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<title>
Entry
- *191040 - TROPONIN C, SLOW; TNNC1
- OMIM
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<span class="h4">*191040</span>
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<strong>Table of Contents</strong>
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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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<a href="#cloning">Cloning and Expression</a>
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<a href="#geneStructure">Gene Structure</a>
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#biochemicalFeatures">Biochemical Features</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#animalModel">Animal Model</a>
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">&#9658;</span> Genome
</a>
</span>
</span>
</div>
<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
<div class="panel-body small mim-panel-body">
<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000114854;t=ENST00000232975" 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>
<div><a href="https://www.ncbi.nlm.nih.gov/genome/gdv/browser/gene/?id=7134" 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>
<div><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&hgFind=omimGeneAcc&position=191040" 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>
</div>
</div>
</div>
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
<span class="panel-title">
<span class="small">
<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">&#9658;</span> DNA
</a>
</span>
</span>
</div>
<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
<div class="panel-body small mim-panel-body">
<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000114854;t=ENST00000232975" 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>
<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_003280" 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>
<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_003280" 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>
<div><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&hgFind=omimGeneAcc&position=191040" 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>
</div>
</div>
</div>
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
<div class="panel-heading mim-panel-heading" role="tab" id="mimProtein">
<span class="panel-title">
<span class="small">
<a href="#mimProteinLinksFold" id="mimProteinLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
<span id="mimProteinLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">&#9658;</span> Protein
</a>
</span>
</span>
</div>
<div id="mimProteinLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
<div class="panel-body small mim-panel-body">
<div><a href="https://hprd.org/summary?hprd_id=08930&isoform_id=08930_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>
<div><a href="https://www.proteinatlas.org/search/TNNC1" 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>
<div><a href="https://www.ncbi.nlm.nih.gov/protein/37208,339946,2460249,4507615,20987725,49456685,49456725,54042075,119585630,119585631,189053976,302313133" 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>
<div><a href="https://www.uniprot.org/uniprotkb/P63316" 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>
</div>
</div>
</div>
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
<div class="panel-heading mim-panel-heading" role="tab" id="mimGeneInfo">
<span class="panel-title">
<span class="small">
<a href="#mimGeneInfoLinksFold" id="mimGeneInfoLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
<div style="display: table-row">
<div id="mimGeneInfoLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">&#9658;</div>
&nbsp;
<div style="display: table-cell;">Gene Info</div>
</div>
</a>
</span>
</span>
</div>
<div id="mimGeneInfoLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
<div class="panel-body small mim-panel-body">
<div><a href="http://biogps.org/#goto=genereport&id=7134" 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>
<div><a href="https://www.ensembl.org/Homo_sapiens/Gene/Summary?db=core;g=ENSG00000114854;t=ENST00000232975" 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>
<div><a href="https://www.genecards.org/cgi-bin/carddisp.pl?gene=TNNC1" 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>
<div><a href="http://amigo.geneontology.org/amigo/search/annotation?q=TNNC1" 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>
<div><a href="https://www.genome.jp/dbget-bin/www_bget?hsa+7134" 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>
<dd><a href="http://v1.marrvel.org/search/gene/TNNC1" 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>
<dd><a href="https://monarchinitiative.org/NCBIGene:7134" class="mim-tip-hint" title="Monarch Initiative." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Monarch', 'domain': 'monarchinitiative.org'})">Monarch</a></dd>
<div><a href="https://www.ncbi.nlm.nih.gov/gene/7134" 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>
<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chr3&hgg_gene=ENST00000232975.8&hgg_start=52451100&hgg_end=52454041&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>
</div>
</div>
</div>
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
<span class="panel-title">
<span class="small">
<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
<div style="display: table-row">
<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">&#9658;</div>
&nbsp;
<div style="display: table-cell;">Clinical Resources</div>
</div>
</a>
</span>
</span>
</div>
<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
<div class="panel-body small mim-panel-body">
<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:11943" 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>
<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=191040[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>
</div>
</div>
</div>
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
<div class="panel-heading mim-panel-heading" role="tab" id="mimVariation">
<span class="panel-title">
<span class="small">
<a href="#mimVariationLinksFold" id="mimVariationLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
<span id="mimVariationLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">&#9660;</span> Variation
</a>
</span>
</span>
</div>
<div id="mimVariationLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel">
<div class="panel-body small mim-panel-body">
<div><a href="https://www.ncbi.nlm.nih.gov/clinvar?term=191040[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>
<div><a href="https://www.deciphergenomics.org/gene/TNNC1/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000114854" 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>
<div><a href="https://www.ebi.ac.uk/gwas/search?query=TNNC1" 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&nbsp;</a></div>
<div><a href="https://www.gwascentral.org/search?q=TNNC1" 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&nbsp;</a></div>
<div><a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=TNNC1" 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>
<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=TNNC1&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>
<div><a href="https://www.pharmgkb.org/gene/PA36632" 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>
</div>
</div>
</div>
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
<span class="panel-title">
<span class="small">
<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
<div style="display: table-row">
<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">&#9658;</div>
&nbsp;
<div style="display: table-cell;">Animal Models</div>
</div>
</a>
</span>
</span>
</div>
<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
<div class="panel-body small mim-panel-body">
<div><a href="https://www.alliancegenome.org/gene/HGNC:11943" 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>
<div><a href="https://www.mousephenotype.org/data/genes/MGI:98779" class="mim-tip-hint" title="International Mouse Phenotyping Consortium." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'IMPC', 'domain': 'knockoutmouse.org'})">IMPC</a></div>
<div><a href="http://v1.marrvel.org/search/gene/TNNC1#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>
<div><a href="http://www.informatics.jax.org/marker/MGI:98779" 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>
<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>
<div><a href="https://www.ncbi.nlm.nih.gov/gene/7134/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>
<div><a href="https://www.orthodb.org/?ncbi=7134" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
<div><a href="https://zfin.org/ZDB-GENE-030523-1" 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>
</div>
</div>
</div>
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
<span class="panel-title">
<span class="small">
<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
<div style="display: table-row">
<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">&#9658;</div>
&nbsp;
<div style="display: table-cell;">Cellular Pathways</div>
</div>
</a>
</span>
</span>
</div>
<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
<div class="panel-body small mim-panel-body">
<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:7134" 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>
<div><a href="https://reactome.org/content/query?q=TNNC1&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>
</div>
</div>
</div>
</div>
</div>
</div>
<span>
<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.">
&nbsp;
</span>
</span>
</div>
<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">
<div>
<a id="title" class="mim-anchor"></a>
<div>
<a id="number" class="mim-anchor"></a>
<div class="text-right">
&nbsp;
</div>
<div>
<span class="h3">
<span class="mim-font mim-tip-hint" title="Gene description">
<span class="text-danger"><strong>*</strong></span>
191040
</span>
</span>
</div>
</div>
<div>
<a id="preferredTitle" class="mim-anchor"></a>
<h3>
<span class="mim-font">
TROPONIN C, SLOW; TNNC1
</span>
</h3>
</div>
<div>
<br />
</div>
<div>
<a id="alternativeTitles" class="mim-anchor"></a>
<div>
<p>
<span class="mim-font">
<em>Alternative titles; symbols</em>
</span>
</p>
</div>
<div>
<h4>
<span class="mim-font">
TROPONIN C, SLOW-TWITCH SKELETAL MUSCLE<br />
TROPONIN C, CARDIAC; TNC
</span>
</h4>
</div>
</div>
<div>
<br />
</div>
</div>
<div>
<a id="approvedGeneSymbols" class="mim-anchor"></a>
<p>
<span class="mim-text-font">
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=TNNC1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">TNNC1</a></em></strong>
</span>
</p>
</div>
<div>
<a id="cytogeneticLocation" class="mim-anchor"></a>
<p>
<span class="mim-text-font">
<strong>
<em>
Cytogenetic location: <a href="/geneMap/3/377?start=-3&limit=10&highlight=377">3p21.1</a>
&nbsp;
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr3:52451100-52454041&dgv=pack&knownGene=pack&omimGene=pack" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">3:52,451,100-52,454,041</a> </span>
</em>
</strong>
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
</span>
</p>
</div>
<div>
<br />
</div>
<div>
<a id="geneMap" class="mim-anchor"></a>
<div style="margin-bottom: 10px;">
<span class="h4 mim-font">
<strong>Gene-Phenotype Relationships</strong>
</span>
</div>
<div>
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
<thead>
<tr class="active">
<th>
Location
</th>
<th>
Phenotype
<span class="hidden-sm hidden-xs pull-right">
<a href="/clinicalSynopsis/table?mimNumber=611879,613243" 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="2">
<span class="mim-font">
<a href="/geneMap/3/377?start=-3&limit=10&highlight=377">
3p21.1
</a>
</span>
</td>
<td>
<span class="mim-font">
Cardiomyopathy, dilated, 1Z
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/611879"> 611879 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
Cardiomyopathy, hypertrophic, 13
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/613243"> 613243 </a>
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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<strong>TEXT</strong>
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<a id="cloning" class="mim-anchor"></a>
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<strong>Cloning and Expression</strong>
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<p>Contraction in striated muscle is regulated by the calcium-ion-sensitive, multiprotein complex troponin and the fibrous protein tropomyosin (see <a href="/entry/191010">191010</a>). As a result of calcium-ion uptake by troponin C, the elements of the muscle thin filament undergo a series of allosteric changes which allow the interaction of actin with myosin, the hydrolysis of ATP, and the generation of tension. <a href="#14" class="mim-tip-reference" title="Roher, A., Lieska, N., Spitz, W. &lt;strong&gt;The amino acid sequence of human cardiac troponin-C.&lt;/strong&gt; Muscle Nerve 9: 73-77, 1986.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3951483/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;3951483&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/mus.880090112&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="3951483">Roher et al. (1986)</a> reported the primary structure (amino acid sequence) of troponin C from human cardiac muscle; it consists of 161 amino acid residues. Comparison with the sequences in the rabbit and the ox shows that troponin C is one of the most highly conserved proteins known. <a href="#15" class="mim-tip-reference" title="Romero-Herrera, A. E., Castillo, O., Lehmann, H. &lt;strong&gt;Human skeletal muscle proteins: the primary structure of troponin C.&lt;/strong&gt; J. Molec. Evol. 8: 251-270, 1976.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/978749/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;978749&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/BF01730999&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="978749">Romero-Herrera et al. (1976)</a> established the primary structure of human skeletal muscle troponin C. They found only a single amino acid difference between rabbit and human skeletal muscle troponin C and possibly only a single amino acid change between human skeletal troponin C and bovine cardiac muscle troponin C. Thus, they concluded that cardiac and slow-twitch skeletal troponin C are presumably identical. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3951483+978749" 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="geneStructure" class="mim-anchor"></a>
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<strong>Gene Structure</strong>
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<p><a href="#17" class="mim-tip-reference" title="Schreier, T., Kedes, L., Gahlmann, R. &lt;strong&gt;Cloning, structural analysis, and expression of the human slow twitch skeletal muscle/cardiac troponin C gene.&lt;/strong&gt; J. Biol. Chem. 265: 21247-21253, 1990.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2250022/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2250022&lt;/a&gt;]" pmid="2250022">Schreier et al. (1990)</a> described the structure of the TNNC gene. It is 3 kb long, with 6 exons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2250022" 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="mapping" class="mim-anchor"></a>
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<strong>Mapping</strong>
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<p>Using a human/rodent monochromosomal mapping panel, <a href="#19" class="mim-tip-reference" title="Song, W.-J., Van Keuren, M. L., Drabkin, H. A., Cypser, J. R., Gemmill, R. M., Kurnit, D. M. &lt;strong&gt;Assignment of the human slow twitch skeletal muscle/cardiac troponin C gene (TNNC1) to human chromosome 3p21.3-3p14.3 using somatic cell hybrids.&lt;/strong&gt; Cytogenet. Cell Genet. 75: 36-37, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8995486/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8995486&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1159/000134453&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8995486">Song et al. (1996)</a> mapped a human slow-twitch skeletal muscle/cardiac troponin C gene (symbolized TNNC1) to chromosome 3 by PCR. Chromosome 3 somatic cell hybrids with various rearrangements were used for finer mapping to 3p21.3-p14.3. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8995486" 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="#1" class="mim-tip-reference" title="Bermingham, N., Hernandez, D., Balfour, A., Gilmour, F., Martin, J. E., Fisher, E. M. C. &lt;strong&gt;Mapping TNNC1, the gene that encodes cardiac troponin I in the human and mouse.&lt;/strong&gt; Genomics 30: 620-622, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8825654/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8825654&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1006/geno.1995.1288&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8825654">Bermingham et al. (1995)</a> mapped a gene they symbolized TNNC1 to 19q13.3-q13.4 using a series of somatic cell hybrid DNAs. By interspecific backcross analysis, they mapped the mouse homolog to a site close to the centromere of chromosome 7. <a href="#18" class="mim-tip-reference" title="Song, W. J. &lt;strong&gt;Personal Communication.&lt;/strong&gt; Ann Arbor, Mich. 1/17/1997."None>Song (1997)</a> indicated that the gene mapped by <a href="#1" class="mim-tip-reference" title="Bermingham, N., Hernandez, D., Balfour, A., Gilmour, F., Martin, J. E., Fisher, E. M. C. &lt;strong&gt;Mapping TNNC1, the gene that encodes cardiac troponin I in the human and mouse.&lt;/strong&gt; Genomics 30: 620-622, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8825654/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8825654&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1006/geno.1995.1288&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8825654">Bermingham et al. (1995)</a> should not be symbolized TNNC1 since it represented cardiac troponin I (TNNI3; <a href="/entry/191044">191044</a>) which had been mapped by others to chromosome 19. <a href="#19" class="mim-tip-reference" title="Song, W.-J., Van Keuren, M. L., Drabkin, H. A., Cypser, J. R., Gemmill, R. M., Kurnit, D. M. &lt;strong&gt;Assignment of the human slow twitch skeletal muscle/cardiac troponin C gene (TNNC1) to human chromosome 3p21.3-3p14.3 using somatic cell hybrids.&lt;/strong&gt; Cytogenet. Cell Genet. 75: 36-37, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8995486/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8995486&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1159/000134453&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8995486">Song et al. (1996)</a> mapped the authentic TNNC1 gene to chromosome 3. Using a 'monochromosomal' hybrid panel, <a href="#21" class="mim-tip-reference" title="Townsend, P. J., Yacoub, M. H., Barton, P. J. R. &lt;strong&gt;Assignment of the human cardiac/slow skeletal muscle troponin C gene (TNNC1) between D3S3118 and GCT4B10 on the short arm of chromosome 3 by somatic cell hybrid analysis.&lt;/strong&gt; Ann. Hum. Genet. 61: 375-377, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9365790/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9365790&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1046/j.1469-1809.1997.6140375.x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9365790">Townsend et al. (1997)</a> mapped the TNNC1 gene to chromosome 3; subsequent analysis of the Genebridge 4 radiation hybrid panel localized the gene to 3p in a region consistent with the earlier assignment. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9365790+8825654+8995486" 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>Biochemical Features</strong>
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<p><strong><em>Crystal Structure</em></strong></p><p>
Troponin consists of 3 subunits, TnC, TnI (see <a href="/entry/191044">191044</a>), and TnT (see <a href="/entry/191045">191045</a>), and, together with tropomyosin, is located on the actin filament. <a href="#20" class="mim-tip-reference" title="Takeda, S., Yamashita, A., Maeda, K., Maeda, Y. &lt;strong&gt;Structure of the core domain of human cardiac troponin in the Ca(2+)-saturated form.&lt;/strong&gt; Nature 424: 35-41, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12840750/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12840750&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/nature01780&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12840750">Takeda et al. (2003)</a> presented the crystal structure of the core domains (relative molecular mass of 46,000 and 52,000) of human cardiac troponin in the calcium-saturated form. Analysis of the 4-molecule structures revealed that the core domain is further divided into structurally distinct subdomains that are connected by flexible linkers, making the entire molecule highly flexible. The alpha-helical coiled-coil formed between TnT and TnI is integrated in a rigid and asymmetric structure about 80 angstroms long, the IT arm, which bridges putative tropomyosin-anchoring regions. The structures of the troponin ternary complex imply that calcium binding to the regulatory site of TnC removes the carboxy-terminal portion of TnI from actin, thereby altering the mobility and/or flexibility of troponin and tropomyosin on the actin filament. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12840750" 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="molecularGenetics" class="mim-anchor"></a>
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<p><strong><em>Hypertrophic Cardiomyopathy 13</em></strong></p><p>
In a German patient with hypertrophic cardiomyopathy (CMH13; <a href="/entry/613243">613243</a>), <a href="#4" class="mim-tip-reference" title="Hoffmann, B., Schmidt-Traub, H., Perrot, A., Osterziel, K. J., Gessner, R. &lt;strong&gt;First mutation in cardiac troponin C, L29Q, in a patient with hypertrophic cardiomyopathy.&lt;/strong&gt; Hum. Mutat. 17: 524 only, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11385718/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11385718&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/humu.1143&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11385718">Hoffmann et al. (2001)</a> identified a heterozygous mutation in the TNNC1 gene (L29Q; <a href="#0002">191040.0002</a>). The authors stated that they could not determine whether this was a disease-causing variant. <a href="#16" class="mim-tip-reference" title="Schmidtmann, A., Lindow, C., Villard, S., Heuser, A., Mugge, A., Gessner, R., Granier, C., Jaquet, K. &lt;strong&gt;Cardiac troponin C-L29Q, related to hypertrophic cardiomyopathy, hinders the transduction of the protein kinase A dependent phosphorylation signal from cardiac troponin I to C.&lt;/strong&gt; FEBS J. 272: 6087-6097, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16302972/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16302972&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1742-4658.2005.05001.x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16302972">Schmidtmann et al. (2005)</a> studied the structural and functional consequences of the L29Q substitution and demonstrated alteration of the dynamics of the actin-myosin interaction as well as impairment of PKA (see <a href="/entry/601639">601639</a>)-dependent signaling from cardiac TnI (<a href="/entry/191044">191044</a>) to cardiac TnC, resulting in an increased sensitivity to Ca(2+) when cardiac TnI is phosphorylated. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16302972+11385718" 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="#8" class="mim-tip-reference" title="Landstrom, A. P., Parvatiyar, M. S., Pinto, J. R., Marquardt, M. L., Bos, J. M., Tester, D. J., Ommen, S. R., Potter, J. D., Ackerman, M. J. &lt;strong&gt;Molecular and functional characterization of novel hypertrophic cardiomyopathy susceptibility mutations in TNNC1-encoded troponin C.&lt;/strong&gt; J. Molec. Cell. Cardiol. 45: 281-288, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18572189/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18572189&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=18572189[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.yjmcc.2008.05.003&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="18572189">Landstrom et al. (2008)</a> analyzed the TNNC1 gene in 1,025 unrelated patients with CMH and identified 4 heterozygous mutations in 4 Caucasian patients (see, e.g., A8V, <a href="#0003">191040.0003</a>; C84Y, <a href="#0004">191040.0004</a>; D145E, <a href="#0005">191040.0005</a>) who were negative for mutation in 15 known CMH-susceptibility genes. Functional studies showed increased Ca(2+) sensitivity of force development and force recovery with 3 of the mutations; the fourth, an E134D substitution, had no effect on the parameters studied. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18572189" 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="Pinto, J. R., Parvatiyar, M. S., Jones, M. A., Liang, J., Ackerman, M. J., Potter, J. D. &lt;strong&gt;A functional and structural study of troponin C mutations related to hypertrophic cardiomyopathy.&lt;/strong&gt; J. Biol. Chem. 284: 19090-19100, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19439414/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19439414&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=19439414[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1074/jbc.M109.007021&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19439414">Pinto et al. (2009)</a> performed a functional and structural analysis of the 4 TNNC1 mutations identified by <a href="#8" class="mim-tip-reference" title="Landstrom, A. P., Parvatiyar, M. S., Pinto, J. R., Marquardt, M. L., Bos, J. M., Tester, D. J., Ommen, S. R., Potter, J. D., Ackerman, M. J. &lt;strong&gt;Molecular and functional characterization of novel hypertrophic cardiomyopathy susceptibility mutations in TNNC1-encoded troponin C.&lt;/strong&gt; J. Molec. Cell. Cardiol. 45: 281-288, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18572189/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18572189&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=18572189[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.yjmcc.2008.05.003&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="18572189">Landstrom et al. (2008)</a> in CMH patients and found that 3 of them (A8V, C84Y, and D145E) increased the Ca(2+) sensitivity of the filament, but they noted that the effects of the mutations on the Ca(2+) affinity of isolated cardiac TnC, cardiac troponin, and thin filaments were not sufficient to explain the large Ca(2+) sensitivity changes seen in reconstituted and fiber assays. Circular dichroism measurements revealed changes in the secondary structures of the TNNC1 mutants A8V, C84Y, and D145E; <a href="#12" class="mim-tip-reference" title="Pinto, J. R., Parvatiyar, M. S., Jones, M. A., Liang, J., Ackerman, M. J., Potter, J. D. &lt;strong&gt;A functional and structural study of troponin C mutations related to hypertrophic cardiomyopathy.&lt;/strong&gt; J. Biol. Chem. 284: 19090-19100, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19439414/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19439414&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=19439414[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1074/jbc.M109.007021&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19439414">Pinto et al. (2009)</a> suggested that these changes in secondary structure might contribute to modified protein-protein interactions along the sarcomere lattice disrupting the coupling between the cross-bridge and Ca(2+) binding to cardiac TnC. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=19439414+18572189" 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 5-year-old boy with CMH and a history of ventricular fibrillation, <a href="#11" class="mim-tip-reference" title="Parvatiyar, M. S., Landstrom, A. P., Figueiredo-Freitas, C., Potter, J. D., Ackerman, M. J., Pinto, J. R. &lt;strong&gt;A mutation in TNNC1-encoded cardiac troponin C, TNNC1-A31S, predisposes to hypertrophic cardiomyopathy and ventricular fibrillation.&lt;/strong&gt; J. Biol. Chem. 287: 31845-31855, 2012.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/22815480/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;22815480&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=22815480[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1074/jbc.M112.377713&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="22815480">Parvatiyar et al. (2012)</a> analyzed 12 CMH-associated genes and identified heterozygosity for a missense mutation in the TNNC1 gene (A31S; <a href="#0006">191040.0006</a>). Functional analysis suggested that the A31S mutation has a direct effect on the Ca(2+) sensitivity of the myofilament, which may alter Ca(2+) handling and contribute to the arrhythmogenesis observed in the proband. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22815480" 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>Dilated Cardiomyopathy 1Z</em></strong></p><p>
<a href="#10" class="mim-tip-reference" title="Mogensen, J., Murphy, R. T., Shaw, T., Bahl, A., Redwood, C., Watkins, H., Burke, M., Elliott, P. M., McKenna, W. J. &lt;strong&gt;Severe disease expression of cardiac troponin C and T mutations in patients with idiopathic dilated cardiomyopathy.&lt;/strong&gt; J. Am. Coll. Cardiol. 44: 2033-2040, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15542288/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15542288&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.jacc.2004.08.027&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15542288">Mogensen et al. (2004)</a> analyzed the TNNC1 gene in 235 consecutive unrelated probands with dilated cardiomyopathy (see CMD1Z, <a href="/entry/611879">611879</a>) and identified heterozygosity for a mutation in the TNNC1 gene (G159D; <a href="#0001">191040.0001</a>) in 5 affected members of a 3-generation family with a severe phenotype. Functional studies showed significant alterations in the interaction of the mutated troponin C with wildtype troponins T and I. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15542288" 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="Mirza, M., Marston, S., Willott, R., Ashley, C., Mogensen, J., McKenna, W., Robinson, P., Redwood, C., Watkins, H. &lt;strong&gt;Dilated cardiomyopathy mutations in three thin filament regulatory proteins result in a common functional phenotype.&lt;/strong&gt; J. Biol. Chem. 280: 28498-28506, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15923195/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15923195&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1074/jbc.M412281200&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15923195">Mirza et al. (2005)</a> studied all 8 published mutations causing dilated cardiomyopathy (CMD), including 5 in the TNNT2 gene (lys210del, R141W, R131W, R205L, and D270N; <a href="/entry/191045#0006">191045.0006</a>-<a href="/entry/191045#0010">191045.0010</a>, respectively), 2 in the TPM1 gene (E54K, <a href="/entry/191010#0004">191010.0004</a>; E40K, <a href="/entry/191010#0005">191010.0005</a>), and 1 in the TNNC1 gene (G159D). Thin filaments, reconstituted with a 1:1 ratio of mutant:wildtype proteins, all showed reduced Ca(2+) sensitivity of activation in ATPase and motility assays, and, except for the E54K alpha-tropomyosin mutant which showed no effect, all showed lower maximum Ca(2+) activation. Incorporation of the TNNT2 mutations R141W and R205L into skinned guinea pig cardiac trabeculae also decreased Ca(2+) sensitivity of force generation. Thus, diverse thin filament CMD mutations appeared to affect different aspects of regulatory function yet change contractility in a consistent manner. <a href="#9" class="mim-tip-reference" title="Mirza, M., Marston, S., Willott, R., Ashley, C., Mogensen, J., McKenna, W., Robinson, P., Redwood, C., Watkins, H. &lt;strong&gt;Dilated cardiomyopathy mutations in three thin filament regulatory proteins result in a common functional phenotype.&lt;/strong&gt; J. Biol. Chem. 280: 28498-28506, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15923195/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15923195&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1074/jbc.M412281200&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15923195">Mirza et al. (2005)</a> stated that the CMD mutations depressed myofibrillar function, an effect opposite to that of CMH-causing thin filament mutations, and suggested that decreased contractility might trigger pathways that ultimately lead to the clinical phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15923195" 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="Dyer, E. C., Jacques, A. M., Hoskins, A. C., Ward, D. G., Gallon, C. E., Messer, A. E., Kaski, J. P., Burch, M., Kentish, J. C., Marston, S. B. &lt;strong&gt;Functional analysis of a unique troponin c mutation, GLY159ASP, that causes familial dilated cardiomyopathy, studied in explanted heart muscle.&lt;/strong&gt; Circ. Heart Fail. 2: 456-464, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19808376/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19808376&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1161/CIRCHEARTFAILURE.108.818237&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19808376">Dyer et al. (2009)</a> performed functional studies of mutant myocytes from an explanted heart with the G159D mutation (<a href="#0001">191040.0001</a>). The G159D myocytes showed an increased sensitivity to Ca(2+) compared to wildtype TNNC1; however, dephosphorylation of troponin did not produce the expected increase in Ca(2+) sensitivity with the mutant cTnC. <a href="#2" class="mim-tip-reference" title="Dyer, E. C., Jacques, A. M., Hoskins, A. C., Ward, D. G., Gallon, C. E., Messer, A. E., Kaski, J. P., Burch, M., Kentish, J. C., Marston, S. B. &lt;strong&gt;Functional analysis of a unique troponin c mutation, GLY159ASP, that causes familial dilated cardiomyopathy, studied in explanted heart muscle.&lt;/strong&gt; Circ. Heart Fail. 2: 456-464, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19808376/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19808376&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1161/CIRCHEARTFAILURE.108.818237&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19808376">Dyer et al. (2009)</a> suggested that uncoupling of the relationship between phosphorylation and Ca(2+) sensitivity might be the cause of the dilated cardiomyopathy phenotype in patients with G159D mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19808376" 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 cohort of 312 probands with dilated cardiomyopathy, <a href="#3" class="mim-tip-reference" title="Hershberger, R. E., Norton, N., Morales, A., Li, D., Siegfried, J. D., Gonzalez-Quintana, J. &lt;strong&gt;Coding sequence rare variants identified in MYBPC3, MYH6, TNNC1, and TNNI3 from 312 patients with familial or idiopathic dilated cardiomyopathy.&lt;/strong&gt; Circ. Cardiovasc. Genet. 3: 155-161, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20215591/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;20215591&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1161/CIRCGENETICS.109.912345&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="20215591">Hershberger et al. (2010)</a> analyzed 5 CMD-associated genes and identified a missense mutation in the TNNC1 gene (M103I; <a href="#0008">191040.0008</a>) in 1 proband (D.2) and an affected relative that was not found in 246 control individuals. Another 3 heterozygous TNNC1 missense variants were identified in 3 CMD probands, but segregation data was lacking for those variants. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20215591" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#23" class="mim-tip-reference" title="Vikhorev, P. G., Smoktunowicz, N., Munster, A. B., Copeland, O., Kostin, S., Montgiraud, C., Messer, A. E., Toliat, M. R., Li, A., Dos Remedios, C. G., Lal, S., Blair, C. A., Campbell, K. S., Guglin, M., Richter, M., Knoll, R., Marston, S. B. &lt;strong&gt;Abnormal contractility in human heart myofibrils from patients with dilated cardiomyopathy due to mutations in TTN and contractile protein genes.&lt;/strong&gt; Sci. Rep. 7: 14829, 2017. Note: Erratum: Sci. Rep. 8: 14485, 2018.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/29093449/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;29093449&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=29093449[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/s41598-017-13675-8&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="29093449">Vikhorev et al. (2017)</a> compared contractility and passive stiffness of cardiac myofibril samples from 3 unrelated patients with dilated cardiomyopathy (DCM) and 2 different truncation mutations in titin (TTN; <a href="/entry/188840">188840</a>), 3 unrelated DCM patients with mutations in different contractile proteins (lys36 to gln in TNNI3 (<a href="/entry/191044#0012">191044.0012</a>), G159D in TNNC1, and glu1426 to lys in MYH7 (<a href="/entry/160760">160760</a>)), and controls. All 3 contractile protein mutations, but not the titin mutations, had faster relaxation kinetics than controls. Myofibril passive stiffness was reduced by about 38% in all DCM samples compared with controls, but there was no change in maximum force or titin N2BA/N2B isoform ratio, and there was no titin haploinsufficiency. The authors concluded that decreased myofibril passive stiffness, a common feature in all DCM samples, may be a causative of DCM. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29093449" 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>By trio whole-exome sequencing in an infant girl with CMD and her unaffected parents, <a href="#5" class="mim-tip-reference" title="Johnston, J. R., Landim-Vieira, M., Marques, M. A., de Oliveira, G. A. P., Gonzalez-Martinez, D., Moraes, A. H., He, H., Iqbal, A., Wilnai, Y., Birk, E., Zucker, N., Silva, J. L., Chase, P. B., Pinto, J. R. &lt;strong&gt;The intrinsically disordered C terminus of troponin T binds to troponin C to modulate myocardial force generation.&lt;/strong&gt; J. Biol. Chem. 294: 20054-20069, 2019.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/31748410/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;31748410&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=31748410[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1074/jbc.RA119.011177&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="31748410">Johnston et al. (2019)</a> identified heterozygosity for a de novo missense mutation in the TNNIC1 gene (I4M; <a href="#0009">191040.0009</a>) that was not found in the gnomAD database. Functional analysis showed a reduction in the magnitude and rate of isometric force generation with the mutant, as well as tighter binding between cTnT (TNNT2; <a href="/entry/191045">191045</a>) and cTnC. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31748410" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using duo whole-exome sequencing in a family in which 3 sibs had severe dilated pediatric cardiomyopathy, <a href="#22" class="mim-tip-reference" title="Udani, R., Schilter, K. F., Tyler, R. C., Smith, B. A., Wendtandrae, J. L., Kappes, U. P., Scharer, G., Lehman, A., Steinraths, M., Reddi, H. V. &lt;strong&gt;A novel variant of TNNC1 associated with severe dilated cardiomyopathy causing infant mortality and stillbirth: a case of germline mosaicism.&lt;/strong&gt; J. Genet. 102: 14, 2023.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/36814108/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;36814108&lt;/a&gt;]" pmid="36814108">Udani et al. (2023)</a> identified a de novo heterozygous missense mutation in the TNNC1 gene (G34R; <a href="#0007">191040.0007</a>) in the proband and first stillborn sib. Sanger sequencing identified the mutation in the second stillborn sib. Both parents and 2 unaffected sibs were negative for the mutation. The presence of the same de novo variant in all 3 affected sibs suggested germline mosaicism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=36814108" 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 sister and brother with severe early-onset CMD, <a href="#7" class="mim-tip-reference" title="Landim-Vieira, M., Johnston, J. R., Ji, W., Mis, E. K., Tijerino, J., Spencer-Manzon, M., Jeffries, L., Hall, E. K., Panisello-Manterola, D., Khokha, M. K., Deniz, E., Chase, P. B., Lakhani, S. A., Pinto, J. R. &lt;strong&gt;Familial dilated cardiomyopathy associated with a novel combination of compound heterozygous TNNC1 variants.&lt;/strong&gt; Front. Physiol. 10: 1612, 2020.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/32038292/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;32038292&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=32038292[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.3389/fphys.2019.01612&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="32038292">Landim-Vieira et al. (2020)</a> identified compound heterozygosity for missense mutations in the TNNC1 gene: the previously reported CMH-associated D145E substitution (<a href="#0005">191040.0005</a>), and a c.394G-A transition resulting in an asp132-to-asn (D132N) substitution, both occurring at highly conserved residues within the C-domain. No other rare or pathogenic variants were found in other known cardiomyopathy genes in either of the sibs. Their unaffected parents, who were in their fifth decade and had normal echocardiograms, were each heterozygous for 1 of the mutations. Functional analysis using porcine cardiac muscle preparations (CMPs) showed that the D132N variant significantly reduced, whereas the D145E variant significantly increased, myofilament Ca(2+) sensitivity of force generation; and there was no significant difference in Ca(2+) sensitivity of tension when CMPs were reconstituted with a 50-50 mixture of D132N and D145E. Thus the incorporation of both mutants appeared to normalize the opposite effects of the 2 variants on Ca(2+) dependence of isometric force, which the authors noted was difficult to reconcile with the severe CMD pathology associated with the presence of the 2 mutations. The proband was a female infant who from birth had gradually increasing left ventricular enlargement and worsening LV function; she died following cardiac arrest at age 14 months while awaiting transplant. She had an 11-year-old brother who was diagnosed as a neonate with severe CMD and underwent transplantation at 13 months of age. He had good function of the transplanted heart, and no signs of skeletal muscle problems. Their mother had experienced 3 miscarriages with in vitro-fertilized pregnancies, and another sib died after premature live birth at 23 weeks' gestation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32038292" 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>Animal Model</strong>
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<p><a href="#7" class="mim-tip-reference" title="Landim-Vieira, M., Johnston, J. R., Ji, W., Mis, E. K., Tijerino, J., Spencer-Manzon, M., Jeffries, L., Hall, E. K., Panisello-Manterola, D., Khokha, M. K., Deniz, E., Chase, P. B., Lakhani, S. A., Pinto, J. R. &lt;strong&gt;Familial dilated cardiomyopathy associated with a novel combination of compound heterozygous TNNC1 variants.&lt;/strong&gt; Front. Physiol. 10: 1612, 2020.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/32038292/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;32038292&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=32038292[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.3389/fphys.2019.01612&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="32038292">Landim-Vieira et al. (2020)</a> used CRISPR/Cas9-mediated gene editing to knock out TNNC1 in Xenopus. Loss of the TNNC1 gene did not prevent the early stages of development, but resulted in a dramatic cardiac phenotype consistent with dilated cardiomyopathy in the mutant tadpoles, which demonstrated ventricular dilation, wall thinning, and almost imperceptible cardiac motion. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32038292" 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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<strong>9 Selected Examples</a>):</strong>
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<a href="/allelicVariants/191040" class="btn btn-default" role="button"> Table View </a>
&nbsp;&nbsp;<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=191040[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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<strong>.0001&nbsp;CARDIOMYOPATHY, DILATED, 1Z</strong>
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TNNC1, GLY159ASP
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs104893823 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104893823;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=rs104893823" 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=rs104893823" 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=RCV000013254 OR RCV000523060" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013254, RCV000523060" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013254...</a>
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<p>In 5 affected members of a family (family A) with severe dilated cardiomyopathy (CMD1Z; <a href="/entry/611879">611879</a>), <a href="#10" class="mim-tip-reference" title="Mogensen, J., Murphy, R. T., Shaw, T., Bahl, A., Redwood, C., Watkins, H., Burke, M., Elliott, P. M., McKenna, W. J. &lt;strong&gt;Severe disease expression of cardiac troponin C and T mutations in patients with idiopathic dilated cardiomyopathy.&lt;/strong&gt; J. Am. Coll. Cardiol. 44: 2033-2040, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15542288/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15542288&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.jacc.2004.08.027&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15542288">Mogensen et al. (2004)</a> identified heterozygosity for a missense mutation in the TNNC1 gene, predicted to result in a gly159-to-asp (G159D) substitution at a conserved residue in a domain of the protein constitutively occupied by Ca(2+). The mutation was not found in unaffected family members or in 200 ethnically matched control chromosomes. Functional studies showed significant impairment of the mutated troponin C interaction with wildtype troponin T, whereas the interaction with wildtype troponin I was significantly enhanced (p less than 0.0001 for both), indicating an altered regulation of myocardial contractility. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15542288" 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 3-year-old boy with severe CMD who underwent cardiac transplantation, who was the nephew of the proband from family A reported by <a href="#10" class="mim-tip-reference" title="Mogensen, J., Murphy, R. T., Shaw, T., Bahl, A., Redwood, C., Watkins, H., Burke, M., Elliott, P. M., McKenna, W. J. &lt;strong&gt;Severe disease expression of cardiac troponin C and T mutations in patients with idiopathic dilated cardiomyopathy.&lt;/strong&gt; J. Am. Coll. Cardiol. 44: 2033-2040, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15542288/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15542288&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.jacc.2004.08.027&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15542288">Mogensen et al. (2004)</a>, <a href="#6" class="mim-tip-reference" title="Kaski, J. P., Burch, M., Elliott, P. M. &lt;strong&gt;Mutations in the cardiac Troponin C gene are a cause of idiopathic dilated cardiomyopathy in childhood.&lt;/strong&gt; Cardiol. Young 17: 675-677, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17977476/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17977476&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1017/S1047951107001291&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17977476">Kaski et al. (2007)</a> identified heterozygosity for the G159D mutation in the TNNC1 gene. <a href="#2" class="mim-tip-reference" title="Dyer, E. C., Jacques, A. M., Hoskins, A. C., Ward, D. G., Gallon, C. E., Messer, A. E., Kaski, J. P., Burch, M., Kentish, J. C., Marston, S. B. &lt;strong&gt;Functional analysis of a unique troponin c mutation, GLY159ASP, that causes familial dilated cardiomyopathy, studied in explanted heart muscle.&lt;/strong&gt; Circ. Heart Fail. 2: 456-464, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19808376/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19808376&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1161/CIRCHEARTFAILURE.108.818237&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19808376">Dyer et al. (2009)</a> analyzed the patient's explanted heart tissue and found that mutant cardiac troponin C (cTnC) was expressed approximately equimolar with wildtype cTnC. Although the sarcomeric structure and maximal Ca(2+)-activated force was similar in both mutant and wildtype skinned ventricular myocytes, mutant myocytes exhibited significantly greater Ca(2+) sensitivity than wildtype myocytes. An in vitro motility assay using reconstituted thin filaments confirmed greater Ca(2+) sensitivity with mutant filaments, although maximally activated sliding speed was unchanged. In addition, dephosphorylation of troponin produced the expected increase in Ca(2+) sensitivity with wildtype heart troponin, but almost no change in Ca(2+) sensitivity with mutant heart troponin. <a href="#2" class="mim-tip-reference" title="Dyer, E. C., Jacques, A. M., Hoskins, A. C., Ward, D. G., Gallon, C. E., Messer, A. E., Kaski, J. P., Burch, M., Kentish, J. C., Marston, S. B. &lt;strong&gt;Functional analysis of a unique troponin c mutation, GLY159ASP, that causes familial dilated cardiomyopathy, studied in explanted heart muscle.&lt;/strong&gt; Circ. Heart Fail. 2: 456-464, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19808376/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19808376&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1161/CIRCHEARTFAILURE.108.818237&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19808376">Dyer et al. (2009)</a> suggested that uncoupling of the relationship between phosphorylation and Ca(2+) sensitivity might be the cause of the dilated cardiomyopathy phenotype in patients with G159D mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17977476+15542288+19808376" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#23" class="mim-tip-reference" title="Vikhorev, P. G., Smoktunowicz, N., Munster, A. B., Copeland, O., Kostin, S., Montgiraud, C., Messer, A. E., Toliat, M. R., Li, A., Dos Remedios, C. G., Lal, S., Blair, C. A., Campbell, K. S., Guglin, M., Richter, M., Knoll, R., Marston, S. B. &lt;strong&gt;Abnormal contractility in human heart myofibrils from patients with dilated cardiomyopathy due to mutations in TTN and contractile protein genes.&lt;/strong&gt; Sci. Rep. 7: 14829, 2017. Note: Erratum: Sci. Rep. 8: 14485, 2018.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/29093449/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;29093449&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=29093449[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/s41598-017-13675-8&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="29093449">Vikhorev et al. (2017)</a> compared contractility and passive stiffness of cardiac myofibril samples from 3 unrelated patients with dilated cardiomyopathy (DCM) and 2 different truncation mutations in titin (TTN; <a href="/entry/188840">188840</a>), 3 unrelated DCM patients with mutations in different contractile proteins, including G159D in TNNC1, and controls. All 3 contractile protein mutations, but not the titin mutations, had faster relaxation kinetics than controls. Myofibril passive stiffness was reduced by about 38% in all DCM samples compared with controls, but there was no change in maximum force or titin N2BA/N2B isoform ratio, and there was no titin haploinsufficiency. The authors concluded that decreased myofibril passive stiffness, a common feature in all DCM samples, may be a causative of DCM. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29093449" 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>.0002&nbsp;CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 13</strong>
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TNNC1, LEU29GLN
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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">&#x25cf;</span> rs267607123 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267607123;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/rs267607123?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">&#x25cf;</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs267607123" 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=rs267607123" 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=RCV000013255 OR RCV000215162 OR RCV000702748 OR RCV000998084 OR RCV004678596" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013255, RCV000215162, RCV000702748, RCV000998084, RCV004678596" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013255...</a>
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<p>In a 60-year-old German man with hypertrophic cardiomyopathy (CMH13; <a href="/entry/613243">613243</a>), <a href="#4" class="mim-tip-reference" title="Hoffmann, B., Schmidt-Traub, H., Perrot, A., Osterziel, K. J., Gessner, R. &lt;strong&gt;First mutation in cardiac troponin C, L29Q, in a patient with hypertrophic cardiomyopathy.&lt;/strong&gt; Hum. Mutat. 17: 524 only, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11385718/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11385718&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/humu.1143&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11385718">Hoffmann et al. (2001)</a> identified an c.86T-A transversion in exon 3 of the TNNC1 gene, leading to a leu29-to-gln (L29Q) substitution at a conserved residue. No family members were available for study. The mutation was not detected in 96 controls, but the authors stated that they could not determine whether this was a disease-causing variant. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11385718" 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="#16" class="mim-tip-reference" title="Schmidtmann, A., Lindow, C., Villard, S., Heuser, A., Mugge, A., Gessner, R., Granier, C., Jaquet, K. &lt;strong&gt;Cardiac troponin C-L29Q, related to hypertrophic cardiomyopathy, hinders the transduction of the protein kinase A dependent phosphorylation signal from cardiac troponin I to C.&lt;/strong&gt; FEBS J. 272: 6087-6097, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16302972/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16302972&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1742-4658.2005.05001.x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16302972">Schmidtmann et al. (2005)</a> studied the structural and functional consequences of the L29Q substitution, located at the transition of helix A to the nonfunctional Ca(+2)-binding loop, and observed only minor effects on secondary structure by circular dichroism (CD) spectroscopy. Peptide array experiments demonstrated interaction of the nonphosphorylated cardiac TnI (TNNI3; <a href="/entry/191044">191044</a>) arm with cardiac TnC around leu29; this interaction did not occur with the L29Q mutant, whether in the phosphorylated or nonphosphorylated state. In vitro assays revealed that with L29Q, the Ca(2+) sensitivity of the actomyosin subfragment 1-ATPase activity and the mean sliding velocity of thin filaments were no longer affected by protein kinase A (see <a href="/entry/601639">601639</a>)-dependent phosphorylation of cTnI. <a href="#16" class="mim-tip-reference" title="Schmidtmann, A., Lindow, C., Villard, S., Heuser, A., Mugge, A., Gessner, R., Granier, C., Jaquet, K. &lt;strong&gt;Cardiac troponin C-L29Q, related to hypertrophic cardiomyopathy, hinders the transduction of the protein kinase A dependent phosphorylation signal from cardiac troponin I to C.&lt;/strong&gt; FEBS J. 272: 6087-6097, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16302972/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16302972&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1742-4658.2005.05001.x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16302972">Schmidtmann et al. (2005)</a> concluded that L29Q hinders transduction of the phosphorylation signal from cardiac TnI to cardiac TnC. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16302972" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0003&nbsp;CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 13</strong>
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TNNC1, ALA8VAL
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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">&#x25cf;</span> rs267607125 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267607125;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/rs267607125?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">&#x25cf;</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs267607125" 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=rs267607125" 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=RCV000013256 OR RCV000037762 OR RCV000159204 OR RCV000618084 OR RCV000824773 OR RCV001034686 OR RCV001582477 OR RCV003147283" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013256, RCV000037762, RCV000159204, RCV000618084, RCV000824773, RCV001034686, RCV001582477, RCV003147283" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013256...</a>
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<p>In a 37-year-old Caucasian man who was diagnosed at 33 years of age with hypertrophic cardiomyopathy (CMH13; <a href="/entry/613243">613243</a>) after presenting with dyspnea, <a href="#8" class="mim-tip-reference" title="Landstrom, A. P., Parvatiyar, M. S., Pinto, J. R., Marquardt, M. L., Bos, J. M., Tester, D. J., Ommen, S. R., Potter, J. D., Ackerman, M. J. &lt;strong&gt;Molecular and functional characterization of novel hypertrophic cardiomyopathy susceptibility mutations in TNNC1-encoded troponin C.&lt;/strong&gt; J. Molec. Cell. Cardiol. 45: 281-288, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18572189/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18572189&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=18572189[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.yjmcc.2008.05.003&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="18572189">Landstrom et al. (2008)</a> identified heterozygosity for a c.23C-T transition in exon 1 of the TNNC1 gene, resulting in an ala8-to-val (A8V) substitution in the N-helix of the N-terminal domain. Functional studies using mutant porcine cardiac skinned fibers showed significantly increased force development and force recovery compared to wildtype. The mutation was not found in 400 Caucasian or 100 African American controls with normal screening ECGs and echocardiograms. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18572189" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0004&nbsp;CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 13</strong>
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TNNC1, CYS84TYR
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs267607126 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267607126;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=rs267607126" 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=rs267607126" 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=RCV000013257 OR RCV002513004" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013257, RCV002513004" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013257...</a>
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<p>In a 17-year-old Caucasian man who was diagnosed at 8 years of age with hypertrophic cardiomyopathy (CMH13; <a href="/entry/613243">613243</a>) after presenting with syncope on exertion, <a href="#8" class="mim-tip-reference" title="Landstrom, A. P., Parvatiyar, M. S., Pinto, J. R., Marquardt, M. L., Bos, J. M., Tester, D. J., Ommen, S. R., Potter, J. D., Ackerman, M. J. &lt;strong&gt;Molecular and functional characterization of novel hypertrophic cardiomyopathy susceptibility mutations in TNNC1-encoded troponin C.&lt;/strong&gt; J. Molec. Cell. Cardiol. 45: 281-288, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18572189/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18572189&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=18572189[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.yjmcc.2008.05.003&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="18572189">Landstrom et al. (2008)</a> identified heterozygosity for a c.251G-A transition in exon 4 of the TNNC1 gene, resulting in a cys84-to-tyr (C84Y) substitution at the beginning of the central helix. Functional studies using mutant porcine cardiac skinned fibers showed significantly increased force development compared to wildtype. The mutation was not found in 400 Caucasian or 100 African American controls with normal screening ECGs and echocardiograms. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18572189" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0005&nbsp;CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 13</strong>
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TNNC1, ASP145GLU
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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">&#x25cf;</span> rs267607124 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267607124;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/rs267607124?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">&#x25cf;</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs267607124" 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=rs267607124" 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=RCV000013258 OR RCV000222787 OR RCV000227883 OR RCV000491539 OR RCV000622135 OR RCV000766925 OR RCV003149570" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013258, RCV000222787, RCV000227883, RCV000491539, RCV000622135, RCV000766925, RCV003149570" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013258...</a>
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<p>In a 58-year-old Caucasian man who presented with chest pain at age 57 years and was diagnosed with hypertrophic cardiomyopathy (CMH13; <a href="/entry/613243">613243</a>), <a href="#8" class="mim-tip-reference" title="Landstrom, A. P., Parvatiyar, M. S., Pinto, J. R., Marquardt, M. L., Bos, J. M., Tester, D. J., Ommen, S. R., Potter, J. D., Ackerman, M. J. &lt;strong&gt;Molecular and functional characterization of novel hypertrophic cardiomyopathy susceptibility mutations in TNNC1-encoded troponin C.&lt;/strong&gt; J. Molec. Cell. Cardiol. 45: 281-288, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18572189/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18572189&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=18572189[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.yjmcc.2008.05.003&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="18572189">Landstrom et al. (2008)</a> identified heterozygosity for a c.435C-A transversion in exon 5 of the TNNC1 gene, resulting in an asp145-to-glu (D145E) substitution. Functional studies using mutant porcine cardiac skinned fibers showed significantly increased force development and force recovery compared to wildtype. The mutation was not found in 400 Caucasian or 100 African American controls with normal screening ECGs and echocardiograms. The patient had a family history consistent with autosomal dominant CMH, with affected individuals including his maternal grandmother, 3 maternal uncles, and 2 daughters of those maternal uncles, all of whom declined to participate in the study. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18572189" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0006&nbsp;CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 13</strong>
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TNNC1, ALA31SER
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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">&#x25cf;</span> rs397514616 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397514616;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/rs397514616?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">&#x25cf;</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs397514616" 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=rs397514616" 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=RCV000033053 OR RCV003764652" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000033053, RCV003764652" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000033053...</a>
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<p>In a 5-year-old boy with hypertrophic cardiomyopathy and a history of ventricular fibrillation (CMH13; <a href="/entry/613243">613243</a>), <a href="#11" class="mim-tip-reference" title="Parvatiyar, M. S., Landstrom, A. P., Figueiredo-Freitas, C., Potter, J. D., Ackerman, M. J., Pinto, J. R. &lt;strong&gt;A mutation in TNNC1-encoded cardiac troponin C, TNNC1-A31S, predisposes to hypertrophic cardiomyopathy and ventricular fibrillation.&lt;/strong&gt; J. Biol. Chem. 287: 31845-31855, 2012.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/22815480/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;22815480&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=22815480[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1074/jbc.M112.377713&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="22815480">Parvatiyar et al. (2012)</a> identified heterozygosity for a c.91G-T transversion in the TNNC1 gene, resulting in an ala31-to-ser (A31S) substitution. The mutation was not found in more than 26,600 reference alleles from apparently healthy controls from a variety of racial and ethnic backgrounds, and the family history was negative for CMH or sudden death, suggesting a de novo mutation. Cardiac troponin-C (cTnC)-depleted porcine cardiac fibers showed increased Ca(2+) sensitivity with the mutant compared to wildtype, with no effect on maximal contractile force generation. In reconstituted thin filaments, the mutant increased the activation of actomyosin ATPase compared to wildtype; however, under relaxing conditions, mutant and wildtype cTnC inhibited the ATPase to the same degree. Fluorescence studies demonstrated increased Ca(2+) affinity in isolated cTnC, the troponin complex, thin filament, and to a lesser degree, thin filament with myosin subfragment 1. <a href="#11" class="mim-tip-reference" title="Parvatiyar, M. S., Landstrom, A. P., Figueiredo-Freitas, C., Potter, J. D., Ackerman, M. J., Pinto, J. R. &lt;strong&gt;A mutation in TNNC1-encoded cardiac troponin C, TNNC1-A31S, predisposes to hypertrophic cardiomyopathy and ventricular fibrillation.&lt;/strong&gt; J. Biol. Chem. 287: 31845-31855, 2012.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/22815480/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;22815480&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=22815480[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1074/jbc.M112.377713&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="22815480">Parvatiyar et al. (2012)</a> suggested that the A31S mutation has a direct effect on the Ca(2+) sensitivity of the myofilament, which may alter Ca(2+) handling and contribute to the arrhythmogenesis observed in the proband. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22815480" 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=RCV003315276" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV003315276" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV003315276</a>
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<p>In 3 sibs with severe dilated pediatric cardiomyopathy (CMD1Z; <a href="/entry/611879">611879</a>), <a href="#22" class="mim-tip-reference" title="Udani, R., Schilter, K. F., Tyler, R. C., Smith, B. A., Wendtandrae, J. L., Kappes, U. P., Scharer, G., Lehman, A., Steinraths, M., Reddi, H. V. &lt;strong&gt;A novel variant of TNNC1 associated with severe dilated cardiomyopathy causing infant mortality and stillbirth: a case of germline mosaicism.&lt;/strong&gt; J. Genet. 102: 14, 2023.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/36814108/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;36814108&lt;/a&gt;]" pmid="36814108">Udani et al. (2023)</a> identified a c.110G-C transversion (c.110G-C, NM_003280) in the TNNC1 gene, resulting in a gly34-to-arg (G34R) substitution. The mutation was found by duo whole-exome sequencing in the proband and first stillborn sib and by Sanger sequencing in the second stillborn sib. Both parents and 2 unaffected sibs were negative for the mutation. The presence of the same de novo mutation in all 3 affected children suggested germline mosaicism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=36814108" 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&nbsp;CARDIOMYOPATHY, DILATED, 1Z</strong>
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TNNC1, MET103ILE
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs2153229926 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2153229926;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=rs2153229926" 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=rs2153229926" 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=RCV002025566 OR RCV003316860" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV002025566, RCV003316860" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV002025566...</a>
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<p>In a proband (D.2) with dilated cardiomyopathy (CMD1Z; <a href="/entry/611879">611879</a>), <a href="#3" class="mim-tip-reference" title="Hershberger, R. E., Norton, N., Morales, A., Li, D., Siegfried, J. D., Gonzalez-Quintana, J. &lt;strong&gt;Coding sequence rare variants identified in MYBPC3, MYH6, TNNC1, and TNNI3 from 312 patients with familial or idiopathic dilated cardiomyopathy.&lt;/strong&gt; Circ. Cardiovasc. Genet. 3: 155-161, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20215591/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;20215591&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1161/CIRCGENETICS.109.912345&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="20215591">Hershberger et al. (2010)</a> identified heterozygosity for a c.4291G-A transition (c.4291G-A, NM_003280.1) in exon 4 of the TNNC1 gene, resulting in a met103-to-ile (M103I) substitution at a conserved residue. The mutation was also present in an affected family member, and was not found in 246 control individuals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20215591" 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="#13" class="mim-tip-reference" title="Pinto, J. R., Siegfried, J. D., Parvatiyar, M. S., Li, D., Norton, N., Jones, M. A., Liang, J., Potter, J. D., Hershberger, R. E. &lt;strong&gt;Functional characterization of TNNC1 rare variants identified in dilated cardiomyopathy.&lt;/strong&gt; J. Biol. Chem. 286: 34404-34412, 2011.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/21832052/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;21832052&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=21832052[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1074/jbc.M111.267211&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="21832052">Pinto et al. (2011)</a> studied the M103I mutation that was identified in 2 sisters with CMD by <a href="#3" class="mim-tip-reference" title="Hershberger, R. E., Norton, N., Morales, A., Li, D., Siegfried, J. D., Gonzalez-Quintana, J. &lt;strong&gt;Coding sequence rare variants identified in MYBPC3, MYH6, TNNC1, and TNNI3 from 312 patients with familial or idiopathic dilated cardiomyopathy.&lt;/strong&gt; Circ. Cardiovasc. Genet. 3: 155-161, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20215591/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;20215591&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1161/CIRCGENETICS.109.912345&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="20215591">Hershberger et al. (2010)</a>. Functional studies in porcine papillary skinned fibers showed decreased Ca(2+) sensitivity of force development with the M103I mutant compared to wildtype TNNC1. In addition, the M103I mutant abolished the effect of PKA (see <a href="/entry/188830">188830</a>) phosphorylation on Ca(2+) sensitivity, and also decreased the troponin activation properties of the actomyosin ATPase in the presence of Ca(2+). Circular dichroism spectroscopic studies revealed that the M103I mutant decreases the alpha-helical content of cTnC. The authors suggested that the mutation alters the function and/or ability of the myofilament to bind Ca(2+) due to modifications in the cTnC structure. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=20215591+21832052" 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&nbsp;CARDIOMYOPATHY, DILATED, 1Z</strong>
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TNNC1, ILE4MET
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV003315472" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV003315472" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV003315472</a>
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<p>In an infant girl with dilated cardiomyopathy (CMD1Z; <a href="/entry/611879">611879</a>), <a href="#5" class="mim-tip-reference" title="Johnston, J. R., Landim-Vieira, M., Marques, M. A., de Oliveira, G. A. P., Gonzalez-Martinez, D., Moraes, A. H., He, H., Iqbal, A., Wilnai, Y., Birk, E., Zucker, N., Silva, J. L., Chase, P. B., Pinto, J. R. &lt;strong&gt;The intrinsically disordered C terminus of troponin T binds to troponin C to modulate myocardial force generation.&lt;/strong&gt; J. Biol. Chem. 294: 20054-20069, 2019.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/31748410/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;31748410&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=31748410[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1074/jbc.RA119.011177&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="31748410">Johnston et al. (2019)</a> identified heterozygosity for a de novo c.12C-G transversion in exon 1 of the TNNC1 gene, resulting in an ile4-to-met (I4M) substitution at a highly conserved residue within the N-helix. The mutation was not found in her unaffected parents or in the gnomAD database. Reconstitution of the I4M variant in permeabilized porcine cardiac muscle preparations revealed a significant decrease in the magnitude and rate of isometric force generation at physiologic Ca(2+) activation levels with the mutant compared to wildtype cTnC. The authors demonstrated that cardiac troponin T (TNNT2; <a href="/entry/191045">191045</a>), in part due through its intrinsically disordered C terminus, directly binds to cTnC, and observed that the mutant displayed tighter binding than wildtype cTnC. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31748410" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>REFERENCES</strong>
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<a id="Bermingham1995" class="mim-anchor"></a>
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Bermingham, N., Hernandez, D., Balfour, A., Gilmour, F., Martin, J. E., Fisher, E. M. C.
<strong>Mapping TNNC1, the gene that encodes cardiac troponin I in the human and mouse.</strong>
Genomics 30: 620-622, 1995.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8825654/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8825654</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8825654" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1006/geno.1995.1288" target="_blank">Full Text</a>]
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<a id="Dyer2009" class="mim-anchor"></a>
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Dyer, E. C., Jacques, A. M., Hoskins, A. C., Ward, D. G., Gallon, C. E., Messer, A. E., Kaski, J. P., Burch, M., Kentish, J. C., Marston, S. B.
<strong>Functional analysis of a unique troponin c mutation, GLY159ASP, that causes familial dilated cardiomyopathy, studied in explanted heart muscle.</strong>
Circ. Heart Fail. 2: 456-464, 2009.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19808376/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19808376</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19808376" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1161/CIRCHEARTFAILURE.108.818237" target="_blank">Full Text</a>]
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<a id="Hershberger2010" class="mim-anchor"></a>
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Hershberger, R. E., Norton, N., Morales, A., Li, D., Siegfried, J. D., Gonzalez-Quintana, J.
<strong>Coding sequence rare variants identified in MYBPC3, MYH6, TNNC1, and TNNI3 from 312 patients with familial or idiopathic dilated cardiomyopathy.</strong>
Circ. Cardiovasc. Genet. 3: 155-161, 2010.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20215591/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20215591</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20215591" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1161/CIRCGENETICS.109.912345" target="_blank">Full Text</a>]
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<a id="Hoffmann2001" class="mim-anchor"></a>
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Hoffmann, B., Schmidt-Traub, H., Perrot, A., Osterziel, K. J., Gessner, R.
<strong>First mutation in cardiac troponin C, L29Q, in a patient with hypertrophic cardiomyopathy.</strong>
Hum. Mutat. 17: 524 only, 2001.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11385718/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11385718</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11385718" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1002/humu.1143" target="_blank">Full Text</a>]
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<a id="Johnston2019" class="mim-anchor"></a>
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Johnston, J. R., Landim-Vieira, M., Marques, M. A., de Oliveira, G. A. P., Gonzalez-Martinez, D., Moraes, A. H., He, H., Iqbal, A., Wilnai, Y., Birk, E., Zucker, N., Silva, J. L., Chase, P. B., Pinto, J. R.
<strong>The intrinsically disordered C terminus of troponin T binds to troponin C to modulate myocardial force generation.</strong>
J. Biol. Chem. 294: 20054-20069, 2019.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31748410/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31748410</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31748410[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=31748410" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1074/jbc.RA119.011177" target="_blank">Full Text</a>]
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<div class="">
<p class="mim-text-font">
Kaski, J. P., Burch, M., Elliott, P. M.
<strong>Mutations in the cardiac Troponin C gene are a cause of idiopathic dilated cardiomyopathy in childhood.</strong>
Cardiol. Young 17: 675-677, 2007.
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[<a href="https://doi.org/10.1017/S1047951107001291" target="_blank">Full Text</a>]
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<a id="Landim-Vieira2020" class="mim-anchor"></a>
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Landim-Vieira, M., Johnston, J. R., Ji, W., Mis, E. K., Tijerino, J., Spencer-Manzon, M., Jeffries, L., Hall, E. K., Panisello-Manterola, D., Khokha, M. K., Deniz, E., Chase, P. B., Lakhani, S. A., Pinto, J. R.
<strong>Familial dilated cardiomyopathy associated with a novel combination of compound heterozygous TNNC1 variants.</strong>
Front. Physiol. 10: 1612, 2020.
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[<a href="https://doi.org/10.3389/fphys.2019.01612" target="_blank">Full Text</a>]
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<a id="Landstrom2008" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Landstrom, A. P., Parvatiyar, M. S., Pinto, J. R., Marquardt, M. L., Bos, J. M., Tester, D. J., Ommen, S. R., Potter, J. D., Ackerman, M. J.
<strong>Molecular and functional characterization of novel hypertrophic cardiomyopathy susceptibility mutations in TNNC1-encoded troponin C.</strong>
J. Molec. Cell. Cardiol. 45: 281-288, 2008.
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[<a href="https://doi.org/10.1016/j.yjmcc.2008.05.003" target="_blank">Full Text</a>]
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<a id="9" class="mim-anchor"></a>
<a id="Mirza2005" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Mirza, M., Marston, S., Willott, R., Ashley, C., Mogensen, J., McKenna, W., Robinson, P., Redwood, C., Watkins, H.
<strong>Dilated cardiomyopathy mutations in three thin filament regulatory proteins result in a common functional phenotype.</strong>
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[<a href="https://doi.org/10.1074/jbc.M412281200" target="_blank">Full Text</a>]
</p>
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<a id="10" class="mim-anchor"></a>
<a id="Mogensen2004" class="mim-anchor"></a>
<div class="">
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Mogensen, J., Murphy, R. T., Shaw, T., Bahl, A., Redwood, C., Watkins, H., Burke, M., Elliott, P. M., McKenna, W. J.
<strong>Severe disease expression of cardiac troponin C and T mutations in patients with idiopathic dilated cardiomyopathy.</strong>
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[<a href="https://doi.org/10.1016/j.jacc.2004.08.027" target="_blank">Full Text</a>]
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<a id="11" class="mim-anchor"></a>
<a id="Parvatiyar2012" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Parvatiyar, M. S., Landstrom, A. P., Figueiredo-Freitas, C., Potter, J. D., Ackerman, M. J., Pinto, J. R.
<strong>A mutation in TNNC1-encoded cardiac troponin C, TNNC1-A31S, predisposes to hypertrophic cardiomyopathy and ventricular fibrillation.</strong>
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[<a href="https://doi.org/10.1074/jbc.M112.377713" target="_blank">Full Text</a>]
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<a id="Pinto2009" class="mim-anchor"></a>
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Pinto, J. R., Parvatiyar, M. S., Jones, M. A., Liang, J., Ackerman, M. J., Potter, J. D.
<strong>A functional and structural study of troponin C mutations related to hypertrophic cardiomyopathy.</strong>
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[<a href="https://doi.org/10.1074/jbc.M109.007021" target="_blank">Full Text</a>]
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<a id="Pinto2011" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Pinto, J. R., Siegfried, J. D., Parvatiyar, M. S., Li, D., Norton, N., Jones, M. A., Liang, J., Potter, J. D., Hershberger, R. E.
<strong>Functional characterization of TNNC1 rare variants identified in dilated cardiomyopathy.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21832052/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21832052</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21832052[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=21832052" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1074/jbc.M111.267211" target="_blank">Full Text</a>]
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Roher, A., Lieska, N., Spitz, W.
<strong>The amino acid sequence of human cardiac troponin-C.</strong>
Muscle Nerve 9: 73-77, 1986.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3951483/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3951483</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3951483" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1002/mus.880090112" target="_blank">Full Text</a>]
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Romero-Herrera, A. E., Castillo, O., Lehmann, H.
<strong>Human skeletal muscle proteins: the primary structure of troponin C.</strong>
J. Molec. Evol. 8: 251-270, 1976.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/978749/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">978749</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=978749" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1007/BF01730999" target="_blank">Full Text</a>]
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<a id="Schmidtmann2005" class="mim-anchor"></a>
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Schmidtmann, A., Lindow, C., Villard, S., Heuser, A., Mugge, A., Gessner, R., Granier, C., Jaquet, K.
<strong>Cardiac troponin C-L29Q, related to hypertrophic cardiomyopathy, hinders the transduction of the protein kinase A dependent phosphorylation signal from cardiac troponin I to C.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16302972/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16302972</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16302972" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1111/j.1742-4658.2005.05001.x" target="_blank">Full Text</a>]
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<a id="Schreier1990" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Schreier, T., Kedes, L., Gahlmann, R.
<strong>Cloning, structural analysis, and expression of the human slow twitch skeletal muscle/cardiac troponin C gene.</strong>
J. Biol. Chem. 265: 21247-21253, 1990.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2250022/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2250022</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2250022" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
</p>
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<div class="">
<p class="mim-text-font">
Song, W. J.
<strong>Personal Communication.</strong>
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<div class="">
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Song, W.-J., Van Keuren, M. L., Drabkin, H. A., Cypser, J. R., Gemmill, R. M., Kurnit, D. M.
<strong>Assignment of the human slow twitch skeletal muscle/cardiac troponin C gene (TNNC1) to human chromosome 3p21.3-3p14.3 using somatic cell hybrids.</strong>
Cytogenet. Cell Genet. 75: 36-37, 1996.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8995486/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8995486</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8995486" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1159/000134453" target="_blank">Full Text</a>]
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Takeda, S., Yamashita, A., Maeda, K., Maeda, Y.
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Nature 424: 35-41, 2003.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12840750/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12840750</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12840750" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1038/nature01780" target="_blank">Full Text</a>]
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<a id="Townsend1997" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Townsend, P. J., Yacoub, M. H., Barton, P. J. R.
<strong>Assignment of the human cardiac/slow skeletal muscle troponin C gene (TNNC1) between D3S3118 and GCT4B10 on the short arm of chromosome 3 by somatic cell hybrid analysis.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9365790/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9365790</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9365790" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1046/j.1469-1809.1997.6140375.x" target="_blank">Full Text</a>]
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<a id="Udani2023" class="mim-anchor"></a>
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Udani, R., Schilter, K. F., Tyler, R. C., Smith, B. A., Wendtandrae, J. L., Kappes, U. P., Scharer, G., Lehman, A., Steinraths, M., Reddi, H. V.
<strong>A novel variant of TNNC1 associated with severe dilated cardiomyopathy causing infant mortality and stillbirth: a case of germline mosaicism.</strong>
J. Genet. 102: 14, 2023.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36814108/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36814108</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=36814108" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<a id="23" class="mim-anchor"></a>
<a id="Vikhorev2017" class="mim-anchor"></a>
<div class="">
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Vikhorev, P. G., Smoktunowicz, N., Munster, A. B., Copeland, O., Kostin, S., Montgiraud, C., Messer, A. E., Toliat, M. R., Li, A., Dos Remedios, C. G., Lal, S., Blair, C. A., Campbell, K. S., Guglin, M., Richter, M., Knoll, R., Marston, S. B.
<strong>Abnormal contractility in human heart myofibrils from patients with dilated cardiomyopathy due to mutations in TTN and contractile protein genes.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29093449/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29093449</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29093449[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=29093449" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1038/s41598-017-13675-8" target="_blank">Full Text</a>]
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Bao Lige - updated : 03/21/2024
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Marla J. F. O'Neill - updated : 07/21/2023<br>Kelly A. Przylepa - updated : 07/18/2023<br>Marla J. F. O'Neill - updated : 11/30/2012<br>Marla J. F. O'Neill - updated : 2/2/2010<br>Marla J. F. O'Neill - updated : 12/2/2008<br>Marla J. F. O'Neill - updated : 3/6/2008<br>Victor A. McKusick - updated : 11/24/2003<br>Ada Hamosh - updated : 7/7/2003<br>Victor A. McKusick - updated : 12/3/1997<br>Victor A. McKusick - updated : 2/11/1997<br>Mark H. Paalman - edited : 1/23/1997<br>Alan F. Scott - updated : 2/29/1996
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Victor A. McKusick : 2/9/1987
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mgross : 03/21/2024<br>alopez : 01/26/2024<br>alopez : 07/21/2023<br>carol : 07/18/2023<br>carol : 12/04/2012<br>terry : 11/30/2012<br>wwang : 4/7/2011<br>carol : 2/16/2010<br>wwang : 2/3/2010<br>terry : 2/2/2010<br>wwang : 12/4/2008<br>wwang : 12/4/2008<br>terry : 12/2/2008<br>carol : 3/6/2008<br>wwang : 6/9/2005<br>carol : 1/29/2004<br>cwells : 11/25/2003<br>terry : 11/24/2003<br>joanna : 9/30/2003<br>alopez : 7/9/2003<br>terry : 7/7/2003<br>dkim : 12/8/1998<br>terry : 6/1/1998<br>terry : 12/3/1997<br>alopez : 7/31/1997<br>terry : 2/11/1997<br>terry : 2/4/1997<br>mark : 1/23/1997<br>mark : 1/23/1997<br>terry : 1/15/1997<br>terry : 4/17/1996<br>mark : 2/29/1996<br>mark : 6/15/1995<br>supermim : 3/16/1992<br>carol : 3/2/1992<br>carol : 7/22/1991<br>carol : 2/14/1991<br>carol : 7/5/1990
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<h3>
<span class="mim-font">
<strong>*</strong> 191040
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<h3>
<span class="mim-font">
TROPONIN C, SLOW; TNNC1
</span>
</h3>
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<div>
<br />
</div>
<div>
<div >
<p>
<span class="mim-font">
<em>Alternative titles; symbols</em>
</span>
</p>
</div>
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<h4>
<span class="mim-font">
TROPONIN C, SLOW-TWITCH SKELETAL MUSCLE<br />
TROPONIN C, CARDIAC; TNC
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</h4>
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<p>
<span class="mim-text-font">
<strong><em>HGNC Approved Gene Symbol: TNNC1</em></strong>
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</p>
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<div>
<p>
<span class="mim-text-font">
<strong>
<em>
Cytogenetic location: 3p21.1
&nbsp;
Genomic coordinates <span class="small">(GRCh38)</span> : 3:52,451,100-52,454,041 </span>
</em>
</strong>
<span class="small">(from NCBI)</span>
</span>
</p>
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<h4>
<span class="mim-font">
<strong>Gene-Phenotype Relationships</strong>
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</h4>
<div>
<table class="table table-bordered table-condensed small mim-table-padding">
<thead>
<tr class="active">
<th>
Location
</th>
<th>
Phenotype
</th>
<th>
Phenotype <br /> MIM number
</th>
<th>
Inheritance
</th>
<th>
Phenotype <br /> mapping key
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<td rowspan="2">
<span class="mim-font">
3p21.1
</span>
</td>
<td>
<span class="mim-font">
Cardiomyopathy, dilated, 1Z
</span>
</td>
<td>
<span class="mim-font">
611879
</span>
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<td>
<span class="mim-font">
Autosomal dominant
</span>
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<td>
<span class="mim-font">
3
</span>
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<td>
<span class="mim-font">
Cardiomyopathy, hypertrophic, 13
</span>
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<td>
<span class="mim-font">
613243
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<span class="mim-font">
Autosomal dominant
</span>
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<td>
<span class="mim-font">
3
</span>
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<h4>
<span class="mim-font">
<strong>TEXT</strong>
</span>
</h4>
<div>
<h4>
<span class="mim-font">
<strong>Cloning and Expression</strong>
</span>
</h4>
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<span class="mim-text-font">
<p>Contraction in striated muscle is regulated by the calcium-ion-sensitive, multiprotein complex troponin and the fibrous protein tropomyosin (see 191010). As a result of calcium-ion uptake by troponin C, the elements of the muscle thin filament undergo a series of allosteric changes which allow the interaction of actin with myosin, the hydrolysis of ATP, and the generation of tension. Roher et al. (1986) reported the primary structure (amino acid sequence) of troponin C from human cardiac muscle; it consists of 161 amino acid residues. Comparison with the sequences in the rabbit and the ox shows that troponin C is one of the most highly conserved proteins known. Romero-Herrera et al. (1976) established the primary structure of human skeletal muscle troponin C. They found only a single amino acid difference between rabbit and human skeletal muscle troponin C and possibly only a single amino acid change between human skeletal troponin C and bovine cardiac muscle troponin C. Thus, they concluded that cardiac and slow-twitch skeletal troponin C are presumably identical. </p>
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<h4>
<span class="mim-font">
<strong>Gene Structure</strong>
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</h4>
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<span class="mim-text-font">
<p>Schreier et al. (1990) described the structure of the TNNC gene. It is 3 kb long, with 6 exons. </p>
</span>
<div>
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<h4>
<span class="mim-font">
<strong>Mapping</strong>
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</h4>
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<span class="mim-text-font">
<p>Using a human/rodent monochromosomal mapping panel, Song et al. (1996) mapped a human slow-twitch skeletal muscle/cardiac troponin C gene (symbolized TNNC1) to chromosome 3 by PCR. Chromosome 3 somatic cell hybrids with various rearrangements were used for finer mapping to 3p21.3-p14.3. </p><p>Bermingham et al. (1995) mapped a gene they symbolized TNNC1 to 19q13.3-q13.4 using a series of somatic cell hybrid DNAs. By interspecific backcross analysis, they mapped the mouse homolog to a site close to the centromere of chromosome 7. Song (1997) indicated that the gene mapped by Bermingham et al. (1995) should not be symbolized TNNC1 since it represented cardiac troponin I (TNNI3; 191044) which had been mapped by others to chromosome 19. Song et al. (1996) mapped the authentic TNNC1 gene to chromosome 3. Using a 'monochromosomal' hybrid panel, Townsend et al. (1997) mapped the TNNC1 gene to chromosome 3; subsequent analysis of the Genebridge 4 radiation hybrid panel localized the gene to 3p in a region consistent with the earlier assignment. </p>
</span>
<div>
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</div>
<div>
<h4>
<span class="mim-font">
<strong>Biochemical Features</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p><strong><em>Crystal Structure</em></strong></p><p>
Troponin consists of 3 subunits, TnC, TnI (see 191044), and TnT (see 191045), and, together with tropomyosin, is located on the actin filament. Takeda et al. (2003) presented the crystal structure of the core domains (relative molecular mass of 46,000 and 52,000) of human cardiac troponin in the calcium-saturated form. Analysis of the 4-molecule structures revealed that the core domain is further divided into structurally distinct subdomains that are connected by flexible linkers, making the entire molecule highly flexible. The alpha-helical coiled-coil formed between TnT and TnI is integrated in a rigid and asymmetric structure about 80 angstroms long, the IT arm, which bridges putative tropomyosin-anchoring regions. The structures of the troponin ternary complex imply that calcium binding to the regulatory site of TnC removes the carboxy-terminal portion of TnI from actin, thereby altering the mobility and/or flexibility of troponin and tropomyosin on the actin filament. </p>
</span>
<div>
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</div>
<div>
<h4>
<span class="mim-font">
<strong>Molecular Genetics</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p><strong><em>Hypertrophic Cardiomyopathy 13</em></strong></p><p>
In a German patient with hypertrophic cardiomyopathy (CMH13; 613243), Hoffmann et al. (2001) identified a heterozygous mutation in the TNNC1 gene (L29Q; 191040.0002). The authors stated that they could not determine whether this was a disease-causing variant. Schmidtmann et al. (2005) studied the structural and functional consequences of the L29Q substitution and demonstrated alteration of the dynamics of the actin-myosin interaction as well as impairment of PKA (see 601639)-dependent signaling from cardiac TnI (191044) to cardiac TnC, resulting in an increased sensitivity to Ca(2+) when cardiac TnI is phosphorylated. </p><p>Landstrom et al. (2008) analyzed the TNNC1 gene in 1,025 unrelated patients with CMH and identified 4 heterozygous mutations in 4 Caucasian patients (see, e.g., A8V, 191040.0003; C84Y, 191040.0004; D145E, 191040.0005) who were negative for mutation in 15 known CMH-susceptibility genes. Functional studies showed increased Ca(2+) sensitivity of force development and force recovery with 3 of the mutations; the fourth, an E134D substitution, had no effect on the parameters studied. </p><p>Pinto et al. (2009) performed a functional and structural analysis of the 4 TNNC1 mutations identified by Landstrom et al. (2008) in CMH patients and found that 3 of them (A8V, C84Y, and D145E) increased the Ca(2+) sensitivity of the filament, but they noted that the effects of the mutations on the Ca(2+) affinity of isolated cardiac TnC, cardiac troponin, and thin filaments were not sufficient to explain the large Ca(2+) sensitivity changes seen in reconstituted and fiber assays. Circular dichroism measurements revealed changes in the secondary structures of the TNNC1 mutants A8V, C84Y, and D145E; Pinto et al. (2009) suggested that these changes in secondary structure might contribute to modified protein-protein interactions along the sarcomere lattice disrupting the coupling between the cross-bridge and Ca(2+) binding to cardiac TnC. </p><p>In a 5-year-old boy with CMH and a history of ventricular fibrillation, Parvatiyar et al. (2012) analyzed 12 CMH-associated genes and identified heterozygosity for a missense mutation in the TNNC1 gene (A31S; 191040.0006). Functional analysis suggested that the A31S mutation has a direct effect on the Ca(2+) sensitivity of the myofilament, which may alter Ca(2+) handling and contribute to the arrhythmogenesis observed in the proband. </p><p><strong><em>Dilated Cardiomyopathy 1Z</em></strong></p><p>
Mogensen et al. (2004) analyzed the TNNC1 gene in 235 consecutive unrelated probands with dilated cardiomyopathy (see CMD1Z, 611879) and identified heterozygosity for a mutation in the TNNC1 gene (G159D; 191040.0001) in 5 affected members of a 3-generation family with a severe phenotype. Functional studies showed significant alterations in the interaction of the mutated troponin C with wildtype troponins T and I. </p><p>Mirza et al. (2005) studied all 8 published mutations causing dilated cardiomyopathy (CMD), including 5 in the TNNT2 gene (lys210del, R141W, R131W, R205L, and D270N; 191045.0006-191045.0010, respectively), 2 in the TPM1 gene (E54K, 191010.0004; E40K, 191010.0005), and 1 in the TNNC1 gene (G159D). Thin filaments, reconstituted with a 1:1 ratio of mutant:wildtype proteins, all showed reduced Ca(2+) sensitivity of activation in ATPase and motility assays, and, except for the E54K alpha-tropomyosin mutant which showed no effect, all showed lower maximum Ca(2+) activation. Incorporation of the TNNT2 mutations R141W and R205L into skinned guinea pig cardiac trabeculae also decreased Ca(2+) sensitivity of force generation. Thus, diverse thin filament CMD mutations appeared to affect different aspects of regulatory function yet change contractility in a consistent manner. Mirza et al. (2005) stated that the CMD mutations depressed myofibrillar function, an effect opposite to that of CMH-causing thin filament mutations, and suggested that decreased contractility might trigger pathways that ultimately lead to the clinical phenotype. </p><p>Dyer et al. (2009) performed functional studies of mutant myocytes from an explanted heart with the G159D mutation (191040.0001). The G159D myocytes showed an increased sensitivity to Ca(2+) compared to wildtype TNNC1; however, dephosphorylation of troponin did not produce the expected increase in Ca(2+) sensitivity with the mutant cTnC. Dyer et al. (2009) suggested that uncoupling of the relationship between phosphorylation and Ca(2+) sensitivity might be the cause of the dilated cardiomyopathy phenotype in patients with G159D mutation. </p><p>In a cohort of 312 probands with dilated cardiomyopathy, Hershberger et al. (2010) analyzed 5 CMD-associated genes and identified a missense mutation in the TNNC1 gene (M103I; 191040.0008) in 1 proband (D.2) and an affected relative that was not found in 246 control individuals. Another 3 heterozygous TNNC1 missense variants were identified in 3 CMD probands, but segregation data was lacking for those variants. </p><p>Vikhorev et al. (2017) compared contractility and passive stiffness of cardiac myofibril samples from 3 unrelated patients with dilated cardiomyopathy (DCM) and 2 different truncation mutations in titin (TTN; 188840), 3 unrelated DCM patients with mutations in different contractile proteins (lys36 to gln in TNNI3 (191044.0012), G159D in TNNC1, and glu1426 to lys in MYH7 (160760)), and controls. All 3 contractile protein mutations, but not the titin mutations, had faster relaxation kinetics than controls. Myofibril passive stiffness was reduced by about 38% in all DCM samples compared with controls, but there was no change in maximum force or titin N2BA/N2B isoform ratio, and there was no titin haploinsufficiency. The authors concluded that decreased myofibril passive stiffness, a common feature in all DCM samples, may be a causative of DCM. </p><p>By trio whole-exome sequencing in an infant girl with CMD and her unaffected parents, Johnston et al. (2019) identified heterozygosity for a de novo missense mutation in the TNNIC1 gene (I4M; 191040.0009) that was not found in the gnomAD database. Functional analysis showed a reduction in the magnitude and rate of isometric force generation with the mutant, as well as tighter binding between cTnT (TNNT2; 191045) and cTnC. </p><p>Using duo whole-exome sequencing in a family in which 3 sibs had severe dilated pediatric cardiomyopathy, Udani et al. (2023) identified a de novo heterozygous missense mutation in the TNNC1 gene (G34R; 191040.0007) in the proband and first stillborn sib. Sanger sequencing identified the mutation in the second stillborn sib. Both parents and 2 unaffected sibs were negative for the mutation. The presence of the same de novo variant in all 3 affected sibs suggested germline mosaicism. </p><p>In a sister and brother with severe early-onset CMD, Landim-Vieira et al. (2020) identified compound heterozygosity for missense mutations in the TNNC1 gene: the previously reported CMH-associated D145E substitution (191040.0005), and a c.394G-A transition resulting in an asp132-to-asn (D132N) substitution, both occurring at highly conserved residues within the C-domain. No other rare or pathogenic variants were found in other known cardiomyopathy genes in either of the sibs. Their unaffected parents, who were in their fifth decade and had normal echocardiograms, were each heterozygous for 1 of the mutations. Functional analysis using porcine cardiac muscle preparations (CMPs) showed that the D132N variant significantly reduced, whereas the D145E variant significantly increased, myofilament Ca(2+) sensitivity of force generation; and there was no significant difference in Ca(2+) sensitivity of tension when CMPs were reconstituted with a 50-50 mixture of D132N and D145E. Thus the incorporation of both mutants appeared to normalize the opposite effects of the 2 variants on Ca(2+) dependence of isometric force, which the authors noted was difficult to reconcile with the severe CMD pathology associated with the presence of the 2 mutations. The proband was a female infant who from birth had gradually increasing left ventricular enlargement and worsening LV function; she died following cardiac arrest at age 14 months while awaiting transplant. She had an 11-year-old brother who was diagnosed as a neonate with severe CMD and underwent transplantation at 13 months of age. He had good function of the transplanted heart, and no signs of skeletal muscle problems. Their mother had experienced 3 miscarriages with in vitro-fertilized pregnancies, and another sib died after premature live birth at 23 weeks' gestation. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Animal Model</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Landim-Vieira et al. (2020) used CRISPR/Cas9-mediated gene editing to knock out TNNC1 in Xenopus. Loss of the TNNC1 gene did not prevent the early stages of development, but resulted in a dramatic cardiac phenotype consistent with dilated cardiomyopathy in the mutant tadpoles, which demonstrated ventricular dilation, wall thinning, and almost imperceptible cardiac motion. </p>
</span>
<div>
<br />
</div>
</div>
<div>
<h4>
<span class="mim-font">
<strong>ALLELIC VARIANTS</strong>
</span>
<strong>9 Selected Examples):</strong>
</span>
</h4>
<div>
<p />
</div>
<div>
<div>
<h4>
<span class="mim-font">
<strong>.0001 &nbsp; CARDIOMYOPATHY, DILATED, 1Z</strong>
</span>
</h4>
</div>
<div>
<span class="mim-text-font">
TNNC1, GLY159ASP
<br />
SNP: rs104893823,
ClinVar: RCV000013254, RCV000523060
</span>
</div>
<div>
<span class="mim-text-font">
<p>In 5 affected members of a family (family A) with severe dilated cardiomyopathy (CMD1Z; 611879), Mogensen et al. (2004) identified heterozygosity for a missense mutation in the TNNC1 gene, predicted to result in a gly159-to-asp (G159D) substitution at a conserved residue in a domain of the protein constitutively occupied by Ca(2+). The mutation was not found in unaffected family members or in 200 ethnically matched control chromosomes. Functional studies showed significant impairment of the mutated troponin C interaction with wildtype troponin T, whereas the interaction with wildtype troponin I was significantly enhanced (p less than 0.0001 for both), indicating an altered regulation of myocardial contractility. </p><p>In a 3-year-old boy with severe CMD who underwent cardiac transplantation, who was the nephew of the proband from family A reported by Mogensen et al. (2004), Kaski et al. (2007) identified heterozygosity for the G159D mutation in the TNNC1 gene. Dyer et al. (2009) analyzed the patient's explanted heart tissue and found that mutant cardiac troponin C (cTnC) was expressed approximately equimolar with wildtype cTnC. Although the sarcomeric structure and maximal Ca(2+)-activated force was similar in both mutant and wildtype skinned ventricular myocytes, mutant myocytes exhibited significantly greater Ca(2+) sensitivity than wildtype myocytes. An in vitro motility assay using reconstituted thin filaments confirmed greater Ca(2+) sensitivity with mutant filaments, although maximally activated sliding speed was unchanged. In addition, dephosphorylation of troponin produced the expected increase in Ca(2+) sensitivity with wildtype heart troponin, but almost no change in Ca(2+) sensitivity with mutant heart troponin. Dyer et al. (2009) suggested that uncoupling of the relationship between phosphorylation and Ca(2+) sensitivity might be the cause of the dilated cardiomyopathy phenotype in patients with G159D mutation. </p><p>Vikhorev et al. (2017) compared contractility and passive stiffness of cardiac myofibril samples from 3 unrelated patients with dilated cardiomyopathy (DCM) and 2 different truncation mutations in titin (TTN; 188840), 3 unrelated DCM patients with mutations in different contractile proteins, including G159D in TNNC1, and controls. All 3 contractile protein mutations, but not the titin mutations, had faster relaxation kinetics than controls. Myofibril passive stiffness was reduced by about 38% in all DCM samples compared with controls, but there was no change in maximum force or titin N2BA/N2B isoform ratio, and there was no titin haploinsufficiency. The authors concluded that decreased myofibril passive stiffness, a common feature in all DCM samples, may be a causative of DCM. </p>
</span>
</div>
<div>
<br />
</div>
</div>
<div>
<div>
<h4>
<span class="mim-font">
<strong>.0002 &nbsp; CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 13</strong>
</span>
</h4>
</div>
<div>
<span class="mim-text-font">
TNNC1, LEU29GLN
<br />
SNP: rs267607123,
gnomAD: rs267607123,
ClinVar: RCV000013255, RCV000215162, RCV000702748, RCV000998084, RCV004678596
</span>
</div>
<div>
<span class="mim-text-font">
<p>In a 60-year-old German man with hypertrophic cardiomyopathy (CMH13; 613243), Hoffmann et al. (2001) identified an c.86T-A transversion in exon 3 of the TNNC1 gene, leading to a leu29-to-gln (L29Q) substitution at a conserved residue. No family members were available for study. The mutation was not detected in 96 controls, but the authors stated that they could not determine whether this was a disease-causing variant. </p><p>Schmidtmann et al. (2005) studied the structural and functional consequences of the L29Q substitution, located at the transition of helix A to the nonfunctional Ca(+2)-binding loop, and observed only minor effects on secondary structure by circular dichroism (CD) spectroscopy. Peptide array experiments demonstrated interaction of the nonphosphorylated cardiac TnI (TNNI3; 191044) arm with cardiac TnC around leu29; this interaction did not occur with the L29Q mutant, whether in the phosphorylated or nonphosphorylated state. In vitro assays revealed that with L29Q, the Ca(2+) sensitivity of the actomyosin subfragment 1-ATPase activity and the mean sliding velocity of thin filaments were no longer affected by protein kinase A (see 601639)-dependent phosphorylation of cTnI. Schmidtmann et al. (2005) concluded that L29Q hinders transduction of the phosphorylation signal from cardiac TnI to cardiac TnC. </p>
</span>
</div>
<div>
<br />
</div>
</div>
<div>
<div>
<h4>
<span class="mim-font">
<strong>.0003 &nbsp; CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 13</strong>
</span>
</h4>
</div>
<div>
<span class="mim-text-font">
TNNC1, ALA8VAL
<br />
SNP: rs267607125,
gnomAD: rs267607125,
ClinVar: RCV000013256, RCV000037762, RCV000159204, RCV000618084, RCV000824773, RCV001034686, RCV001582477, RCV003147283
</span>
</div>
<div>
<span class="mim-text-font">
<p>In a 37-year-old Caucasian man who was diagnosed at 33 years of age with hypertrophic cardiomyopathy (CMH13; 613243) after presenting with dyspnea, Landstrom et al. (2008) identified heterozygosity for a c.23C-T transition in exon 1 of the TNNC1 gene, resulting in an ala8-to-val (A8V) substitution in the N-helix of the N-terminal domain. Functional studies using mutant porcine cardiac skinned fibers showed significantly increased force development and force recovery compared to wildtype. The mutation was not found in 400 Caucasian or 100 African American controls with normal screening ECGs and echocardiograms. </p>
</span>
</div>
<div>
<br />
</div>
</div>
<div>
<div>
<h4>
<span class="mim-font">
<strong>.0004 &nbsp; CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 13</strong>
</span>
</h4>
</div>
<div>
<span class="mim-text-font">
TNNC1, CYS84TYR
<br />
SNP: rs267607126,
ClinVar: RCV000013257, RCV002513004
</span>
</div>
<div>
<span class="mim-text-font">
<p>In a 17-year-old Caucasian man who was diagnosed at 8 years of age with hypertrophic cardiomyopathy (CMH13; 613243) after presenting with syncope on exertion, Landstrom et al. (2008) identified heterozygosity for a c.251G-A transition in exon 4 of the TNNC1 gene, resulting in a cys84-to-tyr (C84Y) substitution at the beginning of the central helix. Functional studies using mutant porcine cardiac skinned fibers showed significantly increased force development compared to wildtype. The mutation was not found in 400 Caucasian or 100 African American controls with normal screening ECGs and echocardiograms. </p>
</span>
</div>
<div>
<br />
</div>
</div>
<div>
<div>
<h4>
<span class="mim-font">
<strong>.0005 &nbsp; CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 13</strong>
</span>
</h4>
</div>
<div>
<span class="mim-text-font">
TNNC1, ASP145GLU
<br />
SNP: rs267607124,
gnomAD: rs267607124,
ClinVar: RCV000013258, RCV000222787, RCV000227883, RCV000491539, RCV000622135, RCV000766925, RCV003149570
</span>
</div>
<div>
<span class="mim-text-font">
<p>In a 58-year-old Caucasian man who presented with chest pain at age 57 years and was diagnosed with hypertrophic cardiomyopathy (CMH13; 613243), Landstrom et al. (2008) identified heterozygosity for a c.435C-A transversion in exon 5 of the TNNC1 gene, resulting in an asp145-to-glu (D145E) substitution. Functional studies using mutant porcine cardiac skinned fibers showed significantly increased force development and force recovery compared to wildtype. The mutation was not found in 400 Caucasian or 100 African American controls with normal screening ECGs and echocardiograms. The patient had a family history consistent with autosomal dominant CMH, with affected individuals including his maternal grandmother, 3 maternal uncles, and 2 daughters of those maternal uncles, all of whom declined to participate in the study. </p>
</span>
</div>
<div>
<br />
</div>
</div>
<div>
<div>
<h4>
<span class="mim-font">
<strong>.0006 &nbsp; CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 13</strong>
</span>
</h4>
</div>
<div>
<span class="mim-text-font">
TNNC1, ALA31SER
<br />
SNP: rs397514616,
gnomAD: rs397514616,
ClinVar: RCV000033053, RCV003764652
</span>
</div>
<div>
<span class="mim-text-font">
<p>In a 5-year-old boy with hypertrophic cardiomyopathy and a history of ventricular fibrillation (CMH13; 613243), Parvatiyar et al. (2012) identified heterozygosity for a c.91G-T transversion in the TNNC1 gene, resulting in an ala31-to-ser (A31S) substitution. The mutation was not found in more than 26,600 reference alleles from apparently healthy controls from a variety of racial and ethnic backgrounds, and the family history was negative for CMH or sudden death, suggesting a de novo mutation. Cardiac troponin-C (cTnC)-depleted porcine cardiac fibers showed increased Ca(2+) sensitivity with the mutant compared to wildtype, with no effect on maximal contractile force generation. In reconstituted thin filaments, the mutant increased the activation of actomyosin ATPase compared to wildtype; however, under relaxing conditions, mutant and wildtype cTnC inhibited the ATPase to the same degree. Fluorescence studies demonstrated increased Ca(2+) affinity in isolated cTnC, the troponin complex, thin filament, and to a lesser degree, thin filament with myosin subfragment 1. Parvatiyar et al. (2012) suggested that the A31S mutation has a direct effect on the Ca(2+) sensitivity of the myofilament, which may alter Ca(2+) handling and contribute to the arrhythmogenesis observed in the proband. </p>
</span>
</div>
<div>
<br />
</div>
</div>
<div>
<div>
<h4>
<span class="mim-font">
<strong>.0007 &nbsp; CARDIOMYOPATHY, DILATED, 1Z</strong>
</span>
</h4>
</div>
<div>
<span class="mim-text-font">
TNNC1, GLY34ARG
<br />
ClinVar: RCV003315276
</span>
</div>
<div>
<span class="mim-text-font">
<p>In 3 sibs with severe dilated pediatric cardiomyopathy (CMD1Z; 611879), Udani et al. (2023) identified a c.110G-C transversion (c.110G-C, NM_003280) in the TNNC1 gene, resulting in a gly34-to-arg (G34R) substitution. The mutation was found by duo whole-exome sequencing in the proband and first stillborn sib and by Sanger sequencing in the second stillborn sib. Both parents and 2 unaffected sibs were negative for the mutation. The presence of the same de novo mutation in all 3 affected children suggested germline mosaicism. </p>
</span>
</div>
<div>
<br />
</div>
</div>
<div>
<div>
<h4>
<span class="mim-font">
<strong>.0008 &nbsp; CARDIOMYOPATHY, DILATED, 1Z</strong>
</span>
</h4>
</div>
<div>
<span class="mim-text-font">
TNNC1, MET103ILE
<br />
SNP: rs2153229926,
ClinVar: RCV002025566, RCV003316860
</span>
</div>
<div>
<span class="mim-text-font">
<p>In a proband (D.2) with dilated cardiomyopathy (CMD1Z; 611879), Hershberger et al. (2010) identified heterozygosity for a c.4291G-A transition (c.4291G-A, NM_003280.1) in exon 4 of the TNNC1 gene, resulting in a met103-to-ile (M103I) substitution at a conserved residue. The mutation was also present in an affected family member, and was not found in 246 control individuals. </p><p>Pinto et al. (2011) studied the M103I mutation that was identified in 2 sisters with CMD by Hershberger et al. (2010). Functional studies in porcine papillary skinned fibers showed decreased Ca(2+) sensitivity of force development with the M103I mutant compared to wildtype TNNC1. In addition, the M103I mutant abolished the effect of PKA (see 188830) phosphorylation on Ca(2+) sensitivity, and also decreased the troponin activation properties of the actomyosin ATPase in the presence of Ca(2+). Circular dichroism spectroscopic studies revealed that the M103I mutant decreases the alpha-helical content of cTnC. The authors suggested that the mutation alters the function and/or ability of the myofilament to bind Ca(2+) due to modifications in the cTnC structure. </p>
</span>
</div>
<div>
<br />
</div>
</div>
<div>
<div>
<h4>
<span class="mim-font">
<strong>.0009 &nbsp; CARDIOMYOPATHY, DILATED, 1Z</strong>
</span>
</h4>
</div>
<div>
<span class="mim-text-font">
TNNC1, ILE4MET
<br />
ClinVar: RCV003315472
</span>
</div>
<div>
<span class="mim-text-font">
<p>In an infant girl with dilated cardiomyopathy (CMD1Z; 611879), Johnston et al. (2019) identified heterozygosity for a de novo c.12C-G transversion in exon 1 of the TNNC1 gene, resulting in an ile4-to-met (I4M) substitution at a highly conserved residue within the N-helix. The mutation was not found in her unaffected parents or in the gnomAD database. Reconstitution of the I4M variant in permeabilized porcine cardiac muscle preparations revealed a significant decrease in the magnitude and rate of isometric force generation at physiologic Ca(2+) activation levels with the mutant compared to wildtype cTnC. The authors demonstrated that cardiac troponin T (TNNT2; 191045), in part due through its intrinsically disordered C terminus, directly binds to cTnC, and observed that the mutant displayed tighter binding than wildtype cTnC. </p>
</span>
</div>
<div>
<br />
</div>
</div>
</div>
<div>
<h4>
<span class="mim-font">
<strong>REFERENCES</strong>
</span>
</h4>
<div>
<p />
</div>
<div>
<ol>
<li>
<p class="mim-text-font">
Bermingham, N., Hernandez, D., Balfour, A., Gilmour, F., Martin, J. E., Fisher, E. M. C.
<strong>Mapping TNNC1, the gene that encodes cardiac troponin I in the human and mouse.</strong>
Genomics 30: 620-622, 1995.
[PubMed: 8825654]
[Full Text: https://doi.org/10.1006/geno.1995.1288]
</p>
</li>
<li>
<p class="mim-text-font">
Dyer, E. C., Jacques, A. M., Hoskins, A. C., Ward, D. G., Gallon, C. E., Messer, A. E., Kaski, J. P., Burch, M., Kentish, J. C., Marston, S. B.
<strong>Functional analysis of a unique troponin c mutation, GLY159ASP, that causes familial dilated cardiomyopathy, studied in explanted heart muscle.</strong>
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[Full Text: https://doi.org/10.1161/CIRCHEARTFAILURE.108.818237]
</p>
</li>
<li>
<p class="mim-text-font">
Hershberger, R. E., Norton, N., Morales, A., Li, D., Siegfried, J. D., Gonzalez-Quintana, J.
<strong>Coding sequence rare variants identified in MYBPC3, MYH6, TNNC1, and TNNI3 from 312 patients with familial or idiopathic dilated cardiomyopathy.</strong>
Circ. Cardiovasc. Genet. 3: 155-161, 2010.
[PubMed: 20215591]
[Full Text: https://doi.org/10.1161/CIRCGENETICS.109.912345]
</p>
</li>
<li>
<p class="mim-text-font">
Hoffmann, B., Schmidt-Traub, H., Perrot, A., Osterziel, K. J., Gessner, R.
<strong>First mutation in cardiac troponin C, L29Q, in a patient with hypertrophic cardiomyopathy.</strong>
Hum. Mutat. 17: 524 only, 2001.
[PubMed: 11385718]
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</p>
</li>
<li>
<p class="mim-text-font">
Johnston, J. R., Landim-Vieira, M., Marques, M. A., de Oliveira, G. A. P., Gonzalez-Martinez, D., Moraes, A. H., He, H., Iqbal, A., Wilnai, Y., Birk, E., Zucker, N., Silva, J. L., Chase, P. B., Pinto, J. R.
<strong>The intrinsically disordered C terminus of troponin T binds to troponin C to modulate myocardial force generation.</strong>
J. Biol. Chem. 294: 20054-20069, 2019.
[PubMed: 31748410]
[Full Text: https://doi.org/10.1074/jbc.RA119.011177]
</p>
</li>
<li>
<p class="mim-text-font">
Kaski, J. P., Burch, M., Elliott, P. M.
<strong>Mutations in the cardiac Troponin C gene are a cause of idiopathic dilated cardiomyopathy in childhood.</strong>
Cardiol. Young 17: 675-677, 2007.
[PubMed: 17977476]
[Full Text: https://doi.org/10.1017/S1047951107001291]
</p>
</li>
<li>
<p class="mim-text-font">
Landim-Vieira, M., Johnston, J. R., Ji, W., Mis, E. K., Tijerino, J., Spencer-Manzon, M., Jeffries, L., Hall, E. K., Panisello-Manterola, D., Khokha, M. K., Deniz, E., Chase, P. B., Lakhani, S. A., Pinto, J. R.
<strong>Familial dilated cardiomyopathy associated with a novel combination of compound heterozygous TNNC1 variants.</strong>
Front. Physiol. 10: 1612, 2020.
[PubMed: 32038292]
[Full Text: https://doi.org/10.3389/fphys.2019.01612]
</p>
</li>
<li>
<p class="mim-text-font">
Landstrom, A. P., Parvatiyar, M. S., Pinto, J. R., Marquardt, M. L., Bos, J. M., Tester, D. J., Ommen, S. R., Potter, J. D., Ackerman, M. J.
<strong>Molecular and functional characterization of novel hypertrophic cardiomyopathy susceptibility mutations in TNNC1-encoded troponin C.</strong>
J. Molec. Cell. Cardiol. 45: 281-288, 2008.
[PubMed: 18572189]
[Full Text: https://doi.org/10.1016/j.yjmcc.2008.05.003]
</p>
</li>
<li>
<p class="mim-text-font">
Mirza, M., Marston, S., Willott, R., Ashley, C., Mogensen, J., McKenna, W., Robinson, P., Redwood, C., Watkins, H.
<strong>Dilated cardiomyopathy mutations in three thin filament regulatory proteins result in a common functional phenotype.</strong>
J. Biol. Chem. 280: 28498-28506, 2005.
[PubMed: 15923195]
[Full Text: https://doi.org/10.1074/jbc.M412281200]
</p>
</li>
<li>
<p class="mim-text-font">
Mogensen, J., Murphy, R. T., Shaw, T., Bahl, A., Redwood, C., Watkins, H., Burke, M., Elliott, P. M., McKenna, W. J.
<strong>Severe disease expression of cardiac troponin C and T mutations in patients with idiopathic dilated cardiomyopathy.</strong>
J. Am. Coll. Cardiol. 44: 2033-2040, 2004.
[PubMed: 15542288]
[Full Text: https://doi.org/10.1016/j.jacc.2004.08.027]
</p>
</li>
<li>
<p class="mim-text-font">
Parvatiyar, M. S., Landstrom, A. P., Figueiredo-Freitas, C., Potter, J. D., Ackerman, M. J., Pinto, J. R.
<strong>A mutation in TNNC1-encoded cardiac troponin C, TNNC1-A31S, predisposes to hypertrophic cardiomyopathy and ventricular fibrillation.</strong>
J. Biol. Chem. 287: 31845-31855, 2012.
[PubMed: 22815480]
[Full Text: https://doi.org/10.1074/jbc.M112.377713]
</p>
</li>
<li>
<p class="mim-text-font">
Pinto, J. R., Parvatiyar, M. S., Jones, M. A., Liang, J., Ackerman, M. J., Potter, J. D.
<strong>A functional and structural study of troponin C mutations related to hypertrophic cardiomyopathy.</strong>
J. Biol. Chem. 284: 19090-19100, 2009.
[PubMed: 19439414]
[Full Text: https://doi.org/10.1074/jbc.M109.007021]
</p>
</li>
<li>
<p class="mim-text-font">
Pinto, J. R., Siegfried, J. D., Parvatiyar, M. S., Li, D., Norton, N., Jones, M. A., Liang, J., Potter, J. D., Hershberger, R. E.
<strong>Functional characterization of TNNC1 rare variants identified in dilated cardiomyopathy.</strong>
J. Biol. Chem. 286: 34404-34412, 2011.
[PubMed: 21832052]
[Full Text: https://doi.org/10.1074/jbc.M111.267211]
</p>
</li>
<li>
<p class="mim-text-font">
Roher, A., Lieska, N., Spitz, W.
<strong>The amino acid sequence of human cardiac troponin-C.</strong>
Muscle Nerve 9: 73-77, 1986.
[PubMed: 3951483]
[Full Text: https://doi.org/10.1002/mus.880090112]
</p>
</li>
<li>
<p class="mim-text-font">
Romero-Herrera, A. E., Castillo, O., Lehmann, H.
<strong>Human skeletal muscle proteins: the primary structure of troponin C.</strong>
J. Molec. Evol. 8: 251-270, 1976.
[PubMed: 978749]
[Full Text: https://doi.org/10.1007/BF01730999]
</p>
</li>
<li>
<p class="mim-text-font">
Schmidtmann, A., Lindow, C., Villard, S., Heuser, A., Mugge, A., Gessner, R., Granier, C., Jaquet, K.
<strong>Cardiac troponin C-L29Q, related to hypertrophic cardiomyopathy, hinders the transduction of the protein kinase A dependent phosphorylation signal from cardiac troponin I to C.</strong>
FEBS J. 272: 6087-6097, 2005.
[PubMed: 16302972]
[Full Text: https://doi.org/10.1111/j.1742-4658.2005.05001.x]
</p>
</li>
<li>
<p class="mim-text-font">
Schreier, T., Kedes, L., Gahlmann, R.
<strong>Cloning, structural analysis, and expression of the human slow twitch skeletal muscle/cardiac troponin C gene.</strong>
J. Biol. Chem. 265: 21247-21253, 1990.
[PubMed: 2250022]
</p>
</li>
<li>
<p class="mim-text-font">
Song, W. J.
<strong>Personal Communication.</strong>
Ann Arbor, Mich. 1/17/1997.
</p>
</li>
<li>
<p class="mim-text-font">
Song, W.-J., Van Keuren, M. L., Drabkin, H. A., Cypser, J. R., Gemmill, R. M., Kurnit, D. M.
<strong>Assignment of the human slow twitch skeletal muscle/cardiac troponin C gene (TNNC1) to human chromosome 3p21.3-3p14.3 using somatic cell hybrids.</strong>
Cytogenet. Cell Genet. 75: 36-37, 1996.
[PubMed: 8995486]
[Full Text: https://doi.org/10.1159/000134453]
</p>
</li>
<li>
<p class="mim-text-font">
Takeda, S., Yamashita, A., Maeda, K., Maeda, Y.
<strong>Structure of the core domain of human cardiac troponin in the Ca(2+)-saturated form.</strong>
Nature 424: 35-41, 2003.
[PubMed: 12840750]
[Full Text: https://doi.org/10.1038/nature01780]
</p>
</li>
<li>
<p class="mim-text-font">
Townsend, P. J., Yacoub, M. H., Barton, P. J. R.
<strong>Assignment of the human cardiac/slow skeletal muscle troponin C gene (TNNC1) between D3S3118 and GCT4B10 on the short arm of chromosome 3 by somatic cell hybrid analysis.</strong>
Ann. Hum. Genet. 61: 375-377, 1997.
[PubMed: 9365790]
[Full Text: https://doi.org/10.1046/j.1469-1809.1997.6140375.x]
</p>
</li>
<li>
<p class="mim-text-font">
Udani, R., Schilter, K. F., Tyler, R. C., Smith, B. A., Wendtandrae, J. L., Kappes, U. P., Scharer, G., Lehman, A., Steinraths, M., Reddi, H. V.
<strong>A novel variant of TNNC1 associated with severe dilated cardiomyopathy causing infant mortality and stillbirth: a case of germline mosaicism.</strong>
J. Genet. 102: 14, 2023.
[PubMed: 36814108]
</p>
</li>
<li>
<p class="mim-text-font">
Vikhorev, P. G., Smoktunowicz, N., Munster, A. B., Copeland, O., Kostin, S., Montgiraud, C., Messer, A. E., Toliat, M. R., Li, A., Dos Remedios, C. G., Lal, S., Blair, C. A., Campbell, K. S., Guglin, M., Richter, M., Knoll, R., Marston, S. B.
<strong>Abnormal contractility in human heart myofibrils from patients with dilated cardiomyopathy due to mutations in TTN and contractile protein genes.</strong>
Sci. Rep. 7: 14829, 2017. Note: Erratum: Sci. Rep. 8: 14485, 2018.
[PubMed: 29093449]
[Full Text: https://doi.org/10.1038/s41598-017-13675-8]
</p>
</li>
</ol>
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<br />
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<span class="mim-text-font">
Bao Lige - updated : 03/21/2024<br>Marla J. F. O&#x27;Neill - updated : 07/21/2023<br>Kelly A. Przylepa - updated : 07/18/2023<br>Marla J. F. O&#x27;Neill - updated : 11/30/2012<br>Marla J. F. O&#x27;Neill - updated : 2/2/2010<br>Marla J. F. O&#x27;Neill - updated : 12/2/2008<br>Marla J. F. O&#x27;Neill - updated : 3/6/2008<br>Victor A. McKusick - updated : 11/24/2003<br>Ada Hamosh - updated : 7/7/2003<br>Victor A. McKusick - updated : 12/3/1997<br>Victor A. McKusick - updated : 2/11/1997<br>Mark H. Paalman - edited : 1/23/1997<br>Alan F. Scott - updated : 2/29/1996
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Victor A. McKusick : 2/9/1987
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