6583 lines
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- *185470 - SUCCINATE DEHYDROGENASE COMPLEX, IRON-SULFUR SUBUNIT B; SDHB
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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">*185470</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="#description">Description</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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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<a href="#mapping">Mapping</a>
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<a href="#geneFunction">Gene Function</a>
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<a href="#molecularGenetics">Molecular Genetics</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/185470">Table View</a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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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>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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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=ENSG00000117118;t=ENST00000375499" 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=6390" 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=185470" 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="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=ENSG00000117118;t=ENST00000375499" 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_001407361,NM_003000" 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_003000" 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=185470" 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=01707&isoform_id=01707_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/SDHB" 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/180917,220070,665925,773300,14043765,20455488,45426858,89573829,115387094,119615234,119615235,189065269,2247446004" 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/P21912" 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=6390" 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=ENSG00000117118;t=ENST00000375499" 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=SDHB" 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=SDHB" 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+6390" 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/SDHB" 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:6390" 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/6390" 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=chr1&hgg_gene=ENST00000375499.8&hgg_start=17018722&hgg_end=17054032&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:10681" 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:10681" 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=185470[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=185470[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/SDHB/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/ENSG00000117118" 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=SDHB" 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=SDHB" 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=SDHB" 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="http://www.LOVD.nl/SDHB" class="mim-tip-hint" title="A gene-specific database of variation." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Locus Specific DBs</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=SDHB&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/PA35606" 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:10681" 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/FBgn0014028.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:1914930" 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/SDHB#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:1914930" 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/6390/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=6390" 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><a href="https://wormbase.org/db/gene/gene?name=WBGene00006433;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-030131-8005" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</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:6390" 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=SDHB&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> 1187383001, 128755003, 420120006, 722377004<br />
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<strong>ICD10CM:</strong> C49.A<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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185470
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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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SUCCINATE DEHYDROGENASE COMPLEX, IRON-SULFUR SUBUNIT B; SDHB
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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>
|
|
<h4>
|
|
<span class="mim-font">
|
|
SUCCINATE DEHYDROGENASE COMPLEX, SUBUNIT B, IRON-SULFUR PROTEIN<br />
|
|
SUCCINATE DEHYDROGENASE 2, S. CEREVISIAE, HOMOLOG OF<br />
|
|
SDH2, HOMOLOG OF
|
|
</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>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=SDHB" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">SDHB</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>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/1/209?start=-3&limit=10&highlight=209">1p36.13</a>
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|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr1:17018722-17054032&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'})">1:17,018,722-17,054,032</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>
|
|
<br />
|
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</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
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<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=606764,619224,606864,115310" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="4">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/1/209?start=-3&limit=10&highlight=209">
|
|
1p36.13
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Gastrointestinal stromal tumor
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/606764"> 606764 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>, <abbr class="mim-tip-hint" title="Isolated cases">IC</abbr>
|
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|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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|
|
</span>
|
|
</td>
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</tr>
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<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Mitochondrial complex II deficiency, nuclear type 4
|
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|
|
</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
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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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<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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<p>Complex II in mitochondria, of which succinate dehydrogenase (<a href="https://enzyme.expasy.org/EC/1.3.99.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'EC\', \'domain\': \'expasy.org\'})">EC 1.3.99.1</a>) is a component, has 4 subunits. In order of decreasing molecular mass, they are the flavoprotein (SDHA; <a href="/entry/600857">600857</a>), the iron-sulfur protein (SDHB), and the 2 integral membrane proteins, SDHC (<a href="/entry/602413">602413</a>) and SDHD (<a href="/entry/602690">602690</a>) (summary by <a href="#22" class="mim-tip-reference" title="Kita, K., Oya, H., Gennis, R. B., Ackrell, B. A. C., Kasahara, M. <strong>Human complex II (succinate-ubiquinone oxidoreductase): cDNA cloning of iron sulphur (Ip) subunit of liver mitochondria.</strong> Biochem. Biophys. Res. Commun. 166: 101-108, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2302193/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2302193</a>] [<a href="https://doi.org/10.1016/0006-291x(90)91916-g" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2302193">Kita et al., 1990</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2302193" 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="#22" class="mim-tip-reference" title="Kita, K., Oya, H., Gennis, R. B., Ackrell, B. A. C., Kasahara, M. <strong>Human complex II (succinate-ubiquinone oxidoreductase): cDNA cloning of iron sulphur (Ip) subunit of liver mitochondria.</strong> Biochem. Biophys. Res. Commun. 166: 101-108, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2302193/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2302193</a>] [<a href="https://doi.org/10.1016/0006-291x(90)91916-g" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2302193">Kita et al. (1990)</a> cloned and sequenced the iron-sulfur protein subunit. A clone was isolated from a human liver cDNA library. The open reading frame encodes a 252-amino acid protein. The amino acid sequence showed approximately 94% homology with that of bovine heart. <a href="#4" class="mim-tip-reference" title="Au, H. C., Ream-Robinson, D., Bellew, L. A., Broomfield, P. L. E., Saghbini, M., Scheffler, I. E. <strong>Structural organization of the gene encoding the human iron-sulfur subunit of succinate dehydrogenase.</strong> Gene 159: 249-253, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7622059/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7622059</a>] [<a href="https://doi.org/10.1016/0378-1119(95)00162-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7622059">Au et al. (1995)</a> described the complete genomic clone for the gene encoding the iron-sulfur protein subunit. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2302193+7622059" 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="#4" class="mim-tip-reference" title="Au, H. C., Ream-Robinson, D., Bellew, L. A., Broomfield, P. L. E., Saghbini, M., Scheffler, I. E. <strong>Structural organization of the gene encoding the human iron-sulfur subunit of succinate dehydrogenase.</strong> Gene 159: 249-253, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7622059/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7622059</a>] [<a href="https://doi.org/10.1016/0378-1119(95)00162-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7622059">Au et al. (1995)</a> determined that the entire SDHB transcript is encoded by 8 exons within approximately 40 kb. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7622059" 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="#23" class="mim-tip-reference" title="Leckschat, S., Ream-Robinson, D., Scheffler, I. E. <strong>The gene for the iron sulfur protein of succinate dehydrogenase (SDH-IP) maps to human chromosome 1p35-36.1.</strong> Somat. Cell Molec. Genet. 19: 505-511, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8291026/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8291026</a>] [<a href="https://doi.org/10.1007/BF01233256" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8291026">Leckschat et al. (1993)</a> used a partial human cDNA clone corresponding to the iron protein subunit of succinate dehydrogenase in Southern analyses of restriction enzyme digests of genomic human and hamster DNA, as well as hamster-human hybrids containing a limited number of human chromosomes, to demonstrate that the gene is located on human chromosome 1. Using the same genomic clone, they subregionalized the gene to 1p36.1-p35 by fluorescence in situ hybridization. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8291026" 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="#26" class="mim-tip-reference" title="Mascarello, J. T., Soderberg, K., Scheffler, I. E. <strong>Assignment of a gene for succinate dehydrogenase to human chromosome 1 by somatic cell hybridization.</strong> Cytogenet. Cell Genet. 28: 121-135, 1980.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6934864/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6934864</a>] [<a href="https://doi.org/10.1159/000131520" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6934864">Mascarello et al. (1980)</a> described an SDH-deficient hamster cell line that was complemented by human chromosome 1. It was presumed that, because it mapped to chromosome 1, the iron-sulfur protein subunit gene complemented the deficiency in the mutant. <a href="#31" class="mim-tip-reference" title="Oostveen, F. G., Au, H. C., Meijer, P.-J., Scheffler, I. E. <strong>A Chinese hamster mutant cell line with a defect in the integral membrane protein C-II-3 of complex II of the mitochondrial electron transport chain.</strong> J. Biol. Chem. 270: 26104-26108, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7592812/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7592812</a>] [<a href="https://doi.org/10.1074/jbc.270.44.26104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7592812">Oostveen et al. (1995)</a> found that in fact it was protein from the bovine SDH3 gene (corresponding to human SDHC and encoding 1 of the 2 integral membrane proteins) that complemented the hamster mutation. Thus there are 2 SDH genes on chromosome 1. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7592812+6934864" 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="#33" class="mim-tip-reference" title="Pollard, P. J., Briere, J. J., Alam, N. A., Barwell, J., Barclay, E., Wortham, N. C., Hunt, T., Mitchell, M., Olpin, S., Moat, S. J., Hargreaves, I. P., Heales, S. J., and 9 others. <strong>Accumulation of Krebs cycle intermediates and over-expression of HIF1-alpha in tumours which result from germline FH and SDH mutations.</strong> Hum. Molec. Genet. 14: 2231-2239, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15987702/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15987702</a>] [<a href="https://doi.org/10.1093/hmg/ddi227" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15987702">Pollard et al. (2005)</a> stated that the nuclear-encoded Krebs cycle enzymes fumarate hydratase (FH; <a href="/entry/136850">136850</a>) and succinate dehydrogenases like SDHB act as tumor suppressors, and germline mutations in these genes predispose individuals to leiomyomas and renal cancer (HLRCC; <a href="/entry/150800">150800</a>) and to paragangliomas, respectively. <a href="#33" class="mim-tip-reference" title="Pollard, P. J., Briere, J. J., Alam, N. A., Barwell, J., Barclay, E., Wortham, N. C., Hunt, T., Mitchell, M., Olpin, S., Moat, S. J., Hargreaves, I. P., Heales, S. J., and 9 others. <strong>Accumulation of Krebs cycle intermediates and over-expression of HIF1-alpha in tumours which result from germline FH and SDH mutations.</strong> Hum. Molec. Genet. 14: 2231-2239, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15987702/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15987702</a>] [<a href="https://doi.org/10.1093/hmg/ddi227" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15987702">Pollard et al. (2005)</a> showed that FH-deficient cells and tumors accumulated fumarate and, to a lesser extent, succinate. SDH-deficient tumors principally accumulated succinate. In situ analysis showed that these tumors also overexpressed HIF1A (<a href="/entry/603348">603348</a>), activation of HIF1A targets like VEGF (<a href="/entry/192240">192240</a>), and high microvessel density. <a href="#33" class="mim-tip-reference" title="Pollard, P. J., Briere, J. J., Alam, N. A., Barwell, J., Barclay, E., Wortham, N. C., Hunt, T., Mitchell, M., Olpin, S., Moat, S. J., Hargreaves, I. P., Heales, S. J., and 9 others. <strong>Accumulation of Krebs cycle intermediates and over-expression of HIF1-alpha in tumours which result from germline FH and SDH mutations.</strong> Hum. Molec. Genet. 14: 2231-2239, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15987702/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15987702</a>] [<a href="https://doi.org/10.1093/hmg/ddi227" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15987702">Pollard et al. (2005)</a> hypothesized that increased succinate and/or fumarate may stabilize HIF1A, and that the basic mechanism of tumorigenesis in paraganglioma and leiomyomas and renal cancer may be pseudohypoxic drive, just as it is in von Hippel-Lindau syndrome (<a href="/entry/193300">193300</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15987702" 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>SDH Complex Function</em></strong></p><p>
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In mammalian cells, <a href="#38" class="mim-tip-reference" title="Spinelli, J. B., Rosen, P. C., Sprenger, H.-G., Puszynska, A. M., Mann, J. L., Roessler, J. M., Cangelosi, A. L., Henne, A., Condon, K. J., Zhang, T., Kunchok, T., Lewis, C. A., Chandel, N. S., Sabatini, D. M. <strong>Fumarate is a terminal electron acceptor in the mammalian electron transport chain.</strong> Science 374: 1227-1237, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34855504/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34855504</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34855504[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/10.1126/science.abi7495" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34855504">Spinelli et al. (2021)</a> found that when oxygen reduction is impeded, mitochondrial complex I and dihydroorotate dehydrogenase (DHODH; <a href="/entry/126064">126064</a>) can still deposit electrons into the electron transport chain because the accumulation of ubiquinol drives the succinate dehydrogenase complex in reverse to enable electron deposition onto fumarate. Fumarate sustains DHODH and complex I activities by acting as the terminal electron acceptor, maintaining mitochondrial function under oxygen limitation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34855504" 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><strong><em>Pheochromocytoma/Paraganglioma Syndrome 4</em></strong></p><p>
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In affected members of families with paragangliomas (PPGL4; <a href="/entry/115310">115310</a>), <a href="#3" class="mim-tip-reference" title="Astuti, D., Latif, F., Dallol, A., Dahia, P. L. M., Douglas, F., George, E., Skoldberg, F., Husebye, E. S., Eng, C., Maher, E. R. <strong>Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma.</strong> Am. J. Hum. Genet. 69: 49-54, 2001. Note: Erratum: Am. J. Hum. Genet. 70: 565 only, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11404820/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11404820</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11404820[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/10.1086/321282" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11404820">Astuti et al. (2001)</a> identified mutations in the SDHB gene (<a href="#0001">185470.0001</a>-<a href="#0002">185470.0002</a>). Clinical manifestations included pheochromocytomas, extraadrenal pheochromocytomas, and paragangliomas. A mutation in the SDHB gene (<a href="#0003">185470.0003</a>) was also identified in the blood and tumor tissue of 1 of 24 cases of sporadic pheochromocytoma. The findings extended the link between mitochondrial dysfunction and tumorigenesis, and suggested that germline SDHB mutations are an important cause of pheochromocytoma susceptibility. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11404820" 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="Young, A. L., Baysal, B. E., Deb, A., Young, W. F., Jr. <strong>Familial malignant catecholamine-secreting paraganglioma with prolonged survival associated with mutation in the succinate dehydrogenase B gene.</strong> J. Clin. Endocr. Metab. 87: 4101-4105, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12213855/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12213855</a>] [<a href="https://doi.org/10.1210/jc.2002-020312" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12213855">Young et al. (2002)</a> identified a mutation in the SDHB gene (<a href="#0004">185470.0004</a>) in a man and his son, both of whom had malignant catecholamine-secreting paragangliomas. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12213855" 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="Gimenez-Roqueplo, A.-P., Favier, J., Rustin, P., Rieubland, C., Kerlan, V., Plouin, P.-F., Rotig, A., Jeunemaitre, X. <strong>Functional consequences of a SDHB gene mutation in an apparently sporadic pheochromocytoma.</strong> J. Clin. Endocr. Metab. 87: 4771-4774, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12364472/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12364472</a>] [<a href="https://doi.org/10.1210/jc.2002-020525" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12364472">Gimenez-Roqueplo et al. (2002)</a> reported a case of a malignant sporadic pheochromocytoma (see <a href="/entry/171300">171300</a>) induced by a germline missense mutation in the SDHB gene. Within the tumor, loss of heterozygosity (LOH) at chromosome 1pter led to a null SDHB allele and to a complete loss of complex II enzymatic activity. In situ hybridization and immunohistochemistry experiments showed a high expression of hypoxic-angiogenic responsive genes, similar to that previously observed in inherited SDHD tumors. The authors concluded that the complex II mitochondrial genes play a role in the oxygen-sensing pathway and in the regulation of angiogenesis of neural crest-derived tumors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12364472" 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 12 (4%) of 271 unrelated patients with sporadic pheochromocytoma, <a href="#29" class="mim-tip-reference" title="Neumann, H. P. H., Bausch, B., McWhinney, S. R., Bender, B. U., Gimm, O., Franke, G., Schipper, J., Klisch, J., Altehoefer, C., Zerres, K., Januszewicz, A., Eng, C. <strong>Germ-line mutations in nonsyndromic pheochromocytoma.</strong> New Eng. J. Med. 346: 1459-1466, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12000816/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12000816</a>] [<a href="https://doi.org/10.1056/NEJMoa020152" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12000816">Neumann et al. (2002)</a> identified 9 different germline mutations in the SDHB gene (see, e.g., <a href="#0004">185470.0004</a>-<a href="#0006">185470.0006</a>; <a href="#0008">185470.0008</a>; <a href="#0009">185470.0009</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12000816" 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="#41" class="mim-tip-reference" title="Vanharanta, S., Buchta, M., McWhinney, S. R., Virta, S. K., Peczkowska, M., Morrison, C. D., Lehtonen, R., Januszewicz, A., Jarvinen, H., Juhola, M., Mecklin, J.-P., Pukkala, E., Herva, R., Kiuru, M., Nupponen, N. N., Aaltonen, L. A., Neumann, H. P. H., Eng, C. <strong>Early-onset renal cell carcinoma as a novel extraparaganglial component of SDHB-associated heritable paraganglioma.</strong> Am. J. Hum. Genet. 74: 153-159, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14685938/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14685938</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14685938[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/10.1086/381054" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14685938">Vanharanta et al. (2004)</a> identified 2 families in which renal cell carcinoma (RCC; see <a href="/entry/144700">144700</a>) occurred in patients carrying SDHB mutations (<a href="#0005">185470.0005</a>; <a href="#0006">185470.0006</a>). In 1 family, both patients with RCC had paragangliomas; in another family, the mother of the patient with RCC had a paraganglioma. Tumor tissues from the RCCs showed loss of the remaining wildtype allele. The authors concluded that germline SDHB mutations can predispose to early-onset kidney cancers in addition to paragangliomas. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14685938" 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="#11" class="mim-tip-reference" title="Cascon, A., Montero-Conde, C., Ruiz-Llorente, S., Mercadillo, F., Leton, R., Rodriguez-Antona, C., Martinez-Delgado, B., Delgado, M., Diez, A., Rovira, A., Diaz, J. A., Robledo, M. <strong>Gross SDHB deletions in patients with paraganglioma detected by multiplex PCR: a possible hot spot?</strong> Genes Chromosomes Cancer 45: 213-219, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16258955/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16258955</a>] [<a href="https://doi.org/10.1002/gcc.20283" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16258955">Cascon et al. (2006)</a> investigated the frequency of gross SDH deletions in 24 patients who tested negative for point mutations and had at least 1 of the recommended features for genetic testing. For this purpose, they used a technique to specifically detect gross deletions affecting SDHB, SDHC (<a href="/entry/602413">602413</a>), and SDHD (<a href="/entry/602690">602690</a>). They identified 3 heterozygous SDHB deletions in 3 independent cases with paraganglioma: 1 whole SDHB deletion and 2 deletions exclusively affecting exon 1 of 15.69 kb and 20.3 kb (<a href="#0017">185470.0017</a> and <a href="#0018">185470.0018</a>, respectively). These latter mutations matched the unique gross deletion of SDHB exon 1 previously reported by <a href="#28" class="mim-tip-reference" title="McWhinney, S. R., Pilarski, R. T., Forrester, S. R., Schneider, M. C., Sarquis, M. M., Dias, E. P., Eng, C. <strong>Large germline deletions of mitochondrial complex II subunits SDHB and SDHD in hereditary paraganglioma.</strong> J. Clin. Endocr. Metab. 89: 5694-5699, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15531530/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15531530</a>] [<a href="https://doi.org/10.1210/jc.2004-0769" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15531530">McWhinney et al. (2004)</a>; see <a href="#0007">185470.0007</a>. Thus, the region of exon 1 could be a hotspot for SDHB deletions. These alterations can account for a considerable number of both familial and apparently sporadic paraganglioma cases. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16258955+15531530" 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="#9" class="mim-tip-reference" title="Brouwers, F. M., Eisenhofer, G., Tao, J. J., Kant, J. A., Adams, K. T., Linehan, W. M., Pacak, K. <strong>High frequency of SDHB germline mutations in patients with malignant catecholamine-producing paragangliomas: implications for genetic testing.</strong> J. Clin. Endocr. Metab. 91: 4505-4509, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16912137/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16912137</a>] [<a href="https://doi.org/10.1210/jc.2006-0423" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16912137">Brouwers et al. (2006)</a> studied the prevalence of germline SDHB mutations in a series of patients with malignant paraganglioma. Pathogenic SDHB mutations were found in 13 of 44 patients (30%). Close to one-third of patients had metastases originating from an adrenal primary tumor, compared with a little over two-thirds from an extraadrenal tumor. Among the latter patients, the frequency of SDHB mutations was 48%. The authors concluded that missense, nonsense, frameshift, and splice site mutations of the SDHB gene are associated with about half of all malignancies originating from extraadrenal paragangliomas. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16912137" 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 northern Spain, where cervical paraganglioma is particularly frequent, <a href="#24" class="mim-tip-reference" title="Lima, J., Feijao, T., Ferreira da Silva, A., Pereira-Castro, I., Fernandez-Ballester, G., Maximo, V., Herrero, A., Serrano, L., Sobrinho-Simoes, M., Garcia-Rostan, G. <strong>High frequency of germline succinate dehydrogenase mutations in sporadic cervical paragangliomas in northern Spain: mitochondrial succinate dehydrogenase structure-function relationships and clinical-pathological correlations.</strong> J. Clin. Endocr. Metab. 92: 4853-4864, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17848412/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17848412</a>] [<a href="https://doi.org/10.1210/jc.2007-0640" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17848412">Lima et al. (2007)</a> screened 48 patients for mutations in the SDHB, SDHC, and SDHD genes. Eight sporadic cases (22.2%) carried pathogenic germline mutations, 6 of which were in SDHB and 2 in SDHD. Three families had mutations in SDHD and 1 in SDHB; 7 of 11 different pathogenic mutations (64%) affected SDHB. Ten mutations were novel. Missense mutations were primarily found in SDHB and frameshift mutations in SDHD. The authors concluded that a significant proportion of sporadic cervical PGLs arise as a consequence of intrinsic genetic factors. In patients with germline SDHB mutations, they found no evidence for distant metastases or extraparaganglial malignancies after 7 years' follow-up. <a href="#24" class="mim-tip-reference" title="Lima, J., Feijao, T., Ferreira da Silva, A., Pereira-Castro, I., Fernandez-Ballester, G., Maximo, V., Herrero, A., Serrano, L., Sobrinho-Simoes, M., Garcia-Rostan, G. <strong>High frequency of germline succinate dehydrogenase mutations in sporadic cervical paragangliomas in northern Spain: mitochondrial succinate dehydrogenase structure-function relationships and clinical-pathological correlations.</strong> J. Clin. Endocr. Metab. 92: 4853-4864, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17848412/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17848412</a>] [<a href="https://doi.org/10.1210/jc.2007-0640" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17848412">Lima et al. (2007)</a> concluded that occult familial cases and familial cases with a proven disease history have a common clinicopathologic signature that distinguishes them from truly sporadic cervical paraganglioma patients without germline mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17848412" 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>Paraganglioma and Gastric Stromal Sarcoma</em></strong></p><p>
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In 3 families with paraganglioma and gastric stromal sarcoma (<a href="/entry/606864">606864</a>), <a href="#27" class="mim-tip-reference" title="McWhinney, S. R., Pasini, B., Stratakis, C. A. <strong>Familial gastrointestinal stromal tumors and germ-line mutations. (Letter)</strong> New Eng. J. Med. 357: 1054-1056, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17804857/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17804857</a>] [<a href="https://doi.org/10.1056/NEJMc071191" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17804857">McWhinney et al. (2007)</a> identified 3 different germline mutations in the SDHB gene (see, e.g., <a href="#0012">185470.0012</a> and <a href="#0013">185470.0013</a>). In 3 other families with the dyad, the authors also found germline mutations in the SDHC (see, e.g., <a href="/entry/602413#0004">602413.0004</a>) and SDHD (<a href="/entry/602690#0027">602690.0027</a>) genes, respectively. None of the patients had mutations in the KIT (<a href="/entry/164920">164920</a>) or PDGFRA (<a href="/entry/173490">173490</a>) genes, which have been associated with gastrointestinal tumors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17804857" 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="#32" class="mim-tip-reference" title="Pasini, B., McWhinney, S. R., Bei, T., Matyakhina, L., Stergiopoulos, S., Muchow, M., Boikos, S. A., Ferrando, B., Pacak, K., Assie, G., Baudin, E., Chompret, A., Ellison, J. W., Briere, J.-J., Rustin, P., Gimenez-Roqueplo, A.-P., Eng, C., Carney, J. A., Stratakis, C. A. <strong>Clinical and molecular genetics of patients with the Carney-Stratakis syndrome and germline mutations of the genes coding for the succinate dehydrogenase subunits SDHB, SDHC, and SDHD.</strong> Europ. J. Hum. Genet. 16: 79-88, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17667967/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17667967</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201904" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17667967">Pasini et al. (2008)</a> provided further clinical and molecular information on patients originally reported by <a href="#27" class="mim-tip-reference" title="McWhinney, S. R., Pasini, B., Stratakis, C. A. <strong>Familial gastrointestinal stromal tumors and germ-line mutations. (Letter)</strong> New Eng. J. Med. 357: 1054-1056, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17804857/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17804857</a>] [<a href="https://doi.org/10.1056/NEJMc071191" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17804857">McWhinney et al. (2007)</a> (see <a href="#0012">185470.0012</a>-<a href="#0013">185470.0013</a>). DNA analysis of tumors from patients with germline mutations in SDHB and SDHC showed loss of heterozygosity in all samples available for study, suggesting that the gene defects act in a recessive manner. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17804857+17667967" 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>Gastrointestinal Stromal Tumors</em></strong></p><p>
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<a href="#20" class="mim-tip-reference" title="Janeway, K. A., Kim, S. Y., Lodish, M., Nose, V., Rustin, P., Gaal, J., Dahia, P. L. M., Liegl, B., Ball, E. R., Raygada, M., Lai, A. H., Kelly, L., and 10 others. <strong>Defects in succinate dehydrogenase in gastrointestinal stromal tumors lacking KIT and PDGFRA mutations.</strong> Proc. Nat. Acad. Sci. 108: 314-318, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21173220/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21173220</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21173220[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.1009199108" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21173220">Janeway et al. (2011)</a> identified 3 germline mutations in the SDHB gene (see, e.g., <a href="#0004">185470.0004</a>) in 3 different patients with sporadic occurrence of gastrointestinal stromal tumor (GIST; <a href="/entry/606764">606764</a>). The patients were 18, 22, and 21 years old, respectively, and none had a personal or family history of paragangliomas. Tumor tissue available from 2 of these patients showed lack of SDHB immunostaining. A fourth patient, who was 16 years old, carried a germline mutation in the SDHC gene (<a href="/entry/602413#0004">602413.0004</a>). Overall, mutations in these genes accounted for 4 (12%) of 34 patients with isolated GIST lacking KIT (<a href="/entry/164920">164920</a>) or PDFGRA (<a href="/entry/173490">173490</a>) mutations. <a href="#20" class="mim-tip-reference" title="Janeway, K. A., Kim, S. Y., Lodish, M., Nose, V., Rustin, P., Gaal, J., Dahia, P. L. M., Liegl, B., Ball, E. R., Raygada, M., Lai, A. H., Kelly, L., and 10 others. <strong>Defects in succinate dehydrogenase in gastrointestinal stromal tumors lacking KIT and PDGFRA mutations.</strong> Proc. Nat. Acad. Sci. 108: 314-318, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21173220/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21173220</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21173220[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.1009199108" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21173220">Janeway et al. (2011)</a> evaluated SDHB (<a href="/entry/185470">185470</a>) expression in 30 GISTs lacking KIT or PDGFRA mutations, 25 of which were also negative for associated SDH mutations confirmed by sequence analysis. Immunohistochemical studies showed lack of SDHB staining in 18 (100%) of 18 pediatric tumors, regardless of SDH mutation status, and in 8 (67%) of 12 adult tumors and weak expression in 4 (33%) of 12 adult tumors. By comparison, only 1 (6%) of 18 KIT-mutant GISTs and 0 of 5 NF1-associated GISTs lacked SDHB expression. These findings implicated a defect in respiration in the pathogenesis of some GIST tumors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21173220" 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>Mitochondrial Complex II Deficiency, Nuclear Type 4</em></strong></p><p>
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In an Asian girl, born of consanguineous parents, with neurologic impairment, leukoencephalopathy, and biochemical evidence of mitochondrial complex II deficiency (MC2DN4; <a href="/entry/619224">619224</a>), <a href="#1" class="mim-tip-reference" title="Alston, C. L., Davison, J. E., Meloni, F., van der Westhuizen, F. H., He, L., Hornig-Do, H.-T., Peet, A. C., Gissen, P., Goffrini, P., Ferrero, I., Wassmer, E., McFarland, R., Taylor, R. W. <strong>Recessive germline SDHA and SDHB mutations causing leukodystrophy and isolated mitochondrial complex II deficiency.</strong> J. Med. Genet. 49: 569-577, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22972948/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22972948</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22972948[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/jmedgenet-2012-101146" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22972948">Alston et al. (2012)</a> identified a homozygous missense mutation in the SDHB gene (D48V; <a href="#0020">185470.0020</a>). Her unaffected parents were heterozygous for the mutation. Patient fibroblasts showed decreased amounts of fully assembled complex II and almost complete absence of the SDHB subunit. Complex II activity was also decreased in patient muscle samples. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22972948" 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 Pakistani girl, born to consanguineous parents, with MC2DN4, <a href="#2" class="mim-tip-reference" title="Ardissone, A., Invernizzi, F., Nasca, A., Moroni, I., Farina, L., Ghezzi, D. <strong>Mitochondrial leukoencephalopathy and complex II deficiency associated with a recessive SDHB mutation with reduced penetrance.</strong> Molec. Genet. Metab. Rep. 5: 51-54, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26925370/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26925370</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26925370[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.ymgmr.2015.10.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26925370">Ardissone et al. (2015)</a> identified homozygosity for the previously reported D48V mutation in the SDHB gene. The mutation was found by sequencing of a panel of 7 genes associated with complex II deficiency. A clinically unaffected sib was also homozygous for the mutation. SDHB protein expression was reduced in patient fibroblasts and lymphocytes as well as in lymphocytes from the clinically unaffected sib. SDHA protein was also reduced in these cells, possibly due to instability of complex II assembly. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26925370" 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 Turkish boy (patient LD_0756.0A), born of consanguineous parents, with MC2DN4, <a href="#40" class="mim-tip-reference" title="Vanderver, A., Simons, C., Helman, G., Crawford, J., Wolf, N. I., Bernard, G., Pizzino, A., Schmidt, J. L., Takanohashi, A., Miller, D., Khouzam, A., Rajan, V., and 17 others. <strong>Whole exome sequencing in patients with white matter abnormalities.</strong> Ann. Neurol. 79: 1031-1037, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27159321/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27159321</a>] [<a href="https://doi.org/10.1002/ana.24650" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27159321">Vanderver et al. (2016)</a> identified homozygosity for the D48V mutation in the SDHB gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27159321" 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 6 patients with MC2DN4, <a href="#18" class="mim-tip-reference" title="Helman, G., Caldovic, L., Whitehead, M. T., Simons, C., Brockmann, K., Edvardson, S., Bai, R., Moroni, I., Taylor, J. M., Van Haren K., SDH Study Group, Taft, R. J., Vanderver, A., van der Knaap, M. S. <strong>Magnetic resonance imaging spectrum of succinate dehydrogenase-related infantile leukoencephalopathy.</strong> Ann. Neurol. 79: 379-386, 2016. Note: Erratum: Ann. Neurol. 84: 481 only, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26642834/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26642834</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26642834[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/10.1002/ana.24572" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26642834">Helman et al. (2016)</a> identified mutations in the SDHB gene. Five patients had the D48V mutation, 4 (patients 10, 11, 16, and 19) in homozygous state and 1 (patient 15) in compound heterozygous state. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26642834" 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 2 unrelated children with MC2DN4, <a href="#16" class="mim-tip-reference" title="Gronborg, S., Darin, N., Miranda, M. J., Damgaard, B., Cayuela, J. A., Oldfors, A., Kollberg, G., Hansen, T. V. O., Ravn, K., Wibrand, F., Ostergaard, E. <strong>Leukoencephalopathy due to complex II deficiency and bi-allelic SDHB mutations: further cases and implications for genetic counselling.</strong> JIMD Rep. 33: 69-77, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27604842/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27604842</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27604842[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/10.1007/8904_2016_582" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27604842">Gronborg et al. (2017)</a> identified mutations in the SDHB gene: a Lebanese girl, born of consanguineous parents, was homozygous for a missense mutation (L257V; <a href="#0022">185470.0022</a>), and a boy, born of nonconsanguineous parents, was compound heterozygous for D48V and another missense mutation (R230H; <a href="#0023">185470.0023</a>). In both patients, SDHB protein content was reduced in patient fibroblasts, muscle fibers showed diffuse and severe lack of SDH staining, and complex II enzyme activity was severely deficient in muscle. The parents of both children were confirmed to be mutation carriers. <a href="#16" class="mim-tip-reference" title="Gronborg, S., Darin, N., Miranda, M. J., Damgaard, B., Cayuela, J. A., Oldfors, A., Kollberg, G., Hansen, T. V. O., Ravn, K., Wibrand, F., Ostergaard, E. <strong>Leukoencephalopathy due to complex II deficiency and bi-allelic SDHB mutations: further cases and implications for genetic counselling.</strong> JIMD Rep. 33: 69-77, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27604842/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27604842</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27604842[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/10.1007/8904_2016_582" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27604842">Gronborg et al. (2017)</a> noted that the R230H mutation was previously reported in heterozygous state in patients with paraganglioma by several authors, including <a href="#12" class="mim-tip-reference" title="Cerecer-Gil, N. Y., Figuera, L. E., Llamas, F. J., Lara, M., Escamilla, J. G., Ramos, R., Estrada, G., Karim Hussain, A., Gaal, J., Korpershoek, E., de Krijger, R. R., Dinjens, W. N. M., Devilee, P., Bayley, J. P. <strong>Mutation of SDHB is a cause of hypoxia-related high-altitude paraganglioma.</strong> Clin. Cancer Res. 16: 4148-4158, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20592014/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20592014</a>] [<a href="https://doi.org/10.1158/1078-0432.CCR-10-0637" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20592014">Cerecer-Gil et al. (2010)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=27604842+20592014" 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 with MC2DN4, who was born to nonconsanguineous Indian parents, <a href="#21" class="mim-tip-reference" title="Kaur, P., Sharma, S., Kadavigere, R., Girisha K. M., Shukla, A. <strong>Novel variant p.(Ala102Thr) in SDHB causes mitochondrial complex II deficiency: case report and review of the literature.</strong> Ann. Hum. Genet. 84: 345-351, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32124427/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32124427</a>] [<a href="https://doi.org/10.1111/ahg.12377" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32124427">Kaur et al. (2020)</a> identified a homozygous missense mutation in the SDHB gene (A102T; <a href="#0024">185470.0024</a>). The parents were heterozygous for the mutation. The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32124427" 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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<p>In affected members of 3 families with pheochromocytoma/paraganglioma syndrome-4 (PPGL4; <a href="/entry/115310">115310</a>), <a href="#3" class="mim-tip-reference" title="Astuti, D., Latif, F., Dallol, A., Dahia, P. L. M., Douglas, F., George, E., Skoldberg, F., Husebye, E. S., Eng, C., Maher, E. R. <strong>Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma.</strong> Am. J. Hum. Genet. 69: 49-54, 2001. Note: Erratum: Am. J. Hum. Genet. 70: 565 only, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11404820/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11404820</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11404820[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/10.1086/321282" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11404820">Astuti et al. (2001)</a> identified a 402C-T transition in the SDHB gene, resulting in an arg90-to-ter (R90X) substitution. The mutation was predicted to result in a truncated SDHB protein lacking the C-terminal 191 amino acids. One of the families had been reported by <a href="#36" class="mim-tip-reference" title="Skoldberg, F., Grimelius, L., Woodward, E. R., Rorsman, F., Van Schothorst, E. W., Winqvist, O., Karlsson, F. A., Akerstrom, G., Kampe, O., Husebye, E. S. <strong>A family with hereditary extra-adrenal paragangliomas without evidence for mutations in the von Hippel-Lindau disease or ret genes.</strong> Clin. Endocr. 48: 11-16, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9509062/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9509062</a>] [<a href="https://doi.org/10.1046/j.1365-2265.1998.00320.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9509062">Skoldberg et al. (1998)</a>. The mutation occurred at a hypermutable CpG dinucleotide; haplotype analysis of the 3 families supported independent origin of the mutations. This mutation was originally published as ARG91TER; the corrected numbering appeared in an erratum. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9509062+11404820" 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> rs74315367 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs74315367;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/rs74315367?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=rs74315367" 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=rs74315367" 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=RCV000013617 OR RCV000030623 OR RCV000213984 OR RCV000465474 OR RCV001810856" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013617, RCV000030623, RCV000213984, RCV000465474, RCV001810856" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013617...</a>
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<p>In a family containing 3 individuals with familial extraadrenal pheochromocytoma and without evidence of cervical paragangliomas (PPGL4; <a href="/entry/115310">115310</a>), <a href="#3" class="mim-tip-reference" title="Astuti, D., Latif, F., Dallol, A., Dahia, P. L. M., Douglas, F., George, E., Skoldberg, F., Husebye, E. S., Eng, C., Maher, E. R. <strong>Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma.</strong> Am. J. Hum. Genet. 69: 49-54, 2001. Note: Erratum: Am. J. Hum. Genet. 70: 565 only, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11404820/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11404820</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11404820[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/10.1086/321282" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11404820">Astuti et al. (2001)</a> identified a heterozygous 724C-G transversion in exon 6 of the SDHB gene, resulting in a pro197-to-arg (P197R) substitution. This proline is conserved throughout all living species analyzed, from human to rat, Drosophila, yeast, and E. coli. This mutation was originally published as PRO198ARG; the corrected numbering appeared in an erratum. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11404820" 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>.0003 PHEOCHROMOCYTOMA/PARAGANGLIOMA SYNDROME 4</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">rs1060503757 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1060503757;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=rs1060503757" 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=rs1060503757" 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=RCV000473527 OR RCV000561023 OR RCV000986261 OR RCV001813782 OR RCV003335344 OR RCV004999485" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000473527, RCV000561023, RCV000986261, RCV001813782, RCV003335344, RCV004999485" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000473527...</a>
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<p>In a 55-year-old woman with a single sporadic adrenal pheochromocytoma (PPGL4; <a href="/entry/115310">115310</a>), <a href="#3" class="mim-tip-reference" title="Astuti, D., Latif, F., Dallol, A., Dahia, P. L. M., Douglas, F., George, E., Skoldberg, F., Husebye, E. S., Eng, C., Maher, E. R. <strong>Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma.</strong> Am. J. Hum. Genet. 69: 49-54, 2001. Note: Erratum: Am. J. Hum. Genet. 70: 565 only, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11404820/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11404820</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11404820[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/10.1086/321282" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11404820">Astuti et al. (2001)</a> identified a heterozygous 1-bp deletion (725delC) in exon 6 of the SDHB gene in both blood and tumor tissue. The tumor DNA did not exhibit loss of heterozygosity for markers flanking SDHB. SDHB mutations were not identified in 23 other cases of sporadic pheochromocytomas. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11404820" 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>.0004 PHEOCHROMOCYTOMA/PARAGANGLIOMA SYNDROME 4</strong>
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GASTROINTESTINAL STROMAL TUMOR, INCLUDED
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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> rs74315368 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs74315368;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/rs74315368?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=rs74315368" 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=rs74315368" 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=RCV000013619 OR RCV000022778 OR RCV000129095 OR RCV000183216 OR RCV000505354 OR RCV000627751 OR RCV001836632 OR RCV004786257" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013619, RCV000022778, RCV000129095, RCV000183216, RCV000505354, RCV000627751, RCV001836632, RCV004786257" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013619...</a>
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<p>In a man and his son, both of whom had metastatic catecholamine-secreting paragangliomas (PPGL4; <a href="/entry/115310">115310</a>), <a href="#42" class="mim-tip-reference" title="Young, A. L., Baysal, B. E., Deb, A., Young, W. F., Jr. <strong>Familial malignant catecholamine-secreting paraganglioma with prolonged survival associated with mutation in the succinate dehydrogenase B gene.</strong> J. Clin. Endocr. Metab. 87: 4101-4105, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12213855/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12213855</a>] [<a href="https://doi.org/10.1210/jc.2002-020312" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12213855">Young et al. (2002)</a> identified a 725G-A transition in exon 7 of the SDHB gene, resulting in an arg242-to-his (R242H) substitution. Sequencing of the SDHB gene in the tumors did not reveal any somatic mutations or loss of heterozygosity of the remaining allele. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12213855" 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="Neumann, H. P. H., Bausch, B., McWhinney, S. R., Bender, B. U., Gimm, O., Franke, G., Schipper, J., Klisch, J., Altehoefer, C., Zerres, K., Januszewicz, A., Eng, C. <strong>Germ-line mutations in nonsyndromic pheochromocytoma.</strong> New Eng. J. Med. 346: 1459-1466, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12000816/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12000816</a>] [<a href="https://doi.org/10.1056/NEJMoa020152" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12000816">Neumann et al. (2002)</a> identified the R242H substitution in the germline of a patient with sporadic pheochromocytoma. The mutation was not identified in 600 control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12000816" 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="#20" class="mim-tip-reference" title="Janeway, K. A., Kim, S. Y., Lodish, M., Nose, V., Rustin, P., Gaal, J., Dahia, P. L. M., Liegl, B., Ball, E. R., Raygada, M., Lai, A. H., Kelly, L., and 10 others. <strong>Defects in succinate dehydrogenase in gastrointestinal stromal tumors lacking KIT and PDGFRA mutations.</strong> Proc. Nat. Acad. Sci. 108: 314-318, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21173220/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21173220</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21173220[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.1009199108" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21173220">Janeway et al. (2011)</a> identified a germline R242H mutation in a 21-year-old patient with a sporadic gastrointestinal stromal tumor (GIST; <a href="/entry/606764">606764</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21173220" 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>.0005 PHEOCHROMOCYTOMA/PARAGANGLIOMA SYNDROME 4</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">rs587781266 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587781266;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=rs587781266" 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=rs587781266" 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=RCV000013621 OR RCV000128877 OR RCV001034689 OR RCV001797588" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013621, RCV000128877, RCV001034689, RCV001797588" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013621...</a>
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<p>Among 16 probands with pheochromocytoma/paragangliomas-4 (PGL4; <a href="/entry/115310">115310</a>), <a href="#41" class="mim-tip-reference" title="Vanharanta, S., Buchta, M., McWhinney, S. R., Virta, S. K., Peczkowska, M., Morrison, C. D., Lehtonen, R., Januszewicz, A., Jarvinen, H., Juhola, M., Mecklin, J.-P., Pukkala, E., Herva, R., Kiuru, M., Nupponen, N. N., Aaltonen, L. A., Neumann, H. P. H., Eng, C. <strong>Early-onset renal cell carcinoma as a novel extraparaganglial component of SDHB-associated heritable paraganglioma.</strong> Am. J. Hum. Genet. 74: 153-159, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14685938/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14685938</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14685938[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/10.1086/381054" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14685938">Vanharanta et al. (2004)</a> found 1 family with an 847_850delTCTC germline mutation in which 2 members had renal cell carcinoma (see <a href="/entry/144700">144700</a>) of solid histology, at ages 24 and 26 years. Both also had paraganglioma. Tumor tissue from the RCCs showed loss of the remaining wildtype allele. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14685938" 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="Neumann, H. P. H., Bausch, B., McWhinney, S. R., Bender, B. U., Gimm, O., Franke, G., Schipper, J., Klisch, J., Altehoefer, C., Zerres, K., Januszewicz, A., Eng, C. <strong>Germ-line mutations in nonsyndromic pheochromocytoma.</strong> New Eng. J. Med. 346: 1459-1466, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12000816/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12000816</a>] [<a href="https://doi.org/10.1056/NEJMoa020152" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12000816">Neumann et al. (2002)</a> identified the 847delTCTC mutation in the germlines of 2 unrelated patients with sporadic pheochromocytoma. The mutation was not identified in 600 control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12000816" 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>.0006 PHEOCHROMOCYTOMA/PARAGANGLIOMA SYNDROME 4</strong>
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SDHB, ARG27TER
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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> rs74315369 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs74315369;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/rs74315369?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=rs74315369" 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=rs74315369" 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=RCV000013623 OR RCV000129929 OR RCV000471400 OR RCV000505368 OR RCV000657585 OR RCV003473085" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013623, RCV000129929, RCV000471400, RCV000505368, RCV000657585, RCV003473085" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013623...</a>
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<p>In a registry of early-onset renal cell carcinomas (see <a href="/entry/144700">144700</a>), <a href="#41" class="mim-tip-reference" title="Vanharanta, S., Buchta, M., McWhinney, S. R., Virta, S. K., Peczkowska, M., Morrison, C. D., Lehtonen, R., Januszewicz, A., Jarvinen, H., Juhola, M., Mecklin, J.-P., Pukkala, E., Herva, R., Kiuru, M., Nupponen, N. N., Aaltonen, L. A., Neumann, H. P. H., Eng, C. <strong>Early-onset renal cell carcinoma as a novel extraparaganglial component of SDHB-associated heritable paraganglioma.</strong> Am. J. Hum. Genet. 74: 153-159, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14685938/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14685938</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14685938[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/10.1086/381054" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14685938">Vanharanta et al. (2004)</a> found a family in which both a son with clear cell RCC and his mother with a cardiac paraganglioma tumor (PPGL4; <a href="/entry/115310">115310</a>) had an arg27-to-ter (R27X) germline mutation in the SDHB gene. Tumor tissue from the RCC showed loss of the remaining wildtype allele. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14685938" 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="Neumann, H. P. H., Bausch, B., McWhinney, S. R., Bender, B. U., Gimm, O., Franke, G., Schipper, J., Klisch, J., Altehoefer, C., Zerres, K., Januszewicz, A., Eng, C. <strong>Germ-line mutations in nonsyndromic pheochromocytoma.</strong> New Eng. J. Med. 346: 1459-1466, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12000816/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12000816</a>] [<a href="https://doi.org/10.1056/NEJMoa020152" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12000816">Neumann et al. (2002)</a> identified the R27X substitution in the germline of patient with sporadic pheochromocytoma. The R27X substitution resulted from a 213C-T transition in exon 2 of the SDHB gene. The mutation was not identified in 600 control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12000816" 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>.0007 PHEOCHROMOCYTOMA/PARAGANGLIOMA SYNDROME 4</strong>
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SDHB, 1.0-KB DEL, EX1
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000013625" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013625" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013625</a>
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<p>In a Brazilian family with 3 affected members in 2 generations with paragangliomas (PPGL4; <a href="/entry/115310">115310</a>), <a href="#28" class="mim-tip-reference" title="McWhinney, S. R., Pilarski, R. T., Forrester, S. R., Schneider, M. C., Sarquis, M. M., Dias, E. P., Eng, C. <strong>Large germline deletions of mitochondrial complex II subunits SDHB and SDHD in hereditary paraganglioma.</strong> J. Clin. Endocr. Metab. 89: 5694-5699, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15531530/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15531530</a>] [<a href="https://doi.org/10.1210/jc.2004-0769" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15531530">McWhinney et al. (2004)</a> identified an approximately 1.0-kb germline deletion of the 5-prime end of the SDHB gene, including all or part of exon 1. Breakpoints were delineated in the 5-prime UTR and in intron 1 of the SDHB gene. See <a href="#0017">185470.0017</a> and <a href="#0018">185470.0018</a> for additional reports of SDHB exon 1 deletions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15531530" 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>.0008 PHEOCHROMOCYTOMA/PARAGANGLIOMA SYNDROME 4</strong>
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SDHB, ARG46GLY
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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> rs74315370 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs74315370;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/rs74315370?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=rs74315370" 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=rs74315370" 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=RCV000216404 OR RCV000800486 OR RCV003335029 OR RCV004732542" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000216404, RCV000800486, RCV003335029, RCV004732542" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000216404...</a>
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<p>In the germlines of 2 unrelated patients with sporadic pheochromocytoma (PPGL4; <a href="/entry/115310">115310</a>), <a href="#29" class="mim-tip-reference" title="Neumann, H. P. H., Bausch, B., McWhinney, S. R., Bender, B. U., Gimm, O., Franke, G., Schipper, J., Klisch, J., Altehoefer, C., Zerres, K., Januszewicz, A., Eng, C. <strong>Germ-line mutations in nonsyndromic pheochromocytoma.</strong> New Eng. J. Med. 346: 1459-1466, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12000816/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12000816</a>] [<a href="https://doi.org/10.1056/NEJMoa020152" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12000816">Neumann et al. (2002)</a> identified a 270C-G transversion in exon 2 of the SDHB gene, resulting in an arg46-to-gly (R46G) substitution. The mutation was not identified in 600 control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12000816" 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="0009" class="mim-anchor"></a>
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<span class="mim-font">
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<strong>.0009 PHEOCHROMOCYTOMA/PARAGANGLIOMA SYNDROME 4</strong>
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SDHB, CYS101TYR
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs74315371 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs74315371;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=rs74315371" 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=rs74315371" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV003335030" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV003335030" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV003335030</a>
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<p>In the germlines of 2 unrelated patients with sporadic pheochromocytoma (PPGL4; <a href="/entry/115310">115310</a>), <a href="#29" class="mim-tip-reference" title="Neumann, H. P. H., Bausch, B., McWhinney, S. R., Bender, B. U., Gimm, O., Franke, G., Schipper, J., Klisch, J., Altehoefer, C., Zerres, K., Januszewicz, A., Eng, C. <strong>Germ-line mutations in nonsyndromic pheochromocytoma.</strong> New Eng. J. Med. 346: 1459-1466, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12000816/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12000816</a>] [<a href="https://doi.org/10.1056/NEJMoa020152" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12000816">Neumann et al. (2002)</a> identified a 436G-A transition in exon 4 of the SDHB gene, resulting in a cys101-to-tyr (C101Y) substitution. The mutation was not identified in 600 control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12000816" 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="0010" class="mim-anchor"></a>
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<span class="mim-font">
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<strong>.0010 PHEOCHROMOCYTOMA/PARAGANGLIOMA SYNDROME 4</strong>
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SDHB, HIS132PRO
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs74315372 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs74315372;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=rs74315372" 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=rs74315372" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000013628 OR RCV001021521 OR RCV001857343" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013628, RCV001021521, RCV001857343" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013628...</a>
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<p>By analysis of the germline DNA from 2 brothers and their mother with malignant extraadrenal abdominal paragangliomas (PPGL4; <a href="/entry/115310">115310</a>), <a href="#25" class="mim-tip-reference" title="Maier-Woelfle, M., Brandle, M., Komminoth, P., Saremaslani, P., Schmid, S., Locher, T., Heitz, P. U., Krull, I., Galeazzi, R. L., Schmid, C., Perren, A. <strong>A novel succinate dehydrogenase subunit B gene mutation, H132P, causes familial malignant sympathetic extraadrenal paragangliomas.</strong> J. Clin. Endocr. Metab. 89: 362-267, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14715873/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14715873</a>] [<a href="https://doi.org/10.1210/jc.2003-031236" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14715873">Maier-Woelfle et al. (2004)</a> identified heterozygosity for an A-to-C transversion in the SDHB gene, resulting in a his132-to-pro (H132P) substitution. The variant was absent in 160 control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14715873" 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="0011" class="mim-anchor"></a>
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<strong>.0011 PHEOCHROMOCYTOMA, SOMATIC</strong>
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SDHB, SER100PHE
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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> rs121917755 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121917755;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/rs121917755?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=rs121917755" 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=rs121917755" 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=RCV000013629 OR RCV001851830 OR RCV004599210" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013629, RCV001851830, RCV004599210" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013629...</a>
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<p>In tumor tissue from a woman with sporadic extraadrenal pheochromocytoma (see <a href="/entry/171300">171300</a>) in the bladder wall, <a href="#39" class="mim-tip-reference" title="van Nederveen, F. H., Korpershoek, E., Lenders, J. W. M., de Krijger, R. R., Dinjens, W. N. M. <strong>Somatic SDHB mutation in an extraadrenal pheochromocytoma. (Letter)</strong> New Eng. J. Med. 357: 306-309, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17634472/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17634472</a>] [<a href="https://doi.org/10.1056/NEJMc070010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17634472">van Nederveen et al. (2007)</a> identified a heterozygous 299C-T transition in exon 4 of the SDHB gene, resulting in a ser100-to-phe (S100F) substitution. Comparative genomic hybridization and FISH analysis showed loss of heterozygosity of chromosome 1p in tumor tissue, indicating biallelic inactivation of the SDHB gene. There was absence of SDHB expression in tumor cells, indicating complete loss of SDHB function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17634472" 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 PARAGANGLIOMA AND GASTRIC STROMAL SARCOMA</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> rs587782703 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587782703;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/rs587782703?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=rs587782703" 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=rs587782703" 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=RCV000013630 OR RCV000132151 OR RCV000153923 OR RCV000232241 OR RCV000505343 OR RCV001001437 OR RCV003148657 OR RCV003474785 OR RCV004732698" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013630, RCV000132151, RCV000153923, RCV000232241, RCV000505343, RCV001001437, RCV003148657, RCV003474785, RCV004732698" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013630...</a>
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<p>In a mother and son with paraganglioma and gastric stromal sarcoma (<a href="/entry/606864">606864</a>), <a href="#27" class="mim-tip-reference" title="McWhinney, S. R., Pasini, B., Stratakis, C. A. <strong>Familial gastrointestinal stromal tumors and germ-line mutations. (Letter)</strong> New Eng. J. Med. 357: 1054-1056, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17804857/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17804857</a>] [<a href="https://doi.org/10.1056/NEJMc071191" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17804857">McWhinney et al. (2007)</a> identified a germline G-to-T transversion at the splice donor site in intron 1 (IVS1DS+1) of the SDHB gene. <a href="#32" class="mim-tip-reference" title="Pasini, B., McWhinney, S. R., Bei, T., Matyakhina, L., Stergiopoulos, S., Muchow, M., Boikos, S. A., Ferrando, B., Pacak, K., Assie, G., Baudin, E., Chompret, A., Ellison, J. W., Briere, J.-J., Rustin, P., Gimenez-Roqueplo, A.-P., Eng, C., Carney, J. A., Stratakis, C. A. <strong>Clinical and molecular genetics of patients with the Carney-Stratakis syndrome and germline mutations of the genes coding for the succinate dehydrogenase subunits SDHB, SDHC, and SDHD.</strong> Europ. J. Hum. Genet. 16: 79-88, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17667967/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17667967</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201904" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17667967">Pasini et al. (2008)</a> provided additional information on this family with a G-T transversion at position 72+1 in the SDHB gene. The son presented at 37 years of age with melena due to a gastric stromal sarcoma and on further evaluation was found to have a nonfunctioning periaortic ganglioma. Sequencing of a heterozygous aberrant transcript from his WBCs indicated that the first part of intron 1 was transcribed, resulting in a significantly truncated protein with a stop codon in the middle of exon 2. DNA analysis of a tumor sample showed loss of heterozygosity with only the mutant SDHB sequence present. The patient's mother underwent surgery for a pheochromocytoma at 57 years of age, but DNA was not available for analysis. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17804857+17667967" 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> rs398122805 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs398122805;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/rs398122805?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=rs398122805" 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=rs398122805" 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=RCV000013631" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013631" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013631</a>
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<p>In male twin sibs with paraganglioma and gastric stromal sarcoma (<a href="/entry/606864">606864</a>), previously described by <a href="#8" class="mim-tip-reference" title="Boccon-Gibod, L., Boman, F., Boudjemaa, S., Fabre, M., Leverger, G., Carney, A. J. <strong>Separate occurrence of extra-adrenal paraganglioma and gastrointestinal stromal tumor in monozygotic twins: probable familial Carney syndrome.</strong> Pediatr. Dev. Pathol. 7: 380-384, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15383933/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15383933</a>] [<a href="https://doi.org/10.1007/s10024-004-8090-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15383933">Boccon-Gibod et al. (2004)</a>, <a href="#27" class="mim-tip-reference" title="McWhinney, S. R., Pasini, B., Stratakis, C. A. <strong>Familial gastrointestinal stromal tumors and germ-line mutations. (Letter)</strong> New Eng. J. Med. 357: 1054-1056, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17804857/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17804857</a>] [<a href="https://doi.org/10.1056/NEJMc071191" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17804857">McWhinney et al. (2007)</a> identified a germline G-C transversion at nucleotide 423+1 in the SDHB gene. Their unaffected mother and an unaffected sister also carried the mutation. <a href="#32" class="mim-tip-reference" title="Pasini, B., McWhinney, S. R., Bei, T., Matyakhina, L., Stergiopoulos, S., Muchow, M., Boikos, S. A., Ferrando, B., Pacak, K., Assie, G., Baudin, E., Chompret, A., Ellison, J. W., Briere, J.-J., Rustin, P., Gimenez-Roqueplo, A.-P., Eng, C., Carney, J. A., Stratakis, C. A. <strong>Clinical and molecular genetics of patients with the Carney-Stratakis syndrome and germline mutations of the genes coding for the succinate dehydrogenase subunits SDHB, SDHC, and SDHD.</strong> Europ. J. Hum. Genet. 16: 79-88, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17667967/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17667967</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201904" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17667967">Pasini et al. (2008)</a> provided additional information on these monozygotic twins with the IVS4+1G-C mutation. One had surgery at 12 years of age for a nonfunctioning paraganglioma of the organ of Zuckerkandl and the other at 13 years of age for a gastric stromal sarcoma. Analysis of lymphocyte DNA from 1 of the brothers showed that the last 18 codons of exon 4 were spliced out, resulting in a truncated protein. The mother and older sister who carried the mutation had negative examinations for gastric stromal carcinoma and paraganglioma. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15383933+17804857+17667967" 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>.0014 RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE</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> rs11203289 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs11203289;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/rs11203289?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=rs11203289" 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=rs11203289" 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=RCV000013632 OR RCV000034690 OR RCV000121999 OR RCV000128921 OR RCV000275977 OR RCV000368190 OR RCV000755699 OR RCV000986270 OR RCV001079357 OR RCV002490359 OR RCV004532333" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013632, RCV000034690, RCV000121999, RCV000128921, RCV000275977, RCV000368190, RCV000755699, RCV000986270, RCV001079357, RCV002490359, RCV004532333" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013632...</a>
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<p>This variant, formerly titled COWDEN SYNDROME 2, has been reclassified based on a review of the ExAC database by <a href="#17" class="mim-tip-reference" title="Hamosh, A. <strong>Personal Communication.</strong> Baltimore, Md. 7/11/2018."None>Hamosh (2018)</a>.</p><p>In a patient with a Cowden-like phenotype (see <a href="/entry/158350">158350</a>), <a href="#30" class="mim-tip-reference" title="Ni, Y., Zbuk, K. M., Sadler, T., Patocs, A., Lobo, G., Edelman, E., Platzer, P., Orloff, M. S., Waite, K. A., Eng, C. <strong>Germline mutations and variants in the succinate dehydrogenase genes in Cowden and Cowden-like syndromes.</strong> Am. J. Hum. Genet. 83: 261-268, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18678321/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18678321</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18678321[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.ajhg.2008.07.011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18678321">Ni et al. (2008)</a> identified a heterozygous C-to-G transversion in the SDHB gene, resulting in an ala3-to-gly (A3G) substitution. The mutation was not identified in 700 control subjects. This mutation was associated with increased manganese superoxide dismutase expression, normal reactive oxygen species, and a 1.2-fold increase in AKT expression and 1.3-fold change in MAPK expression. The patient was a 41-year-old woman with breast cancer and uterine leiomyomas and a family history of endometrial cancer. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18678321" 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="#7" class="mim-tip-reference" title="Bayley, J.-P. <strong>Succinate dehydrogenase gene variants and their role in Cowden syndrome. (Letter)</strong> Am. J. Hum. Genet. 88: 674-675, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21565294/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21565294</a>] [<a href="https://doi.org/10.1016/j.ajhg.2010.12.016" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21565294">Bayley (2011)</a> commented that the findings of <a href="#30" class="mim-tip-reference" title="Ni, Y., Zbuk, K. M., Sadler, T., Patocs, A., Lobo, G., Edelman, E., Platzer, P., Orloff, M. S., Waite, K. A., Eng, C. <strong>Germline mutations and variants in the succinate dehydrogenase genes in Cowden and Cowden-like syndromes.</strong> Am. J. Hum. Genet. 83: 261-268, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18678321/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18678321</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18678321[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.ajhg.2008.07.011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18678321">Ni et al. (2008)</a> require independent confirmation, and suggested that functional studies of the SDH variants are essential before recommendations can be made for appropriate genetic counseling. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=18678321+21565294" 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="#17" class="mim-tip-reference" title="Hamosh, A. <strong>Personal Communication.</strong> Baltimore, Md. 7/11/2018."None>Hamosh (2018)</a> found that the A3G variant was present in heterozygous state in 426 of 97,714 alleles and in 8 homozygotes, with an allele frequency of 0.00436, in the ExAC database (July 11, 2018).</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> rs33927012 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs33927012;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/rs33927012?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=rs33927012" 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=rs33927012" 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=RCV000013633 OR RCV000034688 OR RCV000122002 OR RCV000132153 OR RCV000202946 OR RCV000206861 OR RCV000282667 OR RCV000986263 OR RCV001099292 OR RCV001269360" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013633, RCV000034688, RCV000122002, RCV000132153, RCV000202946, RCV000206861, RCV000282667, RCV000986263, RCV001099292, RCV001269360" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013633...</a>
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<p>This variant, formerly titled COWDEN SYNDROME 2, has been reclassified based on a review of the ExAC database by <a href="#17" class="mim-tip-reference" title="Hamosh, A. <strong>Personal Communication.</strong> Baltimore, Md. 7/11/2018."None>Hamosh (2018)</a>.</p><p>In 2 women with a Cowden-like phenotype (see <a href="/entry/158350">158350</a>), <a href="#30" class="mim-tip-reference" title="Ni, Y., Zbuk, K. M., Sadler, T., Patocs, A., Lobo, G., Edelman, E., Platzer, P., Orloff, M. S., Waite, K. A., Eng, C. <strong>Germline mutations and variants in the succinate dehydrogenase genes in Cowden and Cowden-like syndromes.</strong> Am. J. Hum. Genet. 83: 261-268, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18678321/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18678321</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18678321[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.ajhg.2008.07.011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18678321">Ni et al. (2008)</a> identified a heterozygous ser163-to-pro (S163P) substitution in the SDHB gene. This mutation was not found in 700 control subjects. This mutation was associated with increased manganese superoxide dismutase function, increased reactive oxygen species, and a 2.7-fold change in AKT expression and 1.7-fold increase in MAPK expression. The patients, 29 and 54 years old, had thyroid cancer, and both had a family history of breast cancer and papillary thyroid carcinoma. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18678321" 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="#7" class="mim-tip-reference" title="Bayley, J.-P. <strong>Succinate dehydrogenase gene variants and their role in Cowden syndrome. (Letter)</strong> Am. J. Hum. Genet. 88: 674-675, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21565294/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21565294</a>] [<a href="https://doi.org/10.1016/j.ajhg.2010.12.016" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21565294">Bayley (2011)</a> commented that the findings of <a href="#30" class="mim-tip-reference" title="Ni, Y., Zbuk, K. M., Sadler, T., Patocs, A., Lobo, G., Edelman, E., Platzer, P., Orloff, M. S., Waite, K. A., Eng, C. <strong>Germline mutations and variants in the succinate dehydrogenase genes in Cowden and Cowden-like syndromes.</strong> Am. J. Hum. Genet. 83: 261-268, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18678321/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18678321</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18678321[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.ajhg.2008.07.011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18678321">Ni et al. (2008)</a> require independent confirmation, and suggested that functional studies of the SDH variants are essential before recommendations can be made for appropriate genetic counseling. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=18678321+21565294" 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="#17" class="mim-tip-reference" title="Hamosh, A. <strong>Personal Communication.</strong> Baltimore, Md. 7/11/2018."None>Hamosh (2018)</a> found that the S163P variant was present in heterozygous state in 1,523 of 121,404 alleles and in 21 homozygotes, with an allele frequency of 0.01254, in the ExAC database (July 11, 2018).</p>
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<strong>.0016 PHEOCHROMOCYTOMA/PARAGANGLIOMA SYNDROME 4</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> rs267607032 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267607032;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/rs267607032?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=rs267607032" 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=rs267607032" 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=RCV000013634 OR RCV000132167 OR RCV000505378 OR RCV000505751 OR RCV000627753 OR RCV003473111 OR RCV004732551 OR RCV005007884" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013634, RCV000132167, RCV000505378, RCV000505751, RCV000627753, RCV003473111, RCV004732551, RCV005007884" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013634...</a>
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<p>In 2 sibs with paragangliomas (PPGL4; <a href="/entry/115310">115310</a>), <a href="#35" class="mim-tip-reference" title="Schimke, R. N., Collins, D. L., Stolle, C. A. <strong>Paraganglioma, neuroblastoma, and a SDHB mutation: resolution of a 30-year-old mystery.</strong> Am. J. Med. Genet. 152A: 1531-1535, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20503330/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20503330</a>] [<a href="https://doi.org/10.1002/ajmg.a.33384" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20503330">Schimke et al. (2010)</a> identified a heterozygous 418G-T transversion in the SDHB gene, resulting in a val140-to-phe (V140F) substitution. The 55-year-old sister and 49-year-old brother both had paraspinal paragangliomas. The mutation was also found in their unaffected 76-year-old mother, suggesting decreased penetrance or a 'leaky' mutation. The family was of note because a deceased sib had neuroblastoma as an infant, metastatic extraadrenal sympathetic paragangliomas reminiscent of pheochromocytoma as a young adult, and renal cell carcinoma as an adult; this patient had been previously reported by <a href="#14" class="mim-tip-reference" title="Fairchild, R. S., Kyner, J. L., Hermreck, A., Schimke, R. N. <strong>Neuroblastoma, pheochromocytoma, and renal cell carcinoma: occurrence in a single patient.</strong> JAMA 242: 2210-2211, 1979.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/490809/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">490809</a>]" pmid="490809">Fairchild et al. (1979)</a> as having unique occurrence of these cancers. In addition, a first cousin of these sibs had died from metastatic renal cell carcinoma and had a history of a benign paraaortic PGL. <a href="#35" class="mim-tip-reference" title="Schimke, R. N., Collins, D. L., Stolle, C. A. <strong>Paraganglioma, neuroblastoma, and a SDHB mutation: resolution of a 30-year-old mystery.</strong> Am. J. Med. Genet. 152A: 1531-1535, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20503330/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20503330</a>] [<a href="https://doi.org/10.1002/ajmg.a.33384" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20503330">Schimke et al. (2010)</a> noted the importance of family history in elucidating the etiology of this inherited disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=490809+20503330" 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=RCV000013635" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013635" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013635</a>
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<p><a href="#11" class="mim-tip-reference" title="Cascon, A., Montero-Conde, C., Ruiz-Llorente, S., Mercadillo, F., Leton, R., Rodriguez-Antona, C., Martinez-Delgado, B., Delgado, M., Diez, A., Rovira, A., Diaz, J. A., Robledo, M. <strong>Gross SDHB deletions in patients with paraganglioma detected by multiplex PCR: a possible hot spot?</strong> Genes Chromosomes Cancer 45: 213-219, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16258955/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16258955</a>] [<a href="https://doi.org/10.1002/gcc.20283" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16258955">Cascon et al. (2006)</a> detected a germline deletion affecting SDHB exon 1 in a 30-year-old Portuguese male with a secreting retroperitoneal paraganglioma (PPGL4; <a href="/entry/115310">115310</a>) and an uncertain family history. The authors found the same loss of SDHB exon 1 in a 14-year-old female proband from a Spanish family with a history of PGL. The proband was admitted to hospital with hypertension and later diagnosed with catecholamine-secreting PGL of the retroperitoneum. The proband's father was diagnosed at age 48 with PGL of the Zuckerkandl organ, which metastasized to the liver at age 53. Bone metastases were found 4 years later. The brothers of the proband also had high levels of dopamine in their urine. <a href="#11" class="mim-tip-reference" title="Cascon, A., Montero-Conde, C., Ruiz-Llorente, S., Mercadillo, F., Leton, R., Rodriguez-Antona, C., Martinez-Delgado, B., Delgado, M., Diez, A., Rovira, A., Diaz, J. A., Robledo, M. <strong>Gross SDHB deletions in patients with paraganglioma detected by multiplex PCR: a possible hot spot?</strong> Genes Chromosomes Cancer 45: 213-219, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16258955/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16258955</a>] [<a href="https://doi.org/10.1002/gcc.20283" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16258955">Cascon et al. (2006)</a> detected the germline deletion in all 3 of these relatives of the proband. No deletions affecting the SDHC or SDHD genes were found in any patients. Analysis of the genomic structure of the SDHB gene revealed a high density of Alu repeats within the first intron. The authors suggested that Alu-mediated recombination may account for the observed clustering of a gross deletion hotspot. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16258955" 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="#10" class="mim-tip-reference" title="Cascon, A., Landa, I., Lopez-Jimenez, E., Diez-Hernandez, A., Buchta, M., Montero-Conde, C., Leskela, S., Leandro-Garcia, L. J., Leton, R., Rodriguez-Antona, C., Eng, C., Neumann, H. P. H., Robledo, M. <strong>Molecular characterisation of a common SDHB deletion in paraganglioma patients. (Letter)</strong> J. Med. Genet. 45: 233-238, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18057081/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18057081</a>] [<a href="https://doi.org/10.1136/jmg.2007.054965" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18057081">Cascon et al. (2008)</a> reported 3 additional families, 2 of Spanish and 1 of French origin, with the SDHB exon 1 deletion. In the first Spanish family, the proband was diagnosed at age 19 with retroperitoneal PGL, and multiple metastases in bone, hypophysis, retroperitoneum, and liver. Her sister was diagnosed with an adrenal neuroblastoma with metastasis at age 5 years of age. The proband in the second Spanish family was diagnosed with abdominal PGL and renal oncocytoma at age 17; both were surgically resected. Ten years later she showed bone metastasis. In the French family, the proband had malignant pheochromocytoma (PCC) at age 27 years and died as a result of the disease. He had a relative with benign PCC, diagnosed at age 30 years. Molecular analysis revealed that same deletion breakpoints in all Spanish families resulting in a 15.69-kb deletion, including the 2 families previously reported by <a href="#11" class="mim-tip-reference" title="Cascon, A., Montero-Conde, C., Ruiz-Llorente, S., Mercadillo, F., Leton, R., Rodriguez-Antona, C., Martinez-Delgado, B., Delgado, M., Diez, A., Rovira, A., Diaz, J. A., Robledo, M. <strong>Gross SDHB deletions in patients with paraganglioma detected by multiplex PCR: a possible hot spot?</strong> Genes Chromosomes Cancer 45: 213-219, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16258955/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16258955</a>] [<a href="https://doi.org/10.1002/gcc.20283" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16258955">Cascon et al. (2006)</a>, and a different breakpoint junction in the French family, resulting in a 20.3-kb deletion (<a href="#0018">185470.0018</a>). Haplotype analysis indicated a founder effect in the Spanish families for the 15.69-kb deletion. All Spanish patients originally came from a small area in the northwest region of the Iberian peninsula. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16258955+18057081" 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="#37" class="mim-tip-reference" title="Solis, D. C., Burnichon, N., Timmers, H. J. L. M., Raygada, M. J., Kozupa, A., Merino, M. J., Makey, D., Adams, K. T., Venisse, A., Gimenez-Roqueplo, A.-P., Pacak, K. <strong>Penetrance and clinical consequences of a gross SDHB deletion in a large family.</strong> Clin. Genet. 75: 354-363, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19389109/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19389109</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19389109[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.1399-0004.2009.01157.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19389109">Solis et al. (2009)</a> reported a large 5-generation family of Spanish Mexican descent with the same 15.69-kb SDHB founder deletion previously described by Cascon et al. (<a href="#11" class="mim-tip-reference" title="Cascon, A., Montero-Conde, C., Ruiz-Llorente, S., Mercadillo, F., Leton, R., Rodriguez-Antona, C., Martinez-Delgado, B., Delgado, M., Diez, A., Rovira, A., Diaz, J. A., Robledo, M. <strong>Gross SDHB deletions in patients with paraganglioma detected by multiplex PCR: a possible hot spot?</strong> Genes Chromosomes Cancer 45: 213-219, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16258955/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16258955</a>] [<a href="https://doi.org/10.1002/gcc.20283" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16258955">2006</a>, <a href="#10" class="mim-tip-reference" title="Cascon, A., Landa, I., Lopez-Jimenez, E., Diez-Hernandez, A., Buchta, M., Montero-Conde, C., Leskela, S., Leandro-Garcia, L. J., Leton, R., Rodriguez-Antona, C., Eng, C., Neumann, H. P. H., Robledo, M. <strong>Molecular characterisation of a common SDHB deletion in paraganglioma patients. (Letter)</strong> J. Med. Genet. 45: 233-238, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18057081/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18057081</a>] [<a href="https://doi.org/10.1136/jmg.2007.054965" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18057081">2008</a>). Eleven of 41 mutation carriers developed PGL in various locations, including the carotid body, adrenal gland, pelvis, and thorax. Penetrance of the founder deletion was estimated to be 35% by age 40 years. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16258955+18057081+19389109" 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>See <a href="#0017">185470.0017</a> and <a href="#10" class="mim-tip-reference" title="Cascon, A., Landa, I., Lopez-Jimenez, E., Diez-Hernandez, A., Buchta, M., Montero-Conde, C., Leskela, S., Leandro-Garcia, L. J., Leton, R., Rodriguez-Antona, C., Eng, C., Neumann, H. P. H., Robledo, M. <strong>Molecular characterisation of a common SDHB deletion in paraganglioma patients. (Letter)</strong> J. Med. Genet. 45: 233-238, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18057081/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18057081</a>] [<a href="https://doi.org/10.1136/jmg.2007.054965" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18057081">Cascon et al. (2008)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18057081" 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> rs398122805 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs398122805;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/rs398122805?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=rs398122805" 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=rs398122805" 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=RCV000022779 OR RCV000163600 OR RCV000481826 OR RCV000505379 OR RCV000627750 OR RCV000762867 OR RCV003473120" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000022779, RCV000163600, RCV000481826, RCV000505379, RCV000627750, RCV000762867, RCV003473120" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000022779...</a>
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<p>In 2 unrelated Dutch patients with sporadic occurrence of paragangliomas-4 (PPGL4; <a href="/entry/115310">115310</a>), <a href="#6" class="mim-tip-reference" title="Bayley, J.-P., van Minderhout, I., Weiss, M. M., Jansen, J. C., Oomen, P. H. N., Menko, F. H., Pasini, B., Ferrando, B., Wong, N., Alpert, L. C, Williams, R., Blair, E., Devilee, P., Taschner, P. E. M. <strong>Mutation analysis of SDHB and SDHC: novel germline mutations in sporadic head and neck paraganglioma and familial paraganglioma and/or pheochromocytoma.</strong> BMC Med. Genet. 7: 1, 2006. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16405730/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16405730</a>] [<a href="https://doi.org/10.1186/1471-2350-7-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16405730">Bayley et al. (2006)</a> identified a heterozygous G-to-A transition in intron 4 of the SDHB gene (423+1G-A). RT-PCR analysis from 1 patient showed that the mutation caused a splice site defect and an in-frame deletion of 18 amino acids. The mutation was not found in 300 control chromosomes. One patient was a 50-year-old man who presented with elevated catecholamine levels and a single jugular paraganglioma, and died at the age of 58 due to complications resulting from tumor recurrence. The second patient was a man who presented at age 55 with a single carotid body tumor that was successfully removed. The tumor from this patient was negative for SDH activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16405730" 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="Hensen, E. F., van Duinen, N., Jansen, J. C., Corssmit, E. P. M., Tops, C. M. J., Romijn, J. A., Vriends, A. H. J. T., van der Mey, A. G. L., Cornelisse, C. J., Devilee, P., Bayley, J. P. <strong>High prevalence of founder mutations of the succinate dehydrogenase genes in the Netherlands.</strong> Clin. Genet. 81: 284-288, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21348866/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21348866</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2011.01653.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21348866">Hensen et al. (2012)</a> found the 423+1G-A mutation in 22 patients from 9 Dutch families with paragangliomas, making it the most common mutation in the SDHB gene identified in their cohort of 1,045 patients from 340 families. The findings were consistent with a founder effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21348866" 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 MITOCHONDRIAL COMPLEX II DEFICIENCY, NUCLEAR TYPE 4</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> rs202101384 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs202101384;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/rs202101384?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=rs202101384" 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=rs202101384" 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=RCV000032784 OR RCV000470589 OR RCV001011583 OR RCV001249469 OR RCV001578167 OR RCV003315403 OR RCV003473248" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000032784, RCV000470589, RCV001011583, RCV001249469, RCV001578167, RCV003315403, RCV003473248" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000032784...</a>
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<p>In an Asian girl, born of consanguineous parents, with mitochondrial complex II deficiency nuclear type 4 (MC2DN4; <a href="/entry/619224">619224</a>), <a href="#1" class="mim-tip-reference" title="Alston, C. L., Davison, J. E., Meloni, F., van der Westhuizen, F. H., He, L., Hornig-Do, H.-T., Peet, A. C., Gissen, P., Goffrini, P., Ferrero, I., Wassmer, E., McFarland, R., Taylor, R. W. <strong>Recessive germline SDHA and SDHB mutations causing leukodystrophy and isolated mitochondrial complex II deficiency.</strong> J. Med. Genet. 49: 569-577, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22972948/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22972948</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22972948[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/jmedgenet-2012-101146" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22972948">Alston et al. (2012)</a> identified a homozygous c.143A-T transversion (c.143A-T, NM_003000.2) in exon 2 of the SDHB gene, resulting in an asp48-to-val (D48V) substitution. Her unaffected parents were heterozygous for the mutation. The D48 residue is not conserved between human and yeast, but D48 is conservatively substituted by N42 in the yeast Sdh2 protein (yeast ortholog). Construction of an Sdh2 N42D allele rescued the oxidation growth defect of yeast with a deletion of the Sdh2 gene; the N42D variant showed normal SDH activity. Introduction of an N42V substitution did not impair growth of yeast or oxygen consumption, but did cause decreased SDH activity (about 50% of control). Patient fibroblasts showed decreased amounts of fully assembled complex II and almost complete absence of the SDHB subunit. Complex II activity was also decreased in patient muscle samples. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22972948" 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 Pakistani girl, born to consanguineous parents, with MC2DN4, <a href="#2" class="mim-tip-reference" title="Ardissone, A., Invernizzi, F., Nasca, A., Moroni, I., Farina, L., Ghezzi, D. <strong>Mitochondrial leukoencephalopathy and complex II deficiency associated with a recessive SDHB mutation with reduced penetrance.</strong> Molec. Genet. Metab. Rep. 5: 51-54, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26925370/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26925370</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26925370[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.ymgmr.2015.10.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26925370">Ardissone et al. (2015)</a> identified homozygosity for the D48V mutation in the SDHB gene. The mutation, which was identified by sequencing of a panel of 7 genes associated with complex II deficiency, was confirmed by Sanger sequencing. The parents were confirmed to be carriers, and a clinically unaffected older sib was also homozygous for the mutation. The D48V mutation was observed in ExAC at a low frequency of 0.036% in only South Asian subjects, with no homozygotes reported. SDHB protein expression was reduced in patient fibroblasts and lymphocytes as well as in lymphocytes from the clinically unaffected sib who also homozygous for the mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26925370" 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 Turkish boy (patient LD_0756.0A) with MC2DN4, who was born of consanguineous parents, <a href="#40" class="mim-tip-reference" title="Vanderver, A., Simons, C., Helman, G., Crawford, J., Wolf, N. I., Bernard, G., Pizzino, A., Schmidt, J. L., Takanohashi, A., Miller, D., Khouzam, A., Rajan, V., and 17 others. <strong>Whole exome sequencing in patients with white matter abnormalities.</strong> Ann. Neurol. 79: 1031-1037, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27159321/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27159321</a>] [<a href="https://doi.org/10.1002/ana.24650" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27159321">Vanderver et al. (2016)</a> identified homozygosity for the D48V mutation in the SDHB gene. The mutation was identified by whole-exome sequencing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27159321" 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 5 patients with MC2DN4, <a href="#18" class="mim-tip-reference" title="Helman, G., Caldovic, L., Whitehead, M. T., Simons, C., Brockmann, K., Edvardson, S., Bai, R., Moroni, I., Taylor, J. M., Van Haren K., SDH Study Group, Taft, R. J., Vanderver, A., van der Knaap, M. S. <strong>Magnetic resonance imaging spectrum of succinate dehydrogenase-related infantile leukoencephalopathy.</strong> Ann. Neurol. 79: 379-386, 2016. Note: Erratum: Ann. Neurol. 84: 481 only, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26642834/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26642834</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26642834[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/10.1002/ana.24572" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26642834">Helman et al. (2016)</a> identified the D48V mutation in the SDHB gene. It was present in homozygous state in 4 patients (patients 10, 11, 16, and 19) and in compound heterozygous state in 1 (patient 15). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26642834" 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, born on nonconsanguineous parents, with MC2DN4, <a href="#16" class="mim-tip-reference" title="Gronborg, S., Darin, N., Miranda, M. J., Damgaard, B., Cayuela, J. A., Oldfors, A., Kollberg, G., Hansen, T. V. O., Ravn, K., Wibrand, F., Ostergaard, E. <strong>Leukoencephalopathy due to complex II deficiency and bi-allelic SDHB mutations: further cases and implications for genetic counselling.</strong> JIMD Rep. 33: 69-77, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27604842/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27604842</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27604842[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/10.1007/8904_2016_582" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27604842">Gronborg et al. (2017)</a> identified compound heterozygous mutations in the SDHB gene: D48V and a c.689G-A transition resulting in an arg230-to-his (R230H; <a href="#0023">185470.0023</a>) substitution. The mutations were identified by whole-exome sequencing and confirmed by Sanger sequencing. The parents were confirmed to be mutation carriers. SDHB protein content was reduced in patient fibroblasts, and muscle fibers showed diffuse and severe lack of SDH staining. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27604842" 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 PHEOCHROMOCYTOMA/PARAGANGLIOMA SYNDROME 4</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000626322" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000626322" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000626322</a>
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<p>In 9 apparently unrelated Dutch patients with paragangliomas (PPGL4; <a href="/entry/115310">115310</a>), <a href="#5" class="mim-tip-reference" title="Bayley, J.-P., Grimbergen, A. E. M., van Bunderen, P. A., van der Wielen, M., Kunst, H. P., Lenders, J. W., Jansen, J. C., Dullaart, R. P. F., Devilee, P., Corssmit, E. P., Vriends, A. H., Losekoot, M., Weiss, M. M. <strong>The first Dutch SDHB founder deletion in paraganglioma-pheochromocytoma patients.</strong> BMC Med. Genet. 10: 34, 2009. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19368708/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19368708</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19368708[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/10.1186/1471-2350-10-34" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19368708">Bayley et al. (2009)</a> identified a heterozygous 7.9-kb deletion (c.201-4429_287-933del) including exon 3 of the SDHB gene, predicted to result in a frameshift and premature termination (Cys68HisfsTer21). The deletion was found by multiplex ligation-dependent probe amplification (MLPA) analysis of 126 patients who did not carry point mutations in SDH genes, and all patients had the same breakpoints. Haplotype analysis indicated a founder effect. Only 1 patient had a family history of PGL, 5 patients had no family history, and family information from 3 patients was not available. The patients presented with head and neck PGL, extraadrenal PGL, and pheochromocytoma. <a href="#5" class="mim-tip-reference" title="Bayley, J.-P., Grimbergen, A. E. M., van Bunderen, P. A., van der Wielen, M., Kunst, H. P., Lenders, J. W., Jansen, J. C., Dullaart, R. P. F., Devilee, P., Corssmit, E. P., Vriends, A. H., Losekoot, M., Weiss, M. M. <strong>The first Dutch SDHB founder deletion in paraganglioma-pheochromocytoma patients.</strong> BMC Med. Genet. 10: 34, 2009. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19368708/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19368708</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19368708[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/10.1186/1471-2350-10-34" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19368708">Bayley et al. (2009)</a> suggested incomplete penetrance associated with this mutation. Functional studies of the variant and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19368708" 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="Rijken, J. A., Niemeijer, N. D., Corssmit, E. P. M., Jonker, M. A., Leemans, C. R., Menko, F. H., Hensen, E. F. <strong>Low penetrance of paraganglioma and pheochromocytoma in an extended kindred with a germline SDHB exon 3 deletion.</strong> Clin. Genet. 89: 128-132, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25827221/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25827221</a>] [<a href="https://doi.org/10.1111/cge.12591" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25827221">Rijken et al. (2016)</a> reported a large multigenerational Dutch family with PPGL4 due to the Dutch founder 7.9-kb deletion in the SDGB gene. There were 17 family members who carried the mutation, but only 6 had clinical manifestations; 11 patients were disease-free, indicating incomplete penetrance. The age-dependent penetrance of the mutation in this family was estimated to be 9% at age 50 years. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25827221" 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 MITOCHONDRIAL COMPLEX II DEFICIENCY, NUCLEAR TYPE 4</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> rs761350633 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs761350633;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/rs761350633?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=rs761350633" 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=rs761350633" 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=RCV000708779 OR RCV000819850 OR RCV001310279 OR RCV002268269 OR RCV004659188" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000708779, RCV000819850, RCV001310279, RCV002268269, RCV004659188" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000708779...</a>
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<p>In a Lebanese girl (patient 1), born to consanguineous parents, with mitochondrial complex II deficiency nuclear type 4 (MC2DN4; <a href="/entry/619224">619224</a>), <a href="#16" class="mim-tip-reference" title="Gronborg, S., Darin, N., Miranda, M. J., Damgaard, B., Cayuela, J. A., Oldfors, A., Kollberg, G., Hansen, T. V. O., Ravn, K., Wibrand, F., Ostergaard, E. <strong>Leukoencephalopathy due to complex II deficiency and bi-allelic SDHB mutations: further cases and implications for genetic counselling.</strong> JIMD Rep. 33: 69-77, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27604842/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27604842</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27604842[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/10.1007/8904_2016_582" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27604842">Gronborg et al. (2017)</a> identified homozygosity for a c.769C-G transversion (c.769C-G, NM_003000.2) in the SDHB gene, resulting in a leu257-to-val (L257V) substitution at a highly conserved site. The mutation, which was found by homozygosity mapping and sequencing of the SDHB gene, was present in heterozygous state in the parents. SDHB protein content was reduced in patient fibroblasts, and muscle fibers showed diffuse and severe lack of SDH staining. The mutation was present in 1 of 121,292 alleles in the ExAC database. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27604842" 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 MITOCHONDRIAL COMPLEX II DEFICIENCY, NUCLEAR TYPE 4</strong>
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PHEOCHROMOCYTOMA/PARAGANGLIOMA SYNDROME 4, INCLUDED
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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> rs587782604 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587782604;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/rs587782604?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=rs587782604" 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=rs587782604" 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=RCV000131970 OR RCV000183215 OR RCV000456660 OR RCV000505312 OR RCV000660259 OR RCV000762865 OR RCV001310280 OR RCV003474782" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000131970, RCV000183215, RCV000456660, RCV000505312, RCV000660259, RCV000762865, RCV001310280, RCV003474782" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000131970...</a>
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<p><strong><em>Mitochondrial Complex II Deficiency, Nuclear Type 4</em></strong></p><p>
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For discussion of the c.689G-A transition (c.689G-A, NM_003000.2) in the SDHB gene, resulting in an arg230-to-his (R230H) substitution, that was found in compound heterozygous state in a patient with mitochondrial complex II deficiency nuclear type 4 (MC2DN4; <a href="/entry/619224">619224</a>) by <a href="#16" class="mim-tip-reference" title="Gronborg, S., Darin, N., Miranda, M. J., Damgaard, B., Cayuela, J. A., Oldfors, A., Kollberg, G., Hansen, T. V. O., Ravn, K., Wibrand, F., Ostergaard, E. <strong>Leukoencephalopathy due to complex II deficiency and bi-allelic SDHB mutations: further cases and implications for genetic counselling.</strong> JIMD Rep. 33: 69-77, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27604842/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27604842</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27604842[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/10.1007/8904_2016_582" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27604842">Gronborg et al. (2017)</a>, see <a href="#0020">185470.0020</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27604842" 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>Pheochromocytoma/Paraganglioma Syndrome 4</em></strong></p><p>
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In 2 patients with head and neck paraganglioms (PPGL4; <a href="/entry/115310">115310</a>) from a Mexican family living in Guadalajara, <a href="#12" class="mim-tip-reference" title="Cerecer-Gil, N. Y., Figuera, L. E., Llamas, F. J., Lara, M., Escamilla, J. G., Ramos, R., Estrada, G., Karim Hussain, A., Gaal, J., Korpershoek, E., de Krijger, R. R., Dinjens, W. N. M., Devilee, P., Bayley, J. P. <strong>Mutation of SDHB is a cause of hypoxia-related high-altitude paraganglioma.</strong> Clin. Cancer Res. 16: 4148-4158, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20592014/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20592014</a>] [<a href="https://doi.org/10.1158/1078-0432.CCR-10-0637" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20592014">Cerecer-Gil et al. (2010)</a> identified a heterozygous germline c.689G-A transition in the SDHB gene, resulting in an arg230-to-his (R230H) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20592014" 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>.0024 MITOCHONDRIAL COMPLEX II DEFICIENCY, NUCLEAR TYPE 4</strong>
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SDHB, ALA102THR
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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> rs777578399 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs777578399;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/rs777578399?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=rs777578399" 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=rs777578399" 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=RCV001018296 OR RCV001310281 OR RCV001766844 OR RCV001860902 OR RCV004004577" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001018296, RCV001310281, RCV001766844, RCV001860902, RCV004004577" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001018296...</a>
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<p>In an Indian boy with mitochondrial complex II deficiency nuclear type 4 (MC2DN4; <a href="/entry/619224">619224</a>), <a href="#21" class="mim-tip-reference" title="Kaur, P., Sharma, S., Kadavigere, R., Girisha K. M., Shukla, A. <strong>Novel variant p.(Ala102Thr) in SDHB causes mitochondrial complex II deficiency: case report and review of the literature.</strong> Ann. Hum. Genet. 84: 345-351, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32124427/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32124427</a>] [<a href="https://doi.org/10.1111/ahg.12377" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32124427">Kaur et al. (2020)</a> identified a homozygous c.304G-A transition (c.304G-A, NM_003000.2) in the SDHB gene, resulting in an ala102-to-thr (A102T) substitution at a highly conserved residue. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the parents. The mutation was not present in homozygous state in the gnomAD database or in an in-house database of 569 individuals. In silico protein modeling suggested that the A102T substitution caused a gain of a polar contact in the SDHB protein, thus altering protein structure. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32124427" 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>REFERENCES</strong>
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<div class="">
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Alston, C. L., Davison, J. E., Meloni, F., van der Westhuizen, F. H., He, L., Hornig-Do, H.-T., Peet, A. C., Gissen, P., Goffrini, P., Ferrero, I., Wassmer, E., McFarland, R., Taylor, R. W.
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<strong>Recessive germline SDHA and SDHB mutations causing leukodystrophy and isolated mitochondrial complex II deficiency.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22972948/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22972948</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22972948[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=22972948" 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/10.1136/jmedgenet-2012-101146" target="_blank">Full Text</a>]
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<a id="Ardissone2015" class="mim-anchor"></a>
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Ardissone, A., Invernizzi, F., Nasca, A., Moroni, I., Farina, L., Ghezzi, D.
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<strong>Mitochondrial leukoencephalopathy and complex II deficiency associated with a recessive SDHB mutation with reduced penetrance.</strong>
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Molec. Genet. Metab. Rep. 5: 51-54, 2015.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26925370/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26925370</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26925370[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=26925370" 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.ymgmr.2015.10.006" target="_blank">Full Text</a>]
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Astuti, D., Latif, F., Dallol, A., Dahia, P. L. M., Douglas, F., George, E., Skoldberg, F., Husebye, E. S., Eng, C., Maher, E. R.
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<strong>Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma.</strong>
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Am. J. Hum. Genet. 69: 49-54, 2001. Note: Erratum: Am. J. Hum. Genet. 70: 565 only, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11404820/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11404820</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11404820[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=11404820" 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/10.1086/321282" target="_blank">Full Text</a>]
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<a id="Au1995" class="mim-anchor"></a>
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Au, H. C., Ream-Robinson, D., Bellew, L. A., Broomfield, P. L. E., Saghbini, M., Scheffler, I. E.
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<strong>Structural organization of the gene encoding the human iron-sulfur subunit of succinate dehydrogenase.</strong>
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Gene 159: 249-253, 1995.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7622059/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7622059</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7622059" 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/10.1016/0378-1119(95)00162-y" target="_blank">Full Text</a>]
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<a id="Bayley2009" class="mim-anchor"></a>
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Bayley, J.-P., Grimbergen, A. E. M., van Bunderen, P. A., van der Wielen, M., Kunst, H. P., Lenders, J. W., Jansen, J. C., Dullaart, R. P. F., Devilee, P., Corssmit, E. P., Vriends, A. H., Losekoot, M., Weiss, M. M.
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<strong>The first Dutch SDHB founder deletion in paraganglioma-pheochromocytoma patients.</strong>
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BMC Med. Genet. 10: 34, 2009. Note: Electronic Article.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19368708/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19368708</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19368708[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=19368708" 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/10.1186/1471-2350-10-34" target="_blank">Full Text</a>]
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<a id="Bayley2006" class="mim-anchor"></a>
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Bayley, J.-P., van Minderhout, I., Weiss, M. M., Jansen, J. C., Oomen, P. H. N., Menko, F. H., Pasini, B., Ferrando, B., Wong, N., Alpert, L. C, Williams, R., Blair, E., Devilee, P., Taschner, P. E. M.
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<strong>Mutation analysis of SDHB and SDHC: novel germline mutations in sporadic head and neck paraganglioma and familial paraganglioma and/or pheochromocytoma.</strong>
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BMC Med. Genet. 7: 1, 2006. Note: Electronic Article.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16405730/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16405730</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16405730" 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/10.1186/1471-2350-7-1" target="_blank">Full Text</a>]
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<a id="Bayley2011" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Bayley, J.-P.
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<strong>Succinate dehydrogenase gene variants and their role in Cowden syndrome. (Letter)</strong>
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Am. J. Hum. Genet. 88: 674-675, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21565294/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21565294</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21565294" 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.ajhg.2010.12.016" target="_blank">Full Text</a>]
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<a id="Boccon-Gibod2004" class="mim-anchor"></a>
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Boccon-Gibod, L., Boman, F., Boudjemaa, S., Fabre, M., Leverger, G., Carney, A. J.
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<strong>Separate occurrence of extra-adrenal paraganglioma and gastrointestinal stromal tumor in monozygotic twins: probable familial Carney syndrome.</strong>
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Pediatr. Dev. Pathol. 7: 380-384, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15383933/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15383933</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15383933" 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/10.1007/s10024-004-8090-y" target="_blank">Full Text</a>]
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<a id="Brouwers2006" class="mim-anchor"></a>
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<div class="">
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Brouwers, F. M., Eisenhofer, G., Tao, J. J., Kant, J. A., Adams, K. T., Linehan, W. M., Pacak, K.
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<strong>High frequency of SDHB germline mutations in patients with malignant catecholamine-producing paragangliomas: implications for genetic testing.</strong>
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J. Clin. Endocr. Metab. 91: 4505-4509, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16912137/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16912137</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16912137" 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/10.1210/jc.2006-0423" target="_blank">Full Text</a>]
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<a id="Cascon2008" class="mim-anchor"></a>
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Cascon, A., Landa, I., Lopez-Jimenez, E., Diez-Hernandez, A., Buchta, M., Montero-Conde, C., Leskela, S., Leandro-Garcia, L. J., Leton, R., Rodriguez-Antona, C., Eng, C., Neumann, H. P. H., Robledo, M.
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<strong>Molecular characterisation of a common SDHB deletion in paraganglioma patients. (Letter)</strong>
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J. Med. Genet. 45: 233-238, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18057081/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18057081</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18057081" 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/10.1136/jmg.2007.054965" target="_blank">Full Text</a>]
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<a id="Cascon2006" class="mim-anchor"></a>
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Cascon, A., Montero-Conde, C., Ruiz-Llorente, S., Mercadillo, F., Leton, R., Rodriguez-Antona, C., Martinez-Delgado, B., Delgado, M., Diez, A., Rovira, A., Diaz, J. A., Robledo, M.
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<strong>Gross SDHB deletions in patients with paraganglioma detected by multiplex PCR: a possible hot spot?</strong>
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Genes Chromosomes Cancer 45: 213-219, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16258955/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16258955</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16258955" 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/10.1002/gcc.20283" target="_blank">Full Text</a>]
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<a id="Cerecer-Gil2010" class="mim-anchor"></a>
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<div class="">
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Cerecer-Gil, N. Y., Figuera, L. E., Llamas, F. J., Lara, M., Escamilla, J. G., Ramos, R., Estrada, G., Karim Hussain, A., Gaal, J., Korpershoek, E., de Krijger, R. R., Dinjens, W. N. M., Devilee, P., Bayley, J. P.
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<strong>Mutation of SDHB is a cause of hypoxia-related high-altitude paraganglioma.</strong>
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Clin. Cancer Res. 16: 4148-4158, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20592014/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20592014</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20592014" 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/10.1158/1078-0432.CCR-10-0637" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12000816/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12000816</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12000816" 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/10.1056/NEJMoa020152" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.ajhg.2008.07.011" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1074/jbc.270.44.26104" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/sj.ejhg.5201904" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/ddi227" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1111/cge.12591" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1126/science.abi7495" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ana.24650" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14685938/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14685938</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14685938[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=14685938" 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/10.1086/381054" target="_blank">Full Text</a>]
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Young, A. L., Baysal, B. E., Deb, A., Young, W. F., Jr.
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<strong>Familial malignant catecholamine-secreting paraganglioma with prolonged survival associated with mutation in the succinate dehydrogenase B gene.</strong>
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[<a href="https://doi.org/10.1210/jc.2002-020312" target="_blank">Full Text</a>]
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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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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Ada Hamosh - updated : 11/28/2022
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<span class="mim-text-font">
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Hilary J. Vernon - updated : 03/08/2021<br>Ada Hamosh - updated : 07/11/2018<br>Cassandra L. Kniffin - updated : 04/25/2018<br>Ada Hamosh - updated : 02/21/2017<br>Cassandra L. Kniffin - updated : 1/14/2013<br>Cassandra L. Kniffin - updated : 4/11/2012<br>Cassandra L. Kniffin - updated : 6/2/2011<br>Cassandra L. Kniffin - updated : 12/3/2010<br>Cassandra L. Kniffin - updated : 11/30/2010<br>George E. Tiller - updated : 11/21/2008<br>Ada Hamosh - updated : 9/22/2008<br>Cassandra L. Kniffin - updated : 8/14/2008<br>John A. Phillips, III - updated : 7/3/2008<br>Marla J. F. O'Neill - updated : 5/6/2008<br>John A. Phillips, III - updated : 10/2/2007<br>Marla J. F. O'Neill - updated : 9/24/2007<br>Cassandra L. Kniffin - updated : 7/31/2007<br>John A. Phillips, III - updated : 3/15/2007<br>Victor A. McKusick - updated : 6/9/2006<br>Cassandra L. Kniffin - updated : 1/6/2006<br>John A. Phillips, III - updated : 5/11/2005<br>Victor A. McKusick - updated : 1/6/2004<br>John A. Phillips, III - updated : 4/8/2003<br>John A. Phillips, III - updated : 1/7/2003<br>Victor A. McKusick - updated : 9/4/2001<br>Victor A. McKusick - updated : 3/3/1998
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<a id="creationDate" 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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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 : 6/2/1986
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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="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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mgross : 04/18/2024
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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 : 10/17/2023<br>alopez : 11/28/2022<br>carol : 11/05/2021<br>carol : 04/19/2021<br>carol : 03/10/2021<br>carol : 03/09/2021<br>carol : 03/08/2021<br>carol : 07/19/2019<br>carol : 07/11/2018<br>alopez : 04/30/2018<br>ckniffin : 04/25/2018<br>carol : 01/29/2018<br>alopez : 02/21/2017<br>carol : 08/31/2016<br>carol : 03/15/2016<br>carol : 3/14/2016<br>carol : 1/7/2016<br>carol : 1/6/2016<br>alopez : 10/10/2014<br>alopez : 9/24/2014<br>mcolton : 9/23/2014<br>ckniffin : 9/23/2014<br>terry : 3/5/2013<br>alopez : 2/28/2013<br>alopez : 2/1/2013<br>ckniffin : 1/14/2013<br>alopez : 4/13/2012<br>terry : 4/11/2012<br>ckniffin : 4/11/2012<br>ckniffin : 8/11/2011<br>wwang : 6/9/2011<br>ckniffin : 6/2/2011<br>terry : 3/23/2011<br>terry : 3/23/2011<br>wwang : 3/22/2011<br>wwang : 12/29/2010<br>ckniffin : 12/3/2010<br>wwang : 12/1/2010<br>ckniffin : 11/30/2010<br>wwang : 2/24/2010<br>terry : 2/22/2010<br>ckniffin : 9/16/2009<br>alopez : 9/16/2009<br>ckniffin : 5/29/2009<br>alopez : 12/19/2008<br>wwang : 11/21/2008<br>ckniffin : 10/24/2008<br>terry : 9/22/2008<br>wwang : 8/19/2008<br>ckniffin : 8/14/2008<br>alopez : 7/3/2008<br>carol : 5/20/2008<br>carol : 5/8/2008<br>carol : 5/7/2008<br>terry : 5/7/2008<br>terry : 5/6/2008<br>alopez : 10/2/2007<br>wwang : 9/28/2007<br>terry : 9/24/2007<br>wwang : 8/22/2007<br>ckniffin : 7/31/2007<br>carol : 3/15/2007<br>alopez : 7/5/2006<br>terry : 6/9/2006<br>wwang : 1/17/2006<br>ckniffin : 1/13/2006<br>carol : 1/12/2006<br>ckniffin : 1/6/2006<br>wwang : 5/11/2005<br>wwang : 4/12/2005<br>carol : 1/31/2005<br>ckniffin : 1/19/2005<br>ckniffin : 3/23/2004<br>carol : 3/17/2004<br>cwells : 1/8/2004<br>terry : 1/6/2004<br>cwells : 4/30/2003<br>terry : 4/8/2003<br>alopez : 1/7/2003<br>alopez : 9/7/2001<br>terry : 9/4/2001<br>carol : 6/5/1998<br>alopez : 3/3/1998<br>alopez : 3/3/1998<br>terry : 3/3/1998<br>mark : 12/4/1995<br>jason : 6/28/1994<br>supermim : 3/16/1992<br>supermim : 3/20/1990<br>ddp : 10/27/1989<br>marie : 3/25/1988<br>reenie : 6/2/1986
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</span>
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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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<h3>
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<span class="mim-font">
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<strong>*</strong> 185470
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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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SUCCINATE DEHYDROGENASE COMPLEX, IRON-SULFUR SUBUNIT B; SDHB
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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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<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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SUCCINATE DEHYDROGENASE COMPLEX, SUBUNIT B, IRON-SULFUR PROTEIN<br />
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SUCCINATE DEHYDROGENASE 2, S. CEREVISIAE, HOMOLOG OF<br />
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SDH2, HOMOLOG OF
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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: SDHB</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> 1187383001, 128755003, 420120006, 722377004;
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<strong>ICD10CM:</strong> C49.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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<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: 1p36.13
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Genomic coordinates <span class="small">(GRCh38)</span> : 1:17,018,722-17,054,032 </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>
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<table class="table table-bordered table-condensed 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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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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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>
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<td rowspan="4">
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<span class="mim-font">
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1p36.13
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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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Gastrointestinal stromal tumor
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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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606764
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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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Autosomal dominant; Isolated cases
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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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3
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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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Mitochondrial complex II deficiency, nuclear type 4
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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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619224
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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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Autosomal recessive
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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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3
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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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Paraganglioma and gastric stromal sarcoma
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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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606864
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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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3
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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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Pheochromocytoma/paraganglioma syndrome 4
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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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115310
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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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Autosomal dominant
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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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3
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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>
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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>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</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>Complex II in mitochondria, of which succinate dehydrogenase (EC 1.3.99.1) is a component, has 4 subunits. In order of decreasing molecular mass, they are the flavoprotein (SDHA; 600857), the iron-sulfur protein (SDHB), and the 2 integral membrane proteins, SDHC (602413) and SDHD (602690) (summary by Kita et al., 1990). </p>
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</span>
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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>Cloning and Expression</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>Kita et al. (1990) cloned and sequenced the iron-sulfur protein subunit. A clone was isolated from a human liver cDNA library. The open reading frame encodes a 252-amino acid protein. The amino acid sequence showed approximately 94% homology with that of bovine heart. Au et al. (1995) described the complete genomic clone for the gene encoding the iron-sulfur protein subunit. </p>
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</span>
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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 Structure</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>Au et al. (1995) determined that the entire SDHB transcript is encoded by 8 exons within approximately 40 kb. </p>
|
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</span>
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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>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>Leckschat et al. (1993) used a partial human cDNA clone corresponding to the iron protein subunit of succinate dehydrogenase in Southern analyses of restriction enzyme digests of genomic human and hamster DNA, as well as hamster-human hybrids containing a limited number of human chromosomes, to demonstrate that the gene is located on human chromosome 1. Using the same genomic clone, they subregionalized the gene to 1p36.1-p35 by fluorescence in situ hybridization. </p><p>Mascarello et al. (1980) described an SDH-deficient hamster cell line that was complemented by human chromosome 1. It was presumed that, because it mapped to chromosome 1, the iron-sulfur protein subunit gene complemented the deficiency in the mutant. Oostveen et al. (1995) found that in fact it was protein from the bovine SDH3 gene (corresponding to human SDHC and encoding 1 of the 2 integral membrane proteins) that complemented the hamster mutation. Thus there are 2 SDH genes on chromosome 1. </p>
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</span>
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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 Function</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>Pollard et al. (2005) stated that the nuclear-encoded Krebs cycle enzymes fumarate hydratase (FH; 136850) and succinate dehydrogenases like SDHB act as tumor suppressors, and germline mutations in these genes predispose individuals to leiomyomas and renal cancer (HLRCC; 150800) and to paragangliomas, respectively. Pollard et al. (2005) showed that FH-deficient cells and tumors accumulated fumarate and, to a lesser extent, succinate. SDH-deficient tumors principally accumulated succinate. In situ analysis showed that these tumors also overexpressed HIF1A (603348), activation of HIF1A targets like VEGF (192240), and high microvessel density. Pollard et al. (2005) hypothesized that increased succinate and/or fumarate may stabilize HIF1A, and that the basic mechanism of tumorigenesis in paraganglioma and leiomyomas and renal cancer may be pseudohypoxic drive, just as it is in von Hippel-Lindau syndrome (193300). </p><p><strong><em>SDH Complex Function</em></strong></p><p>
|
|
In mammalian cells, Spinelli et al. (2021) found that when oxygen reduction is impeded, mitochondrial complex I and dihydroorotate dehydrogenase (DHODH; 126064) can still deposit electrons into the electron transport chain because the accumulation of ubiquinol drives the succinate dehydrogenase complex in reverse to enable electron deposition onto fumarate. Fumarate sustains DHODH and complex I activities by acting as the terminal electron acceptor, maintaining mitochondrial function under oxygen limitation. </p>
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</span>
|
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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">
|
|
<strong>Molecular Genetics</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><strong><em>Pheochromocytoma/Paraganglioma Syndrome 4</em></strong></p><p>
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In affected members of families with paragangliomas (PPGL4; 115310), Astuti et al. (2001) identified mutations in the SDHB gene (185470.0001-185470.0002). Clinical manifestations included pheochromocytomas, extraadrenal pheochromocytomas, and paragangliomas. A mutation in the SDHB gene (185470.0003) was also identified in the blood and tumor tissue of 1 of 24 cases of sporadic pheochromocytoma. The findings extended the link between mitochondrial dysfunction and tumorigenesis, and suggested that germline SDHB mutations are an important cause of pheochromocytoma susceptibility. </p><p>Young et al. (2002) identified a mutation in the SDHB gene (185470.0004) in a man and his son, both of whom had malignant catecholamine-secreting paragangliomas. </p><p>Gimenez-Roqueplo et al. (2002) reported a case of a malignant sporadic pheochromocytoma (see 171300) induced by a germline missense mutation in the SDHB gene. Within the tumor, loss of heterozygosity (LOH) at chromosome 1pter led to a null SDHB allele and to a complete loss of complex II enzymatic activity. In situ hybridization and immunohistochemistry experiments showed a high expression of hypoxic-angiogenic responsive genes, similar to that previously observed in inherited SDHD tumors. The authors concluded that the complex II mitochondrial genes play a role in the oxygen-sensing pathway and in the regulation of angiogenesis of neural crest-derived tumors. </p><p>In 12 (4%) of 271 unrelated patients with sporadic pheochromocytoma, Neumann et al. (2002) identified 9 different germline mutations in the SDHB gene (see, e.g., 185470.0004-185470.0006; 185470.0008; 185470.0009). </p><p>Vanharanta et al. (2004) identified 2 families in which renal cell carcinoma (RCC; see 144700) occurred in patients carrying SDHB mutations (185470.0005; 185470.0006). In 1 family, both patients with RCC had paragangliomas; in another family, the mother of the patient with RCC had a paraganglioma. Tumor tissues from the RCCs showed loss of the remaining wildtype allele. The authors concluded that germline SDHB mutations can predispose to early-onset kidney cancers in addition to paragangliomas. </p><p>Cascon et al. (2006) investigated the frequency of gross SDH deletions in 24 patients who tested negative for point mutations and had at least 1 of the recommended features for genetic testing. For this purpose, they used a technique to specifically detect gross deletions affecting SDHB, SDHC (602413), and SDHD (602690). They identified 3 heterozygous SDHB deletions in 3 independent cases with paraganglioma: 1 whole SDHB deletion and 2 deletions exclusively affecting exon 1 of 15.69 kb and 20.3 kb (185470.0017 and 185470.0018, respectively). These latter mutations matched the unique gross deletion of SDHB exon 1 previously reported by McWhinney et al. (2004); see 185470.0007. Thus, the region of exon 1 could be a hotspot for SDHB deletions. These alterations can account for a considerable number of both familial and apparently sporadic paraganglioma cases. </p><p>Brouwers et al. (2006) studied the prevalence of germline SDHB mutations in a series of patients with malignant paraganglioma. Pathogenic SDHB mutations were found in 13 of 44 patients (30%). Close to one-third of patients had metastases originating from an adrenal primary tumor, compared with a little over two-thirds from an extraadrenal tumor. Among the latter patients, the frequency of SDHB mutations was 48%. The authors concluded that missense, nonsense, frameshift, and splice site mutations of the SDHB gene are associated with about half of all malignancies originating from extraadrenal paragangliomas. </p><p>In northern Spain, where cervical paraganglioma is particularly frequent, Lima et al. (2007) screened 48 patients for mutations in the SDHB, SDHC, and SDHD genes. Eight sporadic cases (22.2%) carried pathogenic germline mutations, 6 of which were in SDHB and 2 in SDHD. Three families had mutations in SDHD and 1 in SDHB; 7 of 11 different pathogenic mutations (64%) affected SDHB. Ten mutations were novel. Missense mutations were primarily found in SDHB and frameshift mutations in SDHD. The authors concluded that a significant proportion of sporadic cervical PGLs arise as a consequence of intrinsic genetic factors. In patients with germline SDHB mutations, they found no evidence for distant metastases or extraparaganglial malignancies after 7 years' follow-up. Lima et al. (2007) concluded that occult familial cases and familial cases with a proven disease history have a common clinicopathologic signature that distinguishes them from truly sporadic cervical paraganglioma patients without germline mutations. </p><p><strong><em>Paraganglioma and Gastric Stromal Sarcoma</em></strong></p><p>
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In 3 families with paraganglioma and gastric stromal sarcoma (606864), McWhinney et al. (2007) identified 3 different germline mutations in the SDHB gene (see, e.g., 185470.0012 and 185470.0013). In 3 other families with the dyad, the authors also found germline mutations in the SDHC (see, e.g., 602413.0004) and SDHD (602690.0027) genes, respectively. None of the patients had mutations in the KIT (164920) or PDGFRA (173490) genes, which have been associated with gastrointestinal tumors. </p><p>Pasini et al. (2008) provided further clinical and molecular information on patients originally reported by McWhinney et al. (2007) (see 185470.0012-185470.0013). DNA analysis of tumors from patients with germline mutations in SDHB and SDHC showed loss of heterozygosity in all samples available for study, suggesting that the gene defects act in a recessive manner. </p><p><strong><em>Gastrointestinal Stromal Tumors</em></strong></p><p>
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Janeway et al. (2011) identified 3 germline mutations in the SDHB gene (see, e.g., 185470.0004) in 3 different patients with sporadic occurrence of gastrointestinal stromal tumor (GIST; 606764). The patients were 18, 22, and 21 years old, respectively, and none had a personal or family history of paragangliomas. Tumor tissue available from 2 of these patients showed lack of SDHB immunostaining. A fourth patient, who was 16 years old, carried a germline mutation in the SDHC gene (602413.0004). Overall, mutations in these genes accounted for 4 (12%) of 34 patients with isolated GIST lacking KIT (164920) or PDFGRA (173490) mutations. Janeway et al. (2011) evaluated SDHB (185470) expression in 30 GISTs lacking KIT or PDGFRA mutations, 25 of which were also negative for associated SDH mutations confirmed by sequence analysis. Immunohistochemical studies showed lack of SDHB staining in 18 (100%) of 18 pediatric tumors, regardless of SDH mutation status, and in 8 (67%) of 12 adult tumors and weak expression in 4 (33%) of 12 adult tumors. By comparison, only 1 (6%) of 18 KIT-mutant GISTs and 0 of 5 NF1-associated GISTs lacked SDHB expression. These findings implicated a defect in respiration in the pathogenesis of some GIST tumors. </p><p><strong><em>Mitochondrial Complex II Deficiency, Nuclear Type 4</em></strong></p><p>
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In an Asian girl, born of consanguineous parents, with neurologic impairment, leukoencephalopathy, and biochemical evidence of mitochondrial complex II deficiency (MC2DN4; 619224), Alston et al. (2012) identified a homozygous missense mutation in the SDHB gene (D48V; 185470.0020). Her unaffected parents were heterozygous for the mutation. Patient fibroblasts showed decreased amounts of fully assembled complex II and almost complete absence of the SDHB subunit. Complex II activity was also decreased in patient muscle samples. </p><p>In a Pakistani girl, born to consanguineous parents, with MC2DN4, Ardissone et al. (2015) identified homozygosity for the previously reported D48V mutation in the SDHB gene. The mutation was found by sequencing of a panel of 7 genes associated with complex II deficiency. A clinically unaffected sib was also homozygous for the mutation. SDHB protein expression was reduced in patient fibroblasts and lymphocytes as well as in lymphocytes from the clinically unaffected sib. SDHA protein was also reduced in these cells, possibly due to instability of complex II assembly. </p><p>In a Turkish boy (patient LD_0756.0A), born of consanguineous parents, with MC2DN4, Vanderver et al. (2016) identified homozygosity for the D48V mutation in the SDHB gene. </p><p>In 6 patients with MC2DN4, Helman et al. (2016) identified mutations in the SDHB gene. Five patients had the D48V mutation, 4 (patients 10, 11, 16, and 19) in homozygous state and 1 (patient 15) in compound heterozygous state. </p><p>In 2 unrelated children with MC2DN4, Gronborg et al. (2017) identified mutations in the SDHB gene: a Lebanese girl, born of consanguineous parents, was homozygous for a missense mutation (L257V; 185470.0022), and a boy, born of nonconsanguineous parents, was compound heterozygous for D48V and another missense mutation (R230H; 185470.0023). In both patients, SDHB protein content was reduced in patient fibroblasts, muscle fibers showed diffuse and severe lack of SDH staining, and complex II enzyme activity was severely deficient in muscle. The parents of both children were confirmed to be mutation carriers. Gronborg et al. (2017) noted that the R230H mutation was previously reported in heterozygous state in patients with paraganglioma by several authors, including Cerecer-Gil et al. (2010). </p><p>In a male infant with MC2DN4, who was born to nonconsanguineous Indian parents, Kaur et al. (2020) identified a homozygous missense mutation in the SDHB gene (A102T; 185470.0024). The parents were heterozygous for the mutation. The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. </p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
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For discussion of a possible association between Cowden syndrome (see 158350) and variation in the SDHB gene, see 185470.0014 and 185470.0015.</p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</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>In a study of 1,751 knockout alleles created by the International Mouse Phenotyping Consortium (IMPC), Dickinson et al. (2016) found that knockout of the mouse homolog of human SDHB is homozygous-lethal (defined as absence of homozygous mice after screening of at least 28 pups before weaning). </p>
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</span>
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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>ALLELIC VARIANTS</strong>
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</span>
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<strong>24 Selected Examples):</strong>
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</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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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 PHEOCHROMOCYTOMA/PARAGANGLIOMA SYNDROME 4</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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SDHB, ARG90TER
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<br />
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SNP: rs74315366,
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gnomAD: rs74315366,
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ClinVar: RCV000013616, RCV000037718, RCV000183211, RCV000215883, RCV000627749, RCV000763272, RCV003233026
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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 3 families with pheochromocytoma/paraganglioma syndrome-4 (PPGL4; 115310), Astuti et al. (2001) identified a 402C-T transition in the SDHB gene, resulting in an arg90-to-ter (R90X) substitution. The mutation was predicted to result in a truncated SDHB protein lacking the C-terminal 191 amino acids. One of the families had been reported by Skoldberg et al. (1998). The mutation occurred at a hypermutable CpG dinucleotide; haplotype analysis of the 3 families supported independent origin of the mutations. This mutation was originally published as ARG91TER; the corrected numbering appeared in an erratum. </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>.0002 PHEOCHROMOCYTOMA/PARAGANGLIOMA SYNDROME 4</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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SDHB, PRO197ARG
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<br />
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SNP: rs74315367,
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gnomAD: rs74315367,
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ClinVar: RCV000013617, RCV000030623, RCV000213984, RCV000465474, RCV001810856
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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 containing 3 individuals with familial extraadrenal pheochromocytoma and without evidence of cervical paragangliomas (PPGL4; 115310), Astuti et al. (2001) identified a heterozygous 724C-G transversion in exon 6 of the SDHB gene, resulting in a pro197-to-arg (P197R) substitution. This proline is conserved throughout all living species analyzed, from human to rat, Drosophila, yeast, and E. coli. This mutation was originally published as PRO198ARG; the corrected numbering appeared in an erratum. </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>.0003 PHEOCHROMOCYTOMA/PARAGANGLIOMA SYNDROME 4</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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SDHB, 1-BP DEL, 725C
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<br />
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SNP: rs1060503757,
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ClinVar: RCV000473527, RCV000561023, RCV000986261, RCV001813782, RCV003335344, RCV004999485
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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 55-year-old woman with a single sporadic adrenal pheochromocytoma (PPGL4; 115310), Astuti et al. (2001) identified a heterozygous 1-bp deletion (725delC) in exon 6 of the SDHB gene in both blood and tumor tissue. The tumor DNA did not exhibit loss of heterozygosity for markers flanking SDHB. SDHB mutations were not identified in 23 other cases of sporadic pheochromocytomas. </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>.0004 PHEOCHROMOCYTOMA/PARAGANGLIOMA SYNDROME 4</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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GASTROINTESTINAL STROMAL TUMOR, 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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SDHB, ARG242HIS
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<br />
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SNP: rs74315368,
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gnomAD: rs74315368,
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ClinVar: RCV000013619, RCV000022778, RCV000129095, RCV000183216, RCV000505354, RCV000627751, RCV001836632, RCV004786257
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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 man and his son, both of whom had metastatic catecholamine-secreting paragangliomas (PPGL4; 115310), Young et al. (2002) identified a 725G-A transition in exon 7 of the SDHB gene, resulting in an arg242-to-his (R242H) substitution. Sequencing of the SDHB gene in the tumors did not reveal any somatic mutations or loss of heterozygosity of the remaining allele. </p><p>Neumann et al. (2002) identified the R242H substitution in the germline of a patient with sporadic pheochromocytoma. The mutation was not identified in 600 control chromosomes. </p><p>Janeway et al. (2011) identified a germline R242H mutation in a 21-year-old patient with a sporadic gastrointestinal stromal tumor (GIST; 606764). </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>.0005 PHEOCHROMOCYTOMA/PARAGANGLIOMA SYNDROME 4</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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SDHB, 4-BP DEL, 847TCTC
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<br />
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SNP: rs587781266,
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ClinVar: RCV000013621, RCV000128877, RCV001034689, RCV001797588
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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>Among 16 probands with pheochromocytoma/paragangliomas-4 (PGL4; 115310), Vanharanta et al. (2004) found 1 family with an 847_850delTCTC germline mutation in which 2 members had renal cell carcinoma (see 144700) of solid histology, at ages 24 and 26 years. Both also had paraganglioma. Tumor tissue from the RCCs showed loss of the remaining wildtype allele. </p><p>Neumann et al. (2002) identified the 847delTCTC mutation in the germlines of 2 unrelated patients with sporadic pheochromocytoma. The mutation was not identified in 600 control chromosomes. </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>.0006 PHEOCHROMOCYTOMA/PARAGANGLIOMA SYNDROME 4</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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SDHB, ARG27TER
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<br />
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SNP: rs74315369,
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gnomAD: rs74315369,
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ClinVar: RCV000013623, RCV000129929, RCV000471400, RCV000505368, RCV000657585, RCV003473085
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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 registry of early-onset renal cell carcinomas (see 144700), Vanharanta et al. (2004) found a family in which both a son with clear cell RCC and his mother with a cardiac paraganglioma tumor (PPGL4; 115310) had an arg27-to-ter (R27X) germline mutation in the SDHB gene. Tumor tissue from the RCC showed loss of the remaining wildtype allele. </p><p>Neumann et al. (2002) identified the R27X substitution in the germline of patient with sporadic pheochromocytoma. The R27X substitution resulted from a 213C-T transition in exon 2 of the SDHB gene. The mutation was not identified in 600 control chromosomes. </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>.0007 PHEOCHROMOCYTOMA/PARAGANGLIOMA SYNDROME 4</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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SDHB, 1.0-KB DEL, EX1
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<br />
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ClinVar: RCV000013625
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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 Brazilian family with 3 affected members in 2 generations with paragangliomas (PPGL4; 115310), McWhinney et al. (2004) identified an approximately 1.0-kb germline deletion of the 5-prime end of the SDHB gene, including all or part of exon 1. Breakpoints were delineated in the 5-prime UTR and in intron 1 of the SDHB gene. See 185470.0017 and 185470.0018 for additional reports of SDHB exon 1 deletions. </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>.0008 PHEOCHROMOCYTOMA/PARAGANGLIOMA SYNDROME 4</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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SDHB, ARG46GLY
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<br />
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SNP: rs74315370,
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gnomAD: rs74315370,
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ClinVar: RCV000216404, RCV000800486, RCV003335029, RCV004732542
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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 the germlines of 2 unrelated patients with sporadic pheochromocytoma (PPGL4; 115310), Neumann et al. (2002) identified a 270C-G transversion in exon 2 of the SDHB gene, resulting in an arg46-to-gly (R46G) substitution. The mutation was not identified in 600 control chromosomes. </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>.0009 PHEOCHROMOCYTOMA/PARAGANGLIOMA SYNDROME 4</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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SDHB, CYS101TYR
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<br />
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SNP: rs74315371,
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ClinVar: RCV003335030
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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 the germlines of 2 unrelated patients with sporadic pheochromocytoma (PPGL4; 115310), Neumann et al. (2002) identified a 436G-A transition in exon 4 of the SDHB gene, resulting in a cys101-to-tyr (C101Y) substitution. The mutation was not identified in 600 control chromosomes. </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>.0010 PHEOCHROMOCYTOMA/PARAGANGLIOMA SYNDROME 4</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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SDHB, HIS132PRO
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<br />
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SNP: rs74315372,
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ClinVar: RCV000013628, RCV001021521, RCV001857343
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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>By analysis of the germline DNA from 2 brothers and their mother with malignant extraadrenal abdominal paragangliomas (PPGL4; 115310), Maier-Woelfle et al. (2004) identified heterozygosity for an A-to-C transversion in the SDHB gene, resulting in a his132-to-pro (H132P) substitution. The variant was absent in 160 control chromosomes. </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>.0011 PHEOCHROMOCYTOMA, SOMATIC</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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SDHB, SER100PHE
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<br />
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SNP: rs121917755,
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gnomAD: rs121917755,
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ClinVar: RCV000013629, RCV001851830, RCV004599210
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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 tumor tissue from a woman with sporadic extraadrenal pheochromocytoma (see 171300) in the bladder wall, van Nederveen et al. (2007) identified a heterozygous 299C-T transition in exon 4 of the SDHB gene, resulting in a ser100-to-phe (S100F) substitution. Comparative genomic hybridization and FISH analysis showed loss of heterozygosity of chromosome 1p in tumor tissue, indicating biallelic inactivation of the SDHB gene. There was absence of SDHB expression in tumor cells, indicating complete loss of SDHB function. </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>.0012 PARAGANGLIOMA AND GASTRIC STROMAL SARCOMA</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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SDHB, IVS1DS, G-T, +1
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<br />
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SNP: rs587782703,
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gnomAD: rs587782703,
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ClinVar: RCV000013630, RCV000132151, RCV000153923, RCV000232241, RCV000505343, RCV001001437, RCV003148657, RCV003474785, RCV004732698
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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 paraganglioma and gastric stromal sarcoma (606864), McWhinney et al. (2007) identified a germline G-to-T transversion at the splice donor site in intron 1 (IVS1DS+1) of the SDHB gene. Pasini et al. (2008) provided additional information on this family with a G-T transversion at position 72+1 in the SDHB gene. The son presented at 37 years of age with melena due to a gastric stromal sarcoma and on further evaluation was found to have a nonfunctioning periaortic ganglioma. Sequencing of a heterozygous aberrant transcript from his WBCs indicated that the first part of intron 1 was transcribed, resulting in a significantly truncated protein with a stop codon in the middle of exon 2. DNA analysis of a tumor sample showed loss of heterozygosity with only the mutant SDHB sequence present. The patient's mother underwent surgery for a pheochromocytoma at 57 years of age, but DNA was not available for analysis. </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>.0013 PARAGANGLIOMA AND GASTRIC STROMAL SARCOMA</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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SDHB, IVS4DS, G-C, +1
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<br />
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SNP: rs398122805,
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gnomAD: rs398122805,
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|
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ClinVar: RCV000013631
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|
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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 male twin sibs with paraganglioma and gastric stromal sarcoma (606864), previously described by Boccon-Gibod et al. (2004), McWhinney et al. (2007) identified a germline G-C transversion at nucleotide 423+1 in the SDHB gene. Their unaffected mother and an unaffected sister also carried the mutation. Pasini et al. (2008) provided additional information on these monozygotic twins with the IVS4+1G-C mutation. One had surgery at 12 years of age for a nonfunctioning paraganglioma of the organ of Zuckerkandl and the other at 13 years of age for a gastric stromal sarcoma. Analysis of lymphocyte DNA from 1 of the brothers showed that the last 18 codons of exon 4 were spliced out, resulting in a truncated protein. The mother and older sister who carried the mutation had negative examinations for gastric stromal carcinoma and paraganglioma. </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>.0014 RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE</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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SDHB, ALA3GLY
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<br />
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SNP: rs11203289,
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gnomAD: rs11203289,
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ClinVar: RCV000013632, RCV000034690, RCV000121999, RCV000128921, RCV000275977, RCV000368190, RCV000755699, RCV000986270, RCV001079357, RCV002490359, RCV004532333
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</span>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>This variant, formerly titled COWDEN SYNDROME 2, has been reclassified based on a review of the ExAC database by Hamosh (2018).</p><p>In a patient with a Cowden-like phenotype (see 158350), Ni et al. (2008) identified a heterozygous C-to-G transversion in the SDHB gene, resulting in an ala3-to-gly (A3G) substitution. The mutation was not identified in 700 control subjects. This mutation was associated with increased manganese superoxide dismutase expression, normal reactive oxygen species, and a 1.2-fold increase in AKT expression and 1.3-fold change in MAPK expression. The patient was a 41-year-old woman with breast cancer and uterine leiomyomas and a family history of endometrial cancer. </p><p>Bayley (2011) commented that the findings of Ni et al. (2008) require independent confirmation, and suggested that functional studies of the SDH variants are essential before recommendations can be made for appropriate genetic counseling. </p><p>Hamosh (2018) found that the A3G variant was present in heterozygous state in 426 of 97,714 alleles and in 8 homozygotes, with an allele frequency of 0.00436, in the ExAC database (July 11, 2018).</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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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0015 RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE</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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|
SDHB, SER163PRO
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<br />
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SNP: rs33927012,
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|
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gnomAD: rs33927012,
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|
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ClinVar: RCV000013633, RCV000034688, RCV000122002, RCV000132153, RCV000202946, RCV000206861, RCV000282667, RCV000986263, RCV001099292, RCV001269360
|
|
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|
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</span>
|
|
</div>
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|
|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>This variant, formerly titled COWDEN SYNDROME 2, has been reclassified based on a review of the ExAC database by Hamosh (2018).</p><p>In 2 women with a Cowden-like phenotype (see 158350), Ni et al. (2008) identified a heterozygous ser163-to-pro (S163P) substitution in the SDHB gene. This mutation was not found in 700 control subjects. This mutation was associated with increased manganese superoxide dismutase function, increased reactive oxygen species, and a 2.7-fold change in AKT expression and 1.7-fold increase in MAPK expression. The patients, 29 and 54 years old, had thyroid cancer, and both had a family history of breast cancer and papillary thyroid carcinoma. </p><p>Bayley (2011) commented that the findings of Ni et al. (2008) require independent confirmation, and suggested that functional studies of the SDH variants are essential before recommendations can be made for appropriate genetic counseling. </p><p>Hamosh (2018) found that the S163P variant was present in heterozygous state in 1,523 of 121,404 alleles and in 21 homozygotes, with an allele frequency of 0.01254, in the ExAC database (July 11, 2018).</p>
|
|
</span>
|
|
</div>
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|
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<div>
|
|
<br />
|
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</div>
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</div>
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<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0016 PHEOCHROMOCYTOMA/PARAGANGLIOMA SYNDROME 4</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
SDHB, VAL140PHE
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs267607032,
|
|
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|
|
|
gnomAD: rs267607032,
|
|
|
|
|
|
ClinVar: RCV000013634, RCV000132167, RCV000505378, RCV000505751, RCV000627753, RCV003473111, RCV004732551, RCV005007884
|
|
|
|
|
|
</span>
|
|
</div>
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|
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|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 sibs with paragangliomas (PPGL4; 115310), Schimke et al. (2010) identified a heterozygous 418G-T transversion in the SDHB gene, resulting in a val140-to-phe (V140F) substitution. The 55-year-old sister and 49-year-old brother both had paraspinal paragangliomas. The mutation was also found in their unaffected 76-year-old mother, suggesting decreased penetrance or a 'leaky' mutation. The family was of note because a deceased sib had neuroblastoma as an infant, metastatic extraadrenal sympathetic paragangliomas reminiscent of pheochromocytoma as a young adult, and renal cell carcinoma as an adult; this patient had been previously reported by Fairchild et al. (1979) as having unique occurrence of these cancers. In addition, a first cousin of these sibs had died from metastatic renal cell carcinoma and had a history of a benign paraaortic PGL. Schimke et al. (2010) noted the importance of family history in elucidating the etiology of this inherited disorder. </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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<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0017 PHEOCHROMOCYTOMA/PARAGANGLIOMA SYNDROME 4</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
SDHB, 15.69-KB DEL, EX1
|
|
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|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000013635
|
|
|
|
|
|
</span>
|
|
</div>
|
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|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>Cascon et al. (2006) detected a germline deletion affecting SDHB exon 1 in a 30-year-old Portuguese male with a secreting retroperitoneal paraganglioma (PPGL4; 115310) and an uncertain family history. The authors found the same loss of SDHB exon 1 in a 14-year-old female proband from a Spanish family with a history of PGL. The proband was admitted to hospital with hypertension and later diagnosed with catecholamine-secreting PGL of the retroperitoneum. The proband's father was diagnosed at age 48 with PGL of the Zuckerkandl organ, which metastasized to the liver at age 53. Bone metastases were found 4 years later. The brothers of the proband also had high levels of dopamine in their urine. Cascon et al. (2006) detected the germline deletion in all 3 of these relatives of the proband. No deletions affecting the SDHC or SDHD genes were found in any patients. Analysis of the genomic structure of the SDHB gene revealed a high density of Alu repeats within the first intron. The authors suggested that Alu-mediated recombination may account for the observed clustering of a gross deletion hotspot. </p><p>Cascon et al. (2008) reported 3 additional families, 2 of Spanish and 1 of French origin, with the SDHB exon 1 deletion. In the first Spanish family, the proband was diagnosed at age 19 with retroperitoneal PGL, and multiple metastases in bone, hypophysis, retroperitoneum, and liver. Her sister was diagnosed with an adrenal neuroblastoma with metastasis at age 5 years of age. The proband in the second Spanish family was diagnosed with abdominal PGL and renal oncocytoma at age 17; both were surgically resected. Ten years later she showed bone metastasis. In the French family, the proband had malignant pheochromocytoma (PCC) at age 27 years and died as a result of the disease. He had a relative with benign PCC, diagnosed at age 30 years. Molecular analysis revealed that same deletion breakpoints in all Spanish families resulting in a 15.69-kb deletion, including the 2 families previously reported by Cascon et al. (2006), and a different breakpoint junction in the French family, resulting in a 20.3-kb deletion (185470.0018). Haplotype analysis indicated a founder effect in the Spanish families for the 15.69-kb deletion. All Spanish patients originally came from a small area in the northwest region of the Iberian peninsula. </p><p>Solis et al. (2009) reported a large 5-generation family of Spanish Mexican descent with the same 15.69-kb SDHB founder deletion previously described by Cascon et al. (2006, 2008). Eleven of 41 mutation carriers developed PGL in various locations, including the carotid body, adrenal gland, pelvis, and thorax. Penetrance of the founder deletion was estimated to be 35% by age 40 years. </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>.0018 PHEOCHROMOCYTOMA/PARAGANGLIOMA SYNDROME 4</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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SDHB, 20.3-KB DEL, EX1
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<br />
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ClinVar: RCV000013636
|
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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>See 185470.0017 and Cascon et al. (2008). </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>.0019 PHEOCHROMOCYTOMA/PARAGANGLIOMA SYNDROME 4</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
SDHB, IVS4DS, G-A, +1
|
|
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|
<br />
|
|
|
|
SNP: rs398122805,
|
|
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|
|
|
gnomAD: rs398122805,
|
|
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|
|
|
ClinVar: RCV000022779, RCV000163600, RCV000481826, RCV000505379, RCV000627750, RCV000762867, RCV003473120
|
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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 2 unrelated Dutch patients with sporadic occurrence of paragangliomas-4 (PPGL4; 115310), Bayley et al. (2006) identified a heterozygous G-to-A transition in intron 4 of the SDHB gene (423+1G-A). RT-PCR analysis from 1 patient showed that the mutation caused a splice site defect and an in-frame deletion of 18 amino acids. The mutation was not found in 300 control chromosomes. One patient was a 50-year-old man who presented with elevated catecholamine levels and a single jugular paraganglioma, and died at the age of 58 due to complications resulting from tumor recurrence. The second patient was a man who presented at age 55 with a single carotid body tumor that was successfully removed. The tumor from this patient was negative for SDH activity. </p><p>Hensen et al. (2012) found the 423+1G-A mutation in 22 patients from 9 Dutch families with paragangliomas, making it the most common mutation in the SDHB gene identified in their cohort of 1,045 patients from 340 families. The findings were consistent with a founder effect. </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>.0020 MITOCHONDRIAL COMPLEX II DEFICIENCY, NUCLEAR TYPE 4</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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SDHB, ASP48VAL ({dbSNP rs202101384})
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<br />
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SNP: rs202101384,
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gnomAD: rs202101384,
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ClinVar: RCV000032784, RCV000470589, RCV001011583, RCV001249469, RCV001578167, RCV003315403, RCV003473248
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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 an Asian girl, born of consanguineous parents, with mitochondrial complex II deficiency nuclear type 4 (MC2DN4; 619224), Alston et al. (2012) identified a homozygous c.143A-T transversion (c.143A-T, NM_003000.2) in exon 2 of the SDHB gene, resulting in an asp48-to-val (D48V) substitution. Her unaffected parents were heterozygous for the mutation. The D48 residue is not conserved between human and yeast, but D48 is conservatively substituted by N42 in the yeast Sdh2 protein (yeast ortholog). Construction of an Sdh2 N42D allele rescued the oxidation growth defect of yeast with a deletion of the Sdh2 gene; the N42D variant showed normal SDH activity. Introduction of an N42V substitution did not impair growth of yeast or oxygen consumption, but did cause decreased SDH activity (about 50% of control). Patient fibroblasts showed decreased amounts of fully assembled complex II and almost complete absence of the SDHB subunit. Complex II activity was also decreased in patient muscle samples. </p><p>In a Pakistani girl, born to consanguineous parents, with MC2DN4, Ardissone et al. (2015) identified homozygosity for the D48V mutation in the SDHB gene. The mutation, which was identified by sequencing of a panel of 7 genes associated with complex II deficiency, was confirmed by Sanger sequencing. The parents were confirmed to be carriers, and a clinically unaffected older sib was also homozygous for the mutation. The D48V mutation was observed in ExAC at a low frequency of 0.036% in only South Asian subjects, with no homozygotes reported. SDHB protein expression was reduced in patient fibroblasts and lymphocytes as well as in lymphocytes from the clinically unaffected sib who also homozygous for the mutation. </p><p>In a Turkish boy (patient LD_0756.0A) with MC2DN4, who was born of consanguineous parents, Vanderver et al. (2016) identified homozygosity for the D48V mutation in the SDHB gene. The mutation was identified by whole-exome sequencing. </p><p>In 5 patients with MC2DN4, Helman et al. (2016) identified the D48V mutation in the SDHB gene. It was present in homozygous state in 4 patients (patients 10, 11, 16, and 19) and in compound heterozygous state in 1 (patient 15). </p><p>In a male infant, born on nonconsanguineous parents, with MC2DN4, Gronborg et al. (2017) identified compound heterozygous mutations in the SDHB gene: D48V and a c.689G-A transition resulting in an arg230-to-his (R230H; 185470.0023) substitution. The mutations were identified by whole-exome sequencing and confirmed by Sanger sequencing. The parents were confirmed to be mutation carriers. SDHB protein content was reduced in patient fibroblasts, and muscle fibers showed diffuse and severe lack of SDH staining. </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>.0021 PHEOCHROMOCYTOMA/PARAGANGLIOMA SYNDROME 4</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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SDHB, 7.9-KB DEL
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<br />
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ClinVar: RCV000626322
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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 9 apparently unrelated Dutch patients with paragangliomas (PPGL4; 115310), Bayley et al. (2009) identified a heterozygous 7.9-kb deletion (c.201-4429_287-933del) including exon 3 of the SDHB gene, predicted to result in a frameshift and premature termination (Cys68HisfsTer21). The deletion was found by multiplex ligation-dependent probe amplification (MLPA) analysis of 126 patients who did not carry point mutations in SDH genes, and all patients had the same breakpoints. Haplotype analysis indicated a founder effect. Only 1 patient had a family history of PGL, 5 patients had no family history, and family information from 3 patients was not available. The patients presented with head and neck PGL, extraadrenal PGL, and pheochromocytoma. Bayley et al. (2009) suggested incomplete penetrance associated with this mutation. Functional studies of the variant and studies of patient cells were not performed. </p><p>Rijken et al. (2016) reported a large multigenerational Dutch family with PPGL4 due to the Dutch founder 7.9-kb deletion in the SDGB gene. There were 17 family members who carried the mutation, but only 6 had clinical manifestations; 11 patients were disease-free, indicating incomplete penetrance. The age-dependent penetrance of the mutation in this family was estimated to be 9% at age 50 years. </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>.0022 MITOCHONDRIAL COMPLEX II DEFICIENCY, NUCLEAR TYPE 4</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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SDHB, LEU257VAL
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<br />
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SNP: rs761350633,
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gnomAD: rs761350633,
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ClinVar: RCV000708779, RCV000819850, RCV001310279, RCV002268269, RCV004659188
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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 Lebanese girl (patient 1), born to consanguineous parents, with mitochondrial complex II deficiency nuclear type 4 (MC2DN4; 619224), Gronborg et al. (2017) identified homozygosity for a c.769C-G transversion (c.769C-G, NM_003000.2) in the SDHB gene, resulting in a leu257-to-val (L257V) substitution at a highly conserved site. The mutation, which was found by homozygosity mapping and sequencing of the SDHB gene, was present in heterozygous state in the parents. SDHB protein content was reduced in patient fibroblasts, and muscle fibers showed diffuse and severe lack of SDH staining. The mutation was present in 1 of 121,292 alleles in the ExAC database. </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>.0023 MITOCHONDRIAL COMPLEX II DEFICIENCY, NUCLEAR TYPE 4</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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PHEOCHROMOCYTOMA/PARAGANGLIOMA SYNDROME 4, 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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SDHB, ARG230HIS
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<br />
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SNP: rs587782604,
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gnomAD: rs587782604,
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ClinVar: RCV000131970, RCV000183215, RCV000456660, RCV000505312, RCV000660259, RCV000762865, RCV001310280, RCV003474782
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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 />
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<p><strong><em>Mitochondrial Complex II Deficiency, Nuclear Type 4</em></strong></p><p>
|
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For discussion of the c.689G-A transition (c.689G-A, NM_003000.2) in the SDHB gene, resulting in an arg230-to-his (R230H) substitution, that was found in compound heterozygous state in a patient with mitochondrial complex II deficiency nuclear type 4 (MC2DN4; 619224) by Gronborg et al. (2017), see 185470.0020. </p><p><strong><em>Pheochromocytoma/Paraganglioma Syndrome 4</em></strong></p><p>
|
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In 2 patients with head and neck paraganglioms (PPGL4; 115310) from a Mexican family living in Guadalajara, Cerecer-Gil et al. (2010) identified a heterozygous germline c.689G-A transition in the SDHB gene, resulting in an arg230-to-his (R230H) substitution. </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>.0024 MITOCHONDRIAL COMPLEX II DEFICIENCY, NUCLEAR TYPE 4</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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SDHB, ALA102THR
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<br />
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SNP: rs777578399,
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gnomAD: rs777578399,
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ClinVar: RCV001018296, RCV001310281, RCV001766844, RCV001860902, RCV004004577
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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 an Indian boy with mitochondrial complex II deficiency nuclear type 4 (MC2DN4; 619224), Kaur et al. (2020) identified a homozygous c.304G-A transition (c.304G-A, NM_003000.2) in the SDHB gene, resulting in an ala102-to-thr (A102T) substitution at a highly conserved residue. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the parents. The mutation was not present in homozygous state in the gnomAD database or in an in-house database of 569 individuals. In silico protein modeling suggested that the A102T substitution caused a gain of a polar contact in the SDHB protein, thus altering protein structure. </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>REFERENCES</strong>
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|
</span>
|
|
</h4>
|
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<div>
|
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<p />
|
|
</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">
|
|
Alston, C. L., Davison, J. E., Meloni, F., van der Westhuizen, F. H., He, L., Hornig-Do, H.-T., Peet, A. C., Gissen, P., Goffrini, P., Ferrero, I., Wassmer, E., McFarland, R., Taylor, R. W.
|
|
<strong>Recessive germline SDHA and SDHB mutations causing leukodystrophy and isolated mitochondrial complex II deficiency.</strong>
|
|
J. Med. Genet. 49: 569-577, 2012.
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|
[PubMed: 22972948]
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[Full Text: https://doi.org/10.1136/jmedgenet-2012-101146]
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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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Ardissone, A., Invernizzi, F., Nasca, A., Moroni, I., Farina, L., Ghezzi, D.
|
|
<strong>Mitochondrial leukoencephalopathy and complex II deficiency associated with a recessive SDHB mutation with reduced penetrance.</strong>
|
|
Molec. Genet. Metab. Rep. 5: 51-54, 2015.
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|
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|
|
[PubMed: 26925370]
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[Full Text: https://doi.org/10.1016/j.ymgmr.2015.10.006]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Astuti, D., Latif, F., Dallol, A., Dahia, P. L. M., Douglas, F., George, E., Skoldberg, F., Husebye, E. S., Eng, C., Maher, E. R.
|
|
<strong>Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma.</strong>
|
|
Am. J. Hum. Genet. 69: 49-54, 2001. Note: Erratum: Am. J. Hum. Genet. 70: 565 only, 2002.
|
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[PubMed: 11404820]
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[Full Text: https://doi.org/10.1086/321282]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Au, H. C., Ream-Robinson, D., Bellew, L. A., Broomfield, P. L. E., Saghbini, M., Scheffler, I. E.
|
|
<strong>Structural organization of the gene encoding the human iron-sulfur subunit of succinate dehydrogenase.</strong>
|
|
Gene 159: 249-253, 1995.
|
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|
|
[PubMed: 7622059]
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[Full Text: https://doi.org/10.1016/0378-1119(95)00162-y]
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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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Bayley, J.-P., Grimbergen, A. E. M., van Bunderen, P. A., van der Wielen, M., Kunst, H. P., Lenders, J. W., Jansen, J. C., Dullaart, R. P. F., Devilee, P., Corssmit, E. P., Vriends, A. H., Losekoot, M., Weiss, M. M.
|
|
<strong>The first Dutch SDHB founder deletion in paraganglioma-pheochromocytoma patients.</strong>
|
|
BMC Med. Genet. 10: 34, 2009. Note: Electronic Article.
|
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[PubMed: 19368708]
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[Full Text: https://doi.org/10.1186/1471-2350-10-34]
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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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Bayley, J.-P., van Minderhout, I., Weiss, M. M., Jansen, J. C., Oomen, P. H. N., Menko, F. H., Pasini, B., Ferrando, B., Wong, N., Alpert, L. C, Williams, R., Blair, E., Devilee, P., Taschner, P. E. M.
|
|
<strong>Mutation analysis of SDHB and SDHC: novel germline mutations in sporadic head and neck paraganglioma and familial paraganglioma and/or pheochromocytoma.</strong>
|
|
BMC Med. Genet. 7: 1, 2006. Note: Electronic Article.
|
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|
|
[PubMed: 16405730]
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[Full Text: https://doi.org/10.1186/1471-2350-7-1]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Bayley, J.-P.
|
|
<strong>Succinate dehydrogenase gene variants and their role in Cowden syndrome. (Letter)</strong>
|
|
Am. J. Hum. Genet. 88: 674-675, 2011.
|
|
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|
|
[PubMed: 21565294]
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[Full Text: https://doi.org/10.1016/j.ajhg.2010.12.016]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Boccon-Gibod, L., Boman, F., Boudjemaa, S., Fabre, M., Leverger, G., Carney, A. J.
|
|
<strong>Separate occurrence of extra-adrenal paraganglioma and gastrointestinal stromal tumor in monozygotic twins: probable familial Carney syndrome.</strong>
|
|
Pediatr. Dev. Pathol. 7: 380-384, 2004.
|
|
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|
|
[PubMed: 15383933]
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[Full Text: https://doi.org/10.1007/s10024-004-8090-y]
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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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Brouwers, F. M., Eisenhofer, G., Tao, J. J., Kant, J. A., Adams, K. T., Linehan, W. M., Pacak, K.
|
|
<strong>High frequency of SDHB germline mutations in patients with malignant catecholamine-producing paragangliomas: implications for genetic testing.</strong>
|
|
J. Clin. Endocr. Metab. 91: 4505-4509, 2006.
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|
[PubMed: 16912137]
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[Full Text: https://doi.org/10.1210/jc.2006-0423]
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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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Cascon, A., Landa, I., Lopez-Jimenez, E., Diez-Hernandez, A., Buchta, M., Montero-Conde, C., Leskela, S., Leandro-Garcia, L. J., Leton, R., Rodriguez-Antona, C., Eng, C., Neumann, H. P. H., Robledo, M.
|
|
<strong>Molecular characterisation of a common SDHB deletion in paraganglioma patients. (Letter)</strong>
|
|
J. Med. Genet. 45: 233-238, 2008.
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|
[PubMed: 18057081]
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[Full Text: https://doi.org/10.1136/jmg.2007.054965]
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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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Cascon, A., Montero-Conde, C., Ruiz-Llorente, S., Mercadillo, F., Leton, R., Rodriguez-Antona, C., Martinez-Delgado, B., Delgado, M., Diez, A., Rovira, A., Diaz, J. A., Robledo, M.
|
|
<strong>Gross SDHB deletions in patients with paraganglioma detected by multiplex PCR: a possible hot spot?</strong>
|
|
Genes Chromosomes Cancer 45: 213-219, 2006.
|
|
|
|
|
|
[PubMed: 16258955]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1002/gcc.20283]
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</p>
|
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Cerecer-Gil, N. Y., Figuera, L. E., Llamas, F. J., Lara, M., Escamilla, J. G., Ramos, R., Estrada, G., Karim Hussain, A., Gaal, J., Korpershoek, E., de Krijger, R. R., Dinjens, W. N. M., Devilee, P., Bayley, J. P.
|
|
<strong>Mutation of SDHB is a cause of hypoxia-related high-altitude paraganglioma.</strong>
|
|
Clin. Cancer Res. 16: 4148-4158, 2010.
|
|
|
|
|
|
[PubMed: 20592014]
|
|
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|
|
|
[Full Text: https://doi.org/10.1158/1078-0432.CCR-10-0637]
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|
</p>
|
|
</li>
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<li>
|
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<p class="mim-text-font">
|
|
Dickinson, M. E., Flenniken, A. M., Ji, X., Teboul, L., Wong, M. D., White, J. K., Meehan, T. F., Weninger, W. J., Westerberg, H., Adissu, H., Baker, C. N., Bower, L., and 73 others.
|
|
<strong>High-throughput discovery of novel developmental phenotypes.</strong>
|
|
Nature 537: 508-514, 2016. Note: Erratum: Nature 551: 398 only, 2017.
|
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|
|
|
[PubMed: 27626380]
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|
|
[Full Text: https://doi.org/10.1038/nature19356]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Fairchild, R. S., Kyner, J. L., Hermreck, A., Schimke, R. N.
|
|
<strong>Neuroblastoma, pheochromocytoma, and renal cell carcinoma: occurrence in a single patient.</strong>
|
|
JAMA 242: 2210-2211, 1979.
|
|
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|
|
|
[PubMed: 490809]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Gimenez-Roqueplo, A.-P., Favier, J., Rustin, P., Rieubland, C., Kerlan, V., Plouin, P.-F., Rotig, A., Jeunemaitre, X.
|
|
<strong>Functional consequences of a SDHB gene mutation in an apparently sporadic pheochromocytoma.</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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Ada Hamosh - updated : 11/28/2022<br>Hilary J. Vernon - updated : 03/08/2021<br>Ada Hamosh - updated : 07/11/2018<br>Cassandra L. Kniffin - updated : 04/25/2018<br>Ada Hamosh - updated : 02/21/2017<br>Cassandra L. Kniffin - updated : 1/14/2013<br>Cassandra L. Kniffin - updated : 4/11/2012<br>Cassandra L. Kniffin - updated : 6/2/2011<br>Cassandra L. Kniffin - updated : 12/3/2010<br>Cassandra L. Kniffin - updated : 11/30/2010<br>George E. Tiller - updated : 11/21/2008<br>Ada Hamosh - updated : 9/22/2008<br>Cassandra L. Kniffin - updated : 8/14/2008<br>John A. Phillips, III - updated : 7/3/2008<br>Marla J. F. O'Neill - updated : 5/6/2008<br>John A. Phillips, III - updated : 10/2/2007<br>Marla J. F. O'Neill - updated : 9/24/2007<br>Cassandra L. Kniffin - updated : 7/31/2007<br>John A. Phillips, III - updated : 3/15/2007<br>Victor A. McKusick - updated : 6/9/2006<br>Cassandra L. Kniffin - updated : 1/6/2006<br>John A. Phillips, III - updated : 5/11/2005<br>Victor A. McKusick - updated : 1/6/2004<br>John A. Phillips, III - updated : 4/8/2003<br>John A. Phillips, III - updated : 1/7/2003<br>Victor A. McKusick - updated : 9/4/2001<br>Victor A. McKusick - updated : 3/3/1998
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</span>
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Victor A. McKusick : 6/2/1986
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