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- *602690 - SUCCINATE DEHYDROGENASE COMPLEX, SUBUNIT D; SDHD
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- OMIM
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<p>
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<span class="h4">*602690</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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<a href="#mapping">Mapping</a>
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#history">History</a>
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/602690">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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<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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<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 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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<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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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000204370;t=ENST00000375549" 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=6392" 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=602690" 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 class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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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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</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=ENSG00000204370;t=ENST00000375549" 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_001276503,NM_001276504,NM_001276506,NM_003002,NR_077060" 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_003002" 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=602690" 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=04069&isoform_id=04069_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/SDHD" 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/2351037,3913480,4506865,5295994,13528942,15214939,15929519,16306998,16359051,18490204,30583315,47682403,48145981,48734962,48735312,119587585,119587586,119587587,193786797,452405465,452405678,452406068,957950176,957950179" 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/O14521" 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=6392" 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=ENSG00000204370;t=ENST00000375549" 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=SDHD" 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=SDHD" 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+6392" 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/SDHD" 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:6392" 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/6392" 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=chr11&hgg_gene=ENST00000532699.1&hgg_start=112086873&hgg_end=112095794&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:10683" 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:10683" 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://medlineplus.gov/genetics/gene/sdhd" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=602690[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=602690[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://gnomad.broadinstitute.org/gene/ENSG00000204370" 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=SDHD" 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=SDHD" 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=SDHD" 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/SDHD" 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=SDHD&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/PA35608" 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:10683" 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/FBgn0039112.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:1914175" 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/SDHD#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:1914175" 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/6392/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=6392" 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=WBGene00009353;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-040718-192" 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:6392" 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=SDHD&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> 722377004<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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602690
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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, SUBUNIT D; SDHD
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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 D, INTEGRAL MEMBRANE PROTEIN<br />
|
|
SUCCINATE DEHYDROGENASE 4, INTEGRAL MEMBRANE PROTEIN; SDH4
|
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</span>
|
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</h4>
|
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=SDHD" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">SDHD</a></em></strong>
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</span>
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</p>
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</div>
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<div>
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
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<span class="mim-text-font">
|
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<strong>
|
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<em>
|
|
Cytogenetic location: <a href="/geneMap/11/930?start=-3&limit=10&highlight=930">11q23.1</a>
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|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr11:112086873-112095794&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'})">11:112,086,873-112,095,794</a> </span>
|
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</em>
|
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</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
|
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<br />
|
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</div>
|
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<div>
|
|
<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=619167,606864,168000" 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="3">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/11/930?start=-3&limit=10&highlight=930">
|
|
11q23.1
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Mitochondrial complex II deficiency, nuclear type 3
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/619167"> 619167 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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</span>
|
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</td>
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</tr>
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<tr>
|
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<td>
|
|
<span class="mim-font">
|
|
Paraganglioma and gastric stromal sarcoma
|
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|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/606864"> 606864 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
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<p>The SDHD gene encodes an integral membrane protein subunit of the succinate dehydrogenase (<a href="https://enzyme.expasy.org/EC/1.3.5.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'EC\', \'domain\': \'expasy.org\'})">EC 1.3.5.1</a>) complex (summary by <a href="#16" class="mim-tip-reference" title="Hirawake, H., Taniwaki, M., Tamura, A., Kojima, S., Kita, K. <strong>Cytochrome b in human complex II (succinate-ubiquinone oxidoreductase): cDNA cloning of the components in liver mitochondria and chromosome assignment of the genes for the large (SDHC) and small (SDHD) subunits to 1q21 and 11q23.</strong> Cytogenet. Cell Genet. 79: 132-138, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9533030/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9533030</a>] [<a href="https://doi.org/10.1159/000134700" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9533030">Hirawake et al., 1997</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9533030" 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>Complex II (succinate-ubiquinone oxidoreductase) is an important enzyme complex in both the tricarboxylic acid cycle and the aerobic respiratory chains of mitochondria in eukaryotic cells and prokaryotic organisms. <a href="#16" class="mim-tip-reference" title="Hirawake, H., Taniwaki, M., Tamura, A., Kojima, S., Kita, K. <strong>Cytochrome b in human complex II (succinate-ubiquinone oxidoreductase): cDNA cloning of the components in liver mitochondria and chromosome assignment of the genes for the large (SDHC) and small (SDHD) subunits to 1q21 and 11q23.</strong> Cytogenet. Cell Genet. 79: 132-138, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9533030/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9533030</a>] [<a href="https://doi.org/10.1159/000134700" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9533030">Hirawake et al. (1997)</a> deduced the amino acid sequences of the large (cybL, encoded by the SDHC gene, <a href="/entry/602413">602413</a>) and small (cybS, encoded by the SDHD gene) subunits of cytochrome b in human liver complex II from cDNAs isolated by homology probing with mixed primers for the polymerase chain reaction. The mature cybL and cybS contain 140 and 103 amino acids, respectively, and show little similarity to the amino acid sequences of the subunits from other species, in contrast to the highly conserved features of the flavoprotein (Fp) subunit (SDHA; <a href="/entry/600857">600857</a>) and the iron-sulfur protein (Ip) subunit (SDHB; <a href="/entry/185470">185470</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9533030" 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="#16" class="mim-tip-reference" title="Hirawake, H., Taniwaki, M., Tamura, A., Kojima, S., Kita, K. <strong>Cytochrome b in human complex II (succinate-ubiquinone oxidoreductase): cDNA cloning of the components in liver mitochondria and chromosome assignment of the genes for the large (SDHC) and small (SDHD) subunits to 1q21 and 11q23.</strong> Cytogenet. Cell Genet. 79: 132-138, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9533030/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9533030</a>] [<a href="https://doi.org/10.1159/000134700" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9533030">Hirawake et al. (1997)</a> mapped the genes for cybL (SDHC; <a href="/entry/602413">602413</a>) and cybS (SDHD) to 1q21 and 11q23, respectively, by fluorescence in situ hybridization. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9533030" 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>Pseudogenes</em></strong></p><p>
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<a href="#1" class="mim-tip-reference" title="Aguiar, R. C. T., Cox, G., Pomeroy, S. L., Dahia, P. L. M. <strong>Analysis of the SDHD gene the susceptibility gene for familial paraganglioma syndrome (PGL1), in pheochromocytomas.</strong> J. Clin. Endocr. Metab. 86: 2890-2894, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11397905/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11397905</a>] [<a href="https://doi.org/10.1210/jcem.86.6.7547" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11397905">Aguiar et al. (2001)</a> confirmed a sequence highly homologous to SDHD cDNA on chromosome 1p36-p34, a region commonly deleted in pheochromocytomas. Full analysis of this sequence revealed a heterozygous single base substitution in 70% of their samples that was also present in the germline. This sequence did not appear to be transcribed and is probably a processed pseudogene. Therefore, despite its chromosomal location, it is unlikely that this sequence is a target of LOH in pheochromocytomas. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11397905" 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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In mammalian cells, <a href="#34" 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 1</em></strong></p><p>
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In affected members of families with hereditary paraganglioma (PPGL1; <a href="/entry/168000">168000</a>), <a href="#7" class="mim-tip-reference" title="Baysal, B. E., Ferrell, R. E., Willett-Brozick, J. E., Lawrence, E. C., Myssiorek, D., Bosch, A., van der May, A., Taschner, P. E. M., Rubinstein, W. S., Myers, E. N., Richard, C. W., III, Cornelisse, C. J., Devilee, P., Devlin, B. <strong>Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma.</strong> Science 287: 848-851, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10657297/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10657297</a>] [<a href="https://doi.org/10.1126/science.287.5454.848" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10657297">Baysal et al. (2000)</a> identified heterozygous mutations in the SDHD gene (<a href="#0001">602690.0001</a>-<a href="#0005">602690.0005</a>), including the Dutch founder mutation (D92Y; <a href="#0004">602690.0004</a>). There was no evidence of imprinting; biallelic expression of the SDHD gene was identified in 3 independent fetal brain samples, 1 fetal kidney sample, 2 independent adult brain samples, and adult lymphocytes. The authors suggested that monoallelic expression of SDHD may be confined to the carotid body and other paraganglioma cells, similar to the brain-limited imprinting of UBE3A (<a href="/entry/601623">601623</a>) in Angelman syndrome (<a href="/entry/105830">105830</a>). Germline loss-of-function mutations in the paternal alleles and subsequent somatic loss of normal maternal alleles suggested that SDHD functions as a tumor suppressor gene at the cellular level and needs 2 events for inactivation. On the basis of the phenotypic similarity between PGL tumors and the normal carotid body exposed to chronic hypoxia, <a href="#7" class="mim-tip-reference" title="Baysal, B. E., Ferrell, R. E., Willett-Brozick, J. E., Lawrence, E. C., Myssiorek, D., Bosch, A., van der May, A., Taschner, P. E. M., Rubinstein, W. S., Myers, E. N., Richard, C. W., III, Cornelisse, C. J., Devilee, P., Devlin, B. <strong>Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma.</strong> Science 287: 848-851, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10657297/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10657297</a>] [<a href="https://doi.org/10.1126/science.287.5454.848" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10657297">Baysal et al. (2000)</a> suggested that cybS is a critical component of the oxygen-sensing system of paraganglionic tissue, and that its loss may lead to chronic hypoxic stimulation and cellular proliferation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10657297" 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 commenting on a case of thoracic pheochromocytoma (paraganglioma) in a 19-year-old man whose father received a diagnosis of hypertension in his 50s, <a href="#27" class="mim-tip-reference" title="Neumann, H. P. H., Reincke, M., Eng, C. <strong>Case 13-2001: genetic testing in pheochromocytoma. (Letter)</strong> New Eng. J. Med. 345: 547 only, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11519521/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11519521</a>]" pmid="11519521">Neumann et al. (2001)</a> pointed to evidence indicating that germline mutations in the VHL gene (<a href="/entry/608537">608537</a>), causing von Hippel-Lindau disease (<a href="/entry/193300">193300</a>), and mutations in the SDHD gene together account for 15 to 20% of all nonfamilial presentations of pheochromocytoma. If the father in the case at hand had a pheochromocytoma-paraganglioma syndrome, then the likelihood of finding a germline mutation in SDHD or VHL rises higher than 20%. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11519521" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#12" class="mim-tip-reference" title="Gimm, O., Armanios, M., Dziema, H., Neumann, H. P. H., Eng, C. <strong>Somatic and occult germ-line mutations in SDHD, a mitochondrial complex II gene, in nonfamilial pheochromocytoma.</strong> Cancer Res. 60: 6822-6825, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11156372/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11156372</a>]" pmid="11156372">Gimm et al. (2000)</a> identified several mutations in the SDHD gene in unrelated patients. One patient had a pheochromocytoma and a carotid body paraganglioma (see <a href="#0010">602690.0010</a>); 2 unrelated patients had the same mutation (<a href="#0011">602690.0011</a>), 1 with an extraadrenal intraabdominal pheochromocytoma with involvement of the jugular fossa, suggesting malignancy, and 1 with an isolated intestinal lipoma; and a 33-year-old woman had 2 extraadrenal pheochromocytomas, 1 intraabdominal and 1 intrathoracic (see <a href="#0002">602690.0002</a>). Finally, the authors identified a somatic SDHD mutation in a pheochromocytoma (<a href="#0003">602690.0003</a>). The results indicated that SDHD plays a role in the pathogenesis of pheochromocytoma. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11156372" 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="#5" class="mim-tip-reference" title="Badenhop, R. F., Cherian, S., Lord, R. S. A., Baysal, B. E., Taschner, P. E. M., Schofield, P. R. <strong>Novel mutations in the SDHD gene in pedigrees with familial carotid body paraganglioma and sensorineural hearing loss.</strong> Genes Chromosomes Cancer 31: 255-263, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11391796/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11391796</a>] [<a href="https://doi.org/10.1002/gcc.1142" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11391796">Badenhop et al. (2001)</a> studied 4 families with familial carotid body paragangliomas, 2 of which exhibited coinheritance of PGL and sensorineural hearing loss or tinnitus. Sequence analysis identified mutations in exon 1 and exon 3 of the SDHD gene (<a href="#0003">602690.0003</a>; <a href="#0013">602690.0013</a>; <a href="#0014">602690.0014</a>; <a href="#0015">602690.0015</a>). The PGL1 region contains another gene, DPP2/TIMM8B (<a href="/entry/606659">606659</a>), a homolog of the X-linked TIMM8A gene (<a href="/entry/300356">300356</a>), mutations in which cause dystonia and deafness seen in Mohr-Tranebjaerg syndrome (<a href="/entry/304700">304700</a>). The authors found no base changes in the TIMM8B gene and concluded that the association of paraganglioma with sensorineural hearing loss could not be explained by the proximity of the TIMM8B and SDHD genes. <a href="#5" class="mim-tip-reference" title="Badenhop, R. F., Cherian, S., Lord, R. S. A., Baysal, B. E., Taschner, P. E. M., Schofield, P. R. <strong>Novel mutations in the SDHD gene in pedigrees with familial carotid body paraganglioma and sensorineural hearing loss.</strong> Genes Chromosomes Cancer 31: 255-263, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11391796/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11391796</a>] [<a href="https://doi.org/10.1002/gcc.1142" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11391796">Badenhop et al. (2001)</a> found no apparent loss of heterozygosity at the site of the SDHD mutations in the paraganglioma tumors. However, RT-PCR analysis of tumor samples showed monoallelic expression of the mutant (paternal) allele as expected for imprinting. Thus the inheritance and expression of the SDHD gene is consistent with the PGL1 gene being subject to genomic imprinting. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11391796" 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="#35" class="mim-tip-reference" title="Taschner, P. E. M., Jansen, J. C., Baysal, B. E., Bosch, A., Rosenberg, E. H., Brocker-Vriends, A. H. J. T., van der Mey, A. G. L., van Ommen, G.-J. B., Cornelisse, C. J., Devilee, P. <strong>Nearly all hereditary paragangliomas in the Netherlands are caused by two founder mutations in the SDHD gene.</strong> Genes Chromosomes Cancer 31: 274-281, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11391798/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11391798</a>] [<a href="https://doi.org/10.1002/gcc.1144" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11391798">Taschner et al. (2001)</a> found that 2 founder mutations, asp92 to tyr (<a href="#0004">602690.0004</a>) and leu139 to pro (<a href="#0016">602690.0016</a>), were responsible for paragangliomas in 24 and 6 of 32 independently ascertained Dutch paraganglioma families, respectively. These 2 mutations were detected among 20 of 55 isolated patients as well. Ten of the isolated patients had multiple paragangliomas, and in 8 of these SDHD germline mutations were found, indicating that multicentricity is a strong predictive factor for the hereditary nature of the disorder in isolated patients. In addition, <a href="#35" class="mim-tip-reference" title="Taschner, P. E. M., Jansen, J. C., Baysal, B. E., Bosch, A., Rosenberg, E. H., Brocker-Vriends, A. H. J. T., van der Mey, A. G. L., van Ommen, G.-J. B., Cornelisse, C. J., Devilee, P. <strong>Nearly all hereditary paragangliomas in the Netherlands are caused by two founder mutations in the SDHD gene.</strong> Genes Chromosomes Cancer 31: 274-281, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11391798/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11391798</a>] [<a href="https://doi.org/10.1002/gcc.1144" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11391798">Taschner et al. (2001)</a> demonstrated that the maternally derived wildtype SDHD allele is lost in tumors from mutation-carrying patients, indicating that SDHD functions as a tumor suppressor gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11391798" 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="Cascon, A., Ruiz-Llorente, S., Cebrian, A., Telleria, D., Rivero, J. C., Diez, J. J., Lopez-Ibarra, P., Jaunsolo, M. A., Benitez, J., Robledo, M. <strong>Identification of novel SDHD mutations in patients with phaeochromocytoma and/or paraganglioma.</strong> Europ. J. Hum. Genet. 10: 457-461, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12111639/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12111639</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200829" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12111639">Cascon et al. (2002)</a> performed sequence analysis of the 4 exons of the SDHD gene in 25 consecutive, unrelated patients with pheochromocytoma and/or paraganglioma. There were 18 patients with pheochromocytoma, 4 with paraganglioma alone, and 3 with both, who had tested negative for germline mutations in the VHL (<a href="/entry/608537">608537</a>) and RET (<a href="/entry/164761">164761</a>) genes. They detected 5 heterozygous germline sequence variants: 2 missense mutations also found in control chromosomes, G12S (<a href="#0011">602690.0011</a>) and H50R (<a href="#0019">602690.0019</a>); a silent mutation (S68S) considered to be a polymorphism; and 2 novel truncating mutations. (The H50R and G12S mutations were later reclassified as variants of unknown significance.) The 2 truncating mutations were a 4-bp frameshift deletion in exon 4 (<a href="#0022">602690.0022</a>) in an apparently sporadic case of paraganglioma and pheochromocytoma, and a nonsense mutation in exon 2 (<a href="#0023">602690.0023</a>) in a patient with paraganglioma and a family history of pheochromocytoma. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12111639" 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 11 (4%) of 271 unrelated patients with sporadic pheochromocytoma, <a href="#26" 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 7 different germline mutations in the SDHD gene (see, e.g., <a href="#0002">602690.0002</a>; <a href="#0004">602690.0004</a>; <a href="#0025">602690.0025</a>; <a href="#0026">602690.0026</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="#33" class="mim-tip-reference" title="Riemann, K., Sotlar, K., Kupka, S., Braun, S., Zenner, H.-P., Preyer, S., Pfister, M., Pusch, C. M., Blin, N. <strong>Chromosome 11 monosomy in conjunction with a mutated SDHD initiation codon in nonfamilial paraganglioma cases.</strong> Cancer Genet. Cytogenet. 150: 128-135, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15066320/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15066320</a>] [<a href="https://doi.org/10.1016/j.cancergencyto.2003.10.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15066320">Riemann et al. (2004)</a> provided a tabulation of known mutations in the SDHD gene causing paraganglioma. They noted that in addition to mutation in the SDHD gene, loss of heterozygosity (LOH) on chromosome 11, mainly in 11q23, had been observed in paragangliomas (<a href="#10" class="mim-tip-reference" title="Devilee, P., van Schothorst, E. M., Bardoel, A. F. J., Bonsing, B., Kuipers-Dijkshoorn, N., James, M. R., Fleuren, G., van der Mey, A. G. L., Cornelisse, C. J. <strong>Allelotype of head and neck paragangliomas: allelic imbalance is confined to the long arm of chromosome 11, the site of the predisposing locus PGL.</strong> Genes Chromosomes Cancer 11: 71-78, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7529551/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7529551</a>] [<a href="https://doi.org/10.1002/gcc.2870110202" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7529551">Devilee et al., 1994</a>; <a href="#36" class="mim-tip-reference" title="van Schothorst, E. M., Beekman, M., Torremans, P., Kuipers-Dijkshoorn, N. J., Wessels, H. W., Bardoel, A. F. J., van der Mey, A. G. L., van der Vijver, M. J., van Ommen, G.-J. B., Devilee, P., Cornelisse, C. J. <strong>Paragangliomas of the head and neck region show complete loss of heterozygosity at 11q22-q23 in chief cells and the flow-sorted DNA aneuploid fraction.</strong> Hum. Path. 29: 1045-1049, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9781639/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9781639</a>] [<a href="https://doi.org/10.1016/s0046-8177(98)90411-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9781639">van Schothorst et al., 1998</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9781639+15066320+7529551" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#14" class="mim-tip-reference" title="Hensen, E. F., Jordanova, E. S., van Minderhout, I. J. H. M., Hogendoorn, P. C. W., Taschner, P. E. M., van der Mey, A. G. L., Devilee, P., Cornelisse, C. J. <strong>Somatic loss of maternal chromosome 11 causes parent-of-origin-dependent inheritance in SDHD-linked paraganglioma and phaeochromocytoma families.</strong> Oncogene 23: 4076-4083, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15064708/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15064708</a>] [<a href="https://doi.org/10.1038/sj.onc.1207591" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15064708">Hensen et al. (2004)</a> demonstrated exclusive loss of the entire maternal chromosome 11 in SDHD-linked paragangliomas and pheochromocytomas, suggesting that combined loss of the wildtype SDHD allele and maternal 11p region is essential for tumorigenesis. They hypothesized that this is driven by selective loss of 1 or more imprinted genes in the 11p15 region. In paternally but not maternally derived SDHD mutation carriers, this can be achieved by a single event: nondisjunctional loss of the maternal chromosome 11. <a href="#14" class="mim-tip-reference" title="Hensen, E. F., Jordanova, E. S., van Minderhout, I. J. H. M., Hogendoorn, P. C. W., Taschner, P. E. M., van der Mey, A. G. L., Devilee, P., Cornelisse, C. J. <strong>Somatic loss of maternal chromosome 11 causes parent-of-origin-dependent inheritance in SDHD-linked paraganglioma and phaeochromocytoma families.</strong> Oncogene 23: 4076-4083, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15064708/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15064708</a>] [<a href="https://doi.org/10.1038/sj.onc.1207591" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15064708">Hensen et al. (2004)</a> concluded that the exclusive paternal transmission of the disease can be explained by a somatic genetic mechanism targeting both the SDHD gene on 11q23 and a paternally imprinted gene on 11p15.5, rather than imprinting of SDHD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15064708" 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="#24" 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> reported a 3-generation family with 6 affected members with paraganglioma who carried a germline 96-kb deletion (<a href="#0024">602690.0024</a>) spanning the entire SDHD gene. The family was initially designated mutation-negative for all the PC/PGL-associated genes after PCR-based analysis; fine structure genotyping and semiquantitative duplex PCR analysis were used to detect the whole-gene deletion. <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><p>In northern Spain, where cervical paraganglioma is particularly frequent, <a href="#20" 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. SDHD mutations were primarily frameshift. <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 a male patient with paraganglioma and gastric stromal sarcoma (<a href="/entry/606864">606864</a>), <a href="#23" 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 1-bp heterozygous deletion in the SDHD gene (<a href="#0027">602690.0027</a>). In 5 other families with the dyad, the authors also found germline mutations in the SDHB (see, e.g., <a href="/entry/185470#0012">185470.0012</a> and <a href="/entry/185470#0013">185470.0013</a>) and SDHC (<a href="/entry/602413#0004">602413.0004</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><strong><em>C Cell Hyperplasia and Hypercalcitoninemia</em></strong></p><p>
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<a href="#21" class="mim-tip-reference" title="Lima, J., Teixeira-Gomes, J., Soares, P., Maximo, V., Honavar, M., Williams, D., Sobrinho-Simoes, M. <strong>Germline succinate dehydrogenase subunit D mutation segregating with familial non-RET C cell hyperplasia.</strong> J. Clin. Endocr. Metab. 88: 4932-4937, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14557476/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14557476</a>] [<a href="https://doi.org/10.1210/jc.2002-030008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14557476">Lima et al. (2003)</a> reported a family with C cell hyperplasia and hypercalcitoninemia in which no cases of medullary carcinoma had occurred and which lacked an identifiable causative RET mutation. Four of the family members showed hypercalcitoninemia, and marked C cell hyperplasia was present in each of the 3 in whom thyroidectomy had been performed. A germline mutation in exon 2 of the SDHD gene (149A-G) was found in 6 members of the family; all the 4 available members with hypercalcitoninemia possessed the mutation. One of the 5 available members without hypercalcitoninemia, an 18-year-old female, also showed the mutation. The mutation was also identified in 11 of 474 control chromosomes (2.3%), which caused the authors to question whether the mutation is particularly prevalent in the Portuguese population or is regularly associated with C cell hyperplasia. <a href="#21" class="mim-tip-reference" title="Lima, J., Teixeira-Gomes, J., Soares, P., Maximo, V., Honavar, M., Williams, D., Sobrinho-Simoes, M. <strong>Germline succinate dehydrogenase subunit D mutation segregating with familial non-RET C cell hyperplasia.</strong> J. Clin. Endocr. Metab. 88: 4932-4937, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14557476/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14557476</a>] [<a href="https://doi.org/10.1210/jc.2002-030008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14557476">Lima et al. (2003)</a> noted that other studies of normal individuals did not find this mutation (<a href="#18" class="mim-tip-reference" title="Kytola, S., Nord, B., Elder, E. E., Carling, T., Kjellman, M., Cedermark, B., Juhlin, C., Hoog, A., Isola, J., Larsson, C. <strong>Alterations of the SDHD gene locus in midgut carcinoids, Merkel cell carcinomas, pheochromocytomas, and abdominal paragangliomas.</strong> Genes Chromosomes Cancer 34: 325-332, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12007193/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12007193</a>] [<a href="https://doi.org/10.1002/gcc.10081" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12007193">Kytola et al., 2002</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=14557476+12007193" 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 3</em></strong></p><p>
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In a patient with mitochondrial complex II deficiency nuclear type 3 (MC2DN3; <a href="/entry/619167">619167</a>), <a href="#17" class="mim-tip-reference" title="Jackson, C. B., Nuoffer, J.-M., Hahn, D., Prokisch, H., Haberberger, B., Gautschi, M., Haberli, A., Gallati, S., Schaller, A. <strong>Mutations in SDHD lead to autosomal recessive encephalomyopathy and isolated mitochondrial complex II deficiency.</strong> J. Med. Genet. 51: 170-175, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24367056/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24367056</a>] [<a href="https://doi.org/10.1136/jmedgenet-2013-101932" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24367056">Jackson et al. (2014)</a> identified compound heterozygous mutations in the SDHD gene (E69K, <a href="#0029">602690.0029</a> and X164L, <a href="#0030">602690.0030</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24367056" 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="#2" class="mim-tip-reference" title="Alston, C. L., Ceccatelli Berti, C., Blakely, E. L., Olahova, M., He, L., McMahon, C. J., Olpin, S. E., Hargreaves, I. P., Nolli, C., McFarland, R., Goffrini, P., O'Sullivan, M. J., Taylor, R. W. <strong>A recessive homozygous p.Asp92Gly SDHD mutation causes prenatal cardiomyopathy and a severe mitochondrial complex II deficiency.</strong> Hum. Genet. 134: 869-879, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26008905/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26008905</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26008905[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/s00439-015-1568-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26008905">Alston et al. (2015)</a> identified a homozygous missense mutation in the SDHD gene (D92G; <a href="#0031">602690.0031</a>) in an infant with MC2DN3 who died of cardiac failure and left ventricular noncompaction on the first day of life. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26008905" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
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For discussion of a possible association between Cowden syndrome (see <a href="/entry/158350">158350</a>) and variation in the SDHD gene, see <a href="#0011">602690.0011</a>, <a href="#0019">602690.0019</a>, and <a href="#0028">602690.0028</a>.</p><p>For discussion of a possible association between intestinal carcinoid tumors (see <a href="/entry/114900">114900</a>) and Merkel cell carcinomas and variation in the SDHD gene, see <a href="#0011">602690.0011</a> and <a href="#0019">602690.0019</a>.</p>
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<p><a href="#1" class="mim-tip-reference" title="Aguiar, R. C. T., Cox, G., Pomeroy, S. L., Dahia, P. L. M. <strong>Analysis of the SDHD gene the susceptibility gene for familial paraganglioma syndrome (PGL1), in pheochromocytomas.</strong> J. Clin. Endocr. Metab. 86: 2890-2894, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11397905/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11397905</a>] [<a href="https://doi.org/10.1210/jcem.86.6.7547" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11397905">Aguiar et al. (2001)</a> sequenced the entire coding region of the SDHD genes from a series of pheochromocytomas (see <a href="/entry/171300">171300</a>). Although they did not find mutations, they identified a new intronic SNP (97739A-G) in 15% of the samples. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11397905" 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>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=602690[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs104894303 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894303;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=rs104894303" 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=rs104894303" 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=RCV000007295 OR RCV000492417 OR RCV001851718" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007295, RCV000492417, RCV001851718" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007295...</a>
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<p>In a family with autosomal dominant paraganglioma (PPGL1; <a href="/entry/168000">168000</a>), <a href="#7" class="mim-tip-reference" title="Baysal, B. E., Ferrell, R. E., Willett-Brozick, J. E., Lawrence, E. C., Myssiorek, D., Bosch, A., van der May, A., Taschner, P. E. M., Rubinstein, W. S., Myers, E. N., Richard, C. W., III, Cornelisse, C. J., Devilee, P., Devlin, B. <strong>Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma.</strong> Science 287: 848-851, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10657297/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10657297</a>] [<a href="https://doi.org/10.1126/science.287.5454.848" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10657297">Baysal et al. (2000)</a> identified a heterozygous C-to-T transition in the SDHD gene, resulting in a glu36-to-ter (E36X) mutation within the mitochondrial signal peptide. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10657297" 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> rs80338843 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80338843;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/rs80338843?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=rs80338843" 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=rs80338843" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a family with autosomal dominant paraganglioma (PPGL1; <a href="/entry/168000">168000</a>), <a href="#7" class="mim-tip-reference" title="Baysal, B. E., Ferrell, R. E., Willett-Brozick, J. E., Lawrence, E. C., Myssiorek, D., Bosch, A., van der May, A., Taschner, P. E. M., Rubinstein, W. S., Myers, E. N., Richard, C. W., III, Cornelisse, C. J., Devilee, P., Devlin, B. <strong>Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma.</strong> Science 287: 848-851, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10657297/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10657297</a>] [<a href="https://doi.org/10.1126/science.287.5454.848" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10657297">Baysal et al. (2000)</a> identified a heterozygous C-to-T transition in the SDHD gene, resulting in an arg38-to-ter (R38X) substitution within the mitochondrial signal peptide. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10657297" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#12" class="mim-tip-reference" title="Gimm, O., Armanios, M., Dziema, H., Neumann, H. P. H., Eng, C. <strong>Somatic and occult germ-line mutations in SDHD, a mitochondrial complex II gene, in nonfamilial pheochromocytoma.</strong> Cancer Res. 60: 6822-6825, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11156372/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11156372</a>]" pmid="11156372">Gimm et al. (2000)</a> identified the R38X mutation in a 33-year-old woman with 2 extraadrenal pheochromocytomas, 1 intraabdominal and 1 intrathoracic. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11156372" 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 the germlines of 2 unrelated patients with sporadic pheochromocytomas, <a href="#26" 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 R38X substitution, resulting from a 112C-T transition in exon 2 of the SDHD 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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<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> rs80338844 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80338844;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/rs80338844?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=rs80338844" 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=rs80338844" 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=RCV000007303 OR RCV000007304 OR RCV000020519 OR RCV000162448 OR RCV000216073 OR RCV000763227 OR RCV002221470 OR RCV002228002 OR RCV003472995 OR RCV004748507" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007303, RCV000007304, RCV000020519, RCV000162448, RCV000216073, RCV000763227, RCV002221470, RCV002228002, RCV003472995, RCV004748507" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007303...</a>
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<p>In 5 families with autosomal dominant paraganglioma (PPGL1; <a href="/entry/168000">168000</a>), <a href="#7" class="mim-tip-reference" title="Baysal, B. E., Ferrell, R. E., Willett-Brozick, J. E., Lawrence, E. C., Myssiorek, D., Bosch, A., van der May, A., Taschner, P. E. M., Rubinstein, W. S., Myers, E. N., Richard, C. W., III, Cornelisse, C. J., Devilee, P., Devlin, B. <strong>Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma.</strong> Science 287: 848-851, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10657297/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10657297</a>] [<a href="https://doi.org/10.1126/science.287.5454.848" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10657297">Baysal et al. (2000)</a> identified a heterozygous C-to-T transition in the SDHD gene, resulting in a pro81-to-leu (P81L) substitution. The proline at position 81 is conserved in human, Bos taurus, Ascaris, and Caenorhabditis elegans. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10657297" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#25" class="mim-tip-reference" title="Milunsky, J. M., Maher, T. A., Michels, V. V., Milunsky, A. <strong>Novel mutations and the emergence of a common mutation in the SDHD gene causing familial paraganglioma.</strong> Am. J. Med. Genet. 100: 311-314, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11343322/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11343322</a>] [<a href="https://doi.org/10.1002/ajmg.1270" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11343322">Milunsky et al. (2001)</a> found the P81L mutation in 3 of 7 families with hereditary paraganglioma. Since this mutation results in the elimination of a normally occurring restriction endonuclease site (MspI), <a href="#25" class="mim-tip-reference" title="Milunsky, J. M., Maher, T. A., Michels, V. V., Milunsky, A. <strong>Novel mutations and the emergence of a common mutation in the SDHD gene causing familial paraganglioma.</strong> Am. J. Med. Genet. 100: 311-314, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11343322/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11343322</a>] [<a href="https://doi.org/10.1002/ajmg.1270" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11343322">Milunsky et al. (2001)</a> developed a restriction enzyme assay to screen for this mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11343322" 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="#5" class="mim-tip-reference" title="Badenhop, R. F., Cherian, S., Lord, R. S. A., Baysal, B. E., Taschner, P. E. M., Schofield, P. R. <strong>Novel mutations in the SDHD gene in pedigrees with familial carotid body paraganglioma and sensorineural hearing loss.</strong> Genes Chromosomes Cancer 31: 255-263, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11391796/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11391796</a>] [<a href="https://doi.org/10.1002/gcc.1142" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11391796">Badenhop et al. (2001)</a> found the P81L mutation in an individual with paraganglioma who developed sensorineural hearing loss. The mutation was also found in 3 other family members who had only paraganglioma. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11391796" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In an analysis of 23 families with paragangliomas, <a href="#3" class="mim-tip-reference" title="Astrom, K., Cohen, J. E., Willett-Brozick, J. E., Aston, C. E., Baysal, B. E. <strong>Altitude is a phenotypic modifier in hereditary paraganglioma type 1: evidence for an oxygen-sensing defect.</strong> Hum. Genet. 113: 228-237, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12811540/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12811540</a>] [<a href="https://doi.org/10.1007/s00439-003-0969-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12811540">Astrom et al. (2003)</a> identified the P81L mutation in 14 (approximately 61%). P81L had been implicated both as a founder and as a recurrent mutation among U.S. families (<a href="#8" class="mim-tip-reference" title="Baysal, B. E., Willett-Brozick, J. E., Lawrence, E. C., Drovdlic, C. M., Savul, S. A., McLeod, D. R., Yee, H. A., Brackmann, D. E., Slattery, W. H., III, Myers, E. N., Ferrell, R. E., Rubinstein, W. S. <strong>Prevalence of SDHB, SDHC, and SDHD germline mutations in clinic patients with head and neck paragangliomas.</strong> J. Med. Genet. 39: 178-183, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11897817/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11897817</a>] [<a href="https://doi.org/10.1136/jmg.39.3.178" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11897817">Baysal et al., 2002</a>). Haplotype analyses of the 14 P81L carrier families indicated that 5 lacked the founder haplotype, suggesting independent origin. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12811540+11897817" 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, Somatic</em></strong></p><p>
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<a href="#12" class="mim-tip-reference" title="Gimm, O., Armanios, M., Dziema, H., Neumann, H. P. H., Eng, C. <strong>Somatic and occult germ-line mutations in SDHD, a mitochondrial complex II gene, in nonfamilial pheochromocytoma.</strong> Cancer Res. 60: 6822-6825, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11156372/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11156372</a>]" pmid="11156372">Gimm et al. (2000)</a> found the P81L mutation in the heterozygous state as a somatic mutation in tumor tissue from a patient with sporadic (nonfamilial) pheochromocytoma (see <a href="/entry/171300">171300</a>). Flanking markers also showed loss of heterozygosity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11156372" 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">rs80338845 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80338845;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=rs80338845" 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=rs80338845" 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=RCV000007305 OR RCV000020520 OR RCV000567104 OR RCV001701480 OR RCV002288471 OR RCV002512869" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007305, RCV000020520, RCV000567104, RCV001701480, RCV002288471, RCV002512869" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007305...</a>
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<p><a href="#7" class="mim-tip-reference" title="Baysal, B. E., Ferrell, R. E., Willett-Brozick, J. E., Lawrence, E. C., Myssiorek, D., Bosch, A., van der May, A., Taschner, P. E. M., Rubinstein, W. S., Myers, E. N., Richard, C. W., III, Cornelisse, C. J., Devilee, P., Devlin, B. <strong>Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma.</strong> Science 287: 848-851, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10657297/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10657297</a>] [<a href="https://doi.org/10.1126/science.287.5454.848" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10657297">Baysal et al. (2000)</a> identified a Dutch founder mutation in hereditary paraganglioma (PPGL1; <a href="/entry/168000">168000</a>), a heterozygous G-to-T transversion in the SDHD gene, resulting in an asp92-to-tyr (D92Y) substitution. This residue is conserved in 4 eukaryotic multicellular organisms, including human. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10657297" 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="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 D92Y mutation in the germline of a patient with sporadic pheochromocytoma. The D92Y substitution resulted from a 274G-T transversion in exon 3 of the SDHD 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><p><a href="#15" 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> identified the D92Y mutation in almost 70% of Dutch paraganglioma/pheochromocytoma patients with a mutation in a succinate dehydrogenase gene. The dominance of SDHD mutations was unique to the Netherlands, contrasting with the higher prevalence of SDHB (<a href="/entry/185470">185470</a>) mutations found elsewhere. <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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<p>In affected members of a family with hereditary paraganglioma (PPGL1; <a href="/entry/168000">168000</a>), <a href="#7" class="mim-tip-reference" title="Baysal, B. E., Ferrell, R. E., Willett-Brozick, J. E., Lawrence, E. C., Myssiorek, D., Bosch, A., van der May, A., Taschner, P. E. M., Rubinstein, W. S., Myers, E. N., Richard, C. W., III, Cornelisse, C. J., Devilee, P., Devlin, B. <strong>Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma.</strong> Science 287: 848-851, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10657297/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10657297</a>] [<a href="https://doi.org/10.1126/science.287.5454.848" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10657297">Baysal et al. (2000)</a> identified a heterozygous A-to-T transversion in the SDHD gene, resulting in a his102-to-leu (H102L) substitution. In the E. coli enzyme, his102 is located in a region thought to harbor an axial ligand for heme. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10657297" 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>In affected members of an Italian family with hereditary paraganglioma (PPGL1; <a href="/entry/168000">168000</a>), <a href="#25" class="mim-tip-reference" title="Milunsky, J. M., Maher, T. A., Michels, V. V., Milunsky, A. <strong>Novel mutations and the emergence of a common mutation in the SDHD gene causing familial paraganglioma.</strong> Am. J. Med. Genet. 100: 311-314, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11343322/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11343322</a>] [<a href="https://doi.org/10.1002/ajmg.1270" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11343322">Milunsky et al. (2001)</a> identified a 1-bp insertion (13732insT) in exon 4 of the SDHD gene, leading to a frameshift and truncated protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11343322" 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 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs104894304 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894304;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=rs104894304" 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=rs104894304" 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=RCV000007309 OR RCV000155750 OR RCV000221353 OR RCV001810833 OR RCV002228004" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007309, RCV000155750, RCV000221353, RCV001810833, RCV002228004" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007309...</a>
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<p>In affected members of a German family with hereditary paraganglioma (PPGL1; <a href="/entry/168000">168000</a>), <a href="#25" class="mim-tip-reference" title="Milunsky, J. M., Maher, T. A., Michels, V. V., Milunsky, A. <strong>Novel mutations and the emergence of a common mutation in the SDHD gene causing familial paraganglioma.</strong> Am. J. Med. Genet. 100: 311-314, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11343322/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11343322</a>] [<a href="https://doi.org/10.1002/ajmg.1270" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11343322">Milunsky et al. (2001)</a> identified a heterozygous missense mutation in exon 4 of the SDHD gene, resulting in a tyr114-to-cys (Y114C) substitution. This nonconservative amino acid substitution could alter the conformation of the protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11343322" 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 1</strong>
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SDHD, SER32TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs104894305 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894305;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=rs104894305" 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=rs104894305" 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=RCV000007310 OR RCV000505384 OR RCV002228005 OR RCV002381243 OR RCV004791197" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007310, RCV000505384, RCV002228005, RCV002381243, RCV004791197" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007310...</a>
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<p>In affected members of an English family with hereditary paraganglioma (PPGL1; <a href="/entry/168000">168000</a>), <a href="#25" class="mim-tip-reference" title="Milunsky, J. M., Maher, T. A., Michels, V. V., Milunsky, A. <strong>Novel mutations and the emergence of a common mutation in the SDHD gene causing familial paraganglioma.</strong> Am. J. Med. Genet. 100: 311-314, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11343322/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11343322</a>] [<a href="https://doi.org/10.1002/ajmg.1270" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11343322">Milunsky et al. (2001)</a> identified a heterozygous mutation in exon 2 of the SDHD gene, resulting in a ser32-to-ter (S32X) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11343322" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0009 PHEOCHROMOCYTOMA/PARAGANGLIOMA SYNDROME 1</strong>
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SDHD, 1-BP DEL, 13838G
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs587776646 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587776646;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=rs587776646" 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=rs587776646" 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=RCV000007311" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007311" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007311</a>
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<p>In affected members of a German family with hereditary paraganglioma (PPGL1; <a href="/entry/168000">168000</a>), <a href="#25" class="mim-tip-reference" title="Milunsky, J. M., Maher, T. A., Michels, V. V., Milunsky, A. <strong>Novel mutations and the emergence of a common mutation in the SDHD gene causing familial paraganglioma.</strong> Am. J. Med. Genet. 100: 311-314, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11343322/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11343322</a>] [<a href="https://doi.org/10.1002/ajmg.1270" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11343322">Milunsky et al. (2001)</a> identified a heterozygous 1-bp deletion (13838delG) in exon 4 of the SDHD gene, leading to a frameshift and premature termination of the protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11343322" 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>.0010 PHEOCHROMOCYTOMA/PARAGANGLIOMA SYNDROME 1</strong>
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SDHD, IVS1DS, T-G, +2
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs587776644 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587776644;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=rs587776644" 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=rs587776644" 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=RCV000007298 OR RCV002243626" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007298, RCV002243626" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007298...</a>
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<p>In a patient with a carotid body paraganglioma and a pheochromocytoma (PPGL1; <a href="/entry/168000">168000</a>), <a href="#12" class="mim-tip-reference" title="Gimm, O., Armanios, M., Dziema, H., Neumann, H. P. H., Eng, C. <strong>Somatic and occult germ-line mutations in SDHD, a mitochondrial complex II gene, in nonfamilial pheochromocytoma.</strong> Cancer Res. 60: 6822-6825, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11156372/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11156372</a>]" pmid="11156372">Gimm et al. (2000)</a> identified a heterozygous splice site mutation in the SDHD gene, IVS1+2T-G. The mutation was not identified in 78 control alleles. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11156372" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0011 RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE</strong>
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SDHD, GLY12SER (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs34677591;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs34677591</a>)
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs34677591 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs34677591;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/rs34677591?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=rs34677591" 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=rs34677591" 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=RCV000007299 OR RCV000007300 OR RCV000007302 OR RCV000034697 OR RCV000122006 OR RCV000162470 OR RCV000988742 OR RCV001807000 OR RCV002228001" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007299, RCV000007300, RCV000007302, RCV000034697, RCV000122006, RCV000162470, RCV000988742, RCV001807000, RCV002228001" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007299...</a>
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<p>This variant, formerly titled COWDEN SYNDROME 3, with the Included titles of Intestinal Carcinoid Tumors, Paragangliomas-1, Pheochromocytoma, and Somatic Merkel Cell Carcinoma, has been reclassified based on a review of the ExAC database by <a href="#13" class="mim-tip-reference" title="Hamosh, A. <strong>Personal Communication.</strong> Baltimore, Md. 7/11/2018."None>Hamosh (2018)</a>: the G12S variant was present in 881 of 121,216 alleles and in 5 homozygotes, with an allele frequency of 0.007268 (July 11, 2018).</p><p><strong><em>Cowden Syndrome</em></strong></p><p>
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In 4 unrelated patients with a Cowden-like phenotype (see <a href="/entry/158350">158350</a>), <a href="#28" 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 G12S substitution in the SDHD gene. This mutation was not identified in 700 control subjects. The G12S mutation was associated with increased manganese superoxide dismutase expression, increased reactive oxygen species, and a 1.9-fold increase in both AKT and MAPK expression. All 4 patients were women, ranging in age from 42 to 69 years. Three of 4 manifested breast cancer; 1 had thyroid cancer; 1 had renal cancer; 1 had uterine cancer; and 3 had uterine leiomyomas. <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="#6" 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="#28" 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><strong><em>Pheochromocytoma/Paraganglioma Syndrome 1</em></strong></p><p>
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In a patient with an extraadrenal intraabdominal pheochromocytoma (PPGL1; <a href="/entry/168000">168000</a>), <a href="#12" class="mim-tip-reference" title="Gimm, O., Armanios, M., Dziema, H., Neumann, H. P. H., Eng, C. <strong>Somatic and occult germ-line mutations in SDHD, a mitochondrial complex II gene, in nonfamilial pheochromocytoma.</strong> Cancer Res. 60: 6822-6825, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11156372/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11156372</a>]" pmid="11156372">Gimm et al. (2000)</a> identified a gly12-to-ser (G12S) substitution in the SDHD gene. There was involvement of the jugular fossa, suggesting malignancy, An unrelated patient with an intestinal lipoma had the same mutation. The G12S substitution was identified in 1.3% of control chromosomes, and the authors concluded that it is either a low-penetrance mutation or a rare polymorphism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11156372" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a patient with a caudal equina paraganglioma and cerebellar tumors that had developed 22 years later, <a href="#22" class="mim-tip-reference" title="Masuoka, J., Brandner, S., Paulus, W., Soffer, D., Vital, A., Chimelli, L., Jouvet, A., Yonekawa, Y., Kleihues, P., Ohgaki, H. <strong>Germline SDHD mutation in paraganglioma of the spinal cord.</strong> Oncogene 20: 5084-5086, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11526495/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11526495</a>] [<a href="https://doi.org/10.1038/sj.onc.1204579" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11526495">Masuoka et al. (2001)</a> identified the G12S substitution. There was no family history of paragangliomas. Twenty-one additional cases of spinal paraganglioma had the wildtype SDHD sequence. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11526495" 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="Cascon, A., Ruiz-Llorente, S., Cebrian, A., Telleria, D., Rivero, J. C., Diez, J. J., Lopez-Ibarra, P., Jaunsolo, M. A., Benitez, J., Robledo, M. <strong>Identification of novel SDHD mutations in patients with phaeochromocytoma and/or paraganglioma.</strong> Europ. J. Hum. Genet. 10: 457-461, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12111639/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12111639</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200829" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12111639">Cascon et al. (2002)</a> identified the G12S and S68S substitutions in a patient with sporadic pheochromocytoma. However, the G12S substitution was identified in 5 (2.5%) of 200 control chromosomes, and <a href="#9" class="mim-tip-reference" title="Cascon, A., Ruiz-Llorente, S., Cebrian, A., Telleria, D., Rivero, J. C., Diez, J. J., Lopez-Ibarra, P., Jaunsolo, M. A., Benitez, J., Robledo, M. <strong>Identification of novel SDHD mutations in patients with phaeochromocytoma and/or paraganglioma.</strong> Europ. J. Hum. Genet. 10: 457-461, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12111639/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12111639</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200829" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12111639">Cascon et al. (2002)</a> concluded that G12S is a polymorphism. In addition, the S68S substitution was found in all 5 controls with the G12S substitution, indicating that the 2 substitutions are in linkage disequilibrium. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12111639" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a patient with paragangliomas, <a href="#30" class="mim-tip-reference" title="Perren, A., Barghorn, A., Schmid, S., Saremaslani, P., Roth, J., Heitz, P. U., Komminoth, P. <strong>Absence of somatic SDHD mutations in sporadic neuroendocrine tumors and detection of two germline variants in paraganglioma patients.</strong> Oncogene 21: 7605-7608, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12386824/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12386824</a>] [<a href="https://doi.org/10.1038/sj.onc.1205812" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12386824">Perren et al. (2002)</a> identified a heterozygous G12S substitution. Clinical manifestations included a paratracheal paraganglioma, C-cell hyperplasia of the thyroid, and hyperplasia of ACTH-producing cells of the pituitary. There was no family history of the disorder, and the mutation was not identified in 93 controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12386824" 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>Intestinal Carcinoid Tumors and Merkel Cell Carcinoma</em></strong></p><p>
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<a href="#18" class="mim-tip-reference" title="Kytola, S., Nord, B., Elder, E. E., Carling, T., Kjellman, M., Cedermark, B., Juhlin, C., Hoog, A., Isola, J., Larsson, C. <strong>Alterations of the SDHD gene locus in midgut carcinoids, Merkel cell carcinomas, pheochromocytomas, and abdominal paragangliomas.</strong> Genes Chromosomes Cancer 34: 325-332, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12007193/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12007193</a>] [<a href="https://doi.org/10.1002/gcc.10081" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12007193">Kytola et al. (2002)</a> identified a 34G-A transition in exon 1 of the SDHD gene, resulting in the G12S substitution, in the primary tumor of a man diagnosed with nonfamilial midgut carcinoid (see <a href="/entry/114900">114900</a>) at 71 years of age. The alteration was also present in the constitutional tissue of the patient, confirming its germline origin. Because the G12S variant led to the elimination of a restriction site for BanI, a restriction cleavage assay was applied to confirm the presence of the change in the patient and to exclude its occurrence in 200 normal individuals. The patient also carried a normally occurring silent polymorphism, ser68-to-ser (S68S), which was previously reported by <a href="#7" class="mim-tip-reference" title="Baysal, B. E., Ferrell, R. E., Willett-Brozick, J. E., Lawrence, E. C., Myssiorek, D., Bosch, A., van der May, A., Taschner, P. E. M., Rubinstein, W. S., Myers, E. N., Richard, C. W., III, Cornelisse, C. J., Devilee, P., Devlin, B. <strong>Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma.</strong> Science 287: 848-851, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10657297/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10657297</a>] [<a href="https://doi.org/10.1126/science.287.5454.848" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10657297">Baysal et al. (2000)</a>. The same G12S missense change accompanied by the S68S polymorphism was also observed by <a href="#18" class="mim-tip-reference" title="Kytola, S., Nord, B., Elder, E. E., Carling, T., Kjellman, M., Cedermark, B., Juhlin, C., Hoog, A., Isola, J., Larsson, C. <strong>Alterations of the SDHD gene locus in midgut carcinoids, Merkel cell carcinomas, pheochromocytomas, and abdominal paragangliomas.</strong> Genes Chromosomes Cancer 34: 325-332, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12007193/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12007193</a>] [<a href="https://doi.org/10.1002/gcc.10081" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12007193">Kytola et al. (2002)</a> in a Merkel cell carcinoma tumor. No normal DNA was available to clarify whether the sequence variants occurred somatically or were present in the germline. To determine whether the tumors with G12S/S68S were associated with a common founder haplotype, <a href="#18" class="mim-tip-reference" title="Kytola, S., Nord, B., Elder, E. E., Carling, T., Kjellman, M., Cedermark, B., Juhlin, C., Hoog, A., Isola, J., Larsson, C. <strong>Alterations of the SDHD gene locus in midgut carcinoids, Merkel cell carcinomas, pheochromocytomas, and abdominal paragangliomas.</strong> Genes Chromosomes Cancer 34: 325-332, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12007193/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12007193</a>] [<a href="https://doi.org/10.1002/gcc.10081" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12007193">Kytola et al. (2002)</a> genotyped 4 microsatellites close to and flanking SDHD. The results excluded the existence of a common founder chromosome. The tumor in the patient with midgut carcinoid showed loss of heterozygosity on genotyping with markers D11S5011 and D11S1986. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12007193+10657297" 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">rs104894306 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894306;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=rs104894306" 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=rs104894306" 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=RCV000007312 OR RCV000193132 OR RCV000492341 OR RCV000657641 OR RCV002228006 OR RCV004802924" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007312, RCV000193132, RCV000492341, RCV000657641, RCV002228006, RCV004802924" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007312...</a>
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<p>In affected members of a French family with pheochromocytoma/paraganglioma syndrome-1 (PPGL1; <a href="/entry/168000">168000</a>), <a href="#11" class="mim-tip-reference" title="Gimenez-Roqueplo, A.-P., Favier, J., Rustin, P., Mourad, J.-J., Plouin, P.-F., Corvol, P., Rotig, A., Jeunemaitre, X. <strong>The R22X mutation of the SDHD gene in hereditary paraganglioma abolishes the enzymatic activity of complex II in the mitochondrial respiratory chain and activates the hypoxia pathway.</strong> Am. J. Hum. Genet. 69: 1186-1197, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11605159/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11605159</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11605159[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/10.1086/324413" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11605159">Gimenez-Roqueplo et al. (2001)</a> identified a heterozygous nonsense mutation (R22X) in the SDHD gene. The father and his elder son had bilateral neck paragangliomas, whereas the second son had a left carotid body paraganglioma and an ectopic mediastinal pheochromocytoma. Loss of heterozygosity was observed for the maternal chromosome 11q21-q25 within the tumor, but not in peripheral leukocytes. Assessment of the activity of respiratory-chain enzymes showed a complete and selective loss of complex II enzymatic activity in the inherited pheochromocytoma, which was not detected in 6 sporadic pheochromocytomas. In situ hybridization and immunohistochemistry experiments showed a high level of expression of markers of the angiogenic pathway. RT-PCR measurements confirmed that vascular endothelial growth factor (VEGF; <a href="/entry/192240">192240</a>) and endothelial PAS domain protein-1 (EPAS1; <a href="/entry/603349">603349</a>) mRNA levels were significantly higher than those observed in sporadic benign pheochromocytomas. Thus, inactivation of the SDHD gene in hereditary paraganglioma was associated with a complete loss of mitochondrial complex II activity and with a high expression of angiogenic factors. The overexpression of angiogenic factors may stimulate angiogenesis and therefore promote tumor growth. It has been suggested that mitochondria are the primary site of oxygen sensing in the carotid body (<a href="#32" class="mim-tip-reference" title="Prabhakar, N. R. <strong>Oxygen sensing by the carotid body chemoreceptors.</strong> J. Appl. Physiol. 88: 2287-2295, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10846047/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10846047</a>] [<a href="https://doi.org/10.1152/jappl.2000.88.6.2287" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10846047">Prabhakar, 2000</a>). <a href="#11" class="mim-tip-reference" title="Gimenez-Roqueplo, A.-P., Favier, J., Rustin, P., Mourad, J.-J., Plouin, P.-F., Corvol, P., Rotig, A., Jeunemaitre, X. <strong>The R22X mutation of the SDHD gene in hereditary paraganglioma abolishes the enzymatic activity of complex II in the mitochondrial respiratory chain and activates the hypoxia pathway.</strong> Am. J. Hum. Genet. 69: 1186-1197, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11605159/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11605159</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11605159[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/10.1086/324413" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11605159">Gimenez-Roqueplo et al. (2001)</a> noted that several angiogenic markers that may be involved in tissue adaptation to hypoxia had been observed in inherited paragangliomas. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11605159+10846047" 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=RCV000481193 OR RCV001013655 OR RCV002512870 OR RCV004018581" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000481193, RCV001013655, RCV002512870, RCV004018581" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000481193...</a>
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<p>In affected members of a family with familial carotid body paraganglioma associated with sensorineural hearing loss (PPGL1; <a href="/entry/168000">168000</a>), <a href="#5" class="mim-tip-reference" title="Badenhop, R. F., Cherian, S., Lord, R. S. A., Baysal, B. E., Taschner, P. E. M., Schofield, P. R. <strong>Novel mutations in the SDHD gene in pedigrees with familial carotid body paraganglioma and sensorineural hearing loss.</strong> Genes Chromosomes Cancer 31: 255-263, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11391796/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11391796</a>] [<a href="https://doi.org/10.1002/gcc.1142" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11391796">Badenhop et al. (2001)</a> identified a heterozygous 2-bp deletion in exon 3 of the SDHD gene, creating a premature stop codon at position 67. They had information on 4 generations. One female with both paraganglioma and deafness/tinnitus had 5 children unaffected on both scores; another female with paraganglioma and hearing loss had 2 unaffected children and 1 child with deafness/tinnitus only. The latter finding was consistent with the fact that only affected males transmitted paraganglioma to their children and that monoallelic expression of the mutant (paternal) allele was observed, as expected for imprinting. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11391796" 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 PHEOCHROMOCYTOMA/PARAGANGLIOMA SYNDROME 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121908983 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908983;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=rs121908983" 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=rs121908983" 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=RCV000007314 OR RCV002433446" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007314, RCV002433446" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007314...</a>
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<p>In 5 affected members in 2 generations of a family with paragangliomas (PPGL1; <a href="/entry/168000">168000</a>), <a href="#5" class="mim-tip-reference" title="Badenhop, R. F., Cherian, S., Lord, R. S. A., Baysal, B. E., Taschner, P. E. M., Schofield, P. R. <strong>Novel mutations in the SDHD gene in pedigrees with familial carotid body paraganglioma and sensorineural hearing loss.</strong> Genes Chromosomes Cancer 31: 255-263, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11391796/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11391796</a>] [<a href="https://doi.org/10.1002/gcc.1142" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11391796">Badenhop et al. (2001)</a> identified a heterozygous 3-bp deletion in exon 3 of the SDHD gene, resulting in the deletion of tyr93. An affected male transmitted paragangliomas to 2 of his 3 children; an affected female had 2 unaffected children, consistent with genomic imprinting. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11391796" 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>.0015 PHEOCHROMOCYTOMA/PARAGANGLIOMA SYNDROME 1</strong>
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SDHD, MET1ILE
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs80338842 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80338842;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=rs80338842" 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=rs80338842" 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=RCV000007315 OR RCV000020522 OR RCV000492533 OR RCV002228007" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007315, RCV000020522, RCV000492533, RCV002228007" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007315...</a>
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<p>In a father and his 2 sons with paragangliomas (PPGL1; <a href="/entry/168000">168000</a>), <a href="#5" class="mim-tip-reference" title="Badenhop, R. F., Cherian, S., Lord, R. S. A., Baysal, B. E., Taschner, P. E. M., Schofield, P. R. <strong>Novel mutations in the SDHD gene in pedigrees with familial carotid body paraganglioma and sensorineural hearing loss.</strong> Genes Chromosomes Cancer 31: 255-263, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11391796/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11391796</a>] [<a href="https://doi.org/10.1002/gcc.1142" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11391796">Badenhop et al. (2001)</a> found a heterozygous G-to-C substitution in exon 1 of the SDHD gene, which resulted in change of the initiation methionine codon to isoleucine (M1I). As the next methionine codon in the SDHD gene was not until met91, the met1-to-ile missense mutation was expected to produce a nontranslated transcript. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11391796" 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="0016" class="mim-anchor"></a>
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<strong>.0016 PHEOCHROMOCYTOMA/PARAGANGLIOMA SYNDROME 1</strong>
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SDHD, LEU139PRO
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs80338847 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80338847;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=rs80338847" 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=rs80338847" 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=RCV000007316 OR RCV000020523 OR RCV001529735" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007316, RCV000020523, RCV001529735" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007316...</a>
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<p><a href="#35" class="mim-tip-reference" title="Taschner, P. E. M., Jansen, J. C., Baysal, B. E., Bosch, A., Rosenberg, E. H., Brocker-Vriends, A. H. J. T., van der Mey, A. G. L., van Ommen, G.-J. B., Cornelisse, C. J., Devilee, P. <strong>Nearly all hereditary paragangliomas in the Netherlands are caused by two founder mutations in the SDHD gene.</strong> Genes Chromosomes Cancer 31: 274-281, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11391798/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11391798</a>] [<a href="https://doi.org/10.1002/gcc.1144" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11391798">Taschner et al. (2001)</a> found that a founder mutation in the SDHD gene, resulting in a leu139-to-pro (L139P) substitution, accounted for 6 of 32 independently ascertained Dutch families with paragangliomas (PPGL1; <a href="/entry/168000">168000</a>). The L139P mutation was also found in 1 of 55 'isolated' Dutch families. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11391798" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0017 PHEOCHROMOCYTOMA/PARAGANGLIOMA SYNDROME 1</strong>
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SDHD, 2-BP DEL
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs397514034 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397514034;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=rs397514034" 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=rs397514034" 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=RCV000007317 OR RCV000486940 OR RCV000492163 OR RCV002228008" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007317, RCV000486940, RCV000492163, RCV002228008" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007317...</a>
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<p>In a 2-generation family with pheochromocytomas (PPGL1; <a href="/entry/168000">168000</a>), <a href="#4" class="mim-tip-reference" title="Astuti, D., Douglas, F., Lennard, T. W. J., Aligianis, I. A., Woodward, E. R., Evans, D. G. R., Eng, C., Latif, F., Maher, E. R. <strong>Germline SDHD mutation in familial phaeochromocytoma.</strong> Lancet 357: 1181-1182, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11323050/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11323050</a>] [<a href="https://doi.org/10.1016/S0140-6736(00)04378-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11323050">Astuti et al. (2001)</a> identified a heterozygous 2-bp deletion in exon 2 of the SDHD gene (6799-6800), resulting in a truncated protein of 66 amino acids (compared with 159 in the wildtype protein). The father, who carried the mutation and was unaffected, had 3 affected children by 1 wife and 1 affected child by the second wife. Of the 4 affected children, 2 had unilateral adrenal pheochromocytomas, 1 had bilateral adrenal pheochromocytomas, and 1 had a paraaortic pheochromocytoma. The paternal grandmother of the children, a presumed carrier, developed 2 carotid body tumors in her sixth decade. <a href="#4" class="mim-tip-reference" title="Astuti, D., Douglas, F., Lennard, T. W. J., Aligianis, I. A., Woodward, E. R., Evans, D. G. R., Eng, C., Latif, F., Maher, E. R. <strong>Germline SDHD mutation in familial phaeochromocytoma.</strong> Lancet 357: 1181-1182, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11323050/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11323050</a>] [<a href="https://doi.org/10.1016/S0140-6736(00)04378-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11323050">Astuti et al. (2001)</a> suggested that germline SDHD mutation analysis should be done in individuals with familial, multiple, or early-onset pheochromocytoma, even if a personal or family history of head and neck paraganglioma is absent. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11323050" 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="0018" class="mim-anchor"></a>
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<span class="mim-font">
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<strong>.0018 MOVED TO <a href="/entry/602690#0011">602690.0011</a></strong>
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<a id="0019" class="mim-anchor"></a>
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<strong>.0019 RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE</strong>
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SDHD, HIS50ARG (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs11214077;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs11214077</a>)
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs11214077 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs11214077;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/rs11214077?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=rs11214077" 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=rs11214077" 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=RCV000007318 OR RCV000023207 OR RCV000034696 OR RCV000122007 OR RCV000129149 OR RCV000238643 OR RCV000988743 OR RCV002228009 OR RCV003924810 OR RCV005055437" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007318, RCV000023207, RCV000034696, RCV000122007, RCV000129149, RCV000238643, RCV000988743, RCV002228009, RCV003924810, RCV005055437" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007318...</a>
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<p>This variant, formerly titled CARCINOID TUMORS, INTESTINAL, with the Included titles of Pheochromocytoma and Merkel Cell Carcinoma, Somatic, has been reclassified based on a review of the ExAC database by <a href="#13" class="mim-tip-reference" title="Hamosh, A. <strong>Personal Communication.</strong> Baltimore, Md. 7/11/2018."None>Hamosh (2018)</a>: the H50R mutation was present in 791 of 121,406 alleles and in 6 homozygotes, with an allele frequency of 0.006515 (July 11, 2018).</p><p><a href="#9" class="mim-tip-reference" title="Cascon, A., Ruiz-Llorente, S., Cebrian, A., Telleria, D., Rivero, J. C., Diez, J. J., Lopez-Ibarra, P., Jaunsolo, M. A., Benitez, J., Robledo, M. <strong>Identification of novel SDHD mutations in patients with phaeochromocytoma and/or paraganglioma.</strong> Europ. J. Hum. Genet. 10: 457-461, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12111639/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12111639</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200829" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12111639">Cascon et al. (2002)</a> identified the H50R substitution in 4 (1.4%) of 280 control chromosomes, suggesting it is a polymorphism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12111639" 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>Carcinoid Tumors and Merkel Cell Carinoma</em></strong></p><p>
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In a patient with midgut carcinoid (see <a href="/entry/114900">114900</a>), <a href="#18" class="mim-tip-reference" title="Kytola, S., Nord, B., Elder, E. E., Carling, T., Kjellman, M., Cedermark, B., Juhlin, C., Hoog, A., Isola, J., Larsson, C. <strong>Alterations of the SDHD gene locus in midgut carcinoids, Merkel cell carcinomas, pheochromocytomas, and abdominal paragangliomas.</strong> Genes Chromosomes Cancer 34: 325-332, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12007193/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12007193</a>] [<a href="https://doi.org/10.1002/gcc.10081" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12007193">Kytola et al. (2002)</a> observed a 149A-G transition in exon 2 of the SDHD gene, resulting in a his50-to-arg (H50R) mutation. They also identified the H50R mutation in a Merkel cell carcinoma. The mutation was found to be present constitutionally in the patient with midgut carcinoid; no normal DNA was available from the patient with Merkel cell carcinoma to determine whether the variant was present in the germline. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12007193" 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</em></strong></p><p>
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<a href="#30" class="mim-tip-reference" title="Perren, A., Barghorn, A., Schmid, S., Saremaslani, P., Roth, J., Heitz, P. U., Komminoth, P. <strong>Absence of somatic SDHD mutations in sporadic neuroendocrine tumors and detection of two germline variants in paraganglioma patients.</strong> Oncogene 21: 7605-7608, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12386824/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12386824</a>] [<a href="https://doi.org/10.1038/sj.onc.1205812" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12386824">Perren et al. (2002)</a> identified a heterozygous H50R substitution in the SDHD in a patient with a paraadrenal pheochromocytoma (PPGL1; <a href="/entry/168000">168000</a>). There was no family history of the disorder, and the mutation was not identified in 93 controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12386824" 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>Cowden Syndrome</em></strong></p><p>
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<a href="#28" 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 H50R substitution in 2 unrelated patients with a Cowden-like phenotype (see <a href="/entry/158350">158350</a>). This mutation was not identified in 700 control subjects. Expression studies showed that this mutation resulted in increased manganese superoxide dismutase activity, increased reactive oxygen species, a 2.0-fold increase in AKT expression and a 1.7-fold in MAPK expression. One subject was a 56-year-old woman; the other subject a 55-year-old man. The woman had breast cancer and thyroid cancer, and the man had thyroid cancer. Both had a family history of breast cancer, and the male had a family history of 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="#6" 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="#28" 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>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs587776647 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587776647;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=rs587776647" 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=rs587776647" 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=RCV000007319 OR RCV002257358" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007319, RCV002257358" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007319...</a>
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<p>In a patient of German descent with sporadic bilateral carotid body paraganglioma (PPGL1; <a href="/entry/168000">168000</a>), <a href="#19" class="mim-tip-reference" title="Leube, B., Huber, R., Goecke, T. O., Sandmann, W., Royer-Pokora, B. <strong>SDHD mutation analysis in seven German patients with sporadic carotid body paraganglioma: one novel mutation, no Dutch founder mutation and further evidence that G12S is a polymorphism. (Letter)</strong> Clin. Genet. 65: 61-63, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15032977/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15032977</a>] [<a href="https://doi.org/10.1111/j..2004.00174.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15032977">Leube et al. (2004)</a> identified a heterozygous frameshift mutation, 463delA, in exon 4 of the SDHD gene. The frameshift resulted in an aberrant amino acid sequence from codon 155 onward to a premature stop at codon 167. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15032977" 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> rs104894307 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894307;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/rs104894307?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=rs104894307" 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=rs104894307" 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=RCV002228010 OR RCV004018582 OR RCV004948132" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV002228010, RCV004018582, RCV004948132" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV002228010...</a>
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<p>In 2 unrelated patients with sporadic carotid body paraganglioma (PPGL1; <a href="/entry/168000">168000</a>), <a href="#33" class="mim-tip-reference" title="Riemann, K., Sotlar, K., Kupka, S., Braun, S., Zenner, H.-P., Preyer, S., Pfister, M., Pusch, C. M., Blin, N. <strong>Chromosome 11 monosomy in conjunction with a mutated SDHD initiation codon in nonfamilial paraganglioma cases.</strong> Cancer Genet. Cytogenet. 150: 128-135, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15066320/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15066320</a>] [<a href="https://doi.org/10.1016/j.cancergencyto.2003.10.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15066320">Riemann et al. (2004)</a> identified a heterozygous c.1A-G transition in exon 1 of the SDHD gene, resulting in a met1-to-val (M1V) substitution in the initiation codon. LOH and FISH analyses demonstrated partial/total monosomy for chromosome 11 in the tumor samples tested. In a third patient, the M1V mutation was found only in the tumor tissue. LOH and FISH analyses demonstrated partial/total monosomy for chromosome 11 in the tumor samples tested, consistent with the 2-hit hypothesis of tumor development. A mutation at the same codon, M1I (<a href="#0015">602690.0015</a>), had previously been reported in cases of familial paraganglioma. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15066320" 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">rs587776648 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587776648;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=rs587776648" 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=rs587776648" 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=RCV000007321 OR RCV000485947 OR RCV002228011 OR RCV002453249 OR RCV002504760" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007321, RCV000485947, RCV002228011, RCV002453249, RCV002504760" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007321...</a>
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<p>In an apparently sporadic case of pheochromocytoma and paraganglioma (PPGL1; <a href="/entry/168000">168000</a>), <a href="#9" class="mim-tip-reference" title="Cascon, A., Ruiz-Llorente, S., Cebrian, A., Telleria, D., Rivero, J. C., Diez, J. J., Lopez-Ibarra, P., Jaunsolo, M. A., Benitez, J., Robledo, M. <strong>Identification of novel SDHD mutations in patients with phaeochromocytoma and/or paraganglioma.</strong> Europ. J. Hum. Genet. 10: 457-461, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12111639/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12111639</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200829" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12111639">Cascon et al. (2002)</a> identified a heterozygous 4-bp frameshift deletion in exon 4 of the SDHD gene (13732delGACT), resulting in a truncated protein of 132 amino acids. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12111639" 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">rs104894308 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894308;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=rs104894308" 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=rs104894308" 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=RCV000007322 OR RCV000222413 OR RCV000756632 OR RCV002512871" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007322, RCV000222413, RCV000756632, RCV002512871" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007322...</a>
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<p>In a patient with paragangliomas and a family history of pheochromocytoma (PPGL1; <a href="/entry/168000">168000</a>), <a href="#9" class="mim-tip-reference" title="Cascon, A., Ruiz-Llorente, S., Cebrian, A., Telleria, D., Rivero, J. C., Diez, J. J., Lopez-Ibarra, P., Jaunsolo, M. A., Benitez, J., Robledo, M. <strong>Identification of novel SDHD mutations in patients with phaeochromocytoma and/or paraganglioma.</strong> Europ. J. Hum. Genet. 10: 457-461, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12111639/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12111639</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200829" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12111639">Cascon et al. (2002)</a> identified a heterozygous c.129G-A transition in exon 2 of the SDHD gene, resulting in a trp43-to-ter (W43X) substitution and a truncated protein of 43 amino acids. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12111639" 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="#31" class="mim-tip-reference" title="Pigny, P., Vincent, A., Bauters, C. C., Bertrand, M., de Montpreville, V. T., Crepin, M., Porchet, N., Caron, P. <strong>Paraganglioma after maternal transmission of a succinate dehydrogenase gene mutation.</strong> J. Clin. Endocr. Metab. 93: 1609-1615, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18211978/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18211978</a>] [<a href="https://doi.org/10.1210/jc.2007-1989" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18211978">Pigny et al. (2008)</a> reported a family with maternal transmission of the W43X mutation in the third generation. A boy received the mutation from his mother and developed a glomus tympanicum paraganglioma at 11 years of age. He shared only the 11q23 haplotype with the other affected members of the family. Methylation analysis of the differentially methylated region upstream of the maternally expressed H19 gene, mapped to 11p15, showed that the seventh CTCF binding site was hypermethylated in the germline of the affected boy, suggesting a gain of imprinting. The authors concluded that maternal transmission of a SDHD-linked paraganglioma, even if a rare event, can occur. The authors proposed that children who inherit a pathogenic mutation from their mother should be considered at risk for paraganglioma. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18211978" 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 PHEOCHROMOCYTOMA/PARAGANGLIOMA SYNDROME 1</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007323" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007323" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007323</a>
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<p>In a 2-generation family (family 4194) with 6 affected individuals with pheochromocytoma and paraganglioma (PPGL1; <a href="/entry/168000">168000</a>), <a href="#24" 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 a germline heterozygous whole-gene deletion of SDHD. <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>.0025 PHEOCHROMOCYTOMA/PARAGANGLIOMA SYNDROME 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs104894309 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894309;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/rs104894309?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=rs104894309" 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=rs104894309" 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=RCV000007324 OR RCV000221327 OR RCV002228012 OR RCV002288472" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007324, RCV000221327, RCV002228012, RCV002288472" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007324...</a>
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<p>In the germlines of 4 unrelated patients with sporadic pheochromocytoma (PPGL1; <a href="/entry/168000">168000</a>) <a href="#26" 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 heterozygous c.33C-A transversion in exon 1 of the SDHD gene, resulting in a cys11-to-ter (C11X) 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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<strong>.0026 PHEOCHROMOCYTOMA/PARAGANGLIOMA SYNDROME 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs104894310 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894310;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=rs104894310" 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=rs104894310" 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=RCV001851719 OR RCV004018583 OR RCV004018584" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001851719, RCV004018583, RCV004018584" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001851719...</a>
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<p>In the germline of a patient with sporadic pheochromocytoma (PPGL1; <a href="/entry/168000">168000</a>), <a href="#26" 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 heterozygous c.14G-A transition in exon 1 of the SDHD gene, resulting in a trp5-to-ter (W5X) 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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<strong>.0027 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">rs587776649 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587776649;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=rs587776649" 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=rs587776649" 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=RCV000007326 OR RCV000482313 OR RCV000492772 OR RCV000505302 OR RCV002512872 OR RCV005041998" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007326, RCV000482313, RCV000492772, RCV000505302, RCV002512872, RCV005041998" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007326...</a>
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<p>In a male patient with paraganglioma and gastric stromal sarcoma (<a href="/entry/606864">606864</a>), <a href="#23" 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 heterozygous 1-bp deletion (c.57delG) in the SDHD gene. <a href="#29" 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 information on this patient. He presented at 19 years of age with melena from a gastrointestinal tumor; at age 21 he had a right carotid body tumor and left adrenal pheochromocytoma, and 1 year later a left glomus jugular tumor was excised. At age 32, he presented with metastatic paraganglioma. The mutation was predicted to cause a frameshift and a premature stop codon at position 85. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17667967+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>
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<strong>.0028 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> rs121908984 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908984;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/rs121908984?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=rs121908984" 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=rs121908984" 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=RCV000007327 OR RCV002228013 OR RCV002326667 OR RCV003472996" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007327, RCV002228013, RCV002326667, RCV003472996" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007327...</a>
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<p>This variant, formerly titled COWDEN SYNDROME 3, has been reclassified because its contribution to Cowden syndrome (see <a href="/entry/158350">158350</a>) has not been confirmed.</p><p>In a woman with a Cowden-like phenotype, <a href="#28" 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-A transversion in the SDHD gene, resulting in a his145-to-asn (H145N) substitution. This mutation was not identified in 700 control subjects. The mutation was associated with increased expression of manganese superoxide dismutase, normal reactive oxygen species, and no change in AKT expression but a 1.2-fold increase of MAPK expression. The patient had breast cancer and renal cancer, but no family history of 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="#6" 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="#28" 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>
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<strong>.0029 MITOCHONDRIAL COMPLEX II DEFICIENCY, NUCLEAR TYPE 3</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> rs202198133 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs202198133;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/rs202198133?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=rs202198133" 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=rs202198133" 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=RCV000144171 OR RCV000484125 OR RCV001290090 OR RCV002415627 OR RCV002515941 OR RCV004748597" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000144171, RCV000484125, RCV001290090, RCV002415627, RCV002515941, RCV004748597" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000144171...</a>
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<p>In a girl, born of unrelated Swiss parents, with encephalomyopathy and biochemical evidence of isolated mitochondrial complex II deficiency (MC2DN3; <a href="/entry/619167">619167</a>), <a href="#17" class="mim-tip-reference" title="Jackson, C. B., Nuoffer, J.-M., Hahn, D., Prokisch, H., Haberberger, B., Gautschi, M., Haberli, A., Gallati, S., Schaller, A. <strong>Mutations in SDHD lead to autosomal recessive encephalomyopathy and isolated mitochondrial complex II deficiency.</strong> J. Med. Genet. 51: 170-175, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24367056/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24367056</a>] [<a href="https://doi.org/10.1136/jmedgenet-2013-101932" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24367056">Jackson et al. (2014)</a> identified compound heterozygous mutations in the SDHD gene: a c.205G-A transition in exon 3, resulting in a glu69-to-lys (E69K) substitution at a conserved residue in the first hydrophobic alpha helix, and a c.479G-T transversion in exon 4, predicting a change of the stop codon into a codon for leucine, followed by proline, phenylalanine, and a stop codon (Ter164LeuextTer3; <a href="#0030">602690.0030</a>) in the fourth hydrophobic alpha helix. These variants were predicted to cause impaired integration of SDHD into the inner mitochondrial membrane. The variants were not found in 200 control individuals, and each unaffected parent was heterozygous for one of the mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24367056" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0030 MITOCHONDRIAL COMPLEX II DEFICIENCY, NUCLEAR TYPE 3</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> rs201372601 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs201372601;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/rs201372601?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=rs201372601" 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=rs201372601" 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=RCV000144172 OR RCV000454533 OR RCV000505355 OR RCV000994727 OR RCV001023072 OR RCV002228513" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000144172, RCV000454533, RCV000505355, RCV000994727, RCV001023072, RCV002228513" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000144172...</a>
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<p>For discussion of the ter164-to-leu (X164L) mutation in the SDHD gene that was found in compound heterozygous state in a patient with mitochondrial complex II deficiency nuclear type 3 (MC2DN3; <a href="/entry/619167">619167</a>) by <a href="#17" class="mim-tip-reference" title="Jackson, C. B., Nuoffer, J.-M., Hahn, D., Prokisch, H., Haberberger, B., Gautschi, M., Haberli, A., Gallati, S., Schaller, A. <strong>Mutations in SDHD lead to autosomal recessive encephalomyopathy and isolated mitochondrial complex II deficiency.</strong> J. Med. Genet. 51: 170-175, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24367056/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24367056</a>] [<a href="https://doi.org/10.1136/jmedgenet-2013-101932" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24367056">Jackson et al. (2014)</a>, see <a href="#0029">602690.0029</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24367056" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0031 MITOCHONDRIAL COMPLEX II DEFICIENCY, NUCLEAR TYPE 3</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">rs786205436 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs786205436;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=rs786205436" 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=rs786205436" 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=RCV000171136 OR RCV000186596" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000171136, RCV000186596" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000171136...</a>
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<p>In an infant, born of unrelated Irish parents, with fatal hypertrophic cardiomyopathy due to mitochondrial complex II deficiency nuclear type 3 (MC2DN3; <a href="/entry/619167">619167</a>), <a href="#2" class="mim-tip-reference" title="Alston, C. L., Ceccatelli Berti, C., Blakely, E. L., Olahova, M., He, L., McMahon, C. J., Olpin, S. E., Hargreaves, I. P., Nolli, C., McFarland, R., Goffrini, P., O'Sullivan, M. J., Taylor, R. W. <strong>A recessive homozygous p.Asp92Gly SDHD mutation causes prenatal cardiomyopathy and a severe mitochondrial complex II deficiency.</strong> Hum. Genet. 134: 869-879, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26008905/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26008905</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26008905[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/s00439-015-1568-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26008905">Alston et al. (2015)</a> identified a homozygous c.275A-G transition (c.275A-G, NM_003002.3) in the SDHD gene, resulting in an asp92-to-gly (D92G) substitution at a highly conserved residue. Each unaffected parent was heterozygous for the mutation, which was not found in the Exome Sequencing Project (ESP6500) database. Patient skeletal muscle sample showed isolated complex II deficiency (30% residual activity), as well as a significant decrease in the SDHD protein and a decrease in fully assembled complex II. Complementation studies in yeast deficient in the homologous SDH4 gene showed that the mutation was unable to rescue the oxidative growth defect, consistent with a loss of function. Mutation at the same codon (D92Y; <a href="#0004">602690.0004</a>) has been identified as a founder mutation in the Dutch population and causative of paraganglioma (PGL1; <a href="/entry/168000">168000</a>); yeast studies showed that the D92Y mutation did not affect oxidative growth and caused a milder reduction of SDHD activity compared to D92G. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26008905" 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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Alston, C. L., Ceccatelli Berti, C., Blakely, E. L., Olahova, M., He, L., McMahon, C. J., Olpin, S. E., Hargreaves, I. P., Nolli, C., McFarland, R., Goffrini, P., O'Sullivan, M. J., Taylor, R. W.
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<strong>A recessive homozygous p.Asp92Gly SDHD mutation causes prenatal cardiomyopathy and a severe mitochondrial complex II deficiency.</strong>
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Hum. Genet. 134: 869-879, 2015.
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[<a href="https://doi.org/10.1038/sj.onc.1207591" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1111/j.1399-0004.2011.01653.x" target="_blank">Full Text</a>]
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<strong>Cytochrome b in human complex II (succinate-ubiquinone oxidoreductase): cDNA cloning of the components in liver mitochondria and chromosome assignment of the genes for the large (SDHC) and small (SDHD) subunits to 1q21 and 11q23.</strong>
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[<a href="https://doi.org/10.1159/000134700" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmedgenet-2013-101932" target="_blank">Full Text</a>]
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<strong>Alterations of the SDHD gene locus in midgut carcinoids, Merkel cell carcinomas, pheochromocytomas, and abdominal paragangliomas.</strong>
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[<a href="https://doi.org/10.1002/gcc.10081" target="_blank">Full Text</a>]
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<strong>SDHD mutation analysis in seven German patients with sporadic carotid body paraganglioma: one novel mutation, no Dutch founder mutation and further evidence that G12S is a polymorphism. (Letter)</strong>
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[<a href="https://doi.org/10.1111/j..2004.00174.x" target="_blank">Full Text</a>]
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<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>
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[<a href="https://doi.org/10.1210/jc.2007-0640" target="_blank">Full Text</a>]
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<strong>Germline succinate dehydrogenase subunit D mutation segregating with familial non-RET C cell hyperplasia.</strong>
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[<a href="https://doi.org/10.1210/jc.2002-030008" target="_blank">Full Text</a>]
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<strong>Germline SDHD mutation in paraganglioma of the spinal cord.</strong>
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[<a href="https://doi.org/10.1038/sj.onc.1204579" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1056/NEJMc071191" target="_blank">Full Text</a>]
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<a id="McWhinney2004" class="mim-anchor"></a>
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[<a href="https://doi.org/10.1210/jc.2004-0769" target="_blank">Full Text</a>]
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<a id="Milunsky2001" class="mim-anchor"></a>
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Milunsky, J. M., Maher, T. A., Michels, V. V., Milunsky, A.
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<strong>Novel mutations and the emergence of a common mutation in the SDHD gene causing familial paraganglioma.</strong>
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Am. J. Med. Genet. 100: 311-314, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11343322/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11343322</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11343322" 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/ajmg.1270" target="_blank">Full Text</a>]
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<a id="Neumann2002" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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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.
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<strong>Germ-line mutations in nonsyndromic pheochromocytoma.</strong>
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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 id="Neumann2001" class="mim-anchor"></a>
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<strong>Case 13-2001: genetic testing in pheochromocytoma. (Letter)</strong>
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<a id="Ni2008" class="mim-anchor"></a>
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Ni, Y., Zbuk, K. M., Sadler, T., Patocs, A., Lobo, G., Edelman, E., Platzer, P., Orloff, M. S., Waite, K. A., Eng, C.
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<strong>Germline mutations and variants in the succinate dehydrogenase genes in Cowden and Cowden-like syndromes.</strong>
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[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://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'})">related citations</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 id="Pasini2008" class="mim-anchor"></a>
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<div class="">
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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.
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<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>
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Europ. J. Hum. Genet. 16: 79-88, 2008.
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[<a href="https://doi.org/10.1038/sj.ejhg.5201904" target="_blank">Full Text</a>]
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<a id="Perren2002" class="mim-anchor"></a>
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<div class="">
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<strong>Absence of somatic SDHD mutations in sporadic neuroendocrine tumors and detection of two germline variants in paraganglioma patients.</strong>
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Oncogene 21: 7605-7608, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12386824/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12386824</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12386824" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/sj.onc.1205812" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18211978/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18211978</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18211978" 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.2007-1989" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="32" class="mim-anchor"></a>
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<a id="Prabhakar2000" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Prabhakar, N. R.
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|
<strong>Oxygen sensing by the carotid body chemoreceptors.</strong>
|
|
J. Appl. Physiol. 88: 2287-2295, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10846047/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10846047</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10846047" 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/10.1152/jappl.2000.88.6.2287" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="33" class="mim-anchor"></a>
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<a id="Riemann2004" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Riemann, K., Sotlar, K., Kupka, S., Braun, S., Zenner, H.-P., Preyer, S., Pfister, M., Pusch, C. M., Blin, N.
|
|
<strong>Chromosome 11 monosomy in conjunction with a mutated SDHD initiation codon in nonfamilial paraganglioma cases.</strong>
|
|
Cancer Genet. Cytogenet. 150: 128-135, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15066320/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15066320</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15066320" 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.cancergencyto.2003.10.013" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="34" class="mim-anchor"></a>
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<a id="Spinelli2021" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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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.
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|
<strong>Fumarate is a terminal electron acceptor in the mammalian electron transport chain.</strong>
|
|
Science 374: 1227-1237, 2021.
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[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://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'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.abi7495" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="35" class="mim-anchor"></a>
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<a id="Taschner2001" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Taschner, P. E. M., Jansen, J. C., Baysal, B. E., Bosch, A., Rosenberg, E. H., Brocker-Vriends, A. H. J. T., van der Mey, A. G. L., van Ommen, G.-J. B., Cornelisse, C. J., Devilee, P.
|
|
<strong>Nearly all hereditary paragangliomas in the Netherlands are caused by two founder mutations in the SDHD gene.</strong>
|
|
Genes Chromosomes Cancer 31: 274-281, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11391798/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11391798</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11391798" 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.1144" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="36" class="mim-anchor"></a>
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<a id="van Schothorst1998" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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van Schothorst, E. M., Beekman, M., Torremans, P., Kuipers-Dijkshoorn, N. J., Wessels, H. W., Bardoel, A. F. J., van der Mey, A. G. L., van der Vijver, M. J., van Ommen, G.-J. B., Devilee, P., Cornelisse, C. J.
|
|
<strong>Paragangliomas of the head and neck region show complete loss of heterozygosity at 11q22-q23 in chief cells and the flow-sorted DNA aneuploid fraction.</strong>
|
|
Hum. Path. 29: 1045-1049, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9781639/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9781639</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9781639" 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/s0046-8177(98)90411-7" target="_blank">Full Text</a>]
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</p>
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</div>
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</ol>
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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="contributors" class="mim-anchor"></a>
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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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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Ada Hamosh - updated : 11/28/2022
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 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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Cassandra L. Kniffin - updated : 7/29/2015<br>Cassandra L. Kniffin - updated : 9/23/2014<br>Cassandra L. Kniffin - updated : 4/11/2012<br>Cassandra L. Kniffin - updated : 6/2/2011<br>John A. Phillips, III - updated : 1/14/2009<br>Ada Hamosh - updated : 9/22/2008<br>John A. Phillips, III - updated : 7/25/2008<br>Marla J. F. O'Neill - updated : 5/6/2008<br>Marla J. F. O'Neill - updated : 9/24/2007<br>John A. Phillips, III - updated : 11/13/2006<br>Cassandra L. Kniffin - updated : 1/6/2006<br>John A. Phillips, III - updated : 4/12/2005<br>Victor A. McKusick - updated : 8/24/2004<br>Victor A. McKusick - updated : 2/25/2004<br>Victor A. McKusick - updated : 8/13/2003<br>Michael B. Petersen - updated : 6/23/2003<br>Victor A. McKusick - updated : 8/23/2002<br>Victor A. McKusick - updated : 4/16/2002<br>Victor A. McKusick - updated : 1/30/2002<br>Victor A. McKusick - updated : 12/20/2001<br>Victor A. McKusick - updated : 12/4/2001<br>Victor A. McKusick - updated : 10/9/2001<br>Victor A. McKusick - updated : 9/28/2001<br>Sonja A. Rasmussen - updated : 6/13/2001<br>Ada Hamosh - updated : 2/2/2000
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="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 : 6/5/1998
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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="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>ckniffin : 10/11/2023<br>alopez : 03/20/2023<br>alopez : 11/28/2022<br>carol : 01/29/2021<br>carol : 01/28/2021<br>carol : 07/24/2019<br>carol : 07/19/2019<br>carol : 12/14/2018<br>carol : 07/11/2018<br>carol : 03/14/2016<br>alopez : 7/31/2015<br>mcolton : 7/29/2015<br>ckniffin : 7/29/2015<br>alopez : 10/10/2014<br>alopez : 9/24/2014<br>mcolton : 9/23/2014<br>ckniffin : 9/23/2014<br>joanna : 7/17/2014<br>carol : 9/16/2013<br>alopez : 3/1/2013<br>terry : 4/11/2012<br>ckniffin : 4/11/2012<br>carol : 8/16/2011<br>wwang : 6/9/2011<br>ckniffin : 6/2/2011<br>carol : 5/24/2011<br>alopez : 1/14/2009<br>alopez : 12/19/2008<br>ckniffin : 10/24/2008<br>terry : 9/22/2008<br>alopez : 7/25/2008<br>carol : 5/7/2008<br>terry : 5/6/2008<br>wwang : 9/28/2007<br>terry : 9/24/2007<br>carol : 2/2/2007<br>alopez : 11/13/2006<br>carol : 1/12/2006<br>ckniffin : 1/6/2006<br>wwang : 5/11/2005<br>carol : 4/22/2005<br>wwang : 4/12/2005<br>carol : 1/31/2005<br>ckniffin : 1/19/2005<br>tkritzer : 1/14/2005<br>tkritzer : 9/8/2004<br>tkritzer : 9/7/2004<br>terry : 8/24/2004<br>ckniffin : 3/23/2004<br>tkritzer : 2/27/2004<br>tkritzer : 2/26/2004<br>terry : 2/25/2004<br>cwells : 11/6/2003<br>tkritzer : 8/18/2003<br>terry : 8/13/2003<br>cwells : 6/23/2003<br>mgross : 9/10/2002<br>tkritzer : 9/10/2002<br>tkritzer : 8/28/2002<br>terry : 8/23/2002<br>cwells : 5/2/2002<br>cwells : 4/23/2002<br>terry : 4/16/2002<br>alopez : 2/6/2002<br>terry : 1/30/2002<br>carol : 12/21/2001<br>terry : 12/20/2001<br>carol : 12/10/2001<br>mcapotos : 12/5/2001<br>mcapotos : 12/4/2001<br>mcapotos : 10/9/2001<br>mcapotos : 10/9/2001<br>mcapotos : 10/9/2001<br>mcapotos : 9/28/2001<br>mcapotos : 9/28/2001<br>cwells : 9/26/2001<br>mcapotos : 6/14/2001<br>mcapotos : 6/13/2001<br>alopez : 2/3/2000<br>terry : 2/2/2000<br>carol : 6/5/1998
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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>
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<div>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 602690
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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, SUBUNIT D; SDHD
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<div >
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
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SUCCINATE DEHYDROGENASE COMPLEX, SUBUNIT D, INTEGRAL MEMBRANE PROTEIN<br />
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SUCCINATE DEHYDROGENASE 4, INTEGRAL MEMBRANE PROTEIN; SDH4
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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: SDHD</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> 722377004;
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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: 11q23.1
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Genomic coordinates <span class="small">(GRCh38)</span> : 11:112,086,873-112,095,794 </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="3">
|
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<span class="mim-font">
|
|
11q23.1
|
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</span>
|
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</td>
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<td>
|
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<span class="mim-font">
|
|
Mitochondrial complex II deficiency, nuclear type 3
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
619167
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
Autosomal recessive
|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
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>
|
|
<span class="mim-font">
|
|
Paraganglioma and gastric stromal sarcoma
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
606864
|
|
</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>
|
|
<span class="mim-font">
|
|
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">
|
|
Pheochromocytoma/paraganglioma syndrome 1
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
168000
|
|
</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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<td>
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<span class="mim-font">
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3
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</tr>
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</tbody>
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</table>
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<br />
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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>The SDHD gene encodes an integral membrane protein subunit of the succinate dehydrogenase (EC 1.3.5.1) complex (summary by Hirawake et al., 1997). </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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<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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<span class="mim-text-font">
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<p>Complex II (succinate-ubiquinone oxidoreductase) is an important enzyme complex in both the tricarboxylic acid cycle and the aerobic respiratory chains of mitochondria in eukaryotic cells and prokaryotic organisms. Hirawake et al. (1997) deduced the amino acid sequences of the large (cybL, encoded by the SDHC gene, 602413) and small (cybS, encoded by the SDHD gene) subunits of cytochrome b in human liver complex II from cDNAs isolated by homology probing with mixed primers for the polymerase chain reaction. The mature cybL and cybS contain 140 and 103 amino acids, respectively, and show little similarity to the amino acid sequences of the subunits from other species, in contrast to the highly conserved features of the flavoprotein (Fp) subunit (SDHA; 600857) and the iron-sulfur protein (Ip) subunit (SDHB; 185470). </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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<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>Hirawake et al. (1997) mapped the genes for cybL (SDHC; 602413) and cybS (SDHD) to 1q21 and 11q23, respectively, by fluorescence in situ hybridization. </p><p><strong><em>Pseudogenes</em></strong></p><p>
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Aguiar et al. (2001) confirmed a sequence highly homologous to SDHD cDNA on chromosome 1p36-p34, a region commonly deleted in pheochromocytomas. Full analysis of this sequence revealed a heterozygous single base substitution in 70% of their samples that was also present in the germline. This sequence did not appear to be transcribed and is probably a processed pseudogene. Therefore, despite its chromosomal location, it is unlikely that this sequence is a target of LOH in pheochromocytomas. </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><strong><em>SDH Complex Function</em></strong></p><p>
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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">
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<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 1</em></strong></p><p>
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In affected members of families with hereditary paraganglioma (PPGL1; 168000), Baysal et al. (2000) identified heterozygous mutations in the SDHD gene (602690.0001-602690.0005), including the Dutch founder mutation (D92Y; 602690.0004). There was no evidence of imprinting; biallelic expression of the SDHD gene was identified in 3 independent fetal brain samples, 1 fetal kidney sample, 2 independent adult brain samples, and adult lymphocytes. The authors suggested that monoallelic expression of SDHD may be confined to the carotid body and other paraganglioma cells, similar to the brain-limited imprinting of UBE3A (601623) in Angelman syndrome (105830). Germline loss-of-function mutations in the paternal alleles and subsequent somatic loss of normal maternal alleles suggested that SDHD functions as a tumor suppressor gene at the cellular level and needs 2 events for inactivation. On the basis of the phenotypic similarity between PGL tumors and the normal carotid body exposed to chronic hypoxia, Baysal et al. (2000) suggested that cybS is a critical component of the oxygen-sensing system of paraganglionic tissue, and that its loss may lead to chronic hypoxic stimulation and cellular proliferation. </p><p>In commenting on a case of thoracic pheochromocytoma (paraganglioma) in a 19-year-old man whose father received a diagnosis of hypertension in his 50s, Neumann et al. (2001) pointed to evidence indicating that germline mutations in the VHL gene (608537), causing von Hippel-Lindau disease (193300), and mutations in the SDHD gene together account for 15 to 20% of all nonfamilial presentations of pheochromocytoma. If the father in the case at hand had a pheochromocytoma-paraganglioma syndrome, then the likelihood of finding a germline mutation in SDHD or VHL rises higher than 20%. </p><p>Gimm et al. (2000) identified several mutations in the SDHD gene in unrelated patients. One patient had a pheochromocytoma and a carotid body paraganglioma (see 602690.0010); 2 unrelated patients had the same mutation (602690.0011), 1 with an extraadrenal intraabdominal pheochromocytoma with involvement of the jugular fossa, suggesting malignancy, and 1 with an isolated intestinal lipoma; and a 33-year-old woman had 2 extraadrenal pheochromocytomas, 1 intraabdominal and 1 intrathoracic (see 602690.0002). Finally, the authors identified a somatic SDHD mutation in a pheochromocytoma (602690.0003). The results indicated that SDHD plays a role in the pathogenesis of pheochromocytoma. </p><p>Badenhop et al. (2001) studied 4 families with familial carotid body paragangliomas, 2 of which exhibited coinheritance of PGL and sensorineural hearing loss or tinnitus. Sequence analysis identified mutations in exon 1 and exon 3 of the SDHD gene (602690.0003; 602690.0013; 602690.0014; 602690.0015). The PGL1 region contains another gene, DPP2/TIMM8B (606659), a homolog of the X-linked TIMM8A gene (300356), mutations in which cause dystonia and deafness seen in Mohr-Tranebjaerg syndrome (304700). The authors found no base changes in the TIMM8B gene and concluded that the association of paraganglioma with sensorineural hearing loss could not be explained by the proximity of the TIMM8B and SDHD genes. Badenhop et al. (2001) found no apparent loss of heterozygosity at the site of the SDHD mutations in the paraganglioma tumors. However, RT-PCR analysis of tumor samples showed monoallelic expression of the mutant (paternal) allele as expected for imprinting. Thus the inheritance and expression of the SDHD gene is consistent with the PGL1 gene being subject to genomic imprinting. </p><p>Taschner et al. (2001) found that 2 founder mutations, asp92 to tyr (602690.0004) and leu139 to pro (602690.0016), were responsible for paragangliomas in 24 and 6 of 32 independently ascertained Dutch paraganglioma families, respectively. These 2 mutations were detected among 20 of 55 isolated patients as well. Ten of the isolated patients had multiple paragangliomas, and in 8 of these SDHD germline mutations were found, indicating that multicentricity is a strong predictive factor for the hereditary nature of the disorder in isolated patients. In addition, Taschner et al. (2001) demonstrated that the maternally derived wildtype SDHD allele is lost in tumors from mutation-carrying patients, indicating that SDHD functions as a tumor suppressor gene. </p><p>Cascon et al. (2002) performed sequence analysis of the 4 exons of the SDHD gene in 25 consecutive, unrelated patients with pheochromocytoma and/or paraganglioma. There were 18 patients with pheochromocytoma, 4 with paraganglioma alone, and 3 with both, who had tested negative for germline mutations in the VHL (608537) and RET (164761) genes. They detected 5 heterozygous germline sequence variants: 2 missense mutations also found in control chromosomes, G12S (602690.0011) and H50R (602690.0019); a silent mutation (S68S) considered to be a polymorphism; and 2 novel truncating mutations. (The H50R and G12S mutations were later reclassified as variants of unknown significance.) The 2 truncating mutations were a 4-bp frameshift deletion in exon 4 (602690.0022) in an apparently sporadic case of paraganglioma and pheochromocytoma, and a nonsense mutation in exon 2 (602690.0023) in a patient with paraganglioma and a family history of pheochromocytoma. </p><p>In 11 (4%) of 271 unrelated patients with sporadic pheochromocytoma, Neumann et al. (2002) identified 7 different germline mutations in the SDHD gene (see, e.g., 602690.0002; 602690.0004; 602690.0025; 602690.0026). </p><p>Riemann et al. (2004) provided a tabulation of known mutations in the SDHD gene causing paraganglioma. They noted that in addition to mutation in the SDHD gene, loss of heterozygosity (LOH) on chromosome 11, mainly in 11q23, had been observed in paragangliomas (Devilee et al., 1994; van Schothorst et al., 1998). </p><p>Hensen et al. (2004) demonstrated exclusive loss of the entire maternal chromosome 11 in SDHD-linked paragangliomas and pheochromocytomas, suggesting that combined loss of the wildtype SDHD allele and maternal 11p region is essential for tumorigenesis. They hypothesized that this is driven by selective loss of 1 or more imprinted genes in the 11p15 region. In paternally but not maternally derived SDHD mutation carriers, this can be achieved by a single event: nondisjunctional loss of the maternal chromosome 11. Hensen et al. (2004) concluded that the exclusive paternal transmission of the disease can be explained by a somatic genetic mechanism targeting both the SDHD gene on 11q23 and a paternally imprinted gene on 11p15.5, rather than imprinting of SDHD. </p><p>McWhinney et al. (2004) reported a 3-generation family with 6 affected members with paraganglioma who carried a germline 96-kb deletion (602690.0024) spanning the entire SDHD gene. The family was initially designated mutation-negative for all the PC/PGL-associated genes after PCR-based analysis; fine structure genotyping and semiquantitative duplex PCR analysis were used to detect the whole-gene deletion. </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. SDHD mutations were primarily frameshift. </p><p><strong><em>Paraganglioma and Gastric Stromal Sarcoma</em></strong></p><p>
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In a male patient with paraganglioma and gastric stromal sarcoma (606864), McWhinney et al. (2007) identified a germline 1-bp heterozygous deletion in the SDHD gene (602690.0027). In 5 other families with the dyad, the authors also found germline mutations in the SDHB (see, e.g., 185470.0012 and 185470.0013) and SDHC (602413.0004) 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><strong><em>C Cell Hyperplasia and Hypercalcitoninemia</em></strong></p><p>
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Lima et al. (2003) reported a family with C cell hyperplasia and hypercalcitoninemia in which no cases of medullary carcinoma had occurred and which lacked an identifiable causative RET mutation. Four of the family members showed hypercalcitoninemia, and marked C cell hyperplasia was present in each of the 3 in whom thyroidectomy had been performed. A germline mutation in exon 2 of the SDHD gene (149A-G) was found in 6 members of the family; all the 4 available members with hypercalcitoninemia possessed the mutation. One of the 5 available members without hypercalcitoninemia, an 18-year-old female, also showed the mutation. The mutation was also identified in 11 of 474 control chromosomes (2.3%), which caused the authors to question whether the mutation is particularly prevalent in the Portuguese population or is regularly associated with C cell hyperplasia. Lima et al. (2003) noted that other studies of normal individuals did not find this mutation (Kytola et al., 2002). </p><p><strong><em>Mitochondrial Complex II Deficiency, Nuclear Type 3</em></strong></p><p>
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In a patient with mitochondrial complex II deficiency nuclear type 3 (MC2DN3; 619167), Jackson et al. (2014) identified compound heterozygous mutations in the SDHD gene (E69K, 602690.0029 and X164L, 602690.0030). </p><p>Alston et al. (2015) identified a homozygous missense mutation in the SDHD gene (D92G; 602690.0031) in an infant with MC2DN3 who died of cardiac failure and left ventricular noncompaction on the first day of life. </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 SDHD gene, see 602690.0011, 602690.0019, and 602690.0028.</p><p>For discussion of a possible association between intestinal carcinoid tumors (see 114900) and Merkel cell carcinomas and variation in the SDHD gene, see 602690.0011 and 602690.0019.</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>History</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>Aguiar et al. (2001) sequenced the entire coding region of the SDHD genes from a series of pheochromocytomas (see 171300). Although they did not find mutations, they identified a new intronic SNP (97739A-G) in 15% of the samples. </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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<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>31 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 1</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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SDHD, GLN36TER
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<br />
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SNP: rs104894303,
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ClinVar: RCV000007295, RCV000492417, RCV001851718
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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 with autosomal dominant paraganglioma (PPGL1; 168000), Baysal et al. (2000) identified a heterozygous C-to-T transition in the SDHD gene, resulting in a glu36-to-ter (E36X) mutation within the mitochondrial signal peptide. </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 1</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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SDHD, ARG38TER
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<br />
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SNP: rs80338843,
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gnomAD: rs80338843,
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ClinVar: RCV000007296, RCV000020518, RCV000486967, RCV000492087, RCV002228000
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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 with autosomal dominant paraganglioma (PPGL1; 168000), Baysal et al. (2000) identified a heterozygous C-to-T transition in the SDHD gene, resulting in an arg38-to-ter (R38X) substitution within the mitochondrial signal peptide. </p><p>Gimm et al. (2000) identified the R38X mutation in a 33-year-old woman with 2 extraadrenal pheochromocytomas, 1 intraabdominal and 1 intrathoracic. </p><p>In the germlines of 2 unrelated patients with sporadic pheochromocytomas, Neumann et al. (2002) identified the R38X substitution, resulting from a 112C-T transition in exon 2 of the SDHD 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>.0003 PHEOCHROMOCYTOMA/PARAGANGLIOMA SYNDROME 1</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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PHEOCHROMOCYTOMA, SOMATIC, 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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SDHD, PRO81LEU
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<br />
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SNP: rs80338844,
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gnomAD: rs80338844,
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ClinVar: RCV000007303, RCV000007304, RCV000020519, RCV000162448, RCV000216073, RCV000763227, RCV002221470, RCV002228002, RCV003472995, RCV004748507
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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 5 families with autosomal dominant paraganglioma (PPGL1; 168000), Baysal et al. (2000) identified a heterozygous C-to-T transition in the SDHD gene, resulting in a pro81-to-leu (P81L) substitution. The proline at position 81 is conserved in human, Bos taurus, Ascaris, and Caenorhabditis elegans. </p><p>Milunsky et al. (2001) found the P81L mutation in 3 of 7 families with hereditary paraganglioma. Since this mutation results in the elimination of a normally occurring restriction endonuclease site (MspI), Milunsky et al. (2001) developed a restriction enzyme assay to screen for this mutation. </p><p>Badenhop et al. (2001) found the P81L mutation in an individual with paraganglioma who developed sensorineural hearing loss. The mutation was also found in 3 other family members who had only paraganglioma. </p><p>In an analysis of 23 families with paragangliomas, Astrom et al. (2003) identified the P81L mutation in 14 (approximately 61%). P81L had been implicated both as a founder and as a recurrent mutation among U.S. families (Baysal et al., 2002). Haplotype analyses of the 14 P81L carrier families indicated that 5 lacked the founder haplotype, suggesting independent origin. </p><p><strong><em>Pheochromocytoma, Somatic</em></strong></p><p>
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Gimm et al. (2000) found the P81L mutation in the heterozygous state as a somatic mutation in tumor tissue from a patient with sporadic (nonfamilial) pheochromocytoma (see 171300). Flanking markers also showed loss of heterozygosity. </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 1</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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SDHD, ASP92TYR
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<br />
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SNP: rs80338845,
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ClinVar: RCV000007305, RCV000020520, RCV000567104, RCV001701480, RCV002288471, RCV002512869
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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>Baysal et al. (2000) identified a Dutch founder mutation in hereditary paraganglioma (PPGL1; 168000), a heterozygous G-to-T transversion in the SDHD gene, resulting in an asp92-to-tyr (D92Y) substitution. This residue is conserved in 4 eukaryotic multicellular organisms, including human. </p><p>Neumann et al. (2002) identified the D92Y mutation in the germline of a patient with sporadic pheochromocytoma. The D92Y substitution resulted from a 274G-T transversion in exon 3 of the SDHD gene. The mutation was not identified in 600 control chromosomes. </p><p>Hensen et al. (2012) identified the D92Y mutation in almost 70% of Dutch paraganglioma/pheochromocytoma patients with a mutation in a succinate dehydrogenase gene. The dominance of SDHD mutations was unique to the Netherlands, contrasting with the higher prevalence of SDHB (185470) mutations found elsewhere. </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 1</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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SDHD, HIS102LEU
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<br />
|
|
|
|
SNP: rs104894302,
|
|
|
|
|
|
gnomAD: rs104894302,
|
|
|
|
|
|
ClinVar: RCV000007307, RCV000566289, RCV002228003
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a family with hereditary paraganglioma (PPGL1; 168000), Baysal et al. (2000) identified a heterozygous A-to-T transversion in the SDHD gene, resulting in a his102-to-leu (H102L) substitution. In the E. coli enzyme, his102 is located in a region thought to harbor an axial ligand for heme. </p>
|
|
</span>
|
|
</div>
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<div>
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|
<br />
|
|
</div>
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</div>
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|
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|
|
<div>
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|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 PHEOCHROMOCYTOMA/PARAGANGLIOMA SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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SDHD, 1-BP INS, 13732T
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|
<br />
|
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|
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SNP: rs587776645,
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|
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ClinVar: RCV000007308
|
|
|
|
|
|
</span>
|
|
</div>
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|
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|
|
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<div>
|
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<span class="mim-text-font">
|
|
<p>In affected members of an Italian family with hereditary paraganglioma (PPGL1; 168000), Milunsky et al. (2001) identified a 1-bp insertion (13732insT) in exon 4 of the SDHD gene, leading to a frameshift and truncated protein. </p>
|
|
</span>
|
|
</div>
|
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<div>
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|
<br />
|
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</div>
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</div>
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|
<div>
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 PHEOCHROMOCYTOMA/PARAGANGLIOMA SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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<div>
|
|
<span class="mim-text-font">
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|
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|
SDHD, TYR114CYS
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|
<br />
|
|
|
|
SNP: rs104894304,
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|
|
ClinVar: RCV000007309, RCV000155750, RCV000221353, RCV001810833, RCV002228004
|
|
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|
|
|
</span>
|
|
</div>
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|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a German family with hereditary paraganglioma (PPGL1; 168000), Milunsky et al. (2001) identified a heterozygous missense mutation in exon 4 of the SDHD gene, resulting in a tyr114-to-cys (Y114C) substitution. This nonconservative amino acid substitution could alter the conformation of the protein. </p>
|
|
</span>
|
|
</div>
|
|
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|
<div>
|
|
<br />
|
|
</div>
|
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|
|
</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 PHEOCHROMOCYTOMA/PARAGANGLIOMA SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SDHD, SER32TER
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|
<br />
|
|
|
|
SNP: rs104894305,
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|
|
ClinVar: RCV000007310, RCV000505384, RCV002228005, RCV002381243, RCV004791197
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of an English family with hereditary paraganglioma (PPGL1; 168000), Milunsky et al. (2001) identified a heterozygous mutation in exon 2 of the SDHD gene, resulting in a ser32-to-ter (S32X) substitution. </p>
|
|
</span>
|
|
</div>
|
|
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<div>
|
|
<br />
|
|
</div>
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|
</div>
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|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 PHEOCHROMOCYTOMA/PARAGANGLIOMA SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SDHD, 1-BP DEL, 13838G
|
|
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|
|
|
<br />
|
|
|
|
SNP: rs587776646,
|
|
|
|
|
|
|
|
ClinVar: RCV000007311
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a German family with hereditary paraganglioma (PPGL1; 168000), Milunsky et al. (2001) identified a heterozygous 1-bp deletion (13838delG) in exon 4 of the SDHD gene, leading to a frameshift and premature termination of the protein. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
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|
<div>
|
|
<br />
|
|
</div>
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</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 PHEOCHROMOCYTOMA/PARAGANGLIOMA SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SDHD, IVS1DS, T-G, +2
|
|
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|
|
<br />
|
|
|
|
SNP: rs587776644,
|
|
|
|
|
|
|
|
ClinVar: RCV000007298, RCV002243626
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with a carotid body paraganglioma and a pheochromocytoma (PPGL1; 168000), Gimm et al. (2000) identified a heterozygous splice site mutation in the SDHD gene, IVS1+2T-G. The mutation was not identified in 78 control alleles. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
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|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SDHD, GLY12SER ({dbSNP rs34677591})
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs34677591,
|
|
|
|
|
|
gnomAD: rs34677591,
|
|
|
|
|
|
ClinVar: RCV000007299, RCV000007300, RCV000007302, RCV000034697, RCV000122006, RCV000162470, RCV000988742, RCV001807000, RCV002228001
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>This variant, formerly titled COWDEN SYNDROME 3, with the Included titles of Intestinal Carcinoid Tumors, Paragangliomas-1, Pheochromocytoma, and Somatic Merkel Cell Carcinoma, has been reclassified based on a review of the ExAC database by Hamosh (2018): the G12S variant was present in 881 of 121,216 alleles and in 5 homozygotes, with an allele frequency of 0.007268 (July 11, 2018).</p><p><strong><em>Cowden Syndrome</em></strong></p><p>
|
|
In 4 unrelated patients with a Cowden-like phenotype (see 158350), Ni et al. (2008) identified a heterozygous G12S substitution in the SDHD gene. This mutation was not identified in 700 control subjects. The G12S mutation was associated with increased manganese superoxide dismutase expression, increased reactive oxygen species, and a 1.9-fold increase in both AKT and MAPK expression. All 4 patients were women, ranging in age from 42 to 69 years. Three of 4 manifested breast cancer; 1 had thyroid cancer; 1 had renal cancer; 1 had uterine cancer; and 3 had uterine leiomyomas. </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><strong><em>Pheochromocytoma/Paraganglioma Syndrome 1</em></strong></p><p>
|
|
In a patient with an extraadrenal intraabdominal pheochromocytoma (PPGL1; 168000), Gimm et al. (2000) identified a gly12-to-ser (G12S) substitution in the SDHD gene. There was involvement of the jugular fossa, suggesting malignancy, An unrelated patient with an intestinal lipoma had the same mutation. The G12S substitution was identified in 1.3% of control chromosomes, and the authors concluded that it is either a low-penetrance mutation or a rare polymorphism. </p><p>In a patient with a caudal equina paraganglioma and cerebellar tumors that had developed 22 years later, Masuoka et al. (2001) identified the G12S substitution. There was no family history of paragangliomas. Twenty-one additional cases of spinal paraganglioma had the wildtype SDHD sequence. </p><p>Cascon et al. (2002) identified the G12S and S68S substitutions in a patient with sporadic pheochromocytoma. However, the G12S substitution was identified in 5 (2.5%) of 200 control chromosomes, and Cascon et al. (2002) concluded that G12S is a polymorphism. In addition, the S68S substitution was found in all 5 controls with the G12S substitution, indicating that the 2 substitutions are in linkage disequilibrium. </p><p>In a patient with paragangliomas, Perren et al. (2002) identified a heterozygous G12S substitution. Clinical manifestations included a paratracheal paraganglioma, C-cell hyperplasia of the thyroid, and hyperplasia of ACTH-producing cells of the pituitary. There was no family history of the disorder, and the mutation was not identified in 93 controls. </p><p><strong><em>Intestinal Carcinoid Tumors and Merkel Cell Carcinoma</em></strong></p><p>
|
|
Kytola et al. (2002) identified a 34G-A transition in exon 1 of the SDHD gene, resulting in the G12S substitution, in the primary tumor of a man diagnosed with nonfamilial midgut carcinoid (see 114900) at 71 years of age. The alteration was also present in the constitutional tissue of the patient, confirming its germline origin. Because the G12S variant led to the elimination of a restriction site for BanI, a restriction cleavage assay was applied to confirm the presence of the change in the patient and to exclude its occurrence in 200 normal individuals. The patient also carried a normally occurring silent polymorphism, ser68-to-ser (S68S), which was previously reported by Baysal et al. (2000). The same G12S missense change accompanied by the S68S polymorphism was also observed by Kytola et al. (2002) in a Merkel cell carcinoma tumor. No normal DNA was available to clarify whether the sequence variants occurred somatically or were present in the germline. To determine whether the tumors with G12S/S68S were associated with a common founder haplotype, Kytola et al. (2002) genotyped 4 microsatellites close to and flanking SDHD. The results excluded the existence of a common founder chromosome. The tumor in the patient with midgut carcinoid showed loss of heterozygosity on genotyping with markers D11S5011 and D11S1986. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 PHEOCHROMOCYTOMA/PARAGANGLIOMA SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SDHD, ARG22TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs104894306,
|
|
|
|
|
|
|
|
ClinVar: RCV000007312, RCV000193132, RCV000492341, RCV000657641, RCV002228006, RCV004802924
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a French family with pheochromocytoma/paraganglioma syndrome-1 (PPGL1; 168000), Gimenez-Roqueplo et al. (2001) identified a heterozygous nonsense mutation (R22X) in the SDHD gene. The father and his elder son had bilateral neck paragangliomas, whereas the second son had a left carotid body paraganglioma and an ectopic mediastinal pheochromocytoma. Loss of heterozygosity was observed for the maternal chromosome 11q21-q25 within the tumor, but not in peripheral leukocytes. Assessment of the activity of respiratory-chain enzymes showed a complete and selective loss of complex II enzymatic activity in the inherited pheochromocytoma, which was not detected in 6 sporadic pheochromocytomas. In situ hybridization and immunohistochemistry experiments showed a high level of expression of markers of the angiogenic pathway. RT-PCR measurements confirmed that vascular endothelial growth factor (VEGF; 192240) and endothelial PAS domain protein-1 (EPAS1; 603349) mRNA levels were significantly higher than those observed in sporadic benign pheochromocytomas. Thus, inactivation of the SDHD gene in hereditary paraganglioma was associated with a complete loss of mitochondrial complex II activity and with a high expression of angiogenic factors. The overexpression of angiogenic factors may stimulate angiogenesis and therefore promote tumor growth. It has been suggested that mitochondria are the primary site of oxygen sensing in the carotid body (Prabhakar, 2000). Gimenez-Roqueplo et al. (2001) noted that several angiogenic markers that may be involved in tissue adaptation to hypoxia had been observed in inherited paragangliomas. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 PHEOCHROMOCYTOMA/PARAGANGLIOMA SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SDHD, 2-BP DEL
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs387906358,
|
|
|
|
|
|
|
|
ClinVar: RCV000481193, RCV001013655, RCV002512870, RCV004018581
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a family with familial carotid body paraganglioma associated with sensorineural hearing loss (PPGL1; 168000), Badenhop et al. (2001) identified a heterozygous 2-bp deletion in exon 3 of the SDHD gene, creating a premature stop codon at position 67. They had information on 4 generations. One female with both paraganglioma and deafness/tinnitus had 5 children unaffected on both scores; another female with paraganglioma and hearing loss had 2 unaffected children and 1 child with deafness/tinnitus only. The latter finding was consistent with the fact that only affected males transmitted paraganglioma to their children and that monoallelic expression of the mutant (paternal) allele was observed, as expected for imprinting. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0014 PHEOCHROMOCYTOMA/PARAGANGLIOMA SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SDHD, TYR93DEL
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121908983,
|
|
|
|
|
|
|
|
ClinVar: RCV000007314, RCV002433446
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 5 affected members in 2 generations of a family with paragangliomas (PPGL1; 168000), Badenhop et al. (2001) identified a heterozygous 3-bp deletion in exon 3 of the SDHD gene, resulting in the deletion of tyr93. An affected male transmitted paragangliomas to 2 of his 3 children; an affected female had 2 unaffected children, consistent with genomic imprinting. </p>
|
|
</span>
|
|
</div>
|
|
|
|
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|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0015 PHEOCHROMOCYTOMA/PARAGANGLIOMA SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SDHD, MET1ILE
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs80338842,
|
|
|
|
|
|
|
|
ClinVar: RCV000007315, RCV000020522, RCV000492533, RCV002228007
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a father and his 2 sons with paragangliomas (PPGL1; 168000), Badenhop et al. (2001) found a heterozygous G-to-C substitution in exon 1 of the SDHD gene, which resulted in change of the initiation methionine codon to isoleucine (M1I). As the next methionine codon in the SDHD gene was not until met91, the met1-to-ile missense mutation was expected to produce a nontranslated transcript. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0016 PHEOCHROMOCYTOMA/PARAGANGLIOMA SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SDHD, LEU139PRO
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs80338847,
|
|
|
|
|
|
|
|
ClinVar: RCV000007316, RCV000020523, RCV001529735
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Taschner et al. (2001) found that a founder mutation in the SDHD gene, resulting in a leu139-to-pro (L139P) substitution, accounted for 6 of 32 independently ascertained Dutch families with paragangliomas (PPGL1; 168000). The L139P mutation was also found in 1 of 55 'isolated' Dutch families. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
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|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0017 PHEOCHROMOCYTOMA/PARAGANGLIOMA SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
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SDHD, 2-BP DEL
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<br />
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SNP: rs397514034,
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ClinVar: RCV000007317, RCV000486940, RCV000492163, RCV002228008
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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 2-generation family with pheochromocytomas (PPGL1; 168000), Astuti et al. (2001) identified a heterozygous 2-bp deletion in exon 2 of the SDHD gene (6799-6800), resulting in a truncated protein of 66 amino acids (compared with 159 in the wildtype protein). The father, who carried the mutation and was unaffected, had 3 affected children by 1 wife and 1 affected child by the second wife. Of the 4 affected children, 2 had unilateral adrenal pheochromocytomas, 1 had bilateral adrenal pheochromocytomas, and 1 had a paraaortic pheochromocytoma. The paternal grandmother of the children, a presumed carrier, developed 2 carotid body tumors in her sixth decade. Astuti et al. (2001) suggested that germline SDHD mutation analysis should be done in individuals with familial, multiple, or early-onset pheochromocytoma, even if a personal or family history of head and neck paraganglioma is absent. </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-text-font">
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<strong>.0018 MOVED TO 602690.0011</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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<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>.0019 RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE</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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SDHD, HIS50ARG ({dbSNP rs11214077})
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<br />
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SNP: rs11214077,
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gnomAD: rs11214077,
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ClinVar: RCV000007318, RCV000023207, RCV000034696, RCV000122007, RCV000129149, RCV000238643, RCV000988743, RCV002228009, RCV003924810, RCV005055437
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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>This variant, formerly titled CARCINOID TUMORS, INTESTINAL, with the Included titles of Pheochromocytoma and Merkel Cell Carcinoma, Somatic, has been reclassified based on a review of the ExAC database by Hamosh (2018): the H50R mutation was present in 791 of 121,406 alleles and in 6 homozygotes, with an allele frequency of 0.006515 (July 11, 2018).</p><p>Cascon et al. (2002) identified the H50R substitution in 4 (1.4%) of 280 control chromosomes, suggesting it is a polymorphism. </p><p><strong><em>Carcinoid Tumors and Merkel Cell Carinoma</em></strong></p><p>
|
|
In a patient with midgut carcinoid (see 114900), Kytola et al. (2002) observed a 149A-G transition in exon 2 of the SDHD gene, resulting in a his50-to-arg (H50R) mutation. They also identified the H50R mutation in a Merkel cell carcinoma. The mutation was found to be present constitutionally in the patient with midgut carcinoid; no normal DNA was available from the patient with Merkel cell carcinoma to determine whether the variant was present in the germline. </p><p><strong><em>Pheochromocytoma</em></strong></p><p>
|
|
Perren et al. (2002) identified a heterozygous H50R substitution in the SDHD in a patient with a paraadrenal pheochromocytoma (PPGL1; 168000). There was no family history of the disorder, and the mutation was not identified in 93 controls. </p><p><strong><em>Cowden Syndrome</em></strong></p><p>
|
|
Ni et al. (2008) identified a heterozygous H50R substitution in 2 unrelated patients with a Cowden-like phenotype (see 158350). This mutation was not identified in 700 control subjects. Expression studies showed that this mutation resulted in increased manganese superoxide dismutase activity, increased reactive oxygen species, a 2.0-fold increase in AKT expression and a 1.7-fold in MAPK expression. One subject was a 56-year-old woman; the other subject a 55-year-old man. The woman had breast cancer and thyroid cancer, and the man had thyroid cancer. Both had a family history of breast cancer, and the male had a family history of 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>
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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>.0020 PHEOCHROMOCYTOMA/PARAGANGLIOMA SYNDROME 1</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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SDHD, 1-BP DEL, 463A
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<br />
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SNP: rs587776647,
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ClinVar: RCV000007319, RCV002257358
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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 patient of German descent with sporadic bilateral carotid body paraganglioma (PPGL1; 168000), Leube et al. (2004) identified a heterozygous frameshift mutation, 463delA, in exon 4 of the SDHD gene. The frameshift resulted in an aberrant amino acid sequence from codon 155 onward to a premature stop at codon 167. </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 1</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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SDHD, MET1VAL
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<br />
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SNP: rs104894307,
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gnomAD: rs104894307,
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ClinVar: RCV002228010, RCV004018582, RCV004948132
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</span>
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</div>
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<div>
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|
<span class="mim-text-font">
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|
<p>In 2 unrelated patients with sporadic carotid body paraganglioma (PPGL1; 168000), Riemann et al. (2004) identified a heterozygous c.1A-G transition in exon 1 of the SDHD gene, resulting in a met1-to-val (M1V) substitution in the initiation codon. LOH and FISH analyses demonstrated partial/total monosomy for chromosome 11 in the tumor samples tested. In a third patient, the M1V mutation was found only in the tumor tissue. LOH and FISH analyses demonstrated partial/total monosomy for chromosome 11 in the tumor samples tested, consistent with the 2-hit hypothesis of tumor development. A mutation at the same codon, M1I (602690.0015), had previously been reported in cases of familial paraganglioma. </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>.0022 PHEOCHROMOCYTOMA/PARAGANGLIOMA SYNDROME 1</strong>
|
|
</span>
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</h4>
|
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</div>
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<div>
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<span class="mim-text-font">
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SDHD, 4-BP DEL, 13732GACT
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<br />
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SNP: rs587776648,
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|
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ClinVar: RCV000007321, RCV000485947, RCV002228011, RCV002453249, RCV002504760
|
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|
|
|
</span>
|
|
</div>
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|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In an apparently sporadic case of pheochromocytoma and paraganglioma (PPGL1; 168000), Cascon et al. (2002) identified a heterozygous 4-bp frameshift deletion in exon 4 of the SDHD gene (13732delGACT), resulting in a truncated protein of 132 amino acids. </p>
|
|
</span>
|
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</div>
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<div>
|
|
<br />
|
|
</div>
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|
|
</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0023 PHEOCHROMOCYTOMA/PARAGANGLIOMA SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
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|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
SDHD, TRP43TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs104894308,
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|
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|
|
ClinVar: RCV000007322, RCV000222413, RCV000756632, RCV002512871
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with paragangliomas and a family history of pheochromocytoma (PPGL1; 168000), Cascon et al. (2002) identified a heterozygous c.129G-A transition in exon 2 of the SDHD gene, resulting in a trp43-to-ter (W43X) substitution and a truncated protein of 43 amino acids. </p><p>Pigny et al. (2008) reported a family with maternal transmission of the W43X mutation in the third generation. A boy received the mutation from his mother and developed a glomus tympanicum paraganglioma at 11 years of age. He shared only the 11q23 haplotype with the other affected members of the family. Methylation analysis of the differentially methylated region upstream of the maternally expressed H19 gene, mapped to 11p15, showed that the seventh CTCF binding site was hypermethylated in the germline of the affected boy, suggesting a gain of imprinting. The authors concluded that maternal transmission of a SDHD-linked paraganglioma, even if a rare event, can occur. The authors proposed that children who inherit a pathogenic mutation from their mother should be considered at risk for paraganglioma. </p>
|
|
</span>
|
|
</div>
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|
<div>
|
|
<br />
|
|
</div>
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|
|
|
</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0024 PHEOCHROMOCYTOMA/PARAGANGLIOMA SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SDHD, 96-KB DEL
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000007323
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 2-generation family (family 4194) with 6 affected individuals with pheochromocytoma and paraganglioma (PPGL1; 168000), McWhinney et al. (2004) identified a germline heterozygous whole-gene deletion of SDHD. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
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|
|
<div>
|
|
<br />
|
|
</div>
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|
|
|
</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0025 PHEOCHROMOCYTOMA/PARAGANGLIOMA SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
SDHD, CYS11TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs104894309,
|
|
|
|
|
|
gnomAD: rs104894309,
|
|
|
|
|
|
ClinVar: RCV000007324, RCV000221327, RCV002228012, RCV002288472
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In the germlines of 4 unrelated patients with sporadic pheochromocytoma (PPGL1; 168000) Neumann et al. (2002) identified a heterozygous c.33C-A transversion in exon 1 of the SDHD gene, resulting in a cys11-to-ter (C11X) substitution. The mutation was not identified in 600 control chromosomes. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0026 PHEOCHROMOCYTOMA/PARAGANGLIOMA SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SDHD, TRP5TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs104894310,
|
|
|
|
|
|
|
|
ClinVar: RCV001851719, RCV004018583, RCV004018584
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In the germline of a patient with sporadic pheochromocytoma (PPGL1; 168000), Neumann et al. (2002) identified a heterozygous c.14G-A transition in exon 1 of the SDHD gene, resulting in a trp5-to-ter (W5X) substitution. The mutation was not identified in 600 control chromosomes. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0027 PARAGANGLIOMA AND GASTRIC STROMAL SARCOMA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SDHD, 1-BP DEL, 57G
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs587776649,
|
|
|
|
|
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|
|
ClinVar: RCV000007326, RCV000482313, RCV000492772, RCV000505302, RCV002512872, RCV005041998
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a male patient with paraganglioma and gastric stromal sarcoma (606864), McWhinney et al. (2007) identified a heterozygous 1-bp deletion (c.57delG) in the SDHD gene. Pasini et al. (2008) provided further information on this patient. He presented at 19 years of age with melena from a gastrointestinal tumor; at age 21 he had a right carotid body tumor and left adrenal pheochromocytoma, and 1 year later a left glomus jugular tumor was excised. At age 32, he presented with metastatic paraganglioma. The mutation was predicted to cause a frameshift and a premature stop codon at position 85. </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>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0028 RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
|
|
|
|
SDHD, HIS145ASN
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|
|
|
<br />
|
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|
|
SNP: rs121908984,
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|
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gnomAD: rs121908984,
|
|
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|
|
|
ClinVar: RCV000007327, RCV002228013, RCV002326667, RCV003472996
|
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|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>This variant, formerly titled COWDEN SYNDROME 3, has been reclassified because its contribution to Cowden syndrome (see 158350) has not been confirmed.</p><p>In a woman with a Cowden-like phenotype, Ni et al. (2008) identified a heterozygous C-to-A transversion in the SDHD gene, resulting in a his145-to-asn (H145N) substitution. This mutation was not identified in 700 control subjects. The mutation was associated with increased expression of manganese superoxide dismutase, normal reactive oxygen species, and no change in AKT expression but a 1.2-fold increase of MAPK expression. The patient had breast cancer and renal cancer, but no family history of 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>
|
|
</span>
|
|
</div>
|
|
|
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<div>
|
|
<br />
|
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</div>
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|
</div>
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<div>
|
|
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|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0029 MITOCHONDRIAL COMPLEX II DEFICIENCY, NUCLEAR TYPE 3</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
SDHD, GLU69LYS
|
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|
<br />
|
|
|
|
SNP: rs202198133,
|
|
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|
|
|
gnomAD: rs202198133,
|
|
|
|
|
|
ClinVar: RCV000144171, RCV000484125, RCV001290090, RCV002415627, RCV002515941, RCV004748597
|
|
|
|
|
|
</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a girl, born of unrelated Swiss parents, with encephalomyopathy and biochemical evidence of isolated mitochondrial complex II deficiency (MC2DN3; 619167), Jackson et al. (2014) identified compound heterozygous mutations in the SDHD gene: a c.205G-A transition in exon 3, resulting in a glu69-to-lys (E69K) substitution at a conserved residue in the first hydrophobic alpha helix, and a c.479G-T transversion in exon 4, predicting a change of the stop codon into a codon for leucine, followed by proline, phenylalanine, and a stop codon (Ter164LeuextTer3; 602690.0030) in the fourth hydrophobic alpha helix. These variants were predicted to cause impaired integration of SDHD into the inner mitochondrial membrane. The variants were not found in 200 control individuals, and each unaffected parent was heterozygous for one of the mutations. </p>
|
|
</span>
|
|
</div>
|
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<div>
|
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0030 MITOCHONDRIAL COMPLEX II DEFICIENCY, NUCLEAR TYPE 3</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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SDHD, TER164LEU
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<br />
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SNP: rs201372601,
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gnomAD: rs201372601,
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ClinVar: RCV000144172, RCV000454533, RCV000505355, RCV000994727, RCV001023072, RCV002228513
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>For discussion of the ter164-to-leu (X164L) mutation in the SDHD gene that was found in compound heterozygous state in a patient with mitochondrial complex II deficiency nuclear type 3 (MC2DN3; 619167) by Jackson et al. (2014), see 602690.0029. </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>.0031 MITOCHONDRIAL COMPLEX II DEFICIENCY, NUCLEAR TYPE 3</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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SDHD, ASP92GLY
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<br />
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SNP: rs786205436,
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ClinVar: RCV000171136, RCV000186596
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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 infant, born of unrelated Irish parents, with fatal hypertrophic cardiomyopathy due to mitochondrial complex II deficiency nuclear type 3 (MC2DN3; 619167), Alston et al. (2015) identified a homozygous c.275A-G transition (c.275A-G, NM_003002.3) in the SDHD gene, resulting in an asp92-to-gly (D92G) substitution at a highly conserved residue. Each unaffected parent was heterozygous for the mutation, which was not found in the Exome Sequencing Project (ESP6500) database. Patient skeletal muscle sample showed isolated complex II deficiency (30% residual activity), as well as a significant decrease in the SDHD protein and a decrease in fully assembled complex II. Complementation studies in yeast deficient in the homologous SDH4 gene showed that the mutation was unable to rescue the oxidative growth defect, consistent with a loss of function. Mutation at the same codon (D92Y; 602690.0004) has been identified as a founder mutation in the Dutch population and causative of paraganglioma (PGL1; 168000); yeast studies showed that the D92Y mutation did not affect oxidative growth and caused a milder reduction of SDHD activity compared to D92G. </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>REFERENCES</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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<ol>
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<li>
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<p class="mim-text-font">
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Aguiar, R. C. T., Cox, G., Pomeroy, S. L., Dahia, P. L. M.
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<strong>Analysis of the SDHD gene the susceptibility gene for familial paraganglioma syndrome (PGL1), in pheochromocytomas.</strong>
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J. Clin. Endocr. Metab. 86: 2890-2894, 2001.
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[PubMed: 11397905]
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[Full Text: https://doi.org/10.1210/jcem.86.6.7547]
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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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Alston, C. L., Ceccatelli Berti, C., Blakely, E. L., Olahova, M., He, L., McMahon, C. J., Olpin, S. E., Hargreaves, I. P., Nolli, C., McFarland, R., Goffrini, P., O'Sullivan, M. J., Taylor, R. W.
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<strong>A recessive homozygous p.Asp92Gly SDHD mutation causes prenatal cardiomyopathy and a severe mitochondrial complex II deficiency.</strong>
|
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Hum. Genet. 134: 869-879, 2015.
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[PubMed: 26008905]
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[Full Text: https://doi.org/10.1007/s00439-015-1568-z]
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<p class="mim-text-font">
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Astrom, K., Cohen, J. E., Willett-Brozick, J. E., Aston, C. E., Baysal, B. E.
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<strong>Altitude is a phenotypic modifier in hereditary paraganglioma type 1: evidence for an oxygen-sensing defect.</strong>
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Hum. Genet. 113: 228-237, 2003.
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[PubMed: 12811540]
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[Full Text: https://doi.org/10.1007/s00439-003-0969-6]
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</p>
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<li>
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<p class="mim-text-font">
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Astuti, D., Douglas, F., Lennard, T. W. J., Aligianis, I. A., Woodward, E. R., Evans, D. G. R., Eng, C., Latif, F., Maher, E. R.
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<strong>Germline SDHD mutation in familial phaeochromocytoma.</strong>
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Lancet 357: 1181-1182, 2001.
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[PubMed: 11323050]
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[Full Text: https://doi.org/10.1016/S0140-6736(00)04378-6]
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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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Badenhop, R. F., Cherian, S., Lord, R. S. A., Baysal, B. E., Taschner, P. E. M., Schofield, P. R.
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<strong>Novel mutations in the SDHD gene in pedigrees with familial carotid body paraganglioma and sensorineural hearing loss.</strong>
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Genes Chromosomes Cancer 31: 255-263, 2001.
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[PubMed: 11391796]
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[Full Text: https://doi.org/10.1002/gcc.1142]
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</p>
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<li>
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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: 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">
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Baysal, B. E., Ferrell, R. E., Willett-Brozick, J. E., Lawrence, E. C., Myssiorek, D., Bosch, A., van der May, A., Taschner, P. E. M., Rubinstein, W. S., Myers, E. N., Richard, C. W., III, Cornelisse, C. J., Devilee, P., Devlin, B.
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<strong>Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma.</strong>
|
|
Science 287: 848-851, 2000.
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[PubMed: 10657297]
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[Full Text: https://doi.org/10.1126/science.287.5454.848]
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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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Baysal, B. E., Willett-Brozick, J. E., Lawrence, E. C., Drovdlic, C. M., Savul, S. A., McLeod, D. R., Yee, H. A., Brackmann, D. E., Slattery, W. H., III, Myers, E. N., Ferrell, R. E., Rubinstein, W. S.
|
|
<strong>Prevalence of SDHB, SDHC, and SDHD germline mutations in clinic patients with head and neck paragangliomas.</strong>
|
|
J. Med. Genet. 39: 178-183, 2002.
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[PubMed: 11897817]
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[Full Text: https://doi.org/10.1136/jmg.39.3.178]
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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., Ruiz-Llorente, S., Cebrian, A., Telleria, D., Rivero, J. C., Diez, J. J., Lopez-Ibarra, P., Jaunsolo, M. A., Benitez, J., Robledo, M.
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|
<strong>Identification of novel SDHD mutations in patients with phaeochromocytoma and/or paraganglioma.</strong>
|
|
Europ. J. Hum. Genet. 10: 457-461, 2002.
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[PubMed: 12111639]
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[Full Text: https://doi.org/10.1038/sj.ejhg.5200829]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Devilee, P., van Schothorst, E. M., Bardoel, A. F. J., Bonsing, B., Kuipers-Dijkshoorn, N., James, M. R., Fleuren, G., van der Mey, A. G. L., Cornelisse, C. J.
|
|
<strong>Allelotype of head and neck paragangliomas: allelic imbalance is confined to the long arm of chromosome 11, the site of the predisposing locus PGL.</strong>
|
|
Genes Chromosomes Cancer 11: 71-78, 1994.
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[PubMed: 7529551]
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[Full Text: https://doi.org/10.1002/gcc.2870110202]
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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., Mourad, J.-J., Plouin, P.-F., Corvol, P., Rotig, A., Jeunemaitre, X.
|
|
<strong>The R22X mutation of the SDHD gene in hereditary paraganglioma abolishes the enzymatic activity of complex II in the mitochondrial respiratory chain and activates the hypoxia pathway.</strong>
|
|
Am. J. Hum. Genet. 69: 1186-1197, 2001.
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[PubMed: 11605159]
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[Full Text: https://doi.org/10.1086/324413]
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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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|
Gimm, O., Armanios, M., Dziema, H., Neumann, H. P. H., Eng, C.
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<strong>Somatic and occult germ-line mutations in SDHD, a mitochondrial complex II gene, in nonfamilial pheochromocytoma.</strong>
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|
Cancer Res. 60: 6822-6825, 2000.
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[PubMed: 11156372]
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</p>
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<li>
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<p class="mim-text-font">
|
|
Hamosh, A.
|
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<strong>Personal Communication.</strong>
|
|
Baltimore, Md. 7/11/2018.
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</p>
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<li>
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<p class="mim-text-font">
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|
Hensen, E. F., Jordanova, E. S., van Minderhout, I. J. H. M., Hogendoorn, P. C. W., Taschner, P. E. M., van der Mey, A. G. L., Devilee, P., Cornelisse, C. J.
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<strong>Somatic loss of maternal chromosome 11 causes parent-of-origin-dependent inheritance in SDHD-linked paraganglioma and phaeochromocytoma families.</strong>
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Oncogene 23: 4076-4083, 2004.
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[PubMed: 15064708]
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[Full Text: https://doi.org/10.1038/sj.onc.1207591]
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</p>
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<li>
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<p class="mim-text-font">
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|
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.
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<strong>High prevalence of founder mutations of the succinate dehydrogenase genes in the Netherlands.</strong>
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Clin. Genet. 81: 284-288, 2012.
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[PubMed: 21348866]
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[Full Text: https://doi.org/10.1111/j.1399-0004.2011.01653.x]
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</p>
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<p class="mim-text-font">
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Hirawake, H., Taniwaki, M., Tamura, A., Kojima, S., Kita, K.
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<strong>Cytochrome b in human complex II (succinate-ubiquinone oxidoreductase): cDNA cloning of the components in liver mitochondria and chromosome assignment of the genes for the large (SDHC) and small (SDHD) subunits to 1q21 and 11q23.</strong>
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Cytogenet. Cell Genet. 79: 132-138, 1997.
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[PubMed: 9533030]
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[Full Text: https://doi.org/10.1159/000134700]
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</p>
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<li>
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<p class="mim-text-font">
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Jackson, C. B., Nuoffer, J.-M., Hahn, D., Prokisch, H., Haberberger, B., Gautschi, M., Haberli, A., Gallati, S., Schaller, A.
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<strong>Mutations in SDHD lead to autosomal recessive encephalomyopathy and isolated mitochondrial complex II deficiency.</strong>
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J. Med. Genet. 51: 170-175, 2014.
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[PubMed: 24367056]
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</p>
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<li>
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<p class="mim-text-font">
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Kytola, S., Nord, B., Elder, E. E., Carling, T., Kjellman, M., Cedermark, B., Juhlin, C., Hoog, A., Isola, J., Larsson, C.
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<strong>Alterations of the SDHD gene locus in midgut carcinoids, Merkel cell carcinomas, pheochromocytomas, and abdominal paragangliomas.</strong>
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Genes Chromosomes Cancer 34: 325-332, 2002.
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[PubMed: 12007193]
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[Full Text: https://doi.org/10.1002/gcc.10081]
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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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Leube, B., Huber, R., Goecke, T. O., Sandmann, W., Royer-Pokora, B.
|
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<strong>SDHD mutation analysis in seven German patients with sporadic carotid body paraganglioma: one novel mutation, no Dutch founder mutation and further evidence that G12S is a polymorphism. (Letter)</strong>
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|
Clin. Genet. 65: 61-63, 2004.
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[PubMed: 15032977]
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[Full Text: https://doi.org/10.1111/j..2004.00174.x]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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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.
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|
<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>
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J. Clin. Endocr. Metab. 92: 4853-4864, 2007.
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[PubMed: 17848412]
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[Full Text: https://doi.org/10.1210/jc.2007-0640]
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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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Lima, J., Teixeira-Gomes, J., Soares, P., Maximo, V., Honavar, M., Williams, D., Sobrinho-Simoes, M.
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<strong>Germline succinate dehydrogenase subunit D mutation segregating with familial non-RET C cell hyperplasia.</strong>
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|
J. Clin. Endocr. Metab. 88: 4932-4937, 2003.
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[PubMed: 14557476]
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[Full Text: https://doi.org/10.1210/jc.2002-030008]
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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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Masuoka, J., Brandner, S., Paulus, W., Soffer, D., Vital, A., Chimelli, L., Jouvet, A., Yonekawa, Y., Kleihues, P., Ohgaki, H.
|
|
<strong>Germline SDHD mutation in paraganglioma of the spinal cord.</strong>
|
|
Oncogene 20: 5084-5086, 2001.
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[PubMed: 11526495]
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[Full Text: https://doi.org/10.1038/sj.onc.1204579]
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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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McWhinney, S. R., Pasini, B., Stratakis, C. A.
|
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<strong>Familial gastrointestinal stromal tumors and germ-line mutations. (Letter)</strong>
|
|
New Eng. J. Med. 357: 1054-1056, 2007.
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[PubMed: 17804857]
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[Full Text: https://doi.org/10.1056/NEJMc071191]
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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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McWhinney, S. R., Pilarski, R. T., Forrester, S. R., Schneider, M. C., Sarquis, M. M., Dias, E. P., Eng, C.
|
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<strong>Large germline deletions of mitochondrial complex II subunits SDHB and SDHD in hereditary paraganglioma.</strong>
|
|
J. Clin. Endocr. Metab. 89: 5694-5699, 2004.
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[PubMed: 15531530]
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[Full Text: https://doi.org/10.1210/jc.2004-0769]
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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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Milunsky, J. M., Maher, T. A., Michels, V. V., Milunsky, A.
|
|
<strong>Novel mutations and the emergence of a common mutation in the SDHD gene causing familial paraganglioma.</strong>
|
|
Am. J. Med. Genet. 100: 311-314, 2001.
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[PubMed: 11343322]
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[Full Text: https://doi.org/10.1002/ajmg.1270]
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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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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.
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Perren, A., Barghorn, A., Schmid, S., Saremaslani, P., Roth, J., Heitz, P. U., Komminoth, P.
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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.
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Taschner, P. E. M., Jansen, J. C., Baysal, B. E., Bosch, A., Rosenberg, E. H., Brocker-Vriends, A. H. J. T., van der Mey, A. G. L., van Ommen, G.-J. B., Cornelisse, C. J., Devilee, P.
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Ada Hamosh - updated : 11/28/2022<br>Cassandra L. Kniffin - updated : 7/29/2015<br>Cassandra L. Kniffin - updated : 9/23/2014<br>Cassandra L. Kniffin - updated : 4/11/2012<br>Cassandra L. Kniffin - updated : 6/2/2011<br>John A. Phillips, III - updated : 1/14/2009<br>Ada Hamosh - updated : 9/22/2008<br>John A. Phillips, III - updated : 7/25/2008<br>Marla J. F. O'Neill - updated : 5/6/2008<br>Marla J. F. O'Neill - updated : 9/24/2007<br>John A. Phillips, III - updated : 11/13/2006<br>Cassandra L. Kniffin - updated : 1/6/2006<br>John A. Phillips, III - updated : 4/12/2005<br>Victor A. McKusick - updated : 8/24/2004<br>Victor A. McKusick - updated : 2/25/2004<br>Victor A. McKusick - updated : 8/13/2003<br>Michael B. Petersen - updated : 6/23/2003<br>Victor A. McKusick - updated : 8/23/2002<br>Victor A. McKusick - updated : 4/16/2002<br>Victor A. McKusick - updated : 1/30/2002<br>Victor A. McKusick - updated : 12/20/2001<br>Victor A. McKusick - updated : 12/4/2001<br>Victor A. McKusick - updated : 10/9/2001<br>Victor A. McKusick - updated : 9/28/2001<br>Sonja A. Rasmussen - updated : 6/13/2001<br>Ada Hamosh - updated : 2/2/2000
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