04/23/2019<br>Patricia A. Hartz - updated : 11/16/2016<br>Paul J. Converse - updated : 1/8/2015<br>Marla J. F. O'Neill - updated : 4/29/2014<br>Marla J. F. O'Neill - updated : 1/29/2013<br>Marla J. F. O'Neill - updated : 6/1/2011<br>Marla J. F. O'Neill - updated : 6/8/2009<br>Marla J. F. O'Neill - updated : 12/23/2008<br>Marla J. F. O'Neill - updated : 5/14/2008<br>Marla J. F. O'Neill - updated : 3/6/2008<br>Marla J. F. O'Neill - updated : 2/12/2008<br>Marla J. F. O'Neill - updated : 1/12/2007<br>Marla J. F. O'Neill - updated : 11/9/2006<br>Marla J. F. O'Neill - updated : 7/10/2006<br>Victor A. McKusick - updated : 2/20/2006<br>Marla J. F. O'Neill - updated : 1/31/2006<br>Marla J. F. O'Neill - updated : 10/11/2005<br>Victor A. McKusick - updated : 1/27/2005<br>Victor A. McKusick - updated : 1/3/2005<br>Cassandra L. Kniffin - updated : 10/26/2004<br>Marla J. F. O'Neill - updated : 2/18/2004<br>Victor A. McKusick - updated : 11/18/2003<br>Victor A. McKusick - updated : 6/30/2003<br>Denise L. M. Goh - updated : 1/6/2003<br>Ada Hamosh - updated : 10/18/2002<br>George E. Tiller - updated : 9/23/2002<br>Deborah L. Stone - updated : 6/26/2002<br>Victor A. McKusick - updated : 6/6/2002<br>Paul Brennan - updated : 3/27/2002<br>Paul Brennan - updated : 3/8/2002<br>Ada Hamosh - updated : 1/22/2002<br>Victor A. McKusick - updated : 11/6/2001<br>Ada Hamosh - updated : 2/27/2001<br>Victor A. McKusick - updated : 9/27/2000<br>Victor A. McKusick - updated : 9/15/2000<br>Victor A. McKusick - updated : 6/1/2000<br>Paul Brennan - updated : 4/12/2000<br>Paul Brennan - updated : 4/3/2000<br>Paul Brennan - updated : 4/3/2000<br>Victor A. McKusick - updated : 2/24/2000<br>Victor A. McKusick - updated : 1/12/2000<br>Paul Brennan - updated : 8/31/1999<br>Ada Hamosh - updated : 8/4/1999<br>Ada Hamosh - updated : 5/25/1999<br>Victor A. McKusick - updated : 10/2/1998<br>Victor A. McKusick - updated : 5/12/1998<br>Victor A. McKusick - updated : 3/17/1998<br>Victor A. McKusick - updated : 5/27/1997
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 10/26/1994
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 01/11/2023
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 10/03/2022<br>alopez : 09/30/2022<br>carol : 09/25/2022<br>carol : 09/13/2022<br>carol : 09/12/2022<br>carol : 09/01/2020<br>carol : 05/29/2019<br>mgross : 04/23/2019<br>alopez : 11/07/2018<br>carol : 01/05/2018<br>carol : 10/05/2017<br>alopez : 09/14/2017<br>carol : 01/12/2017<br>alopez : 11/16/2016<br>alopez : 11/09/2016<br>alopez : 11/09/2016<br>carol : 05/24/2016<br>carol : 5/23/2016<br>mgross : 1/30/2015<br>carol : 1/14/2015<br>mcolton : 1/8/2015<br>alopez : 11/12/2014<br>carol : 4/29/2014<br>mcolton : 4/28/2014<br>carol : 4/17/2014<br>carol : 3/19/2014<br>carol : 8/27/2013<br>carol : 3/8/2013<br>alopez : 1/30/2013<br>alopez : 1/29/2013<br>carol : 12/15/2011<br>carol : 11/23/2011<br>terry : 11/4/2011<br>carol : 11/3/2011<br>carol : 7/15/2011<br>wwang : 6/3/2011<br>wwang : 6/3/2011<br>terry : 6/1/2011<br>wwang : 6/30/2009<br>terry : 6/8/2009<br>carol : 6/2/2009<br>carol : 12/24/2008<br>terry : 12/23/2008<br>carol : 12/22/2008<br>carol : 5/14/2008<br>carol : 3/6/2008<br>wwang : 3/5/2008<br>wwang : 2/26/2008<br>terry : 2/12/2008<br>joanna : 2/7/2008<br>carol : 11/15/2007<br>alopez : 10/4/2007<br>carol : 9/10/2007<br>carol : 1/19/2007<br>terry : 1/12/2007<br>carol : 12/8/2006<br>carol : 11/16/2006<br>carol : 11/9/2006<br>carol : 11/9/2006<br>carol : 10/4/2006<br>terry : 8/24/2006<br>wwang : 7/11/2006<br>terry : 7/10/2006<br>joanna : 6/2/2006<br>carol : 2/22/2006<br>carol : 2/22/2006<br>terry : 2/20/2006<br>wwang : 2/20/2006<br>wwang : 2/3/2006<br>terry : 1/31/2006<br>wwang : 10/14/2005<br>terry : 10/11/2005<br>wwang : 2/10/2005<br>wwang : 2/8/2005<br>terry : 1/27/2005<br>wwang : 1/6/2005<br>wwang : 1/6/2005<br>terry : 1/3/2005<br>tkritzer : 10/27/2004<br>ckniffin : 10/26/2004<br>carol : 10/26/2004<br>carol : 10/12/2004<br>joanna : 9/10/2004<br>ckniffin : 4/30/2004<br>carol : 4/30/2004<br>ckniffin : 4/14/2004<br>tkritzer : 3/18/2004<br>tkritzer : 3/16/2004<br>carol : 2/18/2004<br>alopez : 11/25/2003<br>tkritzer : 11/20/2003<br>terry : 11/18/2003<br>carol : 7/14/2003<br>tkritzer : 7/8/2003<br>terry : 6/30/2003<br>carol : 2/5/2003<br>carol : 1/6/2003<br>carol : 1/6/2003<br>alopez : 10/23/2002<br>terry : 10/18/2002<br>cwells : 9/23/2002<br>carol : 6/26/2002<br>mgross : 6/10/2002<br>terry : 6/6/2002<br>alopez : 3/27/2002<br>carol : 3/14/2002<br>alopez : 3/8/2002<br>alopez : 1/23/2002<br>terry : 1/22/2002<br>carol : 11/8/2001<br>carol : 11/8/2001<br>mcapotos : 11/6/2001<br>alopez : 3/7/2001<br>alopez : 3/6/2001<br>terry : 2/27/2001<br>mcapotos : 10/13/2000<br>mcapotos : 10/11/2000<br>terry : 9/27/2000<br>carol : 9/25/2000<br>terry : 9/22/2000<br>terry : 9/15/2000<br>mcapotos : 6/15/2000<br>mcapotos : 6/14/2000<br>terry : 6/1/2000<br>alopez : 4/12/2000<br>alopez : 4/3/2000<br>alopez : 4/3/2000<br>mcapotos : 3/17/2000<br>mcapotos : 3/8/2000<br>terry : 2/24/2000<br>mgross : 2/17/2000<br>terry : 1/12/2000<br>carol : 11/4/1999<br>mgross : 8/31/1999<br>alopez : 8/4/1999<br>terry : 8/4/1999<br>kayiaros : 7/8/1999<br>carol : 7/7/1999<br>carol : 5/25/1999<br>carol : 5/11/1999<br>carol : 10/7/1998<br>terry : 10/2/1998<br>terry : 6/4/1998<br>carol : 5/21/1998<br>terry : 5/12/1998<br>alopez : 3/18/1998<br>terry : 3/17/1998<br>jenny : 5/30/1997<br>terry : 5/27/1997<br>terry : 12/10/1996<br>terry : 12/5/1996<br>terry : 6/5/1996<br>terry : 6/3/1996<br>joanna : 12/29/1995<br>mimadm : 9/23/1995<br>mark : 9/22/1995<br>terry : 4/20/1995<br>mark : 3/30/1995<br>terry : 10/26/1994
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</span>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<div class="container visible-print-block">
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<div class="row">
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<div class="col-md-8 col-md-offset-1">
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<div>
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<div>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 600163
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</span>
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</h3>
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</div>
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<div>
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<h3>
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<span class="mim-font">
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SODIUM VOLTAGE-GATED CHANNEL, ALPHA SUBUNIT 5; SCN5A
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<div >
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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SODIUM CHANNEL, VOLTAGE-GATED, TYPE V, ALPHA SUBUNIT<br />
|
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NAV1.5
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: SCN5A</em></strong>
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</span>
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</p>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 283645003, 51178009, 60423000, 698249005;
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<strong>ICD10CM:</strong> I49.8;
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<strong>ICD9CM:</strong> 427.81, 798.0;
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<p>
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<span class="mim-text-font">
|
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<strong>
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<em>
|
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Cytogenetic location: 3p22.2
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|
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Genomic coordinates <span class="small">(GRCh38)</span> : 3:38,548,062-38,649,687 </span>
|
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</em>
|
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</strong>
|
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>Gene-Phenotype Relationships</strong>
|
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</span>
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</h4>
|
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<div>
|
|
<table class="table table-bordered table-condensed small mim-table-padding">
|
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<thead>
|
|
<tr class="active">
|
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<th>
|
|
Location
|
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</th>
|
|
<th>
|
|
Phenotype
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</th>
|
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<th>
|
|
Phenotype <br /> MIM number
|
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</th>
|
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<th>
|
|
Inheritance
|
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</th>
|
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<th>
|
|
Phenotype <br /> mapping key
|
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</th>
|
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</tr>
|
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</thead>
|
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<tbody>
|
|
|
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<tr>
|
|
<td rowspan="9">
|
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<span class="mim-font">
|
|
3p22.2
|
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</span>
|
|
</td>
|
|
|
|
|
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<td>
|
|
<span class="mim-font">
|
|
{Sudden infant death syndrome, susceptibility to}
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
272120
|
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</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal recessive
|
|
</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
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</span>
|
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</td>
|
|
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|
|
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|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
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</tr>
|
|
|
|
|
|
|
|
|
|
|
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<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Atrial fibrillation, familial, 10
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
614022
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Brugada syndrome 1
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
601144
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Cardiomyopathy, dilated, 1E
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
601154
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Heart block, nonprogressive
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
113900
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Heart block, progressive, type IA
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
113900
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Long QT syndrome 3
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
603830
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Sick sinus syndrome 1
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
608567
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal recessive
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Ventricular fibrillation, familial, 1
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
603829
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
|
|
</tbody>
|
|
</table>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>TEXT</strong>
|
|
</span>
|
|
</h4>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Cloning and Expression</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Gellens et al. (1992) cloned and characterized the cardiac sodium channel gene SCN5A. The deduced 2,016-amino acid protein has a structure similar to that of previously characterized sodium channels (see 182392) and contains 4 homologous domains, each of which has 6 putative membrane-spanning regions. </p><p>Freyermuth et al. (2016) stated that alternative splicing creates fetal and adult isoforms of SCN5A that differ in inclusion of alternative exons 6a or 6b, respectively. Both exons 6 have 92 bp, but encode 7 different amino acids in the voltage-sensor region of SCN5A domain I. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene Structure</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Wang et al. (1996) found that SCN5A consists of 28 exons spanning approximately 80 kb. They described the sequences of all intron/exon boundaries and a dinucleotide repeat polymorphism in intron 16. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Mapping</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>George et al. (1995) mapped the SCN5A gene to chromosome 3p21 by fluorescence in situ hybridization, thus making it an important candidate gene for long QT syndrome-3 (LQT3; 603830). </p><p>Gross (2019) mapped the SCN5A gene to chromosome 3p22.2 based on an alignment of the SCN5A sequence (GenBank BC051374) with the genomic sequence (GRCh38).</p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene Function</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
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<p>By immunoprecipitation and nano-liquid chromatography-mass spectroscopy/mass spectroscopy of transgenic mouse bone marrow macrophages expressing the human macrophage splice variant of SCN5A, followed by Western blot analysis, Jones et al. (2014) identified interaction of SCN5A with activating transcription factor-2 (ATF2; 123811). Microarray analysis of SCN5A-positive macrophages revealed increased expression of Sp100 (604585), an Atf2-regulated gene. Knockdown of Adcy8 (103070), the calcium-dependent isoform of adenylate cyclase, inhibited channel agonist-induced expression of Sp100-related genes. Activation of SCN5A increased expression of cAMP in macrophages. Treatment of macrophages with poly(I:C), a mimic of viral double-stranded RNA, activated the Adcy8 signaling pathway to regulate expression of Sp100-related genes and Ifnb (147640). Electrophysiologic analysis showed that the SCN5A variant mediated nonselective outward currents, as well as a small yet detectable inward current. Jones et al. (2014) proposed that human macrophage SCN5A initiates signaling in an innate immune pathway relevant to antiviral host defense, and that SCN5A is a pathogen sensor. </p><p>Myotonic dystrophy (see DM1, 160900) is caused by expression of mutant RNAs containing expanded CUG repeats. These repeats sequester muscleblind-like (MBNL; see MBNL1, 606516) splicing factors in nuclear RNA foci, resulting in changes in pre-mRNA splicing. Freyermuth et al. (2016) showed that MBNL1 specifically promoted inclusion of exon 6b in SCN5A pre-mRNA and expression of the adult SCN5A isoform. Freyermuth et al. (2016) found that left ventricle samples of 3 adult DM1 patients showed alternative splicing in a number of genes, including SCN5A. A portion of the SCN5A mRNA in these samples was the fetal isoform. When expressed in Xenopus oocytes, the fetal isoform of SCN5A showed reduced excitability compared with the adult SCN5A isoform. In mice, expression of fetal Scn5a promoted heart arrhythmia and cardiac-conduction delay, which are 2 predominant features of myotonic dystrophy. </p>
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<h4>
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<strong>Molecular Genetics</strong>
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<p>Missense mutations in the skeletal muscle sodium channel gene, SCN4A (603967), cause myotonia. Physiologic data show that these mutations affect sodium channel inactivation and lead to repetitive depolarizations, consistent with the myotonic phenotype. By analogy, similar mutations in the cardiac sodium channel gene might be expected to cause a phenotype like LQT. Indeed, Wang et al. (1995) found a mutation in the SCN5A gene in families with chromosome 3-linked LQT (see 600163.0001). </p><p>Bennett et al. (1995) determined the functional defect resulting from the 3-amino acid (KPQ) deletion (600163.0001) in the SCN5A protein. By expression of recombinant human heart sodium channels in Xenopus laevis oocytes, mutant channels showed a sustained inward current during membrane depolarization. Single-channel recordings indicated that mutant channels fluctuate between normal and noninactivating gating modes. Persistent inward sodium current explains prolongation of cardiac action potentials and provides a molecular mechanism for the chromosome 3-linked form of long QT syndrome. </p><p>Wang et al. (1995) identified SCN5A mutations in affected members of 4 additional families with chromosome 3-linked LQT. Two of the families had the same 9-bp deletion found earlier; the other families were found to have missense mutations affecting highly conserved amino acid residues (600163.0002 and 600163.0003). The location and character of the mutation suggested to the authors that this form of LQT results from a delay in cardiac sodium channel fast inactivation or altered voltage-dependence of inactivation. </p><p>Wang et al. (1996) determined the biophysical and functional characteristics of each of the 3 distinct mutations that had been identified in the cardiac sodium channel gene in patients with LQT3 to that time. For this they used heterologous expression of a recombinant human heart sodium channel in a mammalian cell line. Each mutation caused a sustained, noninactivating sodium current amounting to a few percent of the peak inward sodium current, observable during long (more than 50 msec) depolarizations. The voltage dependence and rate of inactivation were altered and the rate of recovery from inactivation was changed compared with wildtype channels. These mutations in diverse regions of the ion channel protein all produced a common defect in channel gating that can cause the long QT phenotype. The sustained inward current caused by these mutations would prolong the action potential. Furthermore, they might create conditions that promote arrhythmias due to prolonged depolarization and the altered recovery from inactivation. </p><p>Wang et al. (1997) explored the potential for targeted suppression of the defect in LQT3 by heterologous expression of mutant channels in cultured human cells. Channel behavior and inhibition by mexiletine were investigated by whole-cell patch-clamp methods. The investigators showed that late-opening LQT3 mutant channels were much more sensitive to inhibition by mexiletine than were wildtype sodium channels. The defective late openings were selectively suppressed more than the peak sodium current and these late openings could be suppressed by concentrations at the lower end of the therapeutic range. </p><p>Using a candidate gene approach, Chen et al. (1998) studied 6 small families and 2 sporadic patients with idiopathic ventricular fibrillation (IVF; 603829) using SSCP and DNA sequence analyses to identify mutations in known ion channel genes, including the cardiac sodium channel gene SCN5A. They identified several mutations in families with a distinct form of IVF known as Brugada syndrome (BRGDA1; 601144). In 1 family all affected members had 2 mutations: an arg1232-to-trp mutation in exon 21 of the gene in the extracellular loop between transmembrane segments S1 and S2 of domain III of the protein, and a thr1620-to-met mutation in exon 28 of the gene in the extracellular loop between S3 and S4 of domain IV of the protein (600163.0004). Additional SCN5A mutations were found in 2 IVF families: insertion of 2 nucleotides (AA) in the splice-donor sequence of intron 7 (600163.0005); and deletion of a single nucleotide (A) at codon 1397, resulting in an in-frame stop codon (600163.0006). The frameshift mutation caused the sodium channel to be nonfunctional. </p><p>Schott et al. (1999) reported a mutation in the SCN5A gene that segregated with progressive familial heart block (PFHB1A; 113900) in an autosomal dominant manner in a large French family. In a smaller Dutch family, another SCN5A mutation cosegregated with familial nonprogressive conduction defect (see 113900). The French family with PFHB1A was identified through a member with right bundle branch block (RBBB) and syncope; a brother had RBBB, and a sister had complete atrioventricular (AV) block and syncope. Clinical and electrocardiographic abnormalities were found in 15 members of the family; mean QRS duration was 135 +/- 7 ms. RBBB was present in 5, left bundle branch block (LBBB) in 2, left anterior or posterior hemiblock in 3, and long PR interval (more than 210 ms) in 8. None had a structural heart disease. Four members of earlier generations had received a pacemaker implantation because of syncope or complete AV block. Long-term follow-up of several affected members demonstrated that their conduction defect increased in severity with age. In the Dutch family, the proband presented after birth with an asymptomatic first-degree AV block associated with RBBB (PR interval and QRS duration, 200 and 120 ms, respectively). In the French family, Schott et al. (1999) excluded the chromosome 19 locus for this disorder (604559) by linkage studies, as well as other loci for inherited cardiac disorders associated with conduction defects. SCN5A was considered a candidate locus, and using markers flanking SCN5A, the authors demonstrated segregation of the disease with D3S1260 in every affected individual (maximum lod score of 6.03 at theta of 0.0). A donor splice site mutation in SCN5A was found in the French family (600163.0009), and a frameshift mutation was identified in the Dutch family (600163.0010). Clinical data and family histories indicated that none of the affected individuals in these 2 families had LQT3 or idiopathic ventricular fibrillation (Brugada syndrome). Therefore, PFHB1 represents a third cardiac disease linked to SCN5A. </p><p>Splawski et al. (2000) screened 262 unrelated individuals with LQT syndrome for mutations in the 5 defined genes (KCNQ1, 607542; KCNH2, 152427; SCN5A; KCNE1, 176261; and KCNE2, 603796) and identified mutations in 177 individuals (68%). KCNQ1 and KCNH2 accounted for 87% of mutations (42% and 45%, respectively), and SCN5A, KCNE1, and KCNE2 for the remaining 13% (8%, 3%, and 2%, respectively). </p><p>Tan et al. (2002) demonstrated that calmodulin (114180) binds to the carboxy terminal 'IQ' domain of the SCN5A in a calcium-dependent manner. This binding interaction significantly enhances slow inactivation, a channel-gating process linked to life-threatening idiopathic ventricular arrhythmias. Mutations targeted to the IQ domain disrupted calmodulin binding and eliminated calcium/calmodulin-dependent slow inactivation, whereas the gating effects of calcium/calmodulin were restored by intracellular application of a peptide modeled after the IQ domain. A naturally occurring mutation (A1924T; 600163.0012) in the IQ domain altered SCN5A function in a manner characteristic of the Brugada syndrome, but at the same time inhibited slow inactivation induced by calcium/calmodulin, yielding a clinically benign (arrhythmia-free) phenotype. </p><p>Splawski et al. (2002) identified a common variant of the SCN5A gene, ser1103 to tyr (S1103Y; 600163.0024), which is present in 13.2% of African Americans and is associated with accelerated channel activation, increasing the likelihood of abnormal cardiac repolarization and arrhythmia. Splawski et al. (2002) suggested that the S1103Y mutation in the African American population may be a useful molecular marker for the prediction of arrhythmia susceptibility in the context of additional acquired risk factors such as the use of certain medications or the presence of hypokalemia. </p><p>Rivolta et al. (2001) identified 2 mutations at the same codon of the SCN5A gene: a tyr1795-to-cys mutation (Y1795C; 600163.0029) in a patient with LQT3, and a Y1795H (600163.0030) mutation in a patient with Brugada syndrome. Functional analysis revealed marked and opposing effects on channel gating consistent with activity associated with the cellular basis of each clinical disorder: Y1795H accelerated and Y1795C slowed the onset of activation; Y1795H, but not Y1795C, caused a marked negative shift in the voltage dependence of inactivation; and neither affected the kinetics of the recovery from inactivation. However, both mutations increased the expression of sustained Na(+) channel activity compared with wildtype channels, although this effect was most pronounced for the Y1795C mutation, and both promoted entrance into an intermediate or slowly developing inactivated state. Rivolta et al. (2001) concluded that these data confirmed the key role of the C-terminal tail of the cardiac Na(+) channel in the control of channel gating and provided further evidence of the close interrelationship between Brugada syndrome and LQT3 at the molecular level. </p><p>Clancy et al. (2002) performed detailed kinetic analyses of the Y1795C mutant described by Rivolta et al. (2001). Theoretical entry and exit rates from the bursting mode of gating were derived from single channels. Computational analysis suggested that the amount of time mutant channels spend bursting (burst mode dwell time) is primarily responsible for rate-dependent changes in single-channel bursting and macroscopic inward sodium channel (I-sus), hence delaying repolarization and prolonging the QT interval. This prediction was experimentally confirmed by analysis of delta-KPQ mutant channels (600163.0001) for which the burst mode exit rate (determined by the burst mode dwell time) was found to be very similar to the derived rate for Y1795C channels. These results provided an explanation of the molecular mechanism for bradycardia-induced QT prolongation in patients carrying LQT3 mutations. </p><p>Veldkamp et al. (2003) studied the effect of the 1795insD SCN5A mutation (600163.0013), which causes LQT3 or Brugada syndrome, on sinoatrial (SA) pacemaking. Activity of 1795insD channels during SA node pacemaking was confirmed by action potential (AP) clamp experiments, and the previously characterized persistent inward current (I-pst) and negative shift were implemented into SA node (AP) models. The -10 mV shift decreased the sinus rate by decreasing the diastolic depolarization rate, whereas the I-pst decreased the sinus rate by AP prolongation, despite a concomitant increase in the diastolic depolarization rate. In combination, a moderate I-pst (1 to 2%) and the shift reduced the sinus rate by about 10%. Veldkamp et al. (2003) concluded that sodium channel mutations displaying an I-pst or a negative shift in inactivation may account for the bradycardia seen in LQT3 patients, whereas SA node pauses or arrest may result from failure of SA node cells to repolarize under conditions of extra net inward current. </p><p>Based on prior associations with disorders of cardiac rhythm and conduction, Benson et al. (2003) screened the SCN5A gene as a candidate gene in 10 pediatric patients from 7 families who were diagnosed with autosomal recessive congenital sick sinus syndrome (SSS1; 608567) during the first decade of life. Probands from 3 kindreds exhibited compound heterozygosity for 6 distinct SCN5A alleles (e.g., 600163.0025), 2 of which had previously been associated with dominant disorders of cardiac excitability. Biophysical characterization of the mutants using heterologously expressed recombinant human heart sodium channels demonstrated loss of function or significant impairment in channel gating that predicted reduced myocardial excitability. Thus Benson et al. (2003) provided a molecular basis for some forms of congenital SSS and defined a recessive disorder of a human heart voltage-gated sodium channel. </p><p>In a patient with Brugada syndrome, Mohler et al. (2004) identified an E1053K mutation (600163.0033) in the ankyrin-binding motif of Na(v)1.5. The mutation abolished binding of Na(v)1.5 to ankyrin-G (ANK3; 600465), and also prevented accumulation of Na(v)1.5 at cell surface sites in ventricular cardiomyocytes. Both ankyrin-G and Na(v)1.5 localized at intercalated disc and T-tubule membranes in cardiomyocytes, and Na(v)1.5 coimmunoprecipitated with the 190-kD ankyrin-G isoform from detergent-soluble lysates from rat heart. These data suggested that Na(v)1.5 associates with ankyrin-G and that ankyrin-G is required for Na(v)1.5 localization at excitable membranes in cardiomyocytes. </p><p>Miller et al. (2004) reported a case of repeated germline transmission of a severe form of LQT syndrome from an asymptomatic mother with somatic mosaicism for a mutation in the SCN5A gene (600163.0007). </p><p>Maekawa et al. (2005) sequenced the SCN5A gene in 166 Japanese patients with arrhythmia who were not diagnosed with LQT or Brugada syndrome and in 232 healthy controls, identifying 69 genetic variations including 66 SNPs. The frequency of a 703+130G-A SNP was significantly higher in patients than in controls (OR, 1.70), suggesting an association with an unknown risk factor for arrhythmia. Haplotype analysis revealed that the so-called GG haplotype with both the leu1988-to-arg and his558-to-arg (600163.0031) SNPs was significantly less frequent in patients than in controls (p = 0.018), suggesting a possible protective effect. </p><p>Tester et al. (2005) analyzed 5 LQTS-associated cardiac channel genes in 541 consecutive unrelated patients with LQT syndrome (average QTc, 482 ms). In 272 (50%) patients, they identified 211 different pathogenic mutations, including 88 in KCNQ1, 89 in KCNH2, 32 in SCN5A, and 1 each in KCNE1 and KCNE2. Mutations considered pathogenic were absent in more than 1,400 reference alleles. Among the mutation-positive patients, 29 (11%) had 2 LQTS-causing mutations, of which 16 (8%) were in 2 different LQTS genes (biallelic digenic). Tester et al. (2005) noted that patients with multiple mutations were younger at diagnosis, but they did not discern any genotype/phenotype correlations associated with location or type of mutation. </p><p>In 44 unrelated patients with LQT syndrome, Millat et al. (2006) used DHLP chromatography to analyze the KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 genes for mutations and SNPs. Most of the patients (84%) showed a complex molecular pattern, with an identified mutation associated with 1 or more SNPs located in several LQTS genes; 4 of the patients also had a second mutation in a different LQTS gene (biallelic digenic inheritance; see, e.g., 600163.0007 and 603796.0005). </p><p>In affected members of the family reported by Greenlee et al. (1986) with a form of dilated cardiomyopathy (CMD1E; 601154), McNair et al. (2004) identified heterozygosity for a missense mutation (D1765N; 600163.0001) in the SCN5A gene. In affected members of a family with atrial standstill (ATRST1; 108770), Groenewegen et al. (2003) had identified coinheritance of the D1275N mutation in the SCN5A gene with polymorphisms in the atria-specific junction channel protein connexin-40 (GJA5; 121013). None of the patients with atrial standstill had dilated cardiomyopathy, leading Groenewegen and Wilde (2005) to question the relationship of the SCN5A mutation to dilated cardiomyopathy in the family reported by McNair et al. (2004). McNair et al. (2005) responded that the younger age of the affected members studied by Groenewegen et al. (2003) as well as additional or genetic environmental factors may account for the difference between the 2 families. </p><p>In a Japanese family in which an 11-year-old boy had sick sinus syndrome that progressed to atrial standstill, Makita et al. (2005) analyzed 3 cardiac ion channel genes previously associated with atrial standstill, atrial fibrillation, or sick sinus syndrome: SCN5A, HCN4 (605206), and GJA5. No mutations were found in HCN4, but the proband and his asymptomatic father were heterozygous for a missense mutation in SCN5A (L212P; 600163.0048). In addition, the proband and his unaffected mother and maternal grandmother were all heterozygous for the same 2 rare GJA5 polymorphisms identified by Groenewegen et al. (2003) in atrial standstill patients, -44A/+71G. Functional analysis with the L212P mutant channels demonstrated large hyperpolarizing shifts in both the voltage dependence of activation and inactivation and delayed recovery from inactivation compared to wildtype. Makita et al. (2005) suggested that defects in SCN5A underlie atrial standstill, and that coinheritance of GJA5 polymorphisms represents a possible genetic modifier of the clinical manifestations. </p><p>Olson et al. (2005) analyzed the SCN5A gene in 156 unrelated patients with dilated cardiomyopathy who were negative for mutations in the known CMD genes encoding cardiac actin (102540), alpha-tropomyosin (191010), and metavinculin (see 193065), and identified 5 heterozygous mutations in 5 probands, respectively (see, e.g., 600163.0027, 600163.0038-600163.0039). All of the mutations altered highly conserved residues in the transmembrane domains of SCN5A. </p><p>Albert et al. (2008) analyzed 5 cardiac ion channel genes, SCN5A, KCNQ1, KCNH2, KCNE1, and KCNE2, in 113 cases of sudden cardiac death. No mutations or rare variants were identified in any of the 53 male subjects, but in 6 (10%) of 60 female subjects, 5 rare missense variants in SCN5A were identified, 2 previously associated with long QT syndrome, 1 with sudden infant death syndrome, and 2 not previously reported in control populations. Functional studies showed that all of the variants resulted in significantly shorter recovery times from inactivation. Albert et al. (2008) concluded that functionally significant mutations and rare variants in the SCN5A gene may contribute to the risk of sudden cardiac death in women. </p><p>Makita et al. (2008) genotyped 66 members of 44 LQT3 families of multiple ethnicities and identified the E1784K mutation (600163.0008) in 41 individuals from 15 (34%) of the kindreds; the diagnoses in these individuals included LQT3 syndrome, Brugada syndrome, and/or sinus node dysfunction (see 608567). In vitro functional characterization of E1784K channels compared to properties reported for other LQT3 variants suggested that a negative shift of steady-state Na channel inactivation and enhanced tonic block in response to Na channel blockers confer an additional Brugada syndrome/sinus node dysfunction phenotype, and further indicated that class IC drugs should be avoided in patients with Na channels displaying these behaviors. </p><p>In a large Finnish family with atrial fibrillation (AF) and conduction defects (ATFB10; 614022), Laitinen-Forsblom et al. (2006) analyzed the SCN5A gene and identified a heterozygous missense mutation (600163.0034) that segregated with disease and was not found in more than 370 control chromosomes. </p><p>Ellinor et al. (2008) analyzed the SCN5A gene in 57 probands with a familial history of isolated or 'lone' atrial fibrillation and identified heterozygosity for a missense mutation (600163.0041) in a 45-year-old male proband and his affected father. The authors concluded that SCN5A gene was not a major cause of familial AF. </p><p>Darbar et al. (2008) analyzed the SCN5A gene in 375 probands with AF, including 118 with lone AF, which was defined as AF occurring in individuals less than 65 years of age who did not have hypertension, overt structural heart disease, or thyroid dysfunction. The authors identified 8 heterozygous variants in 10 probands that were not found in 360 age-, sex-, and ethnicity-matched controls (see, e.g., 600163.0042-600163.0045). In addition, 11 previously reported rare nonsynonymous coding region variants were identified in 12 probands (see, e.g., 600163.0033), and 3 known common nonsynonymous SCN5A polymorphisms were also identified in the AF cohort (see, e.g., 600163.0024 and 600163.0031). Darbar et al. (2008) stated that in their study, nearly 6% of AF probands carried heterozygous mutations or rare variants in the SCN5A gene. </p><p>In affected members of 2 unrelated families with CMD and conduction system disease, Hershberger et al. (2008) identified heterozygosity for 2 different missense mutations in the SCN5A gene, R222Q (600163.0046) and I1835T (600163.0047), respectively. Cheng et al. (2010) restudied the 2 families, noting that all affected individuals were also either homozygous or heterozygous for the SCN5A common polymorphism, H558R (600163.0031). Whole-cell voltage clamp studies in HEK293 cells using the Q1077del background, which is the more abundant alternatively spliced SCN5A transcript present in human hearts (65%), showed that sodium current densities of the R222Q and I1835T mutants were not different from wildtype, but the combined variants R222Q/H558R and I1835T/H558R caused approximately 35% and 30% reduction, respectively, and each showed slower recovery from inactivation than wildtype. With the Q1077del background, R222Q and R222Q/H558R variants also exhibited a significant negative shift in both activation and inactivation, whereas I1835T/H558R showed a significant negative shift in inactivation that tended to decrease window current. In contrast, expression in the Q1077 background showed no changes in peak sodium current densities, decay, or recovery from inactivation for R222Q/H558R or I1835T/H558R. Cheng et al. (2010) concluded that CMD-associated SCN5A rare variants perturb the SCN5A biophysical phenotype that is modulated by SCN5A common variants. </p><p>In 3 unrelated families with multifocal ectopic Purkinje-related premature contractions and dilated cardiomyopathy, Laurent et al. (2012) identified heterozygosity for the R222Q mutation in the SCN5A gene, which was fully penetrant and strictly segregated with the cardiac phenotype in each family. Laurent et al. (2012) stated that the R222Q effects that they observed on channel parameters were similar to those measured by Cheng et al. (2010); in addition, they noted that the effects were intermediate in the heterozygous state and also impaired the window current, which is crucial during the plateau phase of the action potential. In vitro studies recapitulated the normalization of the ventricular action potentials in the presence of quinidine. </p><p>In affected members of a 3-generation Canadian family with CMD and junctional escape ventricular capture bigeminy, Nair et al. (2012) identified the R222Q mutation in the SCN5A gene. Heterologous expression studies revealed a unique biophysical phenotype of R222Q channels in which an approximately 10-mV leftward shift in the sodium current steady-state activation curve occurs without corresponding shifts in steady-state inactivation at cardiomyocyte resting membrane-potential voltages. Nair et al. (2012) noted that the absence of H558R in these patients established that the H558R polymorphism is not required for the induction of cardiomyopathy in patients carrying the R222Q mutation. </p><p>In 16 affected members over 3 generations of a large kindred with CMD and multiple arrhythmias, including premature ventricular complexes (PVCs) of variable morphologies, Mann et al. (2012) identified heterozygosity for the R222Q mutation in the SCN5A gene. The mutation was also identified in 1 clinically unaffected family member, a 56-year-old man with a normal EKG and echocardiogram. None of the R222Q carriers had the common SCN5A variant, H558R. </p><p>O'Neill et al. (2022) studied the effects of 50 previously published, functionally characterized missense variants in the SCN5A gene. Based on their effects on peak currents, variants were divided into loss-of-function (less than 10% of wildtype peak current, 35 variants) and partial loss-of-function (10-50% of wildtype peak current, 15 variants). Using cell lines created to study the effects of the variants in heterozygous coexpression with wildtype SCN5A, the authors found that 32 of 35 loss-of-function variants and 6 of 15 partial loss-of-function variants showed a reduction to less than 75% of wildtype-alone peak current, demonstrating evidence of dominant-negative effects. Using data from a published consortia and gnomAD, they found that patients with dominant-negative variants were 2.7 times more likely to present with Brugada syndrome than individuals with putative haploinsufficient variants (p = 0.019). </p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
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For discussion of a possible association between variants in the SCN5A, SCN10A (604427), and HEY2 (604674) genes and Brugada syndrome, see 601144.</p>
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<strong>Genotype/Phenotype Correlations</strong>
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<p>Westenskow et al. (2004) analyzed the KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 genes in 252 probands with long QT syndrome and identified 19 with biallelic mutations in LQTS genes, of whom 18 were either compound (monogenic) or double (digenic) heterozygotes and 1 was a homozygote. They also identified 1 patient who had triallelic digenic mutations (see 152427.0021). Compared with probands who had 1 or no identified mutation, probands with 2 mutations had longer QTc intervals (p less than 0.001) and were 3.5-fold more likely to undergo cardiac arrest (p less than 0.01). All 20 probands with 2 mutations had experienced cardiac events. Westenskow et al. (2004) concluded that biallelic mono- or digenic mutations (which the authors termed 'compound mutations') cause a severe phenotype and are relatively common in long QT syndrome. The authors noted that these findings support the concept of arrhythmia risk as a multi-hit process and suggested that genotype can be used to predict risk. </p><p>Niu et al. (2006) analyzed the SCN5A gene in 17 members of a 4-generation Han Chinese family with apparent autosomal dominant inheritance of cardiac arrhythmias and sudden death. All affected individuals were heterozygous for a nonsense mutation in the SCN5A gene (W1421X; 600163.0036), and 1 unaffected individual was compound heterozygous for the W1421X mutation and R1193Q (600163.0023). Niu et al. (2006) suggested that the R1193Q mutation, which results in a gain of sodium channel function, may compensate for the deleterious effects of W1421X. </p>
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<strong>Animal Model</strong>
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<p>Nuyens et al. (2001) reported that mice heterozygous for a knockin KPQ deletion (600163.0001) of the Scn5a gene showed the essential features of LQT3 and spontaneously developed life-threatening polymorphous ventricular arrhythmias. Sudden accelerations in heart rate or premature beats caused lengthening of the action potential with early after-depolarization and triggered arrhythmias in mice heterozygous for the deletion. Adrenergic agonists normalized the response to rate acceleration in vitro and suppressed arrhythmias upon premature stimulation in vivo. These results showed the possible risk of sudden heart rate accelerations. The heterozygous knockin mouse with its predisposition for pacing-induced arrhythmia might be a useful model for the development of new treatments for the LQT3 syndrome. </p><p>Papadatos et al. (2002) showed that disruption of the mouse Scn5a gene caused intrauterine lethality in homozygotes with severe defects in ventricular morphogenesis, whereas heterozygotes showed normal survival. Whole-cell patch-clamp analyses of isolated ventricular myocytes from adult Scn5a +/- mice demonstrated a reduction of approximately 50% in sodium conductance. Scn5a +/- hearts had several defects, including impaired atrioventricular conduction, delayed intramyocardial conduction, increased ventricular refractoriness, and ventricular tachycardia with characteristics of reentrant excitation. These findings reconciled reduced activity of the cardiac sodium channel leading to slowed conduction with several apparently diverse clinical phenotypes, providing a model for the detailed analysis of the pathophysiology of arrhythmias. Noble (2002) commented that detailed understanding of the mechanisms of cardiac arrhythmia at all relevant levels is important to the design of therapeutic programs, and cited the work of Papadatos et al. (2002) as an important step. </p>
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<strong>ALLELIC VARIANTS</strong>
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<strong>48 Selected Examples):</strong>
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<strong>.0001 LONG QT SYNDROME 3</strong>
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SCN5A, 9-BP DEL, NT4661
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SNP: rs397514251,
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ClinVar: RCV000009962, RCV000183165, RCV002336463, RCV003318368, RCV004804804
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|
|
</span>
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</div>
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<div>
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<span class="mim-text-font">
|
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<p>In 2 apparently unrelated kindreds with chromosome 3-linked LQT syndrome (LQT3; 603830), Wang et al. (1995) found deletion of 9 basepairs beginning at nucleotide 4661 of their cDNA for SCN5A. The deletion, which was detected by sequencing an aberrant SSCP conformer, resulted in deletion of lys-pro-gln (KPQ), which are 3 conserved amino acids in the cytoplasmic linker between domains III and IV of the channel protein. The 3 amino acids involved in the in-frame deletion are lys1505, pro1506, and gln1507. The effect of this mutation on membrane depolarization was studied by Bennett et al. (1995). </p><p>Clancy and Rudy (1999) developed a model representative of the behavior of the sodium channel in heart muscle cells using a single-channel-based Markov model approach. They showed that the delta-KPQ mutant form of the sodium channel stays open for too long, causing an overlarge inward current of sodium which gives rise to arrhythmia. This model view was corroborated by experiments recording actual sodium currents in cardiac muscle cells. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0002 LONG QT SYNDROME 3</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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SCN5A, ARG1644HIS
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<br />
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SNP: rs28937316,
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gnomAD: rs28937316,
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ClinVar: RCV000009963, RCV000058726, RCV000183090, RCV000246905, RCV002307360, RCV003591624, RCV004545721
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a mother and son with the long QT syndrome (LQT3; 603830), Wang et al. (1995) demonstrated a CGC-to-CAC mutation in codon 1644, resulting in the substitution of a highly conserved arginine residue by histidine. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0003 LONG QT SYNDROME 3</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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SCN5A, ASN1325SER
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<br />
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SNP: rs28937317,
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ClinVar: RCV000009964, RCV000058618, RCV002354154, RCV003234898
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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|
<p>In a family in which members of 4 generations had been affected by the long QT syndrome (LQT3; 603830), Wang et al. (1995) found an AAT-to-AGT transition in codon 1325, predicted to cause substitution of a highly conserved asparagine residue by a serine residue. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0004 BRUGADA SYNDROME 1</strong>
|
|
</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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|
SCN5A, ARG1232TRP AND THR1620MET
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<br />
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SNP: rs199473207, rs199473282,
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gnomAD: rs199473282,
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ClinVar: RCV000009965, RCV000058588, RCV000058715, RCV000144030, RCV000144031, RCV000183042, RCV001836727, RCV001842342, RCV001842371, RCV002345369, RCV002477202
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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|
<p>In affected members of a family with Brugada syndrome (BRGDA1; 601144), a distinct form of idiopathic ventricular fibrillation, Chen et al. (1998) found an arg1232-to-trp (R1232W) and a thr1620-to-met (T1620M) mutation on the same chromosome with no mutation in the other chromosome, suggesting to them that IVF in this family was inherited as an autosomal dominant trait. The presence of both normal and mutated sodium channels in the same tissue would promote heterogeneity of the refractory period, a well established mechanism in arrhythmogenesis, and therefore may be the underlying molecular defect that causes re-entrant arrhythmia in this family. The potential contribution of R1232W and T1620M mutations to the mechanism of IVF was determined by heterologous expression in Xenopus oocytes. They found that sodium channels with the missense mutation recovered from inactivation more rapidly than normal, indicating that IVF with right bundle branch block (RBBB) and ST segment elevation is a defect distinct from long QT syndrome. When studied alone, the R1232W mutant behaved most like normal channels, whereas the T1620M mutant closely followed the kinetic pattern of the double mutant. This indicated that T1620M is the mutation probably responsible for the IVF phenotype in this kindred and that R1232W could be a rare polymorphism. In summary, biophysical analysis of the 2 missense mutations in SCN5A showed a shift in the voltage dependence of steady-state inactivation toward more positive potentials associated with a 25 to 30% acceleration in recovery time from inactivation at potentials near -80mV. </p><p>Commenting that studies of the thr1620-to-met mutant by Chen et al. (1998) revealed an abnormal electrophysiologic profile at room temperature that did not adequately explain the ECG signature of Brugada syndrome, Dumaine et al. (1999) undertook a more detailed electrophysiologic study of the thr1620-to-met mutant protein. Dumaine et al. (1999) expressed the mutant protein in a mammalian cell line and employed a patch-clamp technique to study current kinetics at 32 degrees C. The results indicated that current decay kinetics were faster in mutant than in wildtype channels at this temperature and that recovery from inactivation was slower, with a significant shift in steady-state activation. These findings provided an explanation for the ECG features of Brugada syndrome and represented the first illustration of a cardiac sodium channel mutation in which arrhythmogenicity is revealed only at temperatures approaching the physiologic range. </p><p>Voltage-gated sodium channels are multimeric structures consisting of a large, heavily glycosylated alpha subunit and 1 or 2 smaller beta subunits. The beta subunits are thought necessary for normal gating function. In brain and skeletal muscle, the beta-1 subunit (600235) accelerates sodium channel inactivation. Makita et al. (2000) characterized the functional roles of the auxiliary beta subunit by coexpression of the beta subunit with either wildtype SCN5A or SCN5A carrying the heterologously expressed T1620M mutation in Xenopus oocytes. The midpoint of steady-state inactivation was significantly shifted to positive potentials in the T1620M alpha/beta-1 channel, with an acceleration in recovery from inactivation when compared to other channels. Makita et al. (2000) therefore suggested that coexpression of T1620M alpha/beta-1 subunits exposed a significant electrophysiologic deficit that may predispose to ventricular fibrillation. Expression of both normal and mutant channels, as in the hearts of patients with Brugada syndrome, would promote heterogeneity of the refractory period in their myocardium, which serves as an ideal electrical substrate for reentrant arrhythmia. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0005 BRUGADA SYNDROME 1</strong>
|
|
</span>
|
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</h4>
|
|
</div>
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<div>
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|
<span class="mim-text-font">
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|
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SCN5A, IVS7DS, 2-BP INS
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|
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|
|
|
<br />
|
|
|
|
SNP: rs397514252,
|
|
|
|
|
|
|
|
ClinVar: RCV000009966
|
|
|
|
|
|
</span>
|
|
</div>
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|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a family with idiopathic ventricular fibrillation with right bundle branch block (RBBB) and elevated ST segments, a disorder known as Brugada syndrome (BRGDA1; 601144), Chen et al. (1998) found an insertion of 2 nucleotides, AA, after the first 4 nucleotides (gtaa) in the splice donor sequence of intron 7 of the SCN5A gene. The functional consequences of this splicing mutation were not established. </p>
|
|
</span>
|
|
</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 BRUGADA SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
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|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
SCN5A, 1-BP DEL, VAL1398TER
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|
|
|
|
|
<br />
|
|
|
|
SNP: rs397514446,
|
|
|
|
|
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|
|
ClinVar: RCV000009967, RCV003542270, RCV004018609
|
|
|
|
|
|
</span>
|
|
</div>
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|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a family with idiopathic ventricular fibrillation characterized by RBBB and elevated ST segments, a disorder known as Brugada syndrome (BRGDA1; 601144), Chen et al. (1998) found a deletion of a single nucleotide (A) from codon 1397 of the SCN5A gene. This deletion resulted in an in-frame stop at codon 1398 (normally val). The resulting truncation eliminated DIII/S6, DIV/S1-S6, and the C-terminal portion of the cardiac sodium channel. </p>
|
|
</span>
|
|
</div>
|
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<div>
|
|
<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 LONG QT SYNDROME 3</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
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<div>
|
|
<span class="mim-text-font">
|
|
LONG QT SYNDROME 3/6, DIGENIC, INCLUDED
|
|
</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
SCN5A, ARG1623GLN
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs137854600,
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|
|
|
|
|
|
|
ClinVar: RCV000009970, RCV000009971, RCV000058716, RCV001588806, RCV004984637
|
|
|
|
|
|
</span>
|
|
</div>
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|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In an infant Japanese girl with a severe form of long QT syndrome (LQT3; 603830), Makita et al. (1998) identified a de novo missense mutation, arg1623 to gln (R1623Q), in the S4 segment of domain 4 of the SCN5A gene. When expressed in oocytes, mutant sodium channels exhibited only minor abnormalities in channel activation, but in contrast to 3 previously characterized LQT3 mutations, had significantly delayed macroscopic inactivation. Single channel analysis revealed that R1623Q channels had significantly prolonged open times with bursting behavior, suggesting a novel mechanism of pathophysiology in Na(+) channel-linked long QT syndrome. </p><p>Kambouris et al. (2000) reported that the R1623Q mutation imparts unusual lidocaine sensitivity to the sodium channel that is attributable to its altered functional behavior. Studies of lidocaine on individual R1623Q single-channel openings indicated that the open-time distribution was not changed, indicating the drug does not block the open pore as proposed previously. Rather, the mutant channels have a propensity to inactivate without ever opening ('closed-state inactivation'), and lidocaine augments this gating behavior. An allosteric gating model incorporating closed-state inactivation recapitulated the effects of lidocaine on the pathologic sodium current. These findings explained the unusual drug sensitivity of R1623Q and provided a general and unanticipated mechanism for understanding how sodium channel-blocking agents may suppress the pathologic, sustained sodium current induced by LQT3 mutations. </p><p>In a male infant diagnosed with ventricular arrhythmias and cardiac decompensation in utero at 28 weeks' gestation and with long QT syndrome at birth, Miller et al. (2004) identified heterozygosity for the R1623Q mutation. The mother had no ECG abnormalities, but a previous and a subsequent pregnancy both ended in stillbirth at 7 months. Initial studies detected no genetic abnormality, but a sensitive restriction enzyme-based assay revealed a small percentage (8 to 10%) of cells harboring the mutation in the mother's blood, skin, and buccal mucosa; R1623Q was also identified in cord blood from the third fetus. Miller et al. (2004) concluded that recurrent late-term fetal loss or sudden infant death can result from unsuspected parental mosaicism for LQT-associated mutations. </p><p>In a 1-month-old male infant who had syncope, torsade de pointes, cardiac arrest, and a QTc of 460 ms, Millat et al. (2006) identified biallelic digenic mutations: a 4868G-A transition in exon 28 of the SCN5A gene resulting in the R1623Q substitution; and a missense mutation in the KCNE2 gene (F60L; 603796.0005). </p>
|
|
</span>
|
|
</div>
|
|
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|
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|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
|
|
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|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 LONG QT SYNDROME 3</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
BRUGADA SYNDROME 1, INCLUDED<br />
|
|
SINUS NODE DISEASE, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
SCN5A, GLU1784LYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs137854601,
|
|
|
|
|
|
gnomAD: rs137854601,
|
|
|
|
|
|
ClinVar: RCV000009972, RCV000009973, RCV000009974, RCV000058773, RCV000183117, RCV000208193, RCV000245905, RCV000588022, RCV000824758, RCV003591625, RCV004545722, RCV004795388
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Wei et al. (1999) described a family in which the 13-year-old proband died suddenly at rest with no antecedent illness and no significant findings at postmortem. Her father had sinus bradycardia with occasional sinus pauses and ventricular ectopy together with profound prolongation of his QT interval (QTc = 527 ms) (see LQT3; 603830). He experienced only occasional light-headedness. Other family members experienced occasional syncope and had sinus bradycardia and prolonged QT intervals on their ECGs. In those individuals with prolonged QT intervals, SSCP analysis detected an aberrant conformer in the coding region of the SCN5A gene corresponding to the C terminus. Nucleotide sequencing revealed a G-to-A transition at codon 1784, resulting in a glu-to-lys substitution. This mutation occurs at a highly conserved residue in most voltage-gated sodium channels in most animals, including invertebrates. When the mutation was expressed in Xenopus oocytes, a defect in channel inactivation was demonstrated in the form of a small residual steady state current throughout prolonged depolarization. Wei et al. (1999) explored this further by engineering SCN5A constructs with amino acid substitutions at other positions in the C terminus. All exhibited similar electrophysiologic phenotypes, suggesting that heterozygous charge-neutralizing amino acid substitution at this site causes an allosteric effect on sodium channel gating, resulting in delayed myocardial repolarization. This provided a novel mechanism for LQT3. </p><p>Makita et al. (2008) genotyped 66 members of 44 LQT3 families of multiple ethnicities and identified the E1784K mutation in 41 individuals from 15 (34%) of the kindreds, including the family previously reported by Wei et al. (1999); the diagnoses in these individuals included LQT3 syndrome, Brugada syndrome (BRGDA1; 601144), and/or sinus node disease (see 608567). Heterologously expressed E1784K channels showed a 15.0-mV negative shift in the voltage dependence of Na channel inactivation and a 7.5-fold increase in flecainide affinity for resting-state channels, properties also seen with other LQT3 mutations associated with a mixed clinical phenotype. Furthermore, these properties were absent in Na channels harboring the T1304M mutation, which is associated with LQT3 without a mixed clinical phenotype. Makita et al. (2008) suggested that a negative shift of steady-state Na channel inactivation and enhanced tonic block by class IC drugs represent common biophysical mechanisms underlying the phenotypic overlap of LQT3 and Brugada syndromes, and further indicated that class IC drugs should be avoided in patients with Na channels displaying these behaviors. </p>
|
|
</span>
|
|
</div>
|
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<div>
|
|
<br />
|
|
</div>
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|
|
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</div>
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|
|
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<div>
|
|
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 PROGRESSIVE FAMILIAL HEART BLOCK, TYPE IA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
SCN5A, IVS22DS, T-C, +2
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs397514447,
|
|
|
|
|
|
|
|
ClinVar: RCV000009975, RCV003541536
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a large French family with progressive heart block (PFHB1A; 113900), Schott et al. (1999) identified a T-to-C transition in the highly conserved +2 donor splice site of intron 22 of the SCN5A gene. The abnormal transcript predicted in-frame skipping of exon 22 and an impaired gene product lacking the voltage-sensitive DIIIS4 segment. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
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<div>
|
|
<br />
|
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</div>
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|
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</div>
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|
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<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 HEART BLOCK, NONPROGRESSIVE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
SCN5A, 1-BP DEL, 5280G
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|
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|
|
|
<br />
|
|
|
|
SNP: rs397514448,
|
|
|
|
|
|
|
|
ClinVar: RCV000009976
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|
|
|
|
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</span>
|
|
</div>
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|
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|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Dutch family with asymptomatic first-degree atrioventricular block associated with right bundle branch block from birth, without apparent progression (see 113900), Schott et al. (1999) identified a 1-bp deletion (G) at nucleotide 5280 of the SCN5A gene, resulting in a frameshift predicted to cause a premature stop codon. </p>
|
|
</span>
|
|
</div>
|
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<div>
|
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<br />
|
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</div>
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|
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</div>
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<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 BRUGADA SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
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|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
SCN5A, ARG1512TRP
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs137854602,
|
|
|
|
|
|
gnomAD: rs137854602,
|
|
|
|
|
|
ClinVar: RCV000009977, RCV000058688, RCV000157490, RCV000222521, RCV001841232, RCV004018610
|
|
|
|
|
|
</span>
|
|
</div>
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|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In the screening of SCN5A in 6 individuals with Brugada syndrome (BRGDA1; 601144), Rook et al. (1999) found missense mutations in the coding region of the gene in 2: arg1512 to trp (R1512W) in the DIII-DIV cytoplasmic linker, and ala1924 to thr (A1924T; 600163.0012) in the C-terminal cytoplasmic domain. In 2 other patients mutations were detected near intron/exon junctions. To assess the functional consequences of the R1512W and A1924T mutations, wildtype and mutant sodium channel proteins were expressed in Xenopus oocytes. Both missense mutations affected channel function and seemed to be associated with an increase in inward sodium current during the action potential upstroke. </p>
|
|
</span>
|
|
</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0012 BRUGADA SYNDROME 1</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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SCN5A, ALA1924THR
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<br />
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SNP: rs137854603,
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gnomAD: rs137854603,
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ClinVar: RCV000009978, RCV000058806, RCV000420298, RCV001841233, RCV002251424, RCV004017231
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>For discussion of the ala1924-to-thr (A1924T) substitution in the SCN5A gene that was found in compound heterozygous state in 2 patients with Brugada syndrome (BRGDA1; 601144) by Rook et al. (1999), see 600163.0011. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0013 LONG QT SYNDROME 3</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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BRUGADA SYNDROME 1, INCLUDED
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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SCN5A, 3-BP INS, 5537TGA
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<br />
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SNP: rs397514449,
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ClinVar: RCV000009979, RCV000009980, RCV001530164
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a large Dutch family with electrocardiographic features both of long QT syndrome (LQT3; 603830) and Brugada syndrome (BRGDA1; 601144), Bezzina et al. (1999) demonstrated a 3-bp insertion at nucleotide position 5537 of the SCN5A gene, predicted to cause insertion of an aspartic acid residue at amino acid position 1795 (1795insD) in the C-terminal domain of the protein. Expression of this mutant channel protein in Xenopus oocytes permitted characterization of defects in channel activation and inactivation when compared to a wildtype control. These defects were predicted to cause a reduction in sodium flux during the upstroke of the cardiac action potential. </p><p>The co-occurrence of Brugada syndrome and long QT syndrome in this family was paradoxical, since LQT3 is associated with activating SCN5A mutations and Brugada syndrome with inactivating mutations. Clancy and Rudy (2002) modeled the cellular effects of the 1795insD mutation in a virtual transgenic cell. Since ion channel proteins are expressed nonuniformly throughout the myocardium, there is an intrinsic electrophysiologic heterogeneity. The authors demonstrated that the interplay between this underlying myocardial electrophysiologic heterogeneity and the mutation-induced changes in cardiac sodium channel function provided the substrate for both ST segment elevation (in Brugada syndrome) and QT prolongation (LQT3) in a rate-dependent manner. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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|
<strong>.0014 VENTRICULAR FIBRILLATION, PAROXYSMAL FAMILIAL, 1 (1 patient)</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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SCN5A, SER1710LEU
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<br />
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SNP: rs137854604,
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gnomAD: rs137854604,
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ClinVar: RCV000009981, RCV000058743, RCV000183102, RCV000197520, RCV000246596, RCV001841234, RCV002504774, RCV004017232, RCV004554591
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>Akai et al. (2000) screened 25 Japanese patients with idiopathic ventricular fibrillation (VF1; 603829). The diagnosis was based on the occurrence of at least one episode of syncope and/or cardiac arrest and documentation of ventricular fibrillation. Structural heart disorders were excluded. Eighteen patients were diagnosed as Brugada syndrome. The authors identified a heterozygous ser1710-to-leu missense mutation of the SCN5A gene in a 39-year-old man who was admitted to the hospital for recurrent syncope and suffered an episode of spontaneous ventricular fibrillation while hospitalized. An implanted cardiac defibrillator was successful in preventing further attacks of palpitation or syncope. Brugada syndrome was not present. The paternal grandfather and a paternal uncle had died suddenly in their sixth decade of unknown cause; the parents and sibs were asymptomatic. </p>
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</span>
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</div>
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<div>
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<br />
|
|
</div>
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</div>
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<div>
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|
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<div>
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|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0015 LONG QT SYNDROME 3</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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|
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SCN5A, SER941ASN
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<br />
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SNP: rs137854605,
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|
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ClinVar: RCV000009982, RCV003542271, RCV004018611
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|
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</span>
|
|
</div>
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<div>
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|
<span class="mim-text-font">
|
|
<p>Schwartz et al. (2000) described an infant who nearly died of SIDS (272120), whose parents had normal QT intervals and in whom the long QT syndrome (LQT3; 603830) was diagnosed with identification of a spontaneous mutation of the SCN5A gene: a change of codon 941 from TCC (serine) to AAC (asparagine). The patient had all the classic features of near-SIDS. Before the episode, the infant appeared to be in perfect health. His age at the time of the episode (7 weeks) was within the age range of 5 to 12 weeks during which the incidence of SIDS peaks. The parents found him cyanotic, apneic, and pulseless. Ventricular fibrillation was documented in an emergency room; this point is important given the frequent statements that ventricular arrhythmias have not been recorded in infants at risk for SIDS. Had the infant died--an outcome that was almost a certainty in the absence of cardioversion--the absence of an electrocardiogram and the normal QT intervals of both parents would have eliminated suspicion of the long QT syndrome and would have prompted a diagnosis of SIDS. </p>
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</span>
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</div>
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<div>
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<br />
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|
</div>
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|
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0016 CARDIAC CONDUCTION DEFECT, NONPROGRESSIVE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
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<div>
|
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<span class="mim-text-font">
|
|
|
|
SCN5A, GLY514CYS
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|
|
<br />
|
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|
|
SNP: rs137854606,
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|
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ClinVar: RCV000009984, RCV000058427
|
|
|
|
|
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</span>
|
|
</div>
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|
|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>Tan et al. (2001) studied a family who came to medical attention when the proband, a 3-year-old girl, experienced episodes of fainting during a febrile illness. Her 12-lead ECG showed characteristics of slow conduction throughout the atria and ventricles, including broad P waves, PR interval prolongation, and a wide QRS complex (see 113900). Continuous monitoring revealed episodes of severe bradycardia (25 beats/minute). During these slow periods the cardiac rhythm was maintained by infrequent atrioventricular nodal 'escape' impulses. Conduction disturbance persisted after the febrile illness, but there was no evidence of structural heart disease or systemic diseases associated with conduction defects in children. Therapeutic intervention with a dual-chamber pacemaker was initially limited by inability to pace the atrium (maximal stimulus: 10 V, 1 ms); however, this difficulty resolved with 1 week of empiric steroid treatment. During the 4 years following diagnosis, the patient continuously required dual-chamber pacing. The proband's 6-year-old sister was similarly affected and required pacemaker implantation, with episodes of noncapture that reproducibly resolved with corticosteroid therapy. Three other family members with no structural heart disease had ECG evidence of conduction slowing (prolonged PR and QRS intervals), but did not experience bradycardia or require pacemaker implantation. All affected family members had a G-to-T transition in the first nucleotide of codon 514 in exon 12 of the SCN5A gene resulting in the replacement of glycine by cysteine (G514C). Biophysical characterization of the mutant channel showed that there were abnormalities in voltage-dependent gating behavior that could be partially corrected by dexamethasone, consistent with the salutary effects of glucocorticoids on the clinical phenotype. Computational analysis predicts that the gating defects of G514C selectively slow myocardial conduction, but do not provoke the rapid cardiac arrhythmias associated previously with SCN5A mutations. </p>
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|
</span>
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|
</div>
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<div>
|
|
<br />
|
|
</div>
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|
|
|
</div>
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|
|
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|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0017 PROGRESSIVE FAMILIAL HEART BLOCK, TYPE IA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
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|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SCN5A, ASP1595ASN
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|
|
|
|
|
<br />
|
|
|
|
SNP: rs137854607,
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|
|
|
|
|
|
|
ClinVar: RCV000009983, RCV000058705, RCV000183084, RCV001329632, RCV004528098
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Wang et al. (2002) reported a family in which the proband had presented with first-degree atrioventricular block at the age of 9, progressing to complete AV block by the age of 20 (PFHB1A; 113900). The proband's sister and father had electrocardiographic evidence of right bundle branch block and left axis deviation with normal PR intervals. The corrected QT interval was normal (less than 420 ms) in all 3 individuals. Sequencing of the coding region of SCN5A revealed a G-to-A mutation at nucleotide position 4783, which replaced an aspartic acid residue at amino acid position 1595 with asparagine (D1595N). The G4783A mutation was engineered into a recombinant human heart sodium channel and transiently coexpressed with human sodium channel beta-1 subunit (600760) in a cultured mammalian cell line (tsA201). Functional characterization using a patch-clamp technique revealed a significant defect in the kinetics of fast-channel inactivation distinct from those of SCN5A mutations reported in LQT3 (603830). The authors considered this a plausible mechanism for the observed conduction system disease in this family. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
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|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0018 PROGRESSIVE FAMILIAL HEART BLOCK, TYPE IA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SCN5A, GLN298SER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs137854608,
|
|
|
|
|
|
gnomAD: rs137854608,
|
|
|
|
|
|
ClinVar: RCV000009985, RCV000058858, RCV000151803, RCV000415287, RCV001149035, RCV001149036, RCV001149037, RCV001149038, RCV001149039, RCV001841235, RCV002482852, RCV003137510, RCV004018612
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Wang et al. (2002) reported a child in whom second-degree atrioventricular block had been diagnosed at the age of 6, progressing to complete atrioventricular block by the age of 12 (PFHB1A; 113900). The child's mother had a normal electrocardiogram and the father declined testing. There was no family history of sudden death. Sequencing of the coding region of SCN5A revealed a G-to-A mutation at nucleotide position 892 that replaced a glycine residue at amino acid position 298 with serine (G298S). The G892A mutation was engineered into a recombinant human heart sodium channel and transiently coexpressed with human sodium channel beta-1 subunit (600760) in a cultured mammalian cell line (tsA201). Functional characterization using a patch-clamp technique revealed a significant defect in the kinetics of fast-channel inactivation distinct from those of SCN5A mutations reported in LQT3 (603830). The authors considered this a plausible mechanism for the observed conduction system disease in this family. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0019 LONG QT SYNDROME 3</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SCN5A, ALA997SER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs137854609,
|
|
|
|
|
|
gnomAD: rs137854609,
|
|
|
|
|
|
ClinVar: RCV000009986, RCV000058542, RCV000183020, RCV002504775, RCV003591626, RCV004532320, RCV005051733
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 6-week-old male infant who died of SIDS (272120), Ackerman et al. (2001) identified a heterozygous G-to-T transversion in the SCN5A gene, resulting in an ala997-to-ser substitution. The mutation was not detected in 800 control alleles. Ackerman et al. (2001) determined that amino acid 997 is located in the cytoplasmic connector between the second and third domains of the sodium channel and is highly conserved across species. They demonstrated that the mutant SCN5A channel expressed a sodium current characterized by slower decay and a 2- to 3-fold increase in late sodium current. </p>
|
|
</span>
|
|
</div>
|
|
|
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<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0020 LONG QT SYNDROME 3</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SCN5A, ARG1826HIS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs137854610,
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|
|
|
gnomAD: rs137854610,
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|
|
|
|
|
ClinVar: RCV000009987, RCV000058786, RCV000148848, RCV000154827, RCV000619902, RCV000766811, RCV001841236, RCV002476953
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 42-day-old male infant who died of possible SIDS (272120), Ackerman et al. (2001) identified a heterozygous G-to-A replacement in the SCN5A gene, resulting in an arg1826-to-his substitution. The mutation was not detected in 800 control alleles. Ackerman et al. (2001) determined that amino acid 1826 is located in the cytoplasmic C-terminal region of the sodium channel and is highly conserved. They demonstrated that the SCN5A mutant channel expressed a sodium current characterized by slower decay and a 2- to 3-fold increase in late sodium current. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
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<div>
|
|
<br />
|
|
</div>
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|
|
|
</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0021 BRUGADA SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SCN5A, ARG367HIS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs28937318,
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|
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|
|
|
ClinVar: RCV000009988, RCV000058390, RCV001841237, RCV002426498, RCV003654174, RCV004734509
|
|
|
|
|
|
</span>
|
|
</div>
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|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Sudden unexplained nocturnal death syndrome (SUNDS), a disorder found in southeast Asia, is characterized by an abnormal electrocardiogram with ST segment elevation in leads V1 to V3 and sudden death due to ventricular fibrillation, identical to that seen in Brugada syndrome (BRGDA1; 601144). Vatta et al. (2002) found mutations in the SCN5A gene in 3 of 10 Asian SUNDS patients. In a sporadic Asian SUNDS patient, the authors identified a 1100G-A transition in SCN5A. The mutation is predicted to result in an arg367-to-his (R367H) substitution, which lies in the first P segment of the pore-lining region between the DIS5 and DIS6 transmembrane segments. In transfected Xenopus oocytes, the R367H mutant channel did not express any current. The authors hypothesized that the likely effect of this mutation is to depress peak current due to the loss of one functional allele. </p>
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|
</span>
|
|
</div>
|
|
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|
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<div>
|
|
<br />
|
|
</div>
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|
|
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</div>
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<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0022 BRUGADA SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
SCN5A, ALA735VAL
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|
|
|
|
<br />
|
|
|
|
SNP: rs137854611,
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|
|
|
|
|
gnomAD: rs137854611,
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|
|
|
|
|
ClinVar: RCV000009989, RCV000058488, RCV003591627, RCV003654175, RCV003996084
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a family with SUNDS, a disorder identical to Brugada syndrome (BRGDA1; 601144), that exhibited autosomal dominant inheritance, Vatta et al. (2002) identified among affected members a 2204C-T transition, which is predicted to result in an ala735-to-val (A735V) substitution. The mutation lies in the first transmembrane segment of domain II, (DIIS1), close to the first extracellular loop between DIIS1 and DIIS2. In transfected Xenopus oocytes, the A735V mutant expressed currents with steady-state activation voltage shifted to more positive potentials and exhibited reduced sodium channel current at the end of phase I of the action potential. </p>
|
|
</span>
|
|
</div>
|
|
|
|
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<div>
|
|
<br />
|
|
</div>
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|
|
|
</div>
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<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0023 BRUGADA SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
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<span class="mim-text-font">
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LONG QT SYNDROME 3, ACQUIRED, SUSCEPTIBILITY TO, INCLUDED
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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SCN5A, ARG1193GLN
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<br />
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SNP: rs41261344,
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gnomAD: rs41261344,
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ClinVar: RCV000009990, RCV000009991, RCV000058578, RCV000154828, RCV000157488, RCV000171819, RCV000252422, RCV000755697, RCV001147624, RCV001147625, RCV001147626, RCV001147627, RCV001841238, RCV002476954, RCV003149566
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a pair of Japanese dizygotic twins, one of whom died at 4 months of SUNDS, a disorder identical to Brugada syndrome (BRGDA1; 601144), Vatta et al. (2002) identified a 3575G-A transition in exon 20 of the SCN5A gene, predicted to result in an arg1192-to-gln (R1192Q) substitution in Domain III. In transfected Xenopus oocytes, the mutation accelerated the inactivation of the sodium channel current and exhibited reduced sodium channel current at the end of phase I of the action potential. Wang (2005) stated that this variant was mislabeled in the Vatta et al. (2002) report and should be designated R1993Q. </p><p>In an 82-year-old Caucasian male who developed long QT syndrome after the administration of D-sotolol or quinidine (see LQT3, 603830), Wang et al. (2004) identified heterozygosity for the R1993Q mutation in the SCN5A gene. The mutation was found in 4 of 2,087 predominantly Caucasian controls (0.2%). Electrophysiologic studies showed that mutant R1193Q channels destabilize inactivation gating and generate a persistent, nonactivating current that is expected to prolong the cardiac action potential duration, leading to LQT syndrome; single channel recording revealed the molecular mechanism to be frequent, dispersed reopening of the channels. The patient also carried the H558R SCN5A variant (600163.0031), but due to a lack of family members, it could not be determined whether H558R was in cis or trans with R1993Q. </p><p>Hwang et al. (2005) found the R1993Q mutation in 11 of 94 (12%) randomly selected Han Chinese individuals and concluded that the variant is a common polymorphism in this population. None of the carriers had electrocardiographic signs of Brugada syndrome, although 1 had a prolonged QTc interval (472 ms) and another, who was homozygous for the mutation, had a borderline long QTc (437 ms). </p><p>In an asymptomatic 73-year-old male member of a 4-generation Han Chinese family with autosomal dominant cardiac arrhythmias and sudden death, Niu et al. (2006) identified compound heterozygosity for R1193Q and a nonsense mutation in the SCN5A gene (W1421X; 600163.0036). Niu et al. (2006) suggested that the R1193Q mutation, which results in a gain of sodium channel function, may compensate for the deleterious effects of W1421X. Haplotype analysis of an asymptomatic daughter-in-law and 2 asymptomatic grandchildren who also carried the R1193Q mutation revealed that the children inherited the mutation from their mother rather than their grandfather. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0024 LONG QT SYNDROME 3, ACQUIRED, SUSCEPTIBILITY TO</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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SUDDEN INFANT DEATH SYNDROME, INCLUDED
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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SCN5A, SER1103TYR
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<br />
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SNP: rs7626962,
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gnomAD: rs7626962,
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ClinVar: RCV000009992, RCV000009993, RCV000041615, RCV000058563, RCV000204216, RCV000274325, RCV000304064, RCV000363449, RCV000368908, RCV000396768, RCV000621429, RCV000755696, RCV001094834, RCV001841239, RCV002504776, RCV003125829, RCV003149567
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>Splawski et al. (2002) screened DNA samples from individuals with nonfamilial cardiac arrhythmias and identified a C-to-A transversion in the SCN5A gene leading to a ser1103-to-tyr (S1103Y) substitution 1 patient. Ackerman et al. (2004) noted that the variant was originally published as SER1102TYR from numbering based on the 2,015 amino acid alternatively spliced transcript. Subsequently, numbering was revised to account for the full-length 2,016 amino acid transcript. Serine-1103 is a conserved residue located in the intracellular sequences that link domains II and III of the channel. The proband had idiopathic dilated cardiomyopathy and hypokalemia and developed prolonged QT and torsade de pointes ventricular tachycardia while on amiodarone. Splawski et al. (2002) determined that the Y1103 allele is present in 19.2% of West Africans and Caribbeans and in 13.2% of African Americans. The Y1103 allele was not found in 511 Caucasians or 578 Asians. Splawski et al. (2002) studied 22 African Americans with acquired arrhythmia and 100 population-matched controls. The Y1103 allele was overrepresented among arrhythmia patients, being found in 56.5% of cases and among 13% of controls. The likelihood of displaying signs of arrhythmia in a Y1103 carrier heterozygote or homozygote yielded an odds ratio of 8.7 (95% CI 3.2 to 23.9). The odds ratio was not significantly altered after controlling for age or gender. To determine whether this mutation is an inherited risk factor for arrhythmias, Splawski et al. (2002) examined the extended family of 1 proband. They ascertained and phenotypically characterized 23 members of this kindred. Phenotypic analysis revealed that 11 members of the family had prolonged QT and/or a history of syncope. All 11 phenotypically affected members of this family carried the Y1103 allele (6 were homozygotes and 5 were heterozygotes). Physiologic analysis of the effect of this mutation recorded a small but significant negative shift in the voltage dependence of activation. Splawski et al. (2002) concluded that the Y1103 allele is a common SCN5A variant in Africans and African Americans and causes a small but inherent chronic risk of acquired arrhythmia. In the setting of additional acquired risk factors, including medications, hypokalemia, or structural heart disease, individuals carrying this allele are at increased risk of arrhythmia. </p><p>In 3 white sisters and their father, Chen et al. (2002) identified the S1103Y mutation, thus demonstrating that this mutation does exist in the white population. The mutation was associated with a considerable risk of syncope, ventricular arrhythmia, ventricular fibrillation, and sudden death, Each of the 3 sibs was genotyped for 31 'ancestry informative markers' to provide an estimation of biogeographic ancestry on 3 axes: Native American, West African, and European. The maximum likelihood point estimates for each of the sibs were 100% European, 0.0% African, and 0.0% Native American. The proband had a baseline QTc of 520 ms, and developed 2 episodes of syncope at age 49 years. The first episode was triggered by emotion and excitement. The second episode occurred in the setting of amiodarone and low serum potassium, and progressed to ventricular fibrillation and cardiac arrest. She was resuscitated by cardioversion. The second sister had a QTc of 431 ms, and died suddenly at age 44 years when awakening from sleep. The third sister had a QTc of 452 ms, developed 1 episode of syncope at the age of 33 years, and had complained of palpitations all her life. The father died suddenly in his sleep at age 50 years. Family members without S1103Y had a normal QTc. </p><p>Plant et al. (2006) screened DNA samples from 133 African American autopsy-confirmed cases of sudden infant death syndrome (SIDS; 272120) and identified 3 that were homozygous for the S1103Y variant. Among 1,056 African American controls, 120 were carriers of the heterozygous genotype, suggesting that infants with 2 copies of S1103Y have a 24-fold increased risk for SIDS. Variant Y1103 channels were found to operate normally under baseline conditions in vitro. Because risk factors for SIDS include apnea and respiratory acidosis, Y1103 and wildtype channels were subjected to lowered intracellular pH; only Y1103 channels developed abnormal function, with late reopenings suppressible by the drug mexiletine. Plant et al. (2006) suggested that the Y1103 variant confers susceptibility to acidosis-induced arrhythmia, a gene-environment interaction. </p><p>Darbar et al. (2008) stated that the S1103Y variant was a known common nonsynonymous polymorphism in the SCN5A gene; they detected S1103Y in 1 patient with lone atrial fibrillation and in 5 patients with atrial fibrillation associated with other heart disease, as well as in 15 of 720 control chromosomes, for a minor allele frequency of 0.7%. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0025 SICK SINUS SYNDROME 1</strong>
|
|
</span>
|
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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SCN5A, PRO1298LEU
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<br />
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SNP: rs28937319,
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ClinVar: RCV000009994, RCV000058612, RCV001841240, RCV004819205
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
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<p>In 3 sibs with congenital sick sinus syndrome (SSS1; 608567), Benson et al. (2003) identified compound heterozygosity for 2 mutations in the SCN5A gene. The maternal allele carried a 3893C-T transition, resulting in a pro1298-to-leu (P1298L) change; the paternal allele carried a gly1408-to-arg substitution (600163.0026). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>.0026 SICK SINUS SYNDROME 1</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
|
|
BRUGADA SYNDROME 1, INCLUDED<br />
|
|
CARDIAC CONDUCTION DEFECT, NONSPECIFIC, INCLUDED
|
|
</span>
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</div>
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<div>
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<span class="mim-text-font">
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SCN5A, GLY1408ARG
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<br />
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SNP: rs137854612,
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ClinVar: RCV000009995, RCV000009996, RCV000009997, RCV000058649, RCV000183190, RCV002326672, RCV002496318, RCV003996085
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In 3 sibs with congenital sick sinus syndrome (SSS1; 608567) with compound heterozygosity for mutation in the SCN5A gene, Benson et al. (2003) found on the paternal allele a 4222G-A transition, resulting in a gly1408-to-arg substitution (G1408R). The maternal allele carried a pro1298-to-leu substitution (600163.0025). </p><p>Kyndt et al. (2001) reported the G1408R mutation, which they designated GLY1406ARG, in heterozygous state in a large French family segregating both isolated cardiac conduction defect (see 601144) and Brugada syndrome (BRGDA1; 601144). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0027 SICK SINUS SYNDROME 1</strong>
|
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</span>
|
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</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
|
|
CARDIOMYOPATHY, DILATED, 1E, INCLUDED
|
|
</span>
|
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</div>
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<div>
|
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<span class="mim-text-font">
|
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|
|
SCN5A, THR220ILE
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|
<br />
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|
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SNP: rs45620037,
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|
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gnomAD: rs45620037,
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ClinVar: RCV000009998, RCV000058832, RCV000148857, RCV000151804, RCV000251727, RCV000258831, RCV000586618, RCV000622951, RCV000678935, RCV001841241, RCV004528099
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</span>
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a child with congenital sick sinus syndrome (SSS1; 608567), Benson et al. (2003) identified compound heterozygosity for 2 mutations in the SCN5A gene: the paternal allele carried a 659C-T transition, resulting in a thr220-to-ile (T220I) mutation, and the maternal allele carried a 4867C-T transition, resulting in an arg1623-to-ter mutation (R1623X; 600163.0028). The authors noted that an R1623Q mutation (600163.0007) resulting in congenital long QT syndrome-3 (603830) had previously been described. </p><p>In a 54-year-old man with dilated cardiomyopathy (CMD1E; 601154), atrial fibrillation, and heart block, Olson et al. (2005) identified heterozygosity for a 659C-T transition in exon 6 of the SCN5A gene, resulting in a thr220-to-ile (T220I) substitution at a highly conserved residue in the transmembrane domain. Coronary artery disease was excluded by angiography; cardiac biopsy showed moderate myocyte hypertrophy and marked interstitial fibrosis. He died 13 years later in severe congestive heart failure. A female first cousin once removed who also carried the mutation was diagnosed at 55 years of age with dilated cardiomyopathy (ejection fraction, 10%) and incomplete bundle branch block; she died 2 years later, also in severe congestive heart failure. Other relatives were reported to have enlarged hearts, but were unavailable for evaluation. </p>
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</span>
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</div>
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<div>
|
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<br />
|
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</div>
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</div>
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<div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0028 SICK SINUS SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
|
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|
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SCN5A, ARG1623TER
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<br />
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SNP: rs137854613,
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gnomAD: rs137854613,
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ClinVar: RCV000009968, RCV000183087, RCV000465149, RCV000477950, RCV000622049, RCV001841231, RCV002496317, RCV003996083, RCV004528097
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>For discussion of the arg1623-to-ter (R1623X) mutation that was found in compound heterozygous state in a child with congenital sick sinus syndrome (SSS1; 608567) by Benson et al. (2003), see 600163.0027. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0029 LONG QT SYNDROME 3</strong>
|
|
</span>
|
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</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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SCN5A, TYR1795CYS
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<br />
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SNP: rs137854614,
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ClinVar: RCV000009969, RCV000058778, RCV001561910, RCV002345237
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a patient with long QT syndrome-3 (LQT3; 603830), Rivolta et al. (2001) identified a tyr1795-to-cys (Y1795C) mutation in the SCN5A gene. The mutation slowed the onset of activation, but did not cause a marked negative shift in the voltage dependence of inactivation or affect the kinetics of the recovery from inactivation. The mutation increased the expression of sustained Na(+) channel activity compared with wildtype channels and promoted entrance into an intermediate or slowly developing inactivated state. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0030 BRUGADA SYNDROME 1</strong>
|
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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SCN5A, TYR1795HIS
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<br />
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|
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SNP: rs137854615,
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ClinVar: RCV000009999, RCV000058777
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</span>
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</div>
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<div>
|
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<span class="mim-text-font">
|
|
<p>In a patient with Brugada syndrome (BRGDA1; 601144), Rivolta et al. (2001) identified a tyr1795-to-his (Y1795H) mutation in the SCN5A gene. The mutation accelerated the onset of activation and caused a marked negative shift in the voltage dependence of inactivation. It did not affect the kinetics of the recovery from inactivation. The mutation increased the expression of sustained Na(+) channel activity compared with wildtype channels and promoted entrance into an intermediate or slowly developing inactivated state. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0031 PROGRESSIVE FAMILIAL HEART BLOCK, TYPE IA</strong>
|
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</span>
|
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</h4>
|
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</div>
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<div>
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<span class="mim-text-font">
|
|
|
|
SCN5A, THR512ILE AND HIS558ARG
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<br />
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SNP: rs1805124, rs199473118,
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gnomAD: rs1805124, rs199473118,
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ClinVar: RCV000010000, RCV000041604, RCV000058426, RCV000058440, RCV000144029, RCV000251327, RCV000300603, RCV000304709, RCV000339196, RCV000361696, RCV000405409, RCV000406777, RCV000588264, RCV000987225, RCV001841593, RCV002496658, RCV002498340, RCV003125879, RCV003996525
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</span>
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</div>
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<div>
|
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<span class="mim-text-font">
|
|
<p>In a 2-year-old boy with second-degree atrioventricular conduction block (PFHB1A; 113900) necessitating a pacemaker, Viswanathan et al. (2003) identified a heterozygous 1535C-T transition in the SCN5A gene, resulting in a thr512-to-ile (T512I) substitution. In addition, there was a homozygous 1673A-G transition, resulting in a his558-to-arg (H558R) substitution. H558R (rs1805124) is a polymorphism present in 20% of the population (Yang et al., 2002). One of the patient's alleles contained both T512I and H558R. The patient's father was heterozygous for the H558R substitution, the asymptomatic mother was compound heterozygous for the T512I and H558R substitutions, and 2 sibs were heterozygous for the H558R substitution. Functional expression studies showed that activation and inactivation of wildtype and H558R channels were similar. By contrast, voltage-dependent activation and inactivation of the T512I channel was shifted negatively by 8 to 9 mV and had enhanced slow activation and slower recovery from inactivation compared to the wildtype channel. Studies of the double H558R/T512I channel showed that H558R eliminated the negative shift induced by T512I, but only partially restored the kinetic abnormalities. Viswanathan et al. (2003) suggested that enhanced slow inactivation disproportionately affected Purkinje cells, which have a longer action potential duration and smaller diastolic interval, resulting in slowed atrioventricular conduction. </p><p>Darbar et al. (2008) stated that the H558R variant was a known common nonsynonymous polymorphism in the SCN5A gene; they detected H558R in 59 patients with lone atrial fibrillation and in 130 patients with atrial fibrillation associated with other heart disease, as well as in 128 of 720 control chromosomes, for a minor allele frequency of approximately 25%. </p>
|
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</span>
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</div>
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<div>
|
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<br />
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</div>
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</div>
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<div>
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0032 BRUGADA SYNDROME 1</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<div>
|
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<span class="mim-text-font">
|
|
|
|
SCN5A, GLY1262SER
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<br />
|
|
|
|
SNP: rs137854616,
|
|
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|
|
|
gnomAD: rs137854616,
|
|
|
|
|
|
ClinVar: RCV000010001, RCV000058602, RCV000755698, RCV001146725, RCV001146726, RCV001146727, RCV001753410, RCV003996086, RCV004018613, RCV004528100
|
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|
|
</span>
|
|
</div>
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|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>Shin et al. (2004) studied a family with 9 members as well as 12 unrelated sporadic cases, all Koreans, diagnosed with Brugada syndrome (BRGDA1; 601144). They identified a novel missense mutation associated with Brugada syndrome in the family: a single-nucleotide substitution of G to A at nucleotide position 3934 in exon 21 of the SCN5A gene that changed glycine-1262 to serine (G1262S) in segment 2 of domain III of the SCN5A protein. Four individuals in the family carried the identical mutation, but none of the 12 sporadic patients did. The mutation was not found in 150 unrelated normal individuals. </p>
|
|
</span>
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</div>
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<div>
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|
<br />
|
|
</div>
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|
</div>
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|
|
<div>
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|
<div>
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|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0033 BRUGADA SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
|
|
ATRIAL FIBRILLATION, FAMILIAL, 10, INCLUDED
|
|
</span>
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</div>
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|
<div>
|
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<span class="mim-text-font">
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SCN5A, GLU1053LYS
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|
<br />
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|
|
SNP: rs137854617,
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gnomAD: rs137854617,
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|
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ClinVar: RCV000010002, RCV000022945, RCV000058552, RCV000755695, RCV001528558, RCV001841242, RCV002321478, RCV004526592
|
|
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|
</span>
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with Brugada syndrome (BRGDA1; 601144), Mohler et al. (2004) identified a 3157G-A transition in the SCN5A gene resulting in a glu1053-to-lys (E1053K) mutation in the ankyrin-binding motif of the cardiac sodium channel. The mutation abolished binding of Na(v)1.5 to ankyrin-G (600465) and also prevented accumulation of Na(v)1.5 at cell surface sites in ventricular cardiomyocytes. </p><p>In a patient with lone atrial fibrillation (ATFB10; 614022), Darbar et al. (2008) identified heterozygosity for the E1053K mutation in the SCN5A gene. The mutation was not found in 720 control alleles. </p>
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</span>
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</div>
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<div>
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<br />
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|
</div>
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|
</div>
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|
<div>
|
|
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|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0034 CARDIOMYOPATHY, DILATED, 1E</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
ATRIAL STANDSTILL 1, DIGENIC, INCLUDED<br />
|
|
ATRIAL FIBRILLATION, FAMILIAL, 10, INCLUDED
|
|
</span>
|
|
</div>
|
|
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|
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|
<div>
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|
<span class="mim-text-font">
|
|
|
|
SCN5A, ASP1275ASN
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|
<br />
|
|
|
|
SNP: rs137854618,
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|
|
gnomAD: rs137854618,
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|
|
|
ClinVar: RCV000010003, RCV000022946, RCV000058604, RCV000114992, RCV000183045, RCV000617238, RCV000656563, RCV002222347, RCV004532321
|
|
|
|
|
|
</span>
|
|
</div>
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|
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|
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|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a large family reported by Greenlee et al. (1986) with dilated cardiomyopathy with conduction disorder and arrhythmia (CMD1E; 601154), McNair et al. (2004) identified heterozygosity for a 3823G-A mutation in exon 21 of the SCN5A gene, resulting in an asp1275-to-asn (D1275N) substitution and predicting a change of charge within the S2 segment of domain III. The mutation was present in 22 affected family members and was not found in 300 control chromosomes. </p><p>Groenewegen et al. (2003) reported the D1275N mutation, coinherited with polymorphisms in the atrial-specific gap junction channel protein connexin-40 (GJA5; 121013), in affected members of a family with atrial standstill (ATRST1; 108770). No member of this family had dilated cardiomyopathy, leading Groenewegen and Wilde (2005) to question whether the D1275N mutation was the primary cause of dilated cardiomyopathy as reported by McNair et al. (2004). </p><p>In affected members of a large Finnish family with atrial fibrillation and conduction defects (ATFB10; 614022), Laitinen-Forsblom et al. (2006) identified heterozygosity for the D1275N mutation in the SCN5A gene. The mutation was not found in more than 370 control chromosomes. Echocardiography revealed an enlarged left ventricle with an increased end-diastolic left ventricular diameter in 1 affected individual, and the right ventricle was slightly enlarged in 3 other affected individuals. </p>
|
|
</span>
|
|
</div>
|
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<div>
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|
<br />
|
|
</div>
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|
</div>
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|
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|
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<div>
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|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0035 LONG QT SYNDROME 2/3, DIGENIC</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
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|
|
|
SCN5A, ASP1819ASN
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|
<br />
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|
|
SNP: rs137854619,
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|
|
|
|
|
gnomAD: rs137854619,
|
|
|
|
|
|
ClinVar: RCV000010005, RCV000058782, RCV000171695, RCV000183199, RCV000987198, RCV001507624, RCV001841243, RCV002345238, RCV004772829
|
|
|
|
|
|
</span>
|
|
</div>
|
|
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|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 41-year-old female who had cardiac arrest due to torsade de pointes triggered by exercise and leading to ventricular fibrillation, and a QTc of 520 ms (see 603830), Millat et al. (2006) identified biallelic digenic mutations: a 5455G-A transition in exon 28 of the SCN5A gene, resulting in an asp1819-to-asn (D1819N) substitution; and a missense mutation in the KCNH2 gene (R100G; 152427.0023). </p>
|
|
</span>
|
|
</div>
|
|
|
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|
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|
<div>
|
|
<br />
|
|
</div>
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|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0036 BRUGADA SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SCN5A, TRP1421TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs137854620,
|
|
|
|
|
|
|
|
ClinVar: RCV000010006
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a 4-generation Han Chinese family with autosomal dominant cardiac arrhythmias and sudden death (BRGDA1; 601144), Niu et al. (2006) identified heterozygosity for a G-A transition in exon 24 of the SCN5A gene, resulting in a trp1421-to-ter (W1421X) substitution. The mutation was not found in 95 control subjects. An asymptomatic 73-year-old male family member was found to be compound heterozygous for W1421X and the R1993Q mutation (600163.0023). Niu et al. (2006) suggested that R1193Q, which results in a gain of sodium channel function, may compensate for the deleterious effects of W1421X. </p>
|
|
</span>
|
|
</div>
|
|
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|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-text-font">
|
|
<strong>.0037 MOVED TO 600163.0027</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0038 CARDIOMYOPATHY, DILATED, 1E</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
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|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SCN5A, 2-BP INS, NT2550
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs397514450,
|
|
|
|
|
|
|
|
ClinVar: RCV000010008, RCV000183154, RCV001842933, RCV002433811, RCV002500544, RCV003996817
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a man with dilated cardiomyopathy (CMD1E; 601154) and monomorphic ventricular tachycardia who later developed third-degree heart block requiring pacemaker implantation, Olson et al. (2005) identified heterozygosity for a 2-bp insertion (2550insTG) in exon 17 of the SCN5A gene, resulting in a premature stop codon and a truncated protein. Cardiac biopsy was normal. His father, who carried the mutation, was diagnosed with CMD (ejection fraction, 30%), left bundle branch block, and monomorphic ventricular tachycardia at age 67 years. The mutation was also present in a paternal uncle who had sinus bradycardia, first-degree heart block, and complete left bundle branch block; his paternal grandfather developed congestive heart failure at 50 years of age and died 6 years later, but DNA was unavailable for evaluation. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0039 CARDIOMYOPATHY, DILATED, 1E</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SCN5A, ASP1595HIS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs137854607,
|
|
|
|
|
|
|
|
ClinVar: RCV000010009, RCV000058706, RCV001258074, RCV003156212, RCV005031434
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 7-year-old boy with early manifestations of dilated cardiomyopathy (CMD1E; 601154) including sinus bradycardia, left ventricular dilation, and normal contractile function, Olson et al. (2005) identified heterozygosity for a 4783G-C transversion in exon 27 of the SCN5A gene, resulting in an asp1595-to-his (D1595H) substitution at a highly conserved residue in the transmembrane domain. The mutation was found in DNA from postmortem tissue of a brother who died at 34 years of age with an autopsy diagnosis of cardiomyopathy and only mild coronary artery disease. The mutation was also identified in 2 sibs and a paternal uncle, all of whom had sinus bradycardia, and a paternal aunt with borderline left atrial enlargement. His father, an obligate mutation carrier, had atrial fibrillation and died at 49 years of age from pulmonary embolism; his paternal grandfather, a presumed mutation carrier, developed congestive heart failure at 70 years of age. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0040 BRUGADA SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SCN5A, VAL232ILE and LEU1308PHE
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs41313031, rs45471994,
|
|
|
|
|
|
gnomAD: rs41313031, rs45471994,
|
|
|
|
|
|
ClinVar: RCV000010010, RCV000058614, RCV000058840, RCV000148841, RCV000148856, RCV000176338, RCV000243761, RCV000246365, RCV000724673, RCV000987205, RCV000987235, RCV001842355, RCV001842410
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 45-year-old black man with no history of cardiac disease who developed monomorphic wide-complex ventricular tachycardia with right precordial ST segment elevation consistent with Brugada syndrome (BRGDA1; 601144) after the administration of lidocaine, Barajas-Martinez et al. (2008) identified 2 mutations in the SCN5A gene, a G-to-A transition in exon 6 of the SCN5A gene, resulting in a val232-to-ile (V232I) substitution in the C terminus of the transmembrane segment S4 of domain I, and a C-to-T transition in exon 22, resulting in a leu1308-to-phe (L1308F) substitution, in the C terminus of transmembrane segment S4 of domain III. Although L1308F had previously been identified as a polymorphism found mostly in Americans of African descent (Ackerman et al., 2004), Barajas-Martinez et al. (2008) did not find either mutation in over 400 alleles from 200 ethnically matched controls. The patient's parents were unavailable for study, but given the severity of his clinical manifestations, the authors strongly suspected that both mutations were on the same allele (Dumaine, 2009). Using patch-clamp techniques in mammalian TSA201 cells, Barajas-Martinez et al. (2008) observed use-dependent inhibition of I(Na) by lidocaine that was more pronounced in double-mutant channels than in wildtype; the individual mutations produced a much less accentuated effect. The authors concluded that the double mutation in SCN5A alters the affinity of the cardiac sodium channel for lidocaine such that the drug assumes class IC characteristics with potent use-dependent block of the sodium channel. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0041 ATRIAL FIBRILLATION, FAMILIAL, 10</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SCN5A, ASN1986LYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs199473335,
|
|
|
|
|
|
gnomAD: rs199473335,
|
|
|
|
|
|
ClinVar: RCV000022947, RCV000148858, RCV000154830, RCV000756620, RCV001841252, RCV004018664
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a father and son with atrial fibrillation (ATFB10; 614022), Ellinor et al. (2008) identified heterozygosity for a 5958C-A transversion in the SCN5A gene, resulting in an asn1986-to-lys (N1986K) substitution in the C-terminal region of the protein. The mutation was not found in more than 600 ethnically and racially matched control chromosomes. Expression of the N1986K mutant in Xenopus oocytes revealed a hyperpolarizing shift in channel steady-state inactivation. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0042 ATRIAL FIBRILLATION, FAMILIAL, 10</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SCN5A, HIS445ASP
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs199473112,
|
|
|
|
|
|
gnomAD: rs199473112,
|
|
|
|
|
|
ClinVar: RCV000022948, RCV000058414, RCV000418451, RCV000991041, RCV001841253, RCV002381260, RCV002504819
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In white male proband who was diagnosed with paroxysmal lone atrial fibrillation (ATFB10; 614022) at 39 years of age, Darbar et al. (2008) identified heterozygosity for a G-to-C transversion in the SCN5A gene, resulting in a his445-to-asp (H445D) substitution at a highly conserved residue that was predicted to perturb cardiac sodium channel function. The proband had left atrial enlargement and an ejection fraction of 60% by transthoracic echocardiography. The mutation was also detected in his affected father and brother, but was not found in an unaffected sister or in 720 control alleles. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0043 ATRIAL FIBRILLATION, FAMILIAL, 10</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SCN5A, ASN470LYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs199473115,
|
|
|
|
|
|
gnomAD: rs199473115,
|
|
|
|
|
|
ClinVar: RCV000022949, RCV000058421, RCV002482899, RCV003541160, RCV003996114
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a black male proband who was diagnosed with paroxysmal lone atrial fibrillation (ATFB10; 614022) at 17 years of age, Darbar et al. (2008) identified heterozygosity for a G-to-C transversion in the SCN5A gene, resulting in an asn470-to-lys (N470K) substitution at a highly conserved residue and predicted to perturb cardiac sodium channel function. The proband had left atrial enlargement with an ejection fraction of 60% by transthoracic echocardiography. The mutation was also detected in his affected mother and maternal grandmother, but was not found in an unaffected maternal aunt or in 720 control alleles. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0044 ATRIAL FIBRILLATION, FAMILIAL, 10</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
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<span class="mim-text-font">
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SCN5A, GLU428LYS
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<br />
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SNP: rs199473111,
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gnomAD: rs199473111,
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ClinVar: RCV000022950, RCV000148855, RCV000182967, RCV000765740, RCV001841512, RCV002371781, RCV004541013, RCV004586020
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a white male proband who was diagnosed with paroxysmal lone atrial fibrillation (ATFB10; 614022) at 52 years of age, Darbar et al. (2008) identified heterozygosity for a A-to-G transition in the SCN5A gene, resulting in an glu428-to-lys (E428K) substitution at a highly conserved residue and predicted to perturb cardiac sodium channel function. The proband had left atrial enlargement with an ejection fraction of 58% by transthoracic echocardiography. The mutation was also detected in his affected daughter and granddaughter, but was not found in an unaffected daughter and granddaughter or in 720 control alleles. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0045 ATRIAL FIBRILLATION, FAMILIAL, 10</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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SCN5A, GLU655LYS
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<br />
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SNP: rs199473579,
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gnomAD: rs199473579,
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ClinVar: RCV000022951, RCV000058468, RCV000485732, RCV002482900, RCV003996115, RCV004018665
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a white female proband who was diagnosed with paroxysmal lone atrial fibrillation (ATFB10; 614022) at 37 years of age, Darbar et al. (2008) identified heterozygosity for an A-to-G transition in the SCN5A gene, resulting in a glu655-to-lys (E655K) substitution at a highly conserved residue that was predicted to perturb cardiac sodium channel function. The proband had a normal-sized left atrium and ventricle with an ejection fraction of 55% by transthoracic echocardiography. The mutation was also detected in her affected daughter and maternal grandmother, but was not found in 720 control alleles. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0046 CARDIOMYOPATHY, DILATED, 1E</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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SCN5A, ARG222GLN ({dbSNP rs45546039})
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<br />
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SNP: rs45546039,
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gnomAD: rs45546039,
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ClinVar: RCV000032639, RCV000058833, RCV000182941, RCV000211852, RCV000678965, RCV000763109
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 6 affected members over 3 generations of a non-Hispanic white family with cardiomyopathy and conduction system disease (CMD1E; 601154), Hershberger et al. (2008) identified heterozygosity for a 36683G-A (numbering per SeattleSNP) transition in exon 6 of the SCN5A gene, resulting in an arg222-to-gln (R222Q) substitution at a conserved residue. The mutation was not found in unaffected family members or in 253 controls. </p><p>In 19 affected individuals from 3 unrelated 3-generation families with multifocal ectopic Purkinje-related premature contractions and dilated cardiomyopathy, Laurent et al. (2012) identified heterozygosity for the 665G-A (R222Q) mutation in the SCN5A gene, located in the voltage-sensing S4 segment of domain I. The mutation, which was fully penetrant and strictly segregated with the cardiac phenotype in each family, was not found in 600 control chromosomes; haplotype analysis showed that a founder effect for these 3 families was very unlikely. In vitro studies recapitulated the normalization of the ventricular action potentials in the presence of quinidine. Because only 6 of the 19 patients carrying the R222Q mutation had CMD, and the cardiomyopathy recovered at least partially with antiarrhythmia treatment and a reduction in the number of premature ventricular contractions, Laurent et al. (2012) suggested that CMD might be a consequence of the arrhythmia and not directly linked to the mutation. </p><p>In affected members of a 3-generation Canadian family with CMD and junctional escape ventricular capture bigeminy, Nair et al. (2012) identified the R222Q mutation in the SCN5A gene. Heterologous expression studies in Chinese hamster ovary K1 cells revealed a unique biophysical phenotype of R222Q channels in which an approximately 10-mV leftward shift in the sodium current steady-state activation curve occurs without corresponding shifts in steady-state inactivation at cardiomyocyte resting membrane-potential voltages. The activation and inactivation of cells expressing equimolar combinations of wildtype and R222Q channels showed properties intermediate between those seen in cells expressing either wildtype or mutant channels alone. The changes in mutant channel properties were predicted to produce hyperexcitability of R222Q sodium channels. </p><p>In 16 affected members over 3 generations of a large kindred with CMD and multiple arrhythmias, including premature ventricular complexes (PVCs) of variable morphology, Mann et al. (2012) identified heterozygosity for the R222Q mutation in the SCN5A gene. The mutation was also identified in 1 clinically unaffected family member, a 56-year-old man with a normal EKG and echocardiogram, but was not found in 200 control chromosomes. Patch-clamp studies showed that the R222Q mutation did not alter sodium channel current density, but did shift steady-state parameters of activation and inactivation to the left. Using a voltage ramp protocol, normalized current responses of mutant channels were of earlier onset and greater magnitude than wildtype. Action potential modeling using Purkinje fiber and ventricular cell models suggested that rate-dependent ectopy of Purkinje fiber origin is the predominant ventricular effect of the R222Q variant; this was supported by the clinical observation that PVC frequency increased during periods of low heart rate at rest and at night, and was reduced by high heart rates during exercise. Patients responded to sodium-channel blocking drugs with early and substantial reductions in PVCs followed by normalization of CMD over time. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0047 CARDIOMYOPATHY, DILATED, 1E</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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SCN5A, ILE1835THR
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<br />
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SNP: rs45563942,
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gnomAD: rs45563942,
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ClinVar: RCV000032640, RCV000058788, RCV000148847, RCV000212993, RCV000621032, RCV001841554, RCV004541057
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 3 affected members over 2 generations of an African American family with cardiomyopathy and conduction system disease (CMD1E; 601154), Hershberger et al. (2008) identified heterozygosity for a 99599T-C transition (numbering per SeattleSNP) in exon 28 of the SCN5A gene, resulting in an ile1835-to-thr (I1835T) substitution at a conserved residue. The mutation was not found in unaffected family members or in 253 controls. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0048 ATRIAL STANDSTILL 1, DIGENIC</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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SCN5A, LEU212PRO
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<br />
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SNP: rs199473070,
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ClinVar: RCV000058830, RCV000114993, RCV003539788
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a Japanese boy with atrial standstill (ATRST1; 108770), Makita et al. (2005) identified coinheritance of a heterozygous c.635C-T transition in exon 6 of the SCN5A gene, resulting in a leu212-to-pro (L212P) substitution in the extracellular loop connecting transmembrane segments 3 and 4 of domain 1 of the Nav1.5 cardiac sodium channel, and heterozygous rare polymorphisms in the GJA5 gene (121013). The L212P mutation, which was also present in the proband's asymptomatic father, was not found in 400 control chromosomes. Functional analysis with the L212P mutant channels demonstrated large hyperpolarizing shifts in both the voltage dependence of activation and inactivation and delayed recovery from inactivation compared to wildtype. The asymptomatic father did not carry the rare polymorphisms in the GJA5 gene; the GJA5 polymorphisms were, however, present in heterozygosity in the proband's unaffected mother and maternal grandmother, who did not carry the L212P mutation. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
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</h4>
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<div>
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<p />
|
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</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
|
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Ackerman, M. J., Siu, B. L., Sturner, W. Q., Tester, D. J., Valdivia, C. R., Makielski, J. C., Towbin, J. A.
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<strong>Postmortem molecular analysis of SCN5A defects in sudden infant death syndrome.</strong>
|
|
JAMA 286: 2264-2269, 2001.
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[PubMed: 11710892]
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[Full Text: https://doi.org/10.1001/jama.286.18.2264]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Ackerman, M. J., Splawski, I., Makielski, J. C., Tester, D. J., Will, M. L., Timothy, K. W., Keating, M. T., Jones, G., Chadha, M., Burrow, C. R., Stephens, J. C., Xu, C., Judson, R., Curran, M. E.
|
|
<strong>Spectrum and prevalence of cardiac sodium channel variants among black, white, Asian, and Hispanic individuals: implications for arrhythmogenic susceptibility and Brugada/long QT syndrome genetic testing.</strong>
|
|
Heart Rhythm 1: 600-607, 2004.
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[PubMed: 15851227]
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[Full Text: https://doi.org/10.1016/j.hrthm.2004.07.013]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Akai, J., Makita, N., Sakurada, H., Shirai, N., Ueda, K., Kitabatake, A., Nakazawa, K., Kimura, A., Hiraoka, M.
|
|
<strong>A novel SCN5A mutation associated with idiopathic ventricular fibrillation without typical ECG findings of Brugada syndrome.</strong>
|
|
FEBS Lett. 479: 29-34, 2000.
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[PubMed: 10940383]
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[Full Text: https://doi.org/10.1016/s0014-5793(00)01875-5]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Albert, C. M., Nam, E. G., Rimm, E. B., Jin, H. W., Hajjar, R. J., Hunter, D. J., MacRae, C. A., Ellinor, P. T.
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|
<strong>Cardiac sodium channel gene variants and sudden cardiac death in women.</strong>
|
|
Circulation 117: 16-23, 2008.
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[PubMed: 18071069]
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[Full Text: https://doi.org/10.1161/CIRCULATIONAHA.107.736330]
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<li>
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<p class="mim-text-font">
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Barajas-Martinez, H. M., Hu, D., Cordeiro, J. M., Wu, Y., Kovacs, R. J., Meltser, H., Kui, H., Elena, B., Brugada, R., Antzelevitch, C., Dumaine, R.
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<strong>Lidocaine-induced Brugada syndrome phenotype linked to a novel double mutation in the cardiac sodium channel.</strong>
|
|
Circ. Res. 103: 396-404, 2008.
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[PubMed: 18599870]
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[Full Text: https://doi.org/10.1161/CIRCRESAHA.108.172619]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Bennett, P. B., Yazawa, K., Makita, N., George, A. L., Jr.
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<strong>Molecular mechanism for an inherited cardiac arrhythmia.</strong>
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Nature 376: 683-685, 1995.
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[PubMed: 7651517]
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[Full Text: https://doi.org/10.1038/376683a0]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Benson, D. W., Wang, D. W., Dyment, M., Knilans, T. K., Fish, F. A., Strieper, M. J., Rhodes, T. H., George, A. L., Jr.
|
|
<strong>Congenital sick sinus syndrome caused by recessive mutations in the cardiac sodium channel gene (SCN5A).</strong>
|
|
J. Clin. Invest. 112: 1019-1028, 2003.
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|
|
[PubMed: 14523039]
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[Full Text: https://doi.org/10.1172/JCI18062]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Bezzina, C., Veldkamp, M. W., van den Berg, M. P., Postma, A. V., Rook, M. B., Viersma, J.-W., van Langen, I. M., Tan-Sindhunata, G., Bink-Boelkens, M. T. E., van der Hout, A. H., Mannens, M. M. A. M., Wilde, A. A. M.
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<strong>A single Na+ channel mutation causing both long-QT and Brugada syndromes.</strong>
|
|
Circ. Res. 85: 1206-1213, 1999.
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|
|
|
[PubMed: 10590249]
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|
|
[Full Text: https://doi.org/10.1161/01.res.85.12.1206]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Chen, Q., Kirsch, G. E., Zhang, D., Brugada, R., Brugada, J., Brugada, P., Potenza, D., Moya, A., Borggrefe, M., Breithardt, G., Ortiz-Lopez, R., Wang, Z., Antzelevitch, C., O'Brien, R. E., Schulze-Bahr, E., Keating, M. T., Towbin, J. A., Wang, Q.
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|
<strong>Genetic basis and molecular mechanism for idiopathic ventricular fibrillation.</strong>
|
|
Nature 392: 293-295, 1998.
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[PubMed: 9521325]
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[Full Text: https://doi.org/10.1038/32675]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Chen, S., Chung, M. K., Martin, D., Rozich, R., Tchou, P. J., Wang, Q.
|
|
<strong>SNP S1103Y in the cardiac sodium channel gene SCN5A is associated with cardiac arrhythmias and sudden death in a white family.</strong>
|
|
J. Med. Genet. 39: 913-915, 2002.
|
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|
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|
|
[PubMed: 12471205]
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|
|
[Full Text: https://doi.org/10.1136/jmg.39.12.913]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Cheng, J., Morales, A., Siegfried, J. D., Li, D., Norton, N., Song, J., Gonzalez-Quintana, J., Makielski, J. C., Hershberger, R. E.
|
|
<strong>SCN5A rare variants in familial dilated cardiomyopathy decrease peak sodium current depending on the common polymorphism H558R and common splice variant Q1077del.</strong>
|
|
Clin. Transl. Sci. 3: 287-294, 2010.
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|
|
|
|
[PubMed: 21167004]
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|
[Full Text: https://doi.org/10.1111/j.1752-8062.2010.00249.x]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Clancy, C. E., Rudy, Y.
|
|
<strong>Linking a genetic defect to its cellular phenotype in a cardiac arrhythmia.</strong>
|
|
Nature 400: 566-569, 1999.
|
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|
|
|
|
[PubMed: 10448858]
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|
|
[Full Text: https://doi.org/10.1038/23034]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Clancy, C. E., Rudy, Y.
|
|
<strong>Na+ channel mutation that causes both Brugada and long-QT syndrome phenotypes: a simulation study of mechanism.</strong>
|
|
Circulation 105: 1208-1213, 2002.
|
|
|
|
|
|
[PubMed: 11889015]
|
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|
|
|
|
[Full Text: https://doi.org/10.1161/hc1002.105183]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Clancy, C. E., Tateyama, M., Kass, R. S.
|
|
<strong>Insights into the molecular mechanisms of bradycardia-triggered arrhythmias in long QT-3 syndrome.</strong>
|
|
J. Clin. Invest. 110: 1251-1262, 2002.
|
|
|
|
|
|
[PubMed: 12417563]
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|
|
[Full Text: https://doi.org/10.1172/JCI15928]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Darbar, D., Kannankeril, P. J., Donahue, B. S., Kucera, G., Stubblefield, T., Haines, J. L., George, A. L., Jr., Roden, D. M.
|
|
<strong>Cardiac sodium channel (SCN5A) variants associated with atrial fibrillation.</strong>
|
|
Circulation 117: 1927-1935, 2008.
|
|
|
|
|
|
[PubMed: 18378609]
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|
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[Full Text: https://doi.org/10.1161/CIRCULATIONAHA.107.757955]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Dumaine, R., Towbin, J. A., Brugada, P., Vatta, M., Nesterenko, D. V., Nesterenko, V. V., Brugada, J., Brugada, R., Antzelevitch, C.
|
|
<strong>Ionic mechanisms responsible for the electrocardiographic phenotype of the Brugada syndrome are temperature dependent.</strong>
|
|
Circ. Res. 85: 803-809, 1999.
|
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|
|
[PubMed: 10532948]
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[Full Text: https://doi.org/10.1161/01.res.85.9.803]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Dumaine, R.
|
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<strong>Personal Communication.</strong>
|
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<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
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<span class="text-nowrap mim-text-font">
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Contributors:
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</span>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Sonja A. Rasmussen - updated : 09/12/2022<br>Matthew B. Gross - updated : 04/23/2019<br>Patricia A. Hartz - updated : 11/16/2016<br>Paul J. Converse - updated : 1/8/2015<br>Marla J. F. O'Neill - updated : 4/29/2014<br>Marla J. F. O'Neill - updated : 1/29/2013<br>Marla J. F. O'Neill - updated : 6/1/2011<br>Marla J. F. O'Neill - updated : 6/8/2009<br>Marla J. F. O'Neill - updated : 12/23/2008<br>Marla J. F. O'Neill - updated : 5/14/2008<br>Marla J. F. O'Neill - updated : 3/6/2008<br>Marla J. F. O'Neill - updated : 2/12/2008<br>Marla J. F. O'Neill - updated : 1/12/2007<br>Marla J. F. O'Neill - updated : 11/9/2006<br>Marla J. F. O'Neill - updated : 7/10/2006<br>Victor A. McKusick - updated : 2/20/2006<br>Marla J. F. O'Neill - updated : 1/31/2006<br>Marla J. F. O'Neill - updated : 10/11/2005<br>Victor A. McKusick - updated : 1/27/2005<br>Victor A. McKusick - updated : 1/3/2005<br>Cassandra L. Kniffin - updated : 10/26/2004<br>Marla J. F. O'Neill - updated : 2/18/2004<br>Victor A. McKusick - updated : 11/18/2003<br>Victor A. McKusick - updated : 6/30/2003<br>Denise L. M. Goh - updated : 1/6/2003<br>Ada Hamosh - updated : 10/18/2002<br>George E. Tiller - updated : 9/23/2002<br>Deborah L. Stone - updated : 6/26/2002<br>Victor A. McKusick - updated : 6/6/2002<br>Paul Brennan - updated : 3/27/2002<br>Paul Brennan - updated : 3/8/2002<br>Ada Hamosh - updated : 1/22/2002<br>Victor A. McKusick - updated : 11/6/2001<br>Ada Hamosh - updated : 2/27/2001<br>Victor A. McKusick - updated : 9/27/2000<br>Victor A. McKusick - updated : 9/15/2000<br>Victor A. McKusick - updated : 6/1/2000<br>Paul Brennan - updated : 4/12/2000<br>Paul Brennan - updated : 4/3/2000<br>Paul Brennan - updated : 4/3/2000<br>Victor A. McKusick - updated : 2/24/2000<br>Victor A. McKusick - updated : 1/12/2000<br>Paul Brennan - updated : 8/31/1999<br>Ada Hamosh - updated : 8/4/1999<br>Ada Hamosh - updated : 5/25/1999<br>Victor A. McKusick - updated : 10/2/1998<br>Victor A. McKusick - updated : 5/12/1998<br>Victor A. McKusick - updated : 3/17/1998<br>Victor A. McKusick - updated : 5/27/1997
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<span class="text-nowrap mim-text-font">
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Creation Date:
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 10/26/1994
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carol : 01/11/2023<br>carol : 10/03/2022<br>alopez : 09/30/2022<br>carol : 09/25/2022<br>carol : 09/13/2022<br>carol : 09/12/2022<br>carol : 09/01/2020<br>carol : 05/29/2019<br>mgross : 04/23/2019<br>alopez : 11/07/2018<br>carol : 01/05/2018<br>carol : 10/05/2017<br>alopez : 09/14/2017<br>carol : 01/12/2017<br>alopez : 11/16/2016<br>alopez : 11/09/2016<br>alopez : 11/09/2016<br>carol : 05/24/2016<br>carol : 5/23/2016<br>mgross : 1/30/2015<br>carol : 1/14/2015<br>mcolton : 1/8/2015<br>alopez : 11/12/2014<br>carol : 4/29/2014<br>mcolton : 4/28/2014<br>carol : 4/17/2014<br>carol : 3/19/2014<br>carol : 8/27/2013<br>carol : 3/8/2013<br>alopez : 1/30/2013<br>alopez : 1/29/2013<br>carol : 12/15/2011<br>carol : 11/23/2011<br>terry : 11/4/2011<br>carol : 11/3/2011<br>carol : 7/15/2011<br>wwang : 6/3/2011<br>wwang : 6/3/2011<br>terry : 6/1/2011<br>wwang : 6/30/2009<br>terry : 6/8/2009<br>carol : 6/2/2009<br>carol : 12/24/2008<br>terry : 12/23/2008<br>carol : 12/22/2008<br>carol : 5/14/2008<br>carol : 3/6/2008<br>wwang : 3/5/2008<br>wwang : 2/26/2008<br>terry : 2/12/2008<br>joanna : 2/7/2008<br>carol : 11/15/2007<br>alopez : 10/4/2007<br>carol : 9/10/2007<br>carol : 1/19/2007<br>terry : 1/12/2007<br>carol : 12/8/2006<br>carol : 11/16/2006<br>carol : 11/9/2006<br>carol : 11/9/2006<br>carol : 10/4/2006<br>terry : 8/24/2006<br>wwang : 7/11/2006<br>terry : 7/10/2006<br>joanna : 6/2/2006<br>carol : 2/22/2006<br>carol : 2/22/2006<br>terry : 2/20/2006<br>wwang : 2/20/2006<br>wwang : 2/3/2006<br>terry : 1/31/2006<br>wwang : 10/14/2005<br>terry : 10/11/2005<br>wwang : 2/10/2005<br>wwang : 2/8/2005<br>terry : 1/27/2005<br>wwang : 1/6/2005<br>wwang : 1/6/2005<br>terry : 1/3/2005<br>tkritzer : 10/27/2004<br>ckniffin : 10/26/2004<br>carol : 10/26/2004<br>carol : 10/12/2004<br>joanna : 9/10/2004<br>ckniffin : 4/30/2004<br>carol : 4/30/2004<br>ckniffin : 4/14/2004<br>tkritzer : 3/18/2004<br>tkritzer : 3/16/2004<br>carol : 2/18/2004<br>alopez : 11/25/2003<br>tkritzer : 11/20/2003<br>terry : 11/18/2003<br>carol : 7/14/2003<br>tkritzer : 7/8/2003<br>terry : 6/30/2003<br>carol : 2/5/2003<br>carol : 1/6/2003<br>carol : 1/6/2003<br>alopez : 10/23/2002<br>terry : 10/18/2002<br>cwells : 9/23/2002<br>carol : 6/26/2002<br>mgross : 6/10/2002<br>terry : 6/6/2002<br>alopez : 3/27/2002<br>carol : 3/14/2002<br>alopez : 3/8/2002<br>alopez : 1/23/2002<br>terry : 1/22/2002<br>carol : 11/8/2001<br>carol : 11/8/2001<br>mcapotos : 11/6/2001<br>alopez : 3/7/2001<br>alopez : 3/6/2001<br>terry : 2/27/2001<br>mcapotos : 10/13/2000<br>mcapotos : 10/11/2000<br>terry : 9/27/2000<br>carol : 9/25/2000<br>terry : 9/22/2000<br>terry : 9/15/2000<br>mcapotos : 6/15/2000<br>mcapotos : 6/14/2000<br>terry : 6/1/2000<br>alopez : 4/12/2000<br>alopez : 4/3/2000<br>alopez : 4/3/2000<br>mcapotos : 3/17/2000<br>mcapotos : 3/8/2000<br>terry : 2/24/2000<br>mgross : 2/17/2000<br>terry : 1/12/2000<br>carol : 11/4/1999<br>mgross : 8/31/1999<br>alopez : 8/4/1999<br>terry : 8/4/1999<br>kayiaros : 7/8/1999<br>carol : 7/7/1999<br>carol : 5/25/1999<br>carol : 5/11/1999<br>carol : 10/7/1998<br>terry : 10/2/1998<br>terry : 6/4/1998<br>carol : 5/21/1998<br>terry : 5/12/1998<br>alopez : 3/18/1998<br>terry : 3/17/1998<br>jenny : 5/30/1997<br>terry : 5/27/1997<br>terry : 12/10/1996<br>terry : 12/5/1996<br>terry : 6/5/1996<br>terry : 6/3/1996<br>joanna : 12/29/1995<br>mimadm : 9/23/1995<br>mark : 9/22/1995<br>terry : 4/20/1995<br>mark : 3/30/1995<br>terry : 10/26/1994
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