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Entry
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- *102565 - FILAMIN C; FLNC
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- OMIM
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</ul>
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</nav>
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<div id="mimSearch" class="hidden-print">
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<div class="container">
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<form method="get" action="/search" id="mimEntrySearchForm" name="entrySearchForm" class="form-horizontal">
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<input type="hidden" id="mimSearchIndex" name="index" value="entry" />
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<input type="hidden" id="mimSearchStart" name="start" value="1" />
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<input type="hidden" id="mimSearchLimit" name="limit" value="10" />
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<input type="hidden" id="mimSearchSort" name="sort" value="score desc, prefix_sort desc" />
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<div class="row">
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<div class="col-lg-8 col-md-8 col-sm-8 col-xs-8">
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<div class="form-group">
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<div class="input-group">
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<input type="search" id="mimEntrySearch" name="search" class="form-control" value="" placeholder="Search OMIM..." maxlength="5000" autocomplete="off" autocorrect="off" autocapitalize="none" spellcheck="false" autofocus />
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<div class="input-group-btn">
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<button type="submit" id="mimEntrySearchSubmit" class="btn btn-default" style="width: 5em;"><span class="glyphicon glyphicon-search"></span></button>
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<button type="button" class="btn btn-default dropdown-toggle" data-toggle="dropdown"> Options <span class="caret"></span></button>
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<ul class="dropdown-menu dropdown-menu-right">
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<li class="dropdown-header">
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Advanced Search
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</li>
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<li style="margin-left: 0.5em;">
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<a href="/search/advanced/entry"> OMIM </a>
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</li>
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<li style="margin-left: 0.5em;">
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<a href="/search/advanced/clinicalSynopsis"> Clinical Synopses </a>
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</li>
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<li style="margin-left: 0.5em;">
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<a href="/search/advanced/geneMap"> Gene Map </a>
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</li>
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<li role="separator" class="divider"></li>
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<li>
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<a href="/history"> Search History </a>
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</ul>
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</form>
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<div class="row">
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<p />
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</div>
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<div id="mimAlertBanner">
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<div class="row">
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*102565</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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</li>
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<li role="presentation">
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<li role="presentation">
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#history">History</a>
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</li>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
|
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<a href="/allelicVariants/102565">Table View</a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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</li>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
|
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</nav>
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</div>
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</div>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
|
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<h4 class="panel-title">
|
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
|
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<div style="display: table-row">
|
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
|
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</h4>
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</div>
|
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
|
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<span class="panel-title">
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<span class="small">
|
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
|
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</a>
|
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</span>
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</span>
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</div>
|
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
|
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000128591;t=ENST00000325888" class="mim-tip-hint" title="Genome databases for vertebrates and other eukaryotic species." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/genome/gdv/browser/gene/?id=2318" class="mim-tip-hint" title="Detailed views of the complete genomes of selected organisms from vertebrates to protozoa." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Genome Viewer', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Genome Viewer</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&hgFind=omimGeneAcc&position=102565" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
|
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
|
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</a>
|
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000128591;t=ENST00000325888" class="mim-tip-hint" title="Transcript-based views for coding and noncoding DNA." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl (MANE Select)</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_001127487,NM_001458" class="mim-tip-hint" title="A collection of genome, gene, and transcript sequence data from several sources, including GenBank, RefSeq." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI RefSeq', 'domain': 'ncbi.nlm.nih'})">NCBI RefSeq</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_001458" class="mim-tip-hint" title="A collection of genome, gene, and transcript sequence data from several sources, including GenBank, RefSeq." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI RefSeq (MANE)', 'domain': 'ncbi.nlm.nih'})">NCBI RefSeq (MANE Select)</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&hgFind=omimGeneAcc&position=102565" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
|
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</div>
|
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</div>
|
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</div>
|
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimProtein">
|
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<span class="panel-title">
|
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<span class="small">
|
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<a href="#mimProteinLinksFold" id="mimProteinLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<span id="mimProteinLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Protein
|
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</a>
|
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</span>
|
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</span>
|
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</div>
|
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<div id="mimProteinLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
|
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<div class="panel-body small mim-panel-body">
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<div><a href="https://hprd.org/summary?hprd_id=00018&isoform_id=00018_1&isoform_name=Isoform_1" class="mim-tip-hint" title="The Human Protein Reference Database; manually extracted and visually depicted information on human proteins." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HPRD', 'domain': 'hprd.org'})">HPRD</a></div>
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<div><a href="https://www.proteinatlas.org/search/FLNC" class="mim-tip-hint" title="The Human Protein Atlas contains information for a large majority of all human protein-coding genes regarding the expression and localization of the corresponding proteins based on both RNA and protein data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HumanProteinAtlas', 'domain': 'proteinatlas.org'})">Human Protein Atlas</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/protein/938227,1657315,4218955,5419655,5629917,7677526,7715914,8885790,62087310,116805322,119604095,119604096,119604097,188595687,190192200,193785487,194338409,254763419" class="mim-tip-hint" title="NCBI protein data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Protein', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Protein</a></div>
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<div><a href="https://www.uniprot.org/uniprotkb/Q14315" class="mim-tip-hint" title="Comprehensive protein sequence and functional information, including supporting data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UniProt', 'domain': 'uniprot.org'})">UniProt</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGeneInfo">
|
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<span class="panel-title">
|
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<span class="small">
|
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<a href="#mimGeneInfoLinksFold" id="mimGeneInfoLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
|
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<div id="mimGeneInfoLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Gene Info</div>
|
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</div>
|
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</a>
|
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</span>
|
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</span>
|
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</div>
|
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<div id="mimGeneInfoLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
|
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<div class="panel-body small mim-panel-body">
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<div><a href="http://biogps.org/#goto=genereport&id=2318" class="mim-tip-hint" title="The Gene Portal Hub; customizable portal of gene and protein function information." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'BioGPS', 'domain': 'biogps.org'})">BioGPS</a></div>
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<div><a href="https://www.ensembl.org/Homo_sapiens/Gene/Summary?db=core;g=ENSG00000128591;t=ENST00000325888" class="mim-tip-hint" title="Orthologs, paralogs, regulatory regions, and splice variants." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl</a></div>
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<div><a href="https://www.genecards.org/cgi-bin/carddisp.pl?gene=FLNC" class="mim-tip-hint" title="The Human Genome Compendium; web-based cards integrating automatically mined information on human genes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GeneCards', 'domain': 'genecards.org'})">GeneCards</a></div>
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<div><a href="http://amigo.geneontology.org/amigo/search/annotation?q=FLNC" class="mim-tip-hint" title="Terms, defined using controlled vocabulary, representing gene product properties (biologic process, cellular component, molecular function) across species." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GeneOntology', 'domain': 'amigo.geneontology.org'})">Gene Ontology</a></div>
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<div><a href="https://www.genome.jp/dbget-bin/www_bget?hsa+2318" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<dd><a href="http://v1.marrvel.org/search/gene/FLNC" class="mim-tip-hint" title="Model organism Aggregated Resources for Rare Variant ExpLoration." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MARRVEL', 'domain': 'marrvel.org'})">MARRVEL</a></dd>
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<dd><a href="https://monarchinitiative.org/NCBIGene:2318" class="mim-tip-hint" title="Monarch Initiative." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Monarch', 'domain': 'monarchinitiative.org'})">Monarch</a></dd>
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<div><a href="https://www.ncbi.nlm.nih.gov/gene/2318" class="mim-tip-hint" title="Gene-specific map, sequence, expression, structure, function, citation, and homology data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Gene', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Gene</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chr7&hgg_gene=ENST00000325888.13&hgg_start=128830406&hgg_end=128859272&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:3756" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:3756" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=102565[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimVariation">
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<span class="panel-title">
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<span class="small">
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<a href="#mimVariationLinksFold" id="mimVariationLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimVariationLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">▼</span> Variation
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</a>
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</span>
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</span>
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</div>
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<div id="mimVariationLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ncbi.nlm.nih.gov/clinvar?term=102565[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://www.deciphergenomics.org/gene/FLNC/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000128591" class="mim-tip-hint" title="The Genome Aggregation Database (gnomAD), Broad Institute." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'gnomAD', 'domain': 'gnomad.broadinstitute.org'})">gnomAD</a></div>
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<div><a href="https://www.ebi.ac.uk/gwas/search?query=FLNC" class="mim-tip-hint" title="GWAS Catalog; NHGRI-EBI Catalog of published genome-wide association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Catalog', 'domain': 'gwascatalog.org'})">GWAS Catalog </a></div>
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<div><a href="https://www.gwascentral.org/search?q=FLNC" class="mim-tip-hint" title="GWAS Central; summary level genotype-to-phenotype information from genetic association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Central', 'domain': 'gwascentral.org'})">GWAS Central </a></div>
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<div><a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=FLNC" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="http://www.LOVD.nl/FLNC" class="mim-tip-hint" title="A gene-specific database of variation." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Locus Specific DBs</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=FLNC&upstreamSize=0&downstreamSize=0&x=0&y=0" class="mim-tip-hint" title="National Heart, Lung, and Blood Institute Exome Variant Server." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NHLBI EVS', 'domain': 'evs.gs.washington.edu'})">NHLBI EVS</a></div>
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<div><a href="https://www.pharmgkb.org/gene/PA28174" class="mim-tip-hint" title="Pharmacogenomics Knowledge Base; curated and annotated information regarding the effects of human genetic variations on drug response." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PharmGKB', 'domain': 'pharmgkb.org'})">PharmGKB</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
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<span class="panel-title">
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<span class="small">
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<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Animal Models</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.alliancegenome.org/gene/HGNC:3756" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://flybase.org/reports/FBgn0014141.html" class="mim-tip-hint" title="A Database of Drosophila Genes and Genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'FlyBase', 'domain': 'flybase.org'})">FlyBase</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:95557" class="mim-tip-hint" title="International Mouse Phenotyping Consortium." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'IMPC', 'domain': 'knockoutmouse.org'})">IMPC</a></div>
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<div><a href="http://v1.marrvel.org/search/gene/FLNC#HomologGenesPanel" class="mim-tip-hint" title="Model organism Aggregated Resources for Rare Variant ExpLoration." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MARRVEL', 'domain': 'marrvel.org'})">MARRVEL</a></div>
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<div><a href="http://www.informatics.jax.org/marker/MGI:95557" class="mim-tip-hint" title="Mouse Genome Informatics; international database resource for the laboratory mouse, including integrated genetic, genomic, and biological data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Gene', 'domain': 'informatics.jax.org'})">MGI Mouse Gene</a></div>
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<div><a href="https://www.mmrrc.org/catalog/StrainCatalogSearchForm.php?search_query=" class="mim-tip-hint" title="Mutant Mouse Resource & Research Centers." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MMRRC', 'domain': 'mmrrc.org'})">MMRRC</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gene/2318/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=2318" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00022048;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-041008-175" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:2318" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<div><a href="https://reactome.org/content/query?q=FLNC&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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102565
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</span>
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</span>
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</div>
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</div>
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<div>
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<a id="preferredTitle" class="mim-anchor"></a>
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<h3>
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<span class="mim-font">
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FILAMIN C; FLNC
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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FILAMIN, GAMMA<br />
|
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FILAMIN 2; FLN2<br />
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ACTIN-BINDING PROTEIN 280, AUTOSOMAL FORM; ABP280A<br />
|
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ABPA<br />
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ACTIN-BINDING PROTEIN-LIKE; ABPL
|
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</span>
|
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</h4>
|
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=FLNC" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">FLNC</a></em></strong>
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</span>
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</p>
|
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</div>
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<div>
|
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong>
|
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<em>
|
|
Cytogenetic location: <a href="/geneMap/7/659?start=-3&limit=10&highlight=659">7q32.1</a>
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|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr7:128830406-128859272&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'})">7:128,830,406-128,859,272</a> </span>
|
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</em>
|
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</strong>
|
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<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
|
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<br />
|
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</div>
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<div>
|
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<a id="geneMap" class="mim-anchor"></a>
|
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<div style="margin-bottom: 10px;">
|
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<span class="h4 mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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Location
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Phenotype
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<a href="/clinicalSynopsis/table?mimNumber=617047,617047,617047,614065,609524" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
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View Clinical Synopses
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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<a href="/geneMap/7/659?start=-3&limit=10&highlight=659">
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7q32.1
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Arrhythmogenic right ventricular dysplasia, familial
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<a href="/entry/617047"> 617047 </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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Cardiomyopathy, familial hypertrophic, 26
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<a href="/entry/617047"> 617047 </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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Cardiomyopathy, familial restrictive 5
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<span class="mim-font">
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<a href="/entry/617047"> 617047 </a>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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Myopathy, distal, 4
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<span class="mim-font">
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<a href="/entry/614065"> 614065 </a>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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<span class="mim-font">
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Myopathy, myofibrillar, 5
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<a href="/entry/609524"> 609524 </a>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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<div class="btn-group">
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
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PheneGene Graphics <span class="caret"></span>
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</button>
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<ul class="dropdown-menu" style="width: 17em;">
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<li><a href="/graph/linear/102565" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<li><a href="/graph/radial/102565" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
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</ul>
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</div>
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<a id="text" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<strong>TEXT</strong>
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<strong>Description</strong>
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<p>Filamins, such as FLNC, are a family of actin (see ACTA1; <a href="/entry/102610">102610</a>)-binding proteins involved in reshaping of the cytoskeleton. See FLN1 (FLNA; <a href="/entry/300017">300017</a>) for background information on the filamin gene family.</p>
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<strong>Cloning and Expression</strong>
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<p><a href="#21" class="mim-tip-reference" title="Xie, Z., Xu, W., Davie, E. W., Chung, D. W. <strong>Molecular cloning of human ABPL, an actin-binding protein homologue.</strong> Biochem. Biophys. Res. Commun. 251: 914-919, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9791010/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9791010</a>] [<a href="https://doi.org/10.1006/bbrc.1998.9506" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9791010">Xie et al. (1998)</a> cloned FLNC, which they called ABPL, from a heart cDNA library. The deduced 2,705-amino acid protein has a calculated molecular mass of 289 kD. ABPL contains an N-terminal actin-binding domain, followed by 24 repeats of about 94 amino acids. It has hinge sequences prior to repeats 16 and 24. <a href="#21" class="mim-tip-reference" title="Xie, Z., Xu, W., Davie, E. W., Chung, D. W. <strong>Molecular cloning of human ABPL, an actin-binding protein homologue.</strong> Biochem. Biophys. Res. Commun. 251: 914-919, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9791010/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9791010</a>] [<a href="https://doi.org/10.1006/bbrc.1998.9506" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9791010">Xie et al. (1998)</a> also identified an alternatively spliced transcript that encodes a protein lacking hinge 1. PCR analysis detected transcripts encoding the hinge 1-containing isoform in stomach, uterus, umbilical vein endothelial cells, and prostate. Transcripts encoding both isoforms were detected in heart, thyroid, fetal brain, fetal lung, retina, spinal cord, skeletal muscle, and bone marrow. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9791010" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 sarcoglycan-gamma (SGCG; <a href="/entry/608896">608896</a>) as bait in a yeast 2-hybrid screen of a skeletal muscle cDNA library, followed by EST database analysis and screening of a skeletal muscle cDNA library, <a href="#15" class="mim-tip-reference" title="Thompson, T. G., Chan, Y.-M., Hack, A. A., Brosius, M., Rajala, M., Lidov, H. G. W., McNally, E. M., Watkins, S., Kunkel, L. M. <strong>Filamin 2 (FLN2): a muscle-specific sarcoglycan interacting protein.</strong> J. Cell Biol. 148: 115-126, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10629222/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10629222</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10629222[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1083/jcb.148.1.115" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10629222">Thompson et al. (2000)</a> cloned FLNC, which they called FLN2. The deduced 2,688-amino acid protein shares 74% and 71% identity with FLN1 and filamin-beta (FLNB; <a href="/entry/603381">603381</a>), respectively, and the 3 proteins are nearly 100% identical in the actin-binding domains. FLN2 lacks the first hinge region present in FLN1 and FLNB, but it has the second hinge region. Like FLN1 and FLNB, FLNC has a C-terminal domain containing binding sites for several receptor proteins. Western blot analysis detected a 280-kD protein in heart and skeletal muscle. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10629222" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Mapping</strong>
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<p><a href="#9" class="mim-tip-reference" title="Gariboldi, M., Maestrini, E., Canzian, F., Manenti, G., De Gregorio, L., Rivella, S., Chatterjee, A., Herman, G. E., Archidiacono, N., Antonacci, R., Pierotti, M. A., Dragani, T. A., Toniolo, D. <strong>Comparative mapping of the actin-binding protein 280 genes in human and mouse.</strong> Genomics 21: 428-430, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8088838/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8088838</a>] [<a href="https://doi.org/10.1006/geno.1994.1288" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8088838">Gariboldi et al. (1994)</a> mapped the FLN2 gene to human chromosome 7q32-q35 by analysis of somatic cell hybrids containing portions of chromosome 7. <a href="#6" class="mim-tip-reference" title="Chakarova, C., Wehnert, M. S., Uhl, K., Sakthivel, S., Vosberg, H.-P., van der Ven, P. F. M., Furst, D. O. <strong>Genomic structure and fine mapping of the two human filamin gene paralogues FLNB and FLNC and comparative analysis of the filamin gene family.</strong> Hum. Genet. 107: 597-611, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11153914/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11153914</a>] [<a href="https://doi.org/10.1007/s004390000414" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11153914">Chakarova et al. (2000)</a> assigned the FLNC gene to 7q32 by radiation hybrid analysis. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8088838+11153914" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 interspecific backcross analysis, <a href="#9" class="mim-tip-reference" title="Gariboldi, M., Maestrini, E., Canzian, F., Manenti, G., De Gregorio, L., Rivella, S., Chatterjee, A., Herman, G. E., Archidiacono, N., Antonacci, R., Pierotti, M. A., Dragani, T. A., Toniolo, D. <strong>Comparative mapping of the actin-binding protein 280 genes in human and mouse.</strong> Genomics 21: 428-430, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8088838/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8088838</a>] [<a href="https://doi.org/10.1006/geno.1994.1288" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8088838">Gariboldi et al. (1994)</a> mapped the mouse homolog to chromosome 6 in a region showing homology of synteny to human chromosome 7. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8088838" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Pseudogene</em></strong></p><p>
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An FLNC pseudogene maps to chromosome 7q32-q35 about 53.7 kb downstream from the functional FLNC gene. The pseudogene is 98% homologous to exons 46, 47, and 48 of the functional gene (<a href="#17" class="mim-tip-reference" title="Van der Ven, P. F. M., Odgerel, Z., Furst, D. O., Goldfarb, L. G. <strong>Dominant-negative effects of a novel mutation in the filamin myopathy. (Letter)</strong> Neurology 75: 2137-2138, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21135393/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21135393</a>] [<a href="https://doi.org/10.1212/WNL.0b013e3182031bb3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21135393">van der Ven et al., 2010</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21135393" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By yeast 2-hybrid analysis, <a href="#15" class="mim-tip-reference" title="Thompson, T. G., Chan, Y.-M., Hack, A. A., Brosius, M., Rajala, M., Lidov, H. G. W., McNally, E. M., Watkins, S., Kunkel, L. M. <strong>Filamin 2 (FLN2): a muscle-specific sarcoglycan interacting protein.</strong> J. Cell Biol. 148: 115-126, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10629222/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10629222</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10629222[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1083/jcb.148.1.115" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10629222">Thompson et al. (2000)</a> found that sarcoglycan-gamma and -delta (SGCD; <a href="/entry/601411">601411</a>) interacted with FLN2, but sarcoglycan-alpha (SGCA; <a href="/entry/600119">600119</a>) and -beta (SGCB; <a href="/entry/600900">600900</a>) did not. In vitro binding assays indicated that FLN2 interacted directly with sarcoglycan-gamma and -delta, but not with dystrophin (DMD; <a href="/entry/300377">300377</a>) and syntrophin beta-1 (SNTB1; <a href="/entry/600026">600026</a>). Coimmunoprecipitation analysis of transfected proteins and of endogenous proteins in mouse myotube lysates confirmed that FLN2 interacted with sarcoglycans-gamma and -delta. Fln2 was detected predominantly in the soluble fraction of lysed mouse myotube cultures. Immunoelectron microscopy detected 2 pools of Fln2, one adjacent to the sarcolemmal membrane and the other more diffuse. <a href="#15" class="mim-tip-reference" title="Thompson, T. G., Chan, Y.-M., Hack, A. A., Brosius, M., Rajala, M., Lidov, H. G. W., McNally, E. M., Watkins, S., Kunkel, L. M. <strong>Filamin 2 (FLN2): a muscle-specific sarcoglycan interacting protein.</strong> J. Cell Biol. 148: 115-126, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10629222/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10629222</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10629222[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1083/jcb.148.1.115" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10629222">Thompson et al. (2000)</a> found elevated levels of membrane-associated FLN2 in 2 patients with limb-girdle muscular dystrophy type 2C (LGMD2C; <a href="/entry/253700">253700</a>), a patient with Duchenne muscular dystrophy (DMD; <a href="/entry/310200">310200</a>), and dystrophic mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10629222" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The KY protein (<a href="/entry/605739">605739</a>) has been implicated in a neuromuscular dystrophy in the mouse, but its role in muscle function remains unclear. <a href="#2" class="mim-tip-reference" title="Beatham, J., Romero, R., Townsend, S. K. M., Hacker, T., van der Ven, P. F. M., Blanco, G. <strong>Filamin C interacts with the muscular dystrophy KY protein and is abnormally distributed in mouse KY deficient muscle fibres.</strong> Hum. Molec. Genet. 13: 2863-2874, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15385448/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15385448</a>] [<a href="https://doi.org/10.1093/hmg/ddh308" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15385448">Beatham et al. (2004)</a> showed that KY interacted with several sarcomeric cytoskeletal proteins including filamin C and the slow isoform of the myosin-binding protein C (MYBPC1; <a href="/entry/160794">160794</a>). A role for KY in regulating filamin C function in vivo was supported by the expression analysis of filamin C in the Ky-null mouse mutant, where distinct irregular subcellular localization of filamin C was found in subsets of muscle fibers, which appeared to be a specific outcome of KY deficiency. In vitro assays showed that KY has protease activity, and specific degradation of filamin C by KY was shown in transfected cells. <a href="#2" class="mim-tip-reference" title="Beatham, J., Romero, R., Townsend, S. K. M., Hacker, T., van der Ven, P. F. M., Blanco, G. <strong>Filamin C interacts with the muscular dystrophy KY protein and is abnormally distributed in mouse KY deficient muscle fibres.</strong> Hum. Molec. Genet. 13: 2863-2874, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15385448/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15385448</a>] [<a href="https://doi.org/10.1093/hmg/ddh308" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15385448">Beatham et al. (2004)</a> suggested that KY may be an intrinsic part of the protein networks underlying the molecular mechanism of several limb-girdle muscular dystrophies, particularly those where interactions between filamin C and disease-causing proteins have been shown. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15385448" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><strong><em>Myofibrillar Myopathy 5</em></strong></p><p>
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In affected members of a German family with autosomal dominant myofibrillar myopathy-5 (MFM5; <a href="/entry/609524">609524</a>), <a href="#19" class="mim-tip-reference" title="Vorgerd, M., van der Ven, P. F. M., Bruchertseifer, V., Lowe, T., Kley, R. A., Schroder, R., Lochmuller, H., Himmel, M., Koehler, K., Furst, D. O., Huebner, A. <strong>A mutation in the dimerization domain of filamin C causes a novel type of autosomal dominant myofibrillar myopathy.</strong> Am. J. Hum. Genet. 77: 297-304, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15929027/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15929027</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15929027[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/431959" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15929027">Vorgerd et al. (2005)</a> identified a heterozygous mutation in the FLNC gene (W2710X; <a href="#0001">102565.0001</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15929027" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 German mother and daughter with adult-onset limb-girdle muscle weakness, <a href="#14" class="mim-tip-reference" title="Shatunov, A., Olive, M., Odgerel, Z., Stadelmann-Nessler, C., Irlbacher, K., van Landeghem, F., Bayarsaikhan, M., Lee, H.-S., Goudeau, B., Chinnery, P. F., Straub, V., Hilton-Jones, D., and 9 others. <strong>In-frame deletion in the seventh immunoglobulin-like repeat of filamin C in a family with myofibrillar myopathy.</strong> Europ. J. Hum. Genet. 17: 656-663, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19050726/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19050726</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19050726[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ejhg.2008.226" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19050726">Shatunov et al. (2009)</a> identified a heterozygous deletion in the FLNC gene (<a href="#0002">102565.0002</a>). This family was the only 1 of 127 families with a myopathy examined that was found to have an FLNC mutation, indicating that this subtype of myofibrillar myopathy is rare. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19050726" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 34 Chinese individuals with MFM5 from 9 apparently unrelated families in Hong Kong, <a href="#11" class="mim-tip-reference" title="Lee, H.-C. H., Wong, S., Sheng, B., Pan, N.-Y. K., Leung, Y.-K. F., Lau, K.-K. D., Cheng, Y. S., Ho, C.-C., Li, R., Lee, C.-N., Tsoi, T.-H., Cheung, Y.-F. N., and 21 others. <strong>Clinical and pathological characterization of FLNC-related myofibrillar myopathy caused by founder variant c.8129G-A in Hong Kong Chinese.</strong> Clin. Genet. 97: 747-757, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32022900/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32022900</a>] [<a href="https://doi.org/10.1111/cge.13715" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32022900">Lee et al. (2020)</a> identified a heterozygous c.8129G-A transition in the FLNC gene, resulting in a trp2710-to-ter (W2710X; <a href="#0010">102565.0010</a>) substitution. The mutation has the same amino acid substitution as that in a German family with MFM5 with a different basepair change (c.8130G-A; <a href="#0001">102565.0001</a>) in the same codon. Polymorphic marker analysis on the 9 probands identified a distinct haplotype that was not detected among 20 ethnically matched control chromosomes. The mutation was estimated to have occurred 42 to 71 generations previously, dating it to 844 to 1,315 years earlier. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32022900" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Distal Myopathy 4</em></strong></p><p>
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By linkage analysis followed by candidate gene sequencing of an Australian family with distal myopathy-4 (MPD4; <a href="/entry/614065">614065</a>), reported by <a href="#20" class="mim-tip-reference" title="Williams, D. R., Reardon, K., Roberts, L., Dennet, X., Duff, R., Laing, N. G., Byrne, E. <strong>A new dominant distal myopathy affecting posterior leg and anterior upper limb muscles.</strong> Neurology 64: 1245-1254, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15824355/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15824355</a>] [<a href="https://doi.org/10.1212/01.WNL.0000156524.95261.B9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15824355">Williams et al. (2005)</a>, <a href="#8" class="mim-tip-reference" title="Duff, R. M., Tay, V., Hackman, P., Ravenscroft, G., McLean, C., Kennedy, P., Steinbach, A., Schoffler, W., van der Ven, P. F., Furst, D. O., Song, J., Djinovic-Carugo, K., and 12 others. <strong>Mutations in the N-terminal actin-binding domain of filamin C cause a distal myopathy.</strong> Am. J. Hum. Genet. 88: 729-740, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21620354/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21620354</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21620354[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2011.04.021" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21620354">Duff et al. (2011)</a> identified a heterozygous mutation in the FLNC gene (M251T; <a href="#0003">102565.0003</a>). A different heterozygous mutation (A193T; <a href="#0004">102565.0004</a>) was found in affected members of an Italian family with the same phenotype. Both mutations occurred in the actin-binding domain, and in vitro cellular expression studies showed that both mutations resulted in increased affinity for actin. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15824355+21620354" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 trio exome sequencing in 1 proband and sequencing of a panel of genes involved in muscle diseases in another, <a href="#18" class="mim-tip-reference" title="Velardo, D., D'Angelo, M. G., Citterio, A., Panzeri, E., Napoli, L., Cinnante, C., Moggio, M., Comi, G. P., Ronchi, D., Bassi, M. T. <strong>Case reports: novel missense variants in the filamin C actin binding domain cause variable phenotypes.</strong> Front. Neurol. 13: 930039, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35903116/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35903116</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=35903116[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.3389/fneur.2022.930039" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35903116">Velardo et al. (2022)</a> identified 2 novel variants in the FLNC gene in Italian patients with MPD4. Both patients carried de novo heterozygous missense mutations at evolutionarily conserved positions (M222T, <a href="#0011">102565.0011</a> and V245M, <a href="#0012">102565.0012</a>, respectively). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35903116" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Familial Cardiomyopathy, Hypertrophic, Restrictive, Dilated, or Arrhythmogenic</em></strong></p><p>
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In affected members of 7 Spanish families segregating autosomal dominant hypertrophic cardiomyopathy (CMH26; <a href="/entry/617047">617047</a>) <a href="#16" class="mim-tip-reference" title="Valdes-Mas, R., Gutierrez-Fernandez, A., Gomez, J., Coto, E., Astudillo, A., Puente, D. A., Reguero, J. R., Alvarez, V., Moris, C., Leon, D., Martin, M., Puente, X. S., Lopez-Otin, C. <strong>Mutations in filamin C cause a new form of familial hypertrophic cardiomyopathy.</strong> Nature Commun. 5: 5326, 2014. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25351925/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25351925</a>] [<a href="https://doi.org/10.1038/ncomms6326" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25351925">Valdes-Mas et al. (2014)</a> identified heterozygosity for 5 different missense mutations and 1 nonsense mutation (see, e.g., <a href="#0005">102565.0005</a>-<a href="#0007">102565.0007</a>). The FLNC variants showed strong cosegregation with disease in the families, with 14 of 16 mutation carriers over 40 years of age exhibiting symptoms of CMH, for a penetrance of more than 87%. None of the patients showed symptoms of myofibrillar myopathy, and skeletal muscle biopsies from 2 of the CMH patients showed normal muscle fiber histology and biochemistry, and lacked any of the myopathologic or electrophysiologic abnormalities of MFM patients. Functional analysis suggested that the CMH mutations disrupt the structure of FLNC, resulting in the formation of protein aggregates that likely impair sarcomere function. <a href="#16" class="mim-tip-reference" title="Valdes-Mas, R., Gutierrez-Fernandez, A., Gomez, J., Coto, E., Astudillo, A., Puente, D. A., Reguero, J. R., Alvarez, V., Moris, C., Leon, D., Martin, M., Puente, X. S., Lopez-Otin, C. <strong>Mutations in filamin C cause a new form of familial hypertrophic cardiomyopathy.</strong> Nature Commun. 5: 5326, 2014. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25351925/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25351925</a>] [<a href="https://doi.org/10.1038/ncomms6326" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25351925">Valdes-Mas et al. (2014)</a> noted that expression in cardiac myocytes resulted in larger protein aggregates than when expressed in skeletal muscle myoblasts, supporting a model in which interaction of these mutants with tissue-specific proteins contributes to the predominant cardiac phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25351925" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 Canadian families with restrictive cardiomyopathy (RCM5; see <a href="/entry/617047">617047</a>), <a href="#4" class="mim-tip-reference" title="Brodehl, A., Ferrier, R. A., Hamilton, S. J., Greenway, S. C., Brundler, M.-A., Yu, W., Gibson, W. T., McKinnon, M. L., McGillivray, B., Alvarez, N., Giuffre, M., Schwartzentruber, J., FORGE Canada Consortium, Gerull, B. <strong>Mutations in FLNC are associated with familial restrictive cardiomyopathy.</strong> Hum. Mutat. 37: 269-279, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26666891/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26666891</a>] [<a href="https://doi.org/10.1002/humu.22942" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26666891">Brodehl et al. (2016)</a> identified heterozygosity for 2 different missense mutations in the FLNC gene (<a href="#0008">102565.0008</a> and <a href="#0009">102565.0009</a>). Each mutation segregated fully with disease in the family, and neither was found in controls or public variant databases. Patients exhibited no clinically detectable skeletal involvement, and CK levels were in the normal or slightly elevated range. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26666891" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In affected members of 2 Italian families segregating autosomal dominant dilated cardiomyopathy (CMD1PP; see <a href="/entry/617047">617047</a>), <a href="#3" class="mim-tip-reference" title="Begay, R. L., Tharp, C. A., Martin, A., Graw, S. L., Sinagra, G., Miani, D., Sweet, M. E., Slavov, D. B., Stafford, N., Zeller, M. J., Alnefaie, R., Rowland, T. J., Brun, F., Jones, K. L., Gowan, K., Mestroni, L., Garrity, D. M., Taylor, M. R. <strong>FLNC gene splice mutations cause dilated cardiomyopathy.</strong> JACC Basic Transl. Sci. 1: 344-359, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28008423/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28008423</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28008423[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.jacbts.2016.05.004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28008423">Begay et al. (2016)</a> identified heterozygosity for the same splice site mutation in the FLNC gene (<a href="#0013">102565.0013</a>). The mutation segregated with disease in both families, but was also present in the 34-year-old sister of the proband from family TSFDC029, who had a history of palpitations but an unremarkable echocardiogram, and declined further clinical follow-up. In a sister and brother from the US with CMD, the authors analyzed a panel of 4,813 clinical phenotype-associated genes and identified a different heterozygous splice site mutation in the FLNC gene (<a href="#0014">102565.0014</a>). Neither mutation was found in public variant databases. The authors noted that the FLNC variant carriers in the 3 families showed an arrhythmogenic trait, with high incidence of sudden cardiac death. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28008423" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2,877 patients with various inherited cardiovascular diseases, <a href="#13" class="mim-tip-reference" title="Ortiz-Genga, M. F., Cuenca, S., Dal Ferro, M., Zorio, E., Salgado-Aranda, R., Climent, V., Padron-Barthe, L., Duro-Aguado, I., Jimenez-Jaimez, J., Hidalgo-Olivares, V. M., Garcia-Campo, E., Lanzillo, C., and 24 others. <strong>Truncating FLNC mutations are associated with high-risk dilated and arrhythmogenic cardiomyopathies.</strong> J. Am. Coll. Cardiol. 68: 2440-2451, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27908349/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27908349</a>] [<a href="https://doi.org/10.1016/j.jacc.2016.09.927" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27908349">Ortiz-Genga et al. (2016)</a> analyzed 213 genes associated with inherited cardiovascular disease and sudden death, and identified 28 probands with truncating mutations in the FLNC gene (see, e.g., <a href="#0015">102565.0015</a> and <a href="#0016">102565.0016</a>), including 20 patients previously diagnosed with dilated cardiomyopathy, 7 with arrhythmogenic cardiomyopathy with predominantly left ventricular involvement, and 1 with restrictive cardiomyopathy. Complete cosegregation of the mutation with the cardiac phenotype was shown in the 23 families that agreed to be investigated. Fifty-four carrier relatives were identified, of which 23 (43%) were asymptomatic, although cardiac changes were found in 40 (74%) of them. Immunohistochemical staining of myocardial tissue showed the presence of filamin C only in intercalated discs, in both patients and controls, suggesting that the mechanism involved is different than that previously observed with myofibrillar myopathy. The authors concluded that FLNC truncating mutations are associated with a characteristic cardiac phenotype that includes left ventricular dilation with systolic dysfunction and myocardial fibrosis, frequent ventricular arrhythmias, and a high incidence of sudden cardiac death. There was no evidence of skeletal myopathy in these patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27908349" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In affected members of 2 unrelated families with arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVD15; see <a href="/entry/617047">617047</a>), <a href="#5" class="mim-tip-reference" title="Brun, F., Gigli, M., Graw, S. L., Judge, D. P., Merlo, M., Murray, B., Calkins, H., Sinagra, G., Taylor, M. R. G., Mestroni, L., James, C. A. <strong>FLNC truncations cause arrhythmogenic right ventricular cardiomyopathy.</strong> J. Med. Genet. 57: 254-257, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31924696/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31924696</a>] [<a href="https://doi.org/10.1136/jmedgenet-2019-106394" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31924696">Brun et al. (2020)</a> identified heterozygous truncating mutations in the FLNC gene, a nonsense mutation (E2189X; <a href="#0017">102565.0017</a>) in one family and a 1-bp deletion (<a href="#0018">102565.0018</a>) in the other. Neither mutation was found in gnomAD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31924696" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#7" class="mim-tip-reference" title="Chevessier, F., Schuld, J., Orfanos, Z., Plank, A.-C., Wolf, L., Maerkens, A., Unger, A., Schlotzer-Schrehardt, U., Kley, R. A., Von Horsten, S., Marcus, K., Linke, W. A., Vorgerd, M., van der Ven, P. F. M., Furst, D. O., Schroder, R. <strong>Myofibrillar instability exacerbated by acute exercise in filaminopathy.</strong> Hum. Molec. Genet. 24: 7207-7220, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26472074/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26472074</a>] [<a href="https://doi.org/10.1093/hmg/ddv421" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26472074">Chevessier et al. (2015)</a> created knockin mice harboring a W2711X mutation in Flnc corresponding to the W2710X mutation (<a href="#0001">102565.0001</a>) in human patients with MFM5. Heterozygous knockin mice expressed both wildtype and mutant Flnc alleles at comparable levels. No kyphosis or focal muscle atrophy was observed in mutant mice at any age, but reduced grip strength or muscle weakness was evident beginning at 4 months of age. Histologic analysis of skeletal muscle from sedentary heterozygous knockin mice showed no overt defects up to 8 months of age. However, ultrastructural analysis revealed abnormalities, such as enlarged mitochondria and autophagic vacuoles, in 3-month-old mutant mice. Myofibrillar degeneration in mutant mice started at Z-discs, and myofibrillar lesions were observed. These lesions appeared as electron-dense material between adjacent Z-discs and spanned as little as a single sarcomere or extended across multiple sarcomeres and included several neighboring myofibrils. Similar pathology was also detected in diaphragm and was exacerbated by eccentric exercise. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26472074" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#3" class="mim-tip-reference" title="Begay, R. L., Tharp, C. A., Martin, A., Graw, S. L., Sinagra, G., Miani, D., Sweet, M. E., Slavov, D. B., Stafford, N., Zeller, M. J., Alnefaie, R., Rowland, T. J., Brun, F., Jones, K. L., Gowan, K., Mestroni, L., Garrity, D. M., Taylor, M. R. <strong>FLNC gene splice mutations cause dilated cardiomyopathy.</strong> JACC Basic Transl. Sci. 1: 344-359, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28008423/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28008423</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28008423[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.jacbts.2016.05.004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28008423">Begay et al. (2016)</a> generated zebrafish with knockdown of flncb, the FLNC ortholog with greatest sequence similarity to the human gene. The morphant zebrafish showed pericardial edema, dysmorphic or dilated cardiac chambers, and abnormal looping of the heart tube suggestive of systolic dysfunction at 48 hours postfertilization (hpf) and 72 hpf. At 48 hpf, 9% of the morphants lacked circulation entirely, indicating a functional cardiac defect; the remaining 91% showed varying degrees of reduced blood circulation, with an increase in retrograde flow and overall weaker contractility. In addition, heart rate was slower in the morphants than controls. Ultrastructural analysis of transverse ventricular sections showed myofibrils composed of fewer consecutive sarcomeres in the morphants than wildtype zebrafish, or myofibrils in abnormal arrangements with Z-discs. In most cases, Z-discs appeared irregular or absent; however, cross-sections revealed that the primary arrangement of thick and thin filaments into hexagonal lattices appeared normal, suggesting that initial sarcomerogenesis was normal, but that myofibril growth was impaired. In addition, morphant cardiomyocytes developed small vacuoles associated with or near the cell membrane, suggesting that intercellular attachments had ruptured. The authors suggested that flncb plays an important role in maintaining sarcomere stability and cardiomyocyte attachment as mechanical stress increases in the developing embryonic heart. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28008423" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#10" class="mim-tip-reference" title="Kono, S., Nishio, T., Takahashi, Y., Goto-Inoue, N., Kinoshita, M., Zaima, N., Suzuki, H., Fukutoku-Otsuji, A., Setou, M., Miyajima, H. <strong>Dominant-negative effects of a novel mutation in the filamin myopathy.</strong> Neurology 75: 547-554, 2010. Note: Retraction: Neurology 75: 2138 only, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20697107/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20697107</a>] [<a href="https://doi.org/10.1212/WNL.0b013e3181ec7fbd" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20697107">Kono et al. (2010)</a> identified a heterozygous 1-bp deletion (8107delG) in exon 48 of the FLNC gene in affected members of a Japanese family with adult-onset myofibrillar myopathy primarily affecting the distal limbs, with later involvement of proximal muscles. However, the paper was later retracted by the authors after the mutation was found to occur in the FLNC pseudogene, based on the report of <a href="#17" class="mim-tip-reference" title="Van der Ven, P. F. M., Odgerel, Z., Furst, D. O., Goldfarb, L. G. <strong>Dominant-negative effects of a novel mutation in the filamin myopathy. (Letter)</strong> Neurology 75: 2137-2138, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21135393/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21135393</a>] [<a href="https://doi.org/10.1212/WNL.0b013e3182031bb3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21135393">van der Ven et al. (2010)</a>. <a href="#17" class="mim-tip-reference" title="Van der Ven, P. F. M., Odgerel, Z., Furst, D. O., Goldfarb, L. G. <strong>Dominant-negative effects of a novel mutation in the filamin myopathy. (Letter)</strong> Neurology 75: 2137-2138, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21135393/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21135393</a>] [<a href="https://doi.org/10.1212/WNL.0b013e3182031bb3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21135393">Van der Ven et al. (2010)</a> noted that the pseudogene is 98% homologous to exons 46, 47, and 48 of the functional FLNC gene and that the pseudogene contains the 8107delG variant. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=21135393+20697107" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121909518 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909518;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=rs121909518" 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=rs121909518" 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=RCV000019978 OR RCV001052798 OR RCV001091493" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000019978, RCV001052798, RCV001091493" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000019978...</a>
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<p>In affected members of a German family with autosomal dominant myofibrillar myopathy-5 (MFM5; <a href="/entry/609524">609524</a>), <a href="#19" class="mim-tip-reference" title="Vorgerd, M., van der Ven, P. F. M., Bruchertseifer, V., Lowe, T., Kley, R. A., Schroder, R., Lochmuller, H., Himmel, M., Koehler, K., Furst, D. O., Huebner, A. <strong>A mutation in the dimerization domain of filamin C causes a novel type of autosomal dominant myofibrillar myopathy.</strong> Am. J. Hum. Genet. 77: 297-304, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15929027/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15929027</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15929027[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/431959" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15929027">Vorgerd et al. (2005)</a> identified a heterozygous c.8130G-A transition in exon 48 of the FLNC gene, resulting in a trp2710-to-ter (W2710X) substitution. The mutation leads to a truncation of the filamin C immunoglobulin domain that is responsible for dimerization. Functional expression studies showed that the W2710X protein had improper folding, was unable to form dimers, and showed abnormal aggregation. The findings implied that dimer formation is essential for the biologic function of filamin. The mutation was not identified in 220 control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15929027" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Variant Function</em></strong></p><p>
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By in vitro functional expression studies, <a href="#12" class="mim-tip-reference" title="Lowe, T., Kley, R. A., van der Ven, P. F. M., Himmel, M., Huebner, A., Vorgerd, M., Furst, D. O. <strong>The pathomechanism of filaminopathy: altered biochemical properties explain the cellular phenotype of a protein aggregation myopathy.</strong> Hum. Molec. Genet. 16: 1351-1358, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17412757/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17412757</a>] [<a href="https://doi.org/10.1093/hmg/ddm085" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17412757">Lowe et al. (2007)</a> showed that W2710X-mutant protein was less stable and more susceptible to proteolysis compared to wildtype. The mutant protein did not dimerize properly and formed filamin aggregates in cultured cells. Aggregation of mutant protein did not affect dimerization of wildtype filamin C, and the mutant protein still showed normal binding to actin and sarcoglycans. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17412757" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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=RCV000019979 OR RCV003144109" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000019979, RCV003144109" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000019979...</a>
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<p>In a German mother and daughter with autosomal dominant myofibrillar myopathy-5 (MFM5; <a href="/entry/609524">609524</a>), <a href="#14" class="mim-tip-reference" title="Shatunov, A., Olive, M., Odgerel, Z., Stadelmann-Nessler, C., Irlbacher, K., van Landeghem, F., Bayarsaikhan, M., Lee, H.-S., Goudeau, B., Chinnery, P. F., Straub, V., Hilton-Jones, D., and 9 others. <strong>In-frame deletion in the seventh immunoglobulin-like repeat of filamin C in a family with myofibrillar myopathy.</strong> Europ. J. Hum. Genet. 17: 656-663, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19050726/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19050726</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19050726[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ejhg.2008.226" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19050726">Shatunov et al. (2009)</a> identified a heterozygous 12-bp deletion (c.2997_3008del, NM_001458.4) in exon 18 of the FLNC gene, predicted to result in an in-frame deletion of 4 residues (val930 to thr933) in the seventh repeat and confirmed by RT-PCR analysis of muscle tissue from the affected daughter. The phenotype was characterized by adult-onset muscle weakness initially involving proximal muscles of the lower limbs and spreading to the upper limbs and distal muscles of lower extremities. Both had paraspinal and abdominal muscle involvement and winging of the scapula. Cardiac and respiratory muscles were not affected. Skeletal muscle biopsy from the daughter showed marked variation in fiber size, some fibers with internal nuclei, and type 1 fiber predominance. Several fibers showed polymorphous hyaline and nonhyaline myofibrillary FLNC-positive inclusions with a convoluted, serpentine appearance. Ultrastructural examination showed major myofibrillar abnormalities, with accumulation of Z disc debris, granulofilamentous material, and nemaline rods. There were also mitochondrial aggregates. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19050726" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs387906586 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906586;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=rs387906586" 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=rs387906586" 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=RCV000022428 OR RCV001781296" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000022428, RCV001781296" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000022428...</a>
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<p>In affected members of a large Australian family with autosomal dominant distal myopathy-4 (MPD4; <a href="/entry/614065">614065</a>) originally reported by <a href="#20" class="mim-tip-reference" title="Williams, D. R., Reardon, K., Roberts, L., Dennet, X., Duff, R., Laing, N. G., Byrne, E. <strong>A new dominant distal myopathy affecting posterior leg and anterior upper limb muscles.</strong> Neurology 64: 1245-1254, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15824355/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15824355</a>] [<a href="https://doi.org/10.1212/01.WNL.0000156524.95261.B9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15824355">Williams et al. (2005)</a>, <a href="#8" class="mim-tip-reference" title="Duff, R. M., Tay, V., Hackman, P., Ravenscroft, G., McLean, C., Kennedy, P., Steinbach, A., Schoffler, W., van der Ven, P. F., Furst, D. O., Song, J., Djinovic-Carugo, K., and 12 others. <strong>Mutations in the N-terminal actin-binding domain of filamin C cause a distal myopathy.</strong> Am. J. Hum. Genet. 88: 729-740, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21620354/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21620354</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21620354[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2011.04.021" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21620354">Duff et al. (2011)</a> identified a heterozygous c.752T-C transition (c.752T-C, NM_001127487.1) in exon 4 of the FLNC gene, resulting in a met251-to-thr (M251T) substitution in a highly conserved residue in the CH2 domain in the actin-binding domain. The mutation was not found in 400 control chromosomes. The mutant protein had slightly decreased thermal stability and showed increased actin-binding activity compared to the wildtype protein. Transfection of the mutant M251T protein into cells showed significantly decreased nuclear localization compared to wildtype and resulted in the formation of intracellular protein aggregates. <a href="#8" class="mim-tip-reference" title="Duff, R. M., Tay, V., Hackman, P., Ravenscroft, G., McLean, C., Kennedy, P., Steinbach, A., Schoffler, W., van der Ven, P. F., Furst, D. O., Song, J., Djinovic-Carugo, K., and 12 others. <strong>Mutations in the N-terminal actin-binding domain of filamin C cause a distal myopathy.</strong> Am. J. Hum. Genet. 88: 729-740, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21620354/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21620354</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21620354[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2011.04.021" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21620354">Duff et al. (2011)</a> concluded that the disease mechanism somehow involves increased affinity for actin. The phenotype was characterized by adult onset of distal muscle weakness and atrophy affecting the upper and lower limbs, with nonspecific findings on muscle biopsy. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15824355+21620354" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs387906587 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906587;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/rs387906587?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs387906587" 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=rs387906587" 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=RCV000022429 OR RCV000442836 OR RCV000600715 OR RCV001384941 OR RCV001535684 OR RCV004555848" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000022429, RCV000442836, RCV000600715, RCV001384941, RCV001535684, RCV004555848" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000022429...</a>
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<p>In affected members of an Italian family with autosomal dominant distal myopathy-4 (MPD4; <a href="/entry/614065">614065</a>), <a href="#8" class="mim-tip-reference" title="Duff, R. M., Tay, V., Hackman, P., Ravenscroft, G., McLean, C., Kennedy, P., Steinbach, A., Schoffler, W., van der Ven, P. F., Furst, D. O., Song, J., Djinovic-Carugo, K., and 12 others. <strong>Mutations in the N-terminal actin-binding domain of filamin C cause a distal myopathy.</strong> Am. J. Hum. Genet. 88: 729-740, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21620354/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21620354</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21620354[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2011.04.021" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21620354">Duff et al. (2011)</a> identified a heterozygous c.577G-A transition (c.577G-A, NM_001127487.1) in exon 2 of the FLNC gene, resulting in an ala193-to-thr (A193T) substitution in a highly conserved residue in the CH2 domain in the actin-binding domain. The mutation was not found in 204 control chromosomes. The mutant protein had slightly decreased thermal stability and showed increased actin-binding activity compared to the wildtype protein. Nuclear localization was unaltered, but transfection resulted in the formation of intracellular protein aggregates. <a href="#8" class="mim-tip-reference" title="Duff, R. M., Tay, V., Hackman, P., Ravenscroft, G., McLean, C., Kennedy, P., Steinbach, A., Schoffler, W., van der Ven, P. F., Furst, D. O., Song, J., Djinovic-Carugo, K., and 12 others. <strong>Mutations in the N-terminal actin-binding domain of filamin C cause a distal myopathy.</strong> Am. J. Hum. Genet. 88: 729-740, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21620354/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21620354</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21620354[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2011.04.021" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21620354">Duff et al. (2011)</a> concluded that the disease mechanism somehow involves increased affinity for actin. The phenotype was characterized by adult onset of distal muscle weakness and atrophy affecting the upper and lower limbs, with nonspecific findings on muscle biopsy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21620354" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1562999443 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1562999443;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=rs1562999443" 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=rs1562999443" 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=RCV000239536 OR RCV001854932" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000239536, RCV001854932" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000239536...</a>
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<p>In all affected members of 2 Spanish families with hypertrophic cardiomyopathy (CMH26; <a href="/entry/617047">617047</a>) and a history of sudden death, <a href="#16" class="mim-tip-reference" title="Valdes-Mas, R., Gutierrez-Fernandez, A., Gomez, J., Coto, E., Astudillo, A., Puente, D. A., Reguero, J. R., Alvarez, V., Moris, C., Leon, D., Martin, M., Puente, X. S., Lopez-Otin, C. <strong>Mutations in filamin C cause a new form of familial hypertrophic cardiomyopathy.</strong> Nature Commun. 5: 5326, 2014. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25351925/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25351925</a>] [<a href="https://doi.org/10.1038/ncomms6326" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25351925">Valdes-Mas et al. (2014)</a> identified heterozygosity for a G-A transition (chr7.128,488,649G-A, GRCh37) in the FLNC gene, resulting in an ala1539-to-thr (A1539T) substitution at a highly conserved residue within a C-terminal rod repeat. The mutation showed reduced penetrance, being detected in 2 asymptomatic family members from 1 of the families, a 12-year-old girl and a 52-year-old man, both of whom had normal electrocardiography and echocardiogram. The variant was not found in more than 400 Spanish controls, or the 1000 Genomes Project or Exome Sequencing Project databases. Cardiac muscle histology from 1 family member who underwent heart transplantation showed marked sarcomeric abnormalities, including myofibrillar disarray, sarcomeric aggregates, and fibrosis; immunohistochemical staining confirmed the presence of filamin C in the sarcomeric aggregates. In contrast, skeletal muscle biopsy from an affected individual showed intact sarcomeric structures and normal ATPase, SDH, and NADH staining, as well as the absence of the characteristic small aggregates of myofibrillar myopathy. When the A1539T mutant was expressed in rat neonatal cardiac myocytes, large perinuclear filamin-C aggregates were observed. Overexpression of A1539T in C2C12 mouse skeletal muscle myoblasts also resulted in formation of protein aggregates, although they were smaller than those observed in cardiac myocytes, supporting a model in which interaction of these mutants with tissue-specific proteins contributes to the predominant cardiac phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25351925" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1563003848 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1563003848;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=rs1563003848" 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=rs1563003848" 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=RCV000239587" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000239587" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000239587</a>
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<p>In 3 affected sibs from a Spanish family with hypertrophic cardiomyopathy (CMH26; <a href="/entry/617047">617047</a>), <a href="#16" class="mim-tip-reference" title="Valdes-Mas, R., Gutierrez-Fernandez, A., Gomez, J., Coto, E., Astudillo, A., Puente, D. A., Reguero, J. R., Alvarez, V., Moris, C., Leon, D., Martin, M., Puente, X. S., Lopez-Otin, C. <strong>Mutations in filamin C cause a new form of familial hypertrophic cardiomyopathy.</strong> Nature Commun. 5: 5326, 2014. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25351925/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25351925</a>] [<a href="https://doi.org/10.1038/ncomms6326" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25351925">Valdes-Mas et al. (2014)</a> identified heterozygosity for a C-A transversion (chr7.128,494,682C-A, GRCh37) in the FLNC gene, resulting in a his2315-to-asn (H2315N) substitution at a highly conserved residue within a C-terminal rod repeat. The mutation showed reduced penetrance, being detected in 1 asymptomatic family member, a 29-year-old man with normal electrocardiography and echocardiogram. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25351925" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1562991002 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1562991002;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=rs1562991002" 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=rs1562991002" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a Spanish father and son with hypertrophic cardiomyopathy (CMH26; <a href="/entry/617047">617047</a>), <a href="#16" class="mim-tip-reference" title="Valdes-Mas, R., Gutierrez-Fernandez, A., Gomez, J., Coto, E., Astudillo, A., Puente, D. A., Reguero, J. R., Alvarez, V., Moris, C., Leon, D., Martin, M., Puente, X. S., Lopez-Otin, C. <strong>Mutations in filamin C cause a new form of familial hypertrophic cardiomyopathy.</strong> Nature Commun. 5: 5326, 2014. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25351925/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25351925</a>] [<a href="https://doi.org/10.1038/ncomms6326" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25351925">Valdes-Mas et al. (2014)</a> identified heterozygosity for a T-C transition (chr7.128,475,395T-C, GRCh37) in the FLNC gene, resulting in a val123-to-ala (V123A) substitution at a highly conserved residue within the N-terminal actin-binding domain. Western blot analysis of transiently transfected H9C2 rat cardiomyocytes showed that the V123A mutant was detected in the insoluble fraction, with formation of actin aggregates, whereas wildtype FLNC was exclusively present in the insoluble fraction. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25351925" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 CARDIOMYOPATHY, FAMILIAL RESTRICTIVE, 5</strong>
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CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 26, INCLUDED
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs879255639 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs879255639;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/rs879255639?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs879255639" 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=rs879255639" 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=RCV000239540 OR RCV001223109 OR RCV002255096 OR RCV003150143 OR RCV003372670 OR RCV004547624" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000239540, RCV001223109, RCV002255096, RCV003150143, RCV003372670, RCV004547624" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000239540...</a>
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<p><strong><em>Familial Restrictive Cardiomyopathy 5</em></strong></p><p>
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In a 4-generation Canadian family with restrictive cardiomyopathy (RCM5; see <a href="/entry/617047">617047</a>), <a href="#4" class="mim-tip-reference" title="Brodehl, A., Ferrier, R. A., Hamilton, S. J., Greenway, S. C., Brundler, M.-A., Yu, W., Gibson, W. T., McKinnon, M. L., McGillivray, B., Alvarez, N., Giuffre, M., Schwartzentruber, J., FORGE Canada Consortium, Gerull, B. <strong>Mutations in FLNC are associated with familial restrictive cardiomyopathy.</strong> Hum. Mutat. 37: 269-279, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26666891/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26666891</a>] [<a href="https://doi.org/10.1002/humu.22942" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26666891">Brodehl et al. (2016)</a> identified heterozygosity for a c.4871C-T transition (c.4871C-T, NM_001458.4) in the FLNC gene, resulting in a ser1624-to-leu (S1624L) substitution at a highly conserved residue within the 14th immunoglobulin-like domain. The mutation segregated with disease and was not found in public variant databases, including the ExAC database. Immunohistochemical analysis of explanted cardiac tissue from the left ventricular wall and septum of the proband showed filamin-C aggregates and disturbed Z-disc staining, and did not show the normal intercalated disc localization of desmin (DES; <a href="/entry/125660">125660</a>). Functional analysis in H9C2 rat cardiac myoblasts and C2C12 mouse skeletal myoblasts demonstrated that the S1624L mutant failed to show the wildtype cytoplasmic distribution, instead forming protein aggregates. The proband in this family presented at age 13 years with congestive heart failure and severe biatrial enlargement, and underwent cardiac transplantation at age 14; she later had dizygotic twin daughters, 1 of whom was affected and underwent cardiac transplantation before age 2 years. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26666891" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Familial Hypertrophic Cardiomyopathy 26</em></strong></p><p>
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In a sister and brother with hypertrophic cardiomyopathy (CMH26; <a href="/entry/617047">617047</a>), <a href="#1" class="mim-tip-reference" title="Ader, F., De Groote, P., Reant, P., Rooryck-Thambo, C., Dupin-Deguine, D., Rambaud, C., Khraiche, D., Perret, C., Pruny, J. F., Mathieu-Dramard, M., Gerard, M., Troadec, Y., Gouya, L., Jeunemaitre, X., Van Maldergem, L., Hagege, A., Villard, E., Charron, P., Richard, P. <strong>FLNC pathogenic variants in patients with cardiomyopathies: prevalence and genotype-phenotype correlations.</strong> Clin. Genet. 96: 317-329, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31245841/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31245841</a>] [<a href="https://doi.org/10.1111/cge.13594" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31245841">Ader et al. (2019)</a> identified heterozygosity for the S1624L mutation in the FLNC gene. DNA was not available from their affected mother, who had died at age 42 years during heart transplantation. All 3 patients presented an atypical CMH phenotype with a restrictive profile. The proband (patient 12), who was diagnosed with CMH at age 42 years and had congestive heart failure, exhibited a maximum wall thickness of 18 mm but a preserved interventricular septum (11 mm), with normal systolic function. Her brother was diagnosed with CMH at age 45 years and underwent cardiac transplantation at age 54. The authors suggested that this family presented a mixed phenotype of CMH and RCM, and noted similarities to the Canadian family reported by <a href="#4" class="mim-tip-reference" title="Brodehl, A., Ferrier, R. A., Hamilton, S. J., Greenway, S. C., Brundler, M.-A., Yu, W., Gibson, W. T., McKinnon, M. L., McGillivray, B., Alvarez, N., Giuffre, M., Schwartzentruber, J., FORGE Canada Consortium, Gerull, B. <strong>Mutations in FLNC are associated with familial restrictive cardiomyopathy.</strong> Hum. Mutat. 37: 269-279, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26666891/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26666891</a>] [<a href="https://doi.org/10.1002/humu.22942" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26666891">Brodehl et al. (2016)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=31245841+26666891" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 CARDIOMYOPATHY, FAMILIAL RESTRICTIVE, 5</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs879255640 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs879255640;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=rs879255640" 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=rs879255640" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a 4-generation Canadian family with restrictive cardiomyopathy (RCM5; see <a href="/entry/617047">617047</a>), <a href="#4" class="mim-tip-reference" title="Brodehl, A., Ferrier, R. A., Hamilton, S. J., Greenway, S. C., Brundler, M.-A., Yu, W., Gibson, W. T., McKinnon, M. L., McGillivray, B., Alvarez, N., Giuffre, M., Schwartzentruber, J., FORGE Canada Consortium, Gerull, B. <strong>Mutations in FLNC are associated with familial restrictive cardiomyopathy.</strong> Hum. Mutat. 37: 269-279, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26666891/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26666891</a>] [<a href="https://doi.org/10.1002/humu.22942" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26666891">Brodehl et al. (2016)</a> identified heterozygosity for a c.6478A-T transversion (c.6478A-T, NM_001458.4) in the FLNC gene, resulting in an ile2160-to-phe (I2160F) substitution at a highly conserved residue within the 19th immunoglobulin-like domain. The mutation segregated with disease and was not found in public variant databases, including the ExAC database. Immunohistochemical analysis of explanted cardiac tissue from the proband revealed that the normal intercalated disc localization of desmin (DES; <a href="/entry/125660">125660</a>) was absent, but no obvious filamin-C aggregates were present. This family was evaluated after the asymptomatic 15-year-old female proband was diagnosed with severe diastolic dysfunction, enlarged atria, and elevated pulmonary pressure, suggesting RCM. Her brother, father, and paternal uncle were known to have cardiomyopathy, with features of RCM on echocardiography. In addition, 2 paternal first cousins had RCM. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26666891" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1585173340 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1585173340;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=rs1585173340" 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=rs1585173340" 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=RCV000855733 OR RCV001038999 OR RCV001267920 OR RCV001290001" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000855733, RCV001038999, RCV001267920, RCV001290001" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000855733...</a>
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<p>In 34 Chinese individuals with autosomal dominant myofibrillar myopathy-5 (MFM5; <a href="/entry/609524">609524</a>) from 9 apparently unrelated families in Hong Kong, <a href="#11" class="mim-tip-reference" title="Lee, H.-C. H., Wong, S., Sheng, B., Pan, N.-Y. K., Leung, Y.-K. F., Lau, K.-K. D., Cheng, Y. S., Ho, C.-C., Li, R., Lee, C.-N., Tsoi, T.-H., Cheung, Y.-F. N., and 21 others. <strong>Clinical and pathological characterization of FLNC-related myofibrillar myopathy caused by founder variant c.8129G-A in Hong Kong Chinese.</strong> Clin. Genet. 97: 747-757, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32022900/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32022900</a>] [<a href="https://doi.org/10.1111/cge.13715" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32022900">Lee et al. (2020)</a> identified a heterozygous c.8129G-A transition (c.8129G-A, NM_001458.4) in the FLNC gene, resulting in a trp2710-to-ter (W2710X) substitution. The mutation, which was found by Sanger sequencing of the FLNC gene, was not present in the Exome Sequencing Project, 1000 Genomes Project, gnomAD, ethnic-specific Chinese Millionome, and Virtual Chinese Genome databases. The mutation affects the same amino acid residue as that in a German family with MFM5 with a different basepair substitution in the same codon (c.8130G-A, <a href="#0001">102565.0001</a>). The mutation is predicted to eliminate the last 16 amino acids at the C terminus, resulting in reduced stability of the dimerization domain. Functional studies were not performed. Polymorphic marker analysis on the 9 probands identified a distinct haplotype that was not detected among 20 ethnically matched control chromosomes. The mutation was estimated to have occurred 42 to 71 generations previously, dating it to 844 to 1,315 years earlier. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32022900" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a 53-year-old Italian man (patient 1) with distal myopathy-4 (MPD4; <a href="/entry/614065">614065</a>), <a href="#18" class="mim-tip-reference" title="Velardo, D., D'Angelo, M. G., Citterio, A., Panzeri, E., Napoli, L., Cinnante, C., Moggio, M., Comi, G. P., Ronchi, D., Bassi, M. T. <strong>Case reports: novel missense variants in the filamin C actin binding domain cause variable phenotypes.</strong> Front. Neurol. 13: 930039, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35903116/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35903116</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=35903116[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.3389/fneur.2022.930039" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35903116">Velardo et al. (2022)</a> identified a novel de novo heterozygous T-to-C transition (c.665T-C, NM_001458) in exon 3 of the FLNC gene, resulting in met222-to-thr (M222T) substitution at an evolutionarily conserved position. The mutation was identified by trio exome sequencing. No other family members were affected, and the patient's asymptomatic sibs did not carry the mutation. Functional studies of the mutation were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35903116" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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=RCV002284053 OR RCV002290862 OR RCV002382502" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV002284053, RCV002290862, RCV002382502" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV002284053...</a>
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<p>In a 33-year-old Italian man (patient 2) with distal myopathy-4 (MPD4; <a href="/entry/614065">614065</a>), <a href="#18" class="mim-tip-reference" title="Velardo, D., D'Angelo, M. G., Citterio, A., Panzeri, E., Napoli, L., Cinnante, C., Moggio, M., Comi, G. P., Ronchi, D., Bassi, M. T. <strong>Case reports: novel missense variants in the filamin C actin binding domain cause variable phenotypes.</strong> Front. Neurol. 13: 930039, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35903116/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35903116</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=35903116[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.3389/fneur.2022.930039" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35903116">Velardo et al. (2022)</a> identified a novel heterozygous G-to-A transition (c.733G-A, NM_001458) in exon 4 of the FLNC gene, resulting in a val245-to-met (V245M) substitution at an evolutionarily conserved position. The mutation was identified by sequencing with a panel of genes involved in muscle disorders. Functional studies were not performed. The mutation was inherited from the patient's 65-year-old clinically asymptomatic father, who on testing had abnormal muscle MRI findings. The proband also had 2 affected maternal uncles who carried the mutation: one, age 60, was unable to lift on his toes, and the other, age 57, had a dilated cardiomyopathy without apparent skeletal muscle involvement. <a href="#18" class="mim-tip-reference" title="Velardo, D., D'Angelo, M. G., Citterio, A., Panzeri, E., Napoli, L., Cinnante, C., Moggio, M., Comi, G. P., Ronchi, D., Bassi, M. T. <strong>Case reports: novel missense variants in the filamin C actin binding domain cause variable phenotypes.</strong> Front. Neurol. 13: 930039, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35903116/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35903116</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=35903116[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.3389/fneur.2022.930039" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35903116">Velardo et al. (2022)</a> stated that this family emphasized the extreme intrafamilial variability in clinical manifestations, necessitating testing of asymptomatic relatives. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35903116" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1554401581 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1554401581;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=rs1554401581" 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=rs1554401581" 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=RCV000649067 OR RCV003235326" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000649067, RCV003235326" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000649067...</a>
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<p>In affected members of 2 Italian families (TSFDC029 and TSFDC031) segregating autosomal dominant dilated cardiomyopathy (CMD1PP; see <a href="/entry/617047">617047</a>), <a href="#3" class="mim-tip-reference" title="Begay, R. L., Tharp, C. A., Martin, A., Graw, S. L., Sinagra, G., Miani, D., Sweet, M. E., Slavov, D. B., Stafford, N., Zeller, M. J., Alnefaie, R., Rowland, T. J., Brun, F., Jones, K. L., Gowan, K., Mestroni, L., Garrity, D. M., Taylor, M. R. <strong>FLNC gene splice mutations cause dilated cardiomyopathy.</strong> JACC Basic Transl. Sci. 1: 344-359, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28008423/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28008423</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28008423[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.jacbts.2016.05.004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28008423">Begay et al. (2016)</a> identified heterozygosity for the same splice site mutation in intron 43 (c.7251+1G-A, NM_001458) of the FLNC gene. The mutation segregated with disease in both families, but was also present in the 34-year-old sister of the proband from family TSFDC029, who had a history of palpitations and an unremarkable echocardiogram, and declined further clinical follow-up. The authors noted that the splice site mutation was thus 83% penetrant. Analysis of nearby genotypes in the 2 families, who lived in the same region of Italy, was consistent with a shared ancestral haplotype. Sanger sequencing of patient transcripts confirmed the absence of FLNC exon 43, causing a frameshift predicted to result in premature truncation of the protein 21 amino acids downstream of the mutation site. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28008423" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0014 CARDIOMYOPATHY, FAMILIAL DILATED, 1PP</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1563001548 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1563001548;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=rs1563001548" 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=rs1563001548" 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=RCV000686980 OR RCV003235349" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000686980, RCV003235349" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000686980...</a>
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<p>In a sister and brother (family DNFDC057) with dilated cardiomyopathy (CMD1PP; see <a href="/entry/617047">617047</a>), <a href="#3" class="mim-tip-reference" title="Begay, R. L., Tharp, C. A., Martin, A., Graw, S. L., Sinagra, G., Miani, D., Sweet, M. E., Slavov, D. B., Stafford, N., Zeller, M. J., Alnefaie, R., Rowland, T. J., Brun, F., Jones, K. L., Gowan, K., Mestroni, L., Garrity, D. M., Taylor, M. R. <strong>FLNC gene splice mutations cause dilated cardiomyopathy.</strong> JACC Basic Transl. Sci. 1: 344-359, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28008423/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28008423</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28008423[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.jacbts.2016.05.004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28008423">Begay et al. (2016)</a> identified heterozygosity for a splice site mutation (c.5669-1delG, NM_001458) in the FLNC gene. Mutation status was not reported for their deceased parents. Cardiac tissue from the sister's explanted heart showed decreased FLNC mRNA expression, as well as reduced FLNC protein, compared to control. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28008423" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0015 CARDIOMYOPATHY, FAMILIAL DILATED, 1PP</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV003236956" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV003236956" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV003236956</a>
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<p>In 8 affected members of 2 families (33319 and 29876) segregating autosomal dominant dilated cardiomyopathy (CMD1PP; see <a href="/entry/617047">617047</a>), <a href="#13" class="mim-tip-reference" title="Ortiz-Genga, M. F., Cuenca, S., Dal Ferro, M., Zorio, E., Salgado-Aranda, R., Climent, V., Padron-Barthe, L., Duro-Aguado, I., Jimenez-Jaimez, J., Hidalgo-Olivares, V. M., Garcia-Campo, E., Lanzillo, C., and 24 others. <strong>Truncating FLNC mutations are associated with high-risk dilated and arrhythmogenic cardiomyopathies.</strong> J. Am. Coll. Cardiol. 68: 2440-2451, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27908349/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27908349</a>] [<a href="https://doi.org/10.1016/j.jacc.2016.09.927" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27908349">Ortiz-Genga et al. (2016)</a> identified heterozygosity for a 1-bp deletion (c.4127+1delG, NM_001458.4) in intron 23 of the FLNC gene, abolishing the splice donor site and predicted to cause a frameshift resulting in premature termination. The mutation was also present in the asymptomatic 32-year-old daughter of the proband in family 33319, for whom no cardiac studies were available. Among the 8 symptomatic individuals, 3 were designated as having a phenotype of dilated cardiomyopathy, and 5 as having left-dominant arrhythmogenic cardiomyopathy (LDACM); patients with either designation exhibited frequent ventricular ectopy as well as ventricular tachycardia, sustained or nonsustained. In addition, palmoplantar keratoderma was observed in 4 of the 6 affected individuals in family 29876. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27908349" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0016 CARDIOMYOPATHY, FAMILIAL RESTRICTIVE, 5</strong>
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FLNC, IVS28, 1-BP DEL, 4927+1delG
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV003236957" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV003236957" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV003236957</a>
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<p>In a 55-year-old woman (family 31277) with restrictive cardiomyopathy and first-degree atrioventricular block (RCM5; see <a href="/entry/617047">617047</a>), <a href="#13" class="mim-tip-reference" title="Ortiz-Genga, M. F., Cuenca, S., Dal Ferro, M., Zorio, E., Salgado-Aranda, R., Climent, V., Padron-Barthe, L., Duro-Aguado, I., Jimenez-Jaimez, J., Hidalgo-Olivares, V. M., Garcia-Campo, E., Lanzillo, C., and 24 others. <strong>Truncating FLNC mutations are associated with high-risk dilated and arrhythmogenic cardiomyopathies.</strong> J. Am. Coll. Cardiol. 68: 2440-2451, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27908349/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27908349</a>] [<a href="https://doi.org/10.1016/j.jacc.2016.09.927" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27908349">Ortiz-Genga et al. (2016)</a> identified heterozygosity for a 1-bp deletion (c.4927+1delG, NM_001458.4) in intron 28 of the FLNC gene, abolishing the splice donor site and predicted to cause a frameshift resulting in premature termination. Familial segregation was not reported. The patient was diagnosed with RCM at age 29 years and underwent cardiac transplantation at age 45. She showed muscle weakness of the lower extremities during follow-up, and electromyography showed moderate myopathic changes; however, those changes were attributed to her treatment with simvastatin and corticosteroids. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27908349" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0017 ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA, FAMILIAL, 15</strong>
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FLNC, GLU2189TER
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV003236958" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV003236958" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV003236958</a>
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<p>In a 66-year-old woman and her 45-year-old nephew (family TSRVD029) with arrhythmogenic right ventricular cardiomyopathy (ARVD15; see <a href="/entry/617047">617047</a>), <a href="#5" class="mim-tip-reference" title="Brun, F., Gigli, M., Graw, S. L., Judge, D. P., Merlo, M., Murray, B., Calkins, H., Sinagra, G., Taylor, M. R. G., Mestroni, L., James, C. A. <strong>FLNC truncations cause arrhythmogenic right ventricular cardiomyopathy.</strong> J. Med. Genet. 57: 254-257, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31924696/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31924696</a>] [<a href="https://doi.org/10.1136/jmedgenet-2019-106394" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31924696">Brun et al. (2020)</a> identified heterozygosity for a c.6565G-T transversion (c.6565G-T, NM_001458) in exon 40 of the FLNC gene, resulting in a glu2189-to-ter (E2189X) substitution. The proband's sister had refractory supraventricular arrhythmias, and a male cousin died of progressive heart failure while awaiting heart transplantation; their mutation status was not reported. The mutation was not found in the gnomAD database. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31924696" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0018" class="mim-anchor"></a>
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<strong>.0018 ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA, FAMILIAL, 15</strong>
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FLNC, 1-BP DEL, 8107G
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1563006160 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1563006160;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=rs1563006160" 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=rs1563006160" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000685726 OR RCV003226966 OR RCV003237321 OR RCV004026209" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000685726, RCV003226966, RCV003237321, RCV004026209" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000685726...</a>
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<p>In a 37-year-old woman (family JHRVD0001) with arrhythmogenic right ventricular cardiomyopathy (ARVD15; see <a href="/entry/617047">617047</a>), <a href="#5" class="mim-tip-reference" title="Brun, F., Gigli, M., Graw, S. L., Judge, D. P., Merlo, M., Murray, B., Calkins, H., Sinagra, G., Taylor, M. R. G., Mestroni, L., James, C. A. <strong>FLNC truncations cause arrhythmogenic right ventricular cardiomyopathy.</strong> J. Med. Genet. 57: 254-257, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31924696/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31924696</a>] [<a href="https://doi.org/10.1136/jmedgenet-2019-106394" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31924696">Brun et al. (2020)</a> identified heterozygosity for a de novo 1-bp deletion (c.8107delG, NM_001458) in exon 48 of the FLNC gene, causing a frameshift predicted to result in a premature termination codon (Asp2703ThrfsTer69). The mutation was not found in her unaffected parents or in the gnomAD database. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31924696" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="references"class="mim-anchor"></a>
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<h4 href="#mimReferencesFold" id="mimReferencesToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimReferencesToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<strong>REFERENCES</strong>
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<a id="1" class="mim-anchor"></a>
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<a id="Ader2019" class="mim-anchor"></a>
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Ader, F., De Groote, P., Reant, P., Rooryck-Thambo, C., Dupin-Deguine, D., Rambaud, C., Khraiche, D., Perret, C., Pruny, J. F., Mathieu-Dramard, M., Gerard, M., Troadec, Y., Gouya, L., Jeunemaitre, X., Van Maldergem, L., Hagege, A., Villard, E., Charron, P., Richard, P.
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<strong>FLNC pathogenic variants in patients with cardiomyopathies: prevalence and genotype-phenotype correlations.</strong>
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Clin. Genet. 96: 317-329, 2019.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31245841/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31245841</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31245841" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1111/cge.13594" target="_blank">Full Text</a>]
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<a id="Beatham2004" class="mim-anchor"></a>
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Beatham, J., Romero, R., Townsend, S. K. M., Hacker, T., van der Ven, P. F. M., Blanco, G.
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<strong>Filamin C interacts with the muscular dystrophy KY protein and is abnormally distributed in mouse KY deficient muscle fibres.</strong>
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Hum. Molec. Genet. 13: 2863-2874, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15385448/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15385448</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15385448" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddh308" target="_blank">Full Text</a>]
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<a id="Begay2016" class="mim-anchor"></a>
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Begay, R. L., Tharp, C. A., Martin, A., Graw, S. L., Sinagra, G., Miani, D., Sweet, M. E., Slavov, D. B., Stafford, N., Zeller, M. J., Alnefaie, R., Rowland, T. J., Brun, F., Jones, K. L., Gowan, K., Mestroni, L., Garrity, D. M., Taylor, M. R.
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<strong>FLNC gene splice mutations cause dilated cardiomyopathy.</strong>
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JACC Basic Transl. Sci. 1: 344-359, 2016.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28008423/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28008423</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28008423[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=28008423" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.jacbts.2016.05.004" target="_blank">Full Text</a>]
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<a id="4" class="mim-anchor"></a>
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<a id="Brodehl2016" class="mim-anchor"></a>
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Brodehl, A., Ferrier, R. A., Hamilton, S. J., Greenway, S. C., Brundler, M.-A., Yu, W., Gibson, W. T., McKinnon, M. L., McGillivray, B., Alvarez, N., Giuffre, M., Schwartzentruber, J., FORGE Canada Consortium, Gerull, B.
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<strong>Mutations in FLNC are associated with familial restrictive cardiomyopathy.</strong>
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Hum. Mutat. 37: 269-279, 2016.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26666891/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26666891</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26666891" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/humu.22942" target="_blank">Full Text</a>]
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<a id="Brun2020" class="mim-anchor"></a>
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Brun, F., Gigli, M., Graw, S. L., Judge, D. P., Merlo, M., Murray, B., Calkins, H., Sinagra, G., Taylor, M. R. G., Mestroni, L., James, C. A.
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<strong>FLNC truncations cause arrhythmogenic right ventricular cardiomyopathy.</strong>
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J. Med. Genet. 57: 254-257, 2020.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31924696/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31924696</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31924696" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1136/jmedgenet-2019-106394" target="_blank">Full Text</a>]
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<a id="Chakarova2000" class="mim-anchor"></a>
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Chakarova, C., Wehnert, M. S., Uhl, K., Sakthivel, S., Vosberg, H.-P., van der Ven, P. F. M., Furst, D. O.
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<strong>Genomic structure and fine mapping of the two human filamin gene paralogues FLNB and FLNC and comparative analysis of the filamin gene family.</strong>
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Hum. Genet. 107: 597-611, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11153914/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11153914</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11153914" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s004390000414" target="_blank">Full Text</a>]
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<a id="7" class="mim-anchor"></a>
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<a id="Chevessier2015" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Chevessier, F., Schuld, J., Orfanos, Z., Plank, A.-C., Wolf, L., Maerkens, A., Unger, A., Schlotzer-Schrehardt, U., Kley, R. A., Von Horsten, S., Marcus, K., Linke, W. A., Vorgerd, M., van der Ven, P. F. M., Furst, D. O., Schroder, R.
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<strong>Myofibrillar instability exacerbated by acute exercise in filaminopathy.</strong>
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Hum. Molec. Genet. 24: 7207-7220, 2015.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26472074/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26472074</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26472074" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddv421" target="_blank">Full Text</a>]
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<a id="Duff2011" class="mim-anchor"></a>
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Duff, R. M., Tay, V., Hackman, P., Ravenscroft, G., McLean, C., Kennedy, P., Steinbach, A., Schoffler, W., van der Ven, P. F., Furst, D. O., Song, J., Djinovic-Carugo, K., and 12 others.
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<strong>Mutations in the N-terminal actin-binding domain of filamin C cause a distal myopathy.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21620354/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21620354</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21620354[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=21620354" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ajhg.2011.04.021" target="_blank">Full Text</a>]
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<a id="Gariboldi1994" class="mim-anchor"></a>
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<div class="">
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Gariboldi, M., Maestrini, E., Canzian, F., Manenti, G., De Gregorio, L., Rivella, S., Chatterjee, A., Herman, G. E., Archidiacono, N., Antonacci, R., Pierotti, M. A., Dragani, T. A., Toniolo, D.
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[<a href="https://doi.org/10.1006/geno.1994.1288" target="_blank">Full Text</a>]
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<div class="">
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Kono, S., Nishio, T., Takahashi, Y., Goto-Inoue, N., Kinoshita, M., Zaima, N., Suzuki, H., Fukutoku-Otsuji, A., Setou, M., Miyajima, H.
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<strong>Dominant-negative effects of a novel mutation in the filamin myopathy.</strong>
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Neurology 75: 547-554, 2010. Note: Retraction: Neurology 75: 2138 only, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20697107/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20697107</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20697107" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1212/WNL.0b013e3181ec7fbd" target="_blank">Full Text</a>]
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<a id="Lee2020" class="mim-anchor"></a>
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Lee, H.-C. H., Wong, S., Sheng, B., Pan, N.-Y. K., Leung, Y.-K. F., Lau, K.-K. D., Cheng, Y. S., Ho, C.-C., Li, R., Lee, C.-N., Tsoi, T.-H., Cheung, Y.-F. N., and 21 others.
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<strong>Clinical and pathological characterization of FLNC-related myofibrillar myopathy caused by founder variant c.8129G-A in Hong Kong Chinese.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32022900/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32022900</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32022900" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1111/cge.13715" target="_blank">Full Text</a>]
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<a id="Lowe2007" class="mim-anchor"></a>
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Lowe, T., Kley, R. A., van der Ven, P. F. M., Himmel, M., Huebner, A., Vorgerd, M., Furst, D. O.
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<strong>The pathomechanism of filaminopathy: altered biochemical properties explain the cellular phenotype of a protein aggregation myopathy.</strong>
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[<a href="https://doi.org/10.1093/hmg/ddm085" target="_blank">Full Text</a>]
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<a id="Ortiz-Genga2016" class="mim-anchor"></a>
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<div class="">
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Ortiz-Genga, M. F., Cuenca, S., Dal Ferro, M., Zorio, E., Salgado-Aranda, R., Climent, V., Padron-Barthe, L., Duro-Aguado, I., Jimenez-Jaimez, J., Hidalgo-Olivares, V. M., Garcia-Campo, E., Lanzillo, C., and 24 others.
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<strong>Truncating FLNC mutations are associated with high-risk dilated and arrhythmogenic cardiomyopathies.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27908349/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27908349</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27908349" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.jacc.2016.09.927" target="_blank">Full Text</a>]
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<a id="Shatunov2009" class="mim-anchor"></a>
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Shatunov, A., Olive, M., Odgerel, Z., Stadelmann-Nessler, C., Irlbacher, K., van Landeghem, F., Bayarsaikhan, M., Lee, H.-S., Goudeau, B., Chinnery, P. F., Straub, V., Hilton-Jones, D., and 9 others.
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<strong>In-frame deletion in the seventh immunoglobulin-like repeat of filamin C in a family with myofibrillar myopathy.</strong>
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Europ. J. Hum. Genet. 17: 656-663, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19050726/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19050726</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19050726[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=19050726" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ejhg.2008.226" target="_blank">Full Text</a>]
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<a id="Thompson2000" class="mim-anchor"></a>
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Thompson, T. G., Chan, Y.-M., Hack, A. A., Brosius, M., Rajala, M., Lidov, H. G. W., McNally, E. M., Watkins, S., Kunkel, L. M.
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<strong>Filamin 2 (FLN2): a muscle-specific sarcoglycan interacting protein.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10629222/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10629222</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10629222[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=10629222" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1083/jcb.148.1.115" target="_blank">Full Text</a>]
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<a id="16" class="mim-anchor"></a>
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<a id="Valdes-Mas2014" class="mim-anchor"></a>
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Valdes-Mas, R., Gutierrez-Fernandez, A., Gomez, J., Coto, E., Astudillo, A., Puente, D. A., Reguero, J. R., Alvarez, V., Moris, C., Leon, D., Martin, M., Puente, X. S., Lopez-Otin, C.
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<strong>Mutations in filamin C cause a new form of familial hypertrophic cardiomyopathy.</strong>
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Nature Commun. 5: 5326, 2014. Note: Electronic Article.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25351925/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25351925</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25351925" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ncomms6326" target="_blank">Full Text</a>]
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<a id="Van der Ven2010" class="mim-anchor"></a>
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Van der Ven, P. F. M., Odgerel, Z., Furst, D. O., Goldfarb, L. G.
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<strong>Dominant-negative effects of a novel mutation in the filamin myopathy. (Letter)</strong>
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Neurology 75: 2137-2138, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21135393/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21135393</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21135393" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1212/WNL.0b013e3182031bb3" target="_blank">Full Text</a>]
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<a id="Velardo2022" class="mim-anchor"></a>
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Velardo, D., D'Angelo, M. G., Citterio, A., Panzeri, E., Napoli, L., Cinnante, C., Moggio, M., Comi, G. P., Ronchi, D., Bassi, M. T.
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<strong>Case reports: novel missense variants in the filamin C actin binding domain cause variable phenotypes.</strong>
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Front. Neurol. 13: 930039, 2022.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35903116/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35903116</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=35903116[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=35903116" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.3389/fneur.2022.930039" target="_blank">Full Text</a>]
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<a id="Vorgerd2005" class="mim-anchor"></a>
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Vorgerd, M., van der Ven, P. F. M., Bruchertseifer, V., Lowe, T., Kley, R. A., Schroder, R., Lochmuller, H., Himmel, M., Koehler, K., Furst, D. O., Huebner, A.
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<strong>A mutation in the dimerization domain of filamin C causes a novel type of autosomal dominant myofibrillar myopathy.</strong>
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Am. J. Hum. Genet. 77: 297-304, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15929027/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15929027</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15929027[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=15929027" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1086/431959" target="_blank">Full Text</a>]
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Williams, D. R., Reardon, K., Roberts, L., Dennet, X., Duff, R., Laing, N. G., Byrne, E.
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<strong>A new dominant distal myopathy affecting posterior leg and anterior upper limb muscles.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15824355/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15824355</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15824355" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1212/01.WNL.0000156524.95261.B9" target="_blank">Full Text</a>]
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Xie, Z., Xu, W., Davie, E. W., Chung, D. W.
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<strong>Molecular cloning of human ABPL, an actin-binding protein homologue.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9791010/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9791010</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9791010" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1006/bbrc.1998.9506" target="_blank">Full Text</a>]
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Marla J. F. O'Neill - updated : 06/26/2023
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<span class="mim-text-font">
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Marla J. F. O'Neill - updated : 06/16/2023<br>Sonja A. Rasmussen - updated : 09/14/2022<br>Hilary J. Vernon - updated : 01/21/2021<br>Patricia A. Hartz - updated : 09/21/2016<br>Marla J. F. O'Neill - updated : 07/21/2016<br>Cassandra L. Kniffin - updated : 6/29/2011<br>Cassandra L. Kniffin - updated : 1/28/2011<br>Cassandra L. Kniffin - updated : 11/2/2010<br>Cassandra L. Kniffin - updated : 2/22/2010<br>George E. Tiller - updated : 5/22/2007<br>Patricia A. Hartz - updated : 9/21/2005<br>Cassandra L. Kniffin - updated : 8/9/2005<br>Victor A. McKusick - updated : 12/18/2000
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Creation Date:
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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Victor A. McKusick : 7/8/1993
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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alopez : 06/26/2023
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alopez : 06/16/2023<br>carol : 02/06/2023<br>carol : 01/10/2023<br>alopez : 09/14/2022<br>carol : 01/22/2021<br>carol : 01/21/2021<br>mgross : 09/21/2016<br>carol : 07/21/2016<br>carol : 08/07/2013<br>alopez : 2/3/2012<br>wwang : 7/1/2011<br>ckniffin : 6/29/2011<br>wwang : 2/24/2011<br>wwang : 2/21/2011<br>ckniffin : 1/28/2011<br>wwang : 12/7/2010<br>ckniffin : 11/2/2010<br>wwang : 2/23/2010<br>ckniffin : 2/22/2010<br>wwang : 6/15/2007<br>terry : 5/22/2007<br>mgross : 10/10/2005<br>mgross : 10/10/2005<br>terry : 9/21/2005<br>wwang : 8/30/2005<br>wwang : 8/12/2005<br>ckniffin : 8/9/2005<br>mcapotos : 1/18/2001<br>terry : 12/18/2000<br>alopez : 9/5/2000<br>alopez : 10/20/1999<br>carol : 3/30/1999<br>alopez : 12/4/1998<br>dkim : 7/17/1998<br>mark : 4/10/1997<br>jason : 6/8/1994<br>carol : 4/13/1994<br>carol : 8/16/1993<br>carol : 7/8/1993
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<span class="mim-font">
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<strong>*</strong> 102565
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<h3>
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FILAMIN C; FLNC
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<br />
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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<h4>
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FILAMIN, GAMMA<br />
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FILAMIN 2; FLN2<br />
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ACTIN-BINDING PROTEIN 280, AUTOSOMAL FORM; ABP280A<br />
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ABPA<br />
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ACTIN-BINDING PROTEIN-LIKE; ABPL
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: FLNC</em></strong>
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<strong>
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<em>
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Cytogenetic location: 7q32.1
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Genomic coordinates <span class="small">(GRCh38)</span> : 7:128,830,406-128,859,272 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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<strong>Gene-Phenotype Relationships</strong>
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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<span class="mim-font">
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7q32.1
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<span class="mim-font">
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Arrhythmogenic right ventricular dysplasia, familial
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<span class="mim-font">
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617047
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<span class="mim-font">
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Autosomal dominant
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<span class="mim-font">
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3
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Cardiomyopathy, familial hypertrophic, 26
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<span class="mim-font">
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617047
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<span class="mim-font">
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Autosomal dominant
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<span class="mim-font">
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3
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<span class="mim-font">
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Cardiomyopathy, familial restrictive 5
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<span class="mim-font">
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617047
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<span class="mim-font">
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Autosomal dominant
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<span class="mim-font">
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3
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<span class="mim-font">
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Myopathy, distal, 4
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<span class="mim-font">
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614065
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<span class="mim-font">
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Autosomal dominant
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<span class="mim-font">
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3
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Myopathy, myofibrillar, 5
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<span class="mim-font">
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609524
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<span class="mim-font">
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Autosomal dominant
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<span class="mim-font">
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3
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</table>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Filamins, such as FLNC, are a family of actin (see ACTA1; 102610)-binding proteins involved in reshaping of the cytoskeleton. See FLN1 (FLNA; 300017) for background information on the filamin gene family.</p>
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</span>
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<div>
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<br />
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</div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</h4>
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<span class="mim-text-font">
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<p>Xie et al. (1998) cloned FLNC, which they called ABPL, from a heart cDNA library. The deduced 2,705-amino acid protein has a calculated molecular mass of 289 kD. ABPL contains an N-terminal actin-binding domain, followed by 24 repeats of about 94 amino acids. It has hinge sequences prior to repeats 16 and 24. Xie et al. (1998) also identified an alternatively spliced transcript that encodes a protein lacking hinge 1. PCR analysis detected transcripts encoding the hinge 1-containing isoform in stomach, uterus, umbilical vein endothelial cells, and prostate. Transcripts encoding both isoforms were detected in heart, thyroid, fetal brain, fetal lung, retina, spinal cord, skeletal muscle, and bone marrow. </p><p>Using sarcoglycan-gamma (SGCG; 608896) as bait in a yeast 2-hybrid screen of a skeletal muscle cDNA library, followed by EST database analysis and screening of a skeletal muscle cDNA library, Thompson et al. (2000) cloned FLNC, which they called FLN2. The deduced 2,688-amino acid protein shares 74% and 71% identity with FLN1 and filamin-beta (FLNB; 603381), respectively, and the 3 proteins are nearly 100% identical in the actin-binding domains. FLN2 lacks the first hinge region present in FLN1 and FLNB, but it has the second hinge region. Like FLN1 and FLNB, FLNC has a C-terminal domain containing binding sites for several receptor proteins. Western blot analysis detected a 280-kD protein in heart and skeletal muscle. </p>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Gariboldi et al. (1994) mapped the FLN2 gene to human chromosome 7q32-q35 by analysis of somatic cell hybrids containing portions of chromosome 7. Chakarova et al. (2000) assigned the FLNC gene to 7q32 by radiation hybrid analysis. </p><p>By interspecific backcross analysis, Gariboldi et al. (1994) mapped the mouse homolog to chromosome 6 in a region showing homology of synteny to human chromosome 7. </p><p><strong><em>Pseudogene</em></strong></p><p>
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An FLNC pseudogene maps to chromosome 7q32-q35 about 53.7 kb downstream from the functional FLNC gene. The pseudogene is 98% homologous to exons 46, 47, and 48 of the functional gene (van der Ven et al., 2010). </p>
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</span>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By yeast 2-hybrid analysis, Thompson et al. (2000) found that sarcoglycan-gamma and -delta (SGCD; 601411) interacted with FLN2, but sarcoglycan-alpha (SGCA; 600119) and -beta (SGCB; 600900) did not. In vitro binding assays indicated that FLN2 interacted directly with sarcoglycan-gamma and -delta, but not with dystrophin (DMD; 300377) and syntrophin beta-1 (SNTB1; 600026). Coimmunoprecipitation analysis of transfected proteins and of endogenous proteins in mouse myotube lysates confirmed that FLN2 interacted with sarcoglycans-gamma and -delta. Fln2 was detected predominantly in the soluble fraction of lysed mouse myotube cultures. Immunoelectron microscopy detected 2 pools of Fln2, one adjacent to the sarcolemmal membrane and the other more diffuse. Thompson et al. (2000) found elevated levels of membrane-associated FLN2 in 2 patients with limb-girdle muscular dystrophy type 2C (LGMD2C; 253700), a patient with Duchenne muscular dystrophy (DMD; 310200), and dystrophic mice. </p><p>The KY protein (605739) has been implicated in a neuromuscular dystrophy in the mouse, but its role in muscle function remains unclear. Beatham et al. (2004) showed that KY interacted with several sarcomeric cytoskeletal proteins including filamin C and the slow isoform of the myosin-binding protein C (MYBPC1; 160794). A role for KY in regulating filamin C function in vivo was supported by the expression analysis of filamin C in the Ky-null mouse mutant, where distinct irregular subcellular localization of filamin C was found in subsets of muscle fibers, which appeared to be a specific outcome of KY deficiency. In vitro assays showed that KY has protease activity, and specific degradation of filamin C by KY was shown in transfected cells. Beatham et al. (2004) suggested that KY may be an intrinsic part of the protein networks underlying the molecular mechanism of several limb-girdle muscular dystrophies, particularly those where interactions between filamin C and disease-causing proteins have been shown. </p>
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<br />
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>Myofibrillar Myopathy 5</em></strong></p><p>
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In affected members of a German family with autosomal dominant myofibrillar myopathy-5 (MFM5; 609524), Vorgerd et al. (2005) identified a heterozygous mutation in the FLNC gene (W2710X; 102565.0001). </p><p>In a German mother and daughter with adult-onset limb-girdle muscle weakness, Shatunov et al. (2009) identified a heterozygous deletion in the FLNC gene (102565.0002). This family was the only 1 of 127 families with a myopathy examined that was found to have an FLNC mutation, indicating that this subtype of myofibrillar myopathy is rare. </p><p>In 34 Chinese individuals with MFM5 from 9 apparently unrelated families in Hong Kong, Lee et al. (2020) identified a heterozygous c.8129G-A transition in the FLNC gene, resulting in a trp2710-to-ter (W2710X; 102565.0010) substitution. The mutation has the same amino acid substitution as that in a German family with MFM5 with a different basepair change (c.8130G-A; 102565.0001) in the same codon. Polymorphic marker analysis on the 9 probands identified a distinct haplotype that was not detected among 20 ethnically matched control chromosomes. The mutation was estimated to have occurred 42 to 71 generations previously, dating it to 844 to 1,315 years earlier. </p><p><strong><em>Distal Myopathy 4</em></strong></p><p>
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By linkage analysis followed by candidate gene sequencing of an Australian family with distal myopathy-4 (MPD4; 614065), reported by Williams et al. (2005), Duff et al. (2011) identified a heterozygous mutation in the FLNC gene (M251T; 102565.0003). A different heterozygous mutation (A193T; 102565.0004) was found in affected members of an Italian family with the same phenotype. Both mutations occurred in the actin-binding domain, and in vitro cellular expression studies showed that both mutations resulted in increased affinity for actin. </p><p>Using trio exome sequencing in 1 proband and sequencing of a panel of genes involved in muscle diseases in another, Velardo et al. (2022) identified 2 novel variants in the FLNC gene in Italian patients with MPD4. Both patients carried de novo heterozygous missense mutations at evolutionarily conserved positions (M222T, 102565.0011 and V245M, 102565.0012, respectively). </p><p><strong><em>Familial Cardiomyopathy, Hypertrophic, Restrictive, Dilated, or Arrhythmogenic</em></strong></p><p>
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In affected members of 7 Spanish families segregating autosomal dominant hypertrophic cardiomyopathy (CMH26; 617047) Valdes-Mas et al. (2014) identified heterozygosity for 5 different missense mutations and 1 nonsense mutation (see, e.g., 102565.0005-102565.0007). The FLNC variants showed strong cosegregation with disease in the families, with 14 of 16 mutation carriers over 40 years of age exhibiting symptoms of CMH, for a penetrance of more than 87%. None of the patients showed symptoms of myofibrillar myopathy, and skeletal muscle biopsies from 2 of the CMH patients showed normal muscle fiber histology and biochemistry, and lacked any of the myopathologic or electrophysiologic abnormalities of MFM patients. Functional analysis suggested that the CMH mutations disrupt the structure of FLNC, resulting in the formation of protein aggregates that likely impair sarcomere function. Valdes-Mas et al. (2014) noted that expression in cardiac myocytes resulted in larger protein aggregates than when expressed in skeletal muscle myoblasts, supporting a model in which interaction of these mutants with tissue-specific proteins contributes to the predominant cardiac phenotype. </p><p>In 2 Canadian families with restrictive cardiomyopathy (RCM5; see 617047), Brodehl et al. (2016) identified heterozygosity for 2 different missense mutations in the FLNC gene (102565.0008 and 102565.0009). Each mutation segregated fully with disease in the family, and neither was found in controls or public variant databases. Patients exhibited no clinically detectable skeletal involvement, and CK levels were in the normal or slightly elevated range. </p><p>In affected members of 2 Italian families segregating autosomal dominant dilated cardiomyopathy (CMD1PP; see 617047), Begay et al. (2016) identified heterozygosity for the same splice site mutation in the FLNC gene (102565.0013). The mutation segregated with disease in both families, but was also present in the 34-year-old sister of the proband from family TSFDC029, who had a history of palpitations but an unremarkable echocardiogram, and declined further clinical follow-up. In a sister and brother from the US with CMD, the authors analyzed a panel of 4,813 clinical phenotype-associated genes and identified a different heterozygous splice site mutation in the FLNC gene (102565.0014). Neither mutation was found in public variant databases. The authors noted that the FLNC variant carriers in the 3 families showed an arrhythmogenic trait, with high incidence of sudden cardiac death. </p><p>In 2,877 patients with various inherited cardiovascular diseases, Ortiz-Genga et al. (2016) analyzed 213 genes associated with inherited cardiovascular disease and sudden death, and identified 28 probands with truncating mutations in the FLNC gene (see, e.g., 102565.0015 and 102565.0016), including 20 patients previously diagnosed with dilated cardiomyopathy, 7 with arrhythmogenic cardiomyopathy with predominantly left ventricular involvement, and 1 with restrictive cardiomyopathy. Complete cosegregation of the mutation with the cardiac phenotype was shown in the 23 families that agreed to be investigated. Fifty-four carrier relatives were identified, of which 23 (43%) were asymptomatic, although cardiac changes were found in 40 (74%) of them. Immunohistochemical staining of myocardial tissue showed the presence of filamin C only in intercalated discs, in both patients and controls, suggesting that the mechanism involved is different than that previously observed with myofibrillar myopathy. The authors concluded that FLNC truncating mutations are associated with a characteristic cardiac phenotype that includes left ventricular dilation with systolic dysfunction and myocardial fibrosis, frequent ventricular arrhythmias, and a high incidence of sudden cardiac death. There was no evidence of skeletal myopathy in these patients. </p><p>In affected members of 2 unrelated families with arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVD15; see 617047), Brun et al. (2020) identified heterozygous truncating mutations in the FLNC gene, a nonsense mutation (E2189X; 102565.0017) in one family and a 1-bp deletion (102565.0018) in the other. Neither mutation was found in gnomAD. </p>
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</span>
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<div>
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<br />
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Chevessier et al. (2015) created knockin mice harboring a W2711X mutation in Flnc corresponding to the W2710X mutation (102565.0001) in human patients with MFM5. Heterozygous knockin mice expressed both wildtype and mutant Flnc alleles at comparable levels. No kyphosis or focal muscle atrophy was observed in mutant mice at any age, but reduced grip strength or muscle weakness was evident beginning at 4 months of age. Histologic analysis of skeletal muscle from sedentary heterozygous knockin mice showed no overt defects up to 8 months of age. However, ultrastructural analysis revealed abnormalities, such as enlarged mitochondria and autophagic vacuoles, in 3-month-old mutant mice. Myofibrillar degeneration in mutant mice started at Z-discs, and myofibrillar lesions were observed. These lesions appeared as electron-dense material between adjacent Z-discs and spanned as little as a single sarcomere or extended across multiple sarcomeres and included several neighboring myofibrils. Similar pathology was also detected in diaphragm and was exacerbated by eccentric exercise. </p><p>Begay et al. (2016) generated zebrafish with knockdown of flncb, the FLNC ortholog with greatest sequence similarity to the human gene. The morphant zebrafish showed pericardial edema, dysmorphic or dilated cardiac chambers, and abnormal looping of the heart tube suggestive of systolic dysfunction at 48 hours postfertilization (hpf) and 72 hpf. At 48 hpf, 9% of the morphants lacked circulation entirely, indicating a functional cardiac defect; the remaining 91% showed varying degrees of reduced blood circulation, with an increase in retrograde flow and overall weaker contractility. In addition, heart rate was slower in the morphants than controls. Ultrastructural analysis of transverse ventricular sections showed myofibrils composed of fewer consecutive sarcomeres in the morphants than wildtype zebrafish, or myofibrils in abnormal arrangements with Z-discs. In most cases, Z-discs appeared irregular or absent; however, cross-sections revealed that the primary arrangement of thick and thin filaments into hexagonal lattices appeared normal, suggesting that initial sarcomerogenesis was normal, but that myofibril growth was impaired. In addition, morphant cardiomyocytes developed small vacuoles associated with or near the cell membrane, suggesting that intercellular attachments had ruptured. The authors suggested that flncb plays an important role in maintaining sarcomere stability and cardiomyocyte attachment as mechanical stress increases in the developing embryonic heart. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>History</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Kono et al. (2010) identified a heterozygous 1-bp deletion (8107delG) in exon 48 of the FLNC gene in affected members of a Japanese family with adult-onset myofibrillar myopathy primarily affecting the distal limbs, with later involvement of proximal muscles. However, the paper was later retracted by the authors after the mutation was found to occur in the FLNC pseudogene, based on the report of van der Ven et al. (2010). Van der Ven et al. (2010) noted that the pseudogene is 98% homologous to exons 46, 47, and 48 of the functional FLNC gene and that the pseudogene contains the 8107delG variant. </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>18 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 MYOPATHY, MYOFIBRILLAR, 5</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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FLNC, TRP2710TER, c.8130G-A
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<br />
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SNP: rs121909518,
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ClinVar: RCV000019978, RCV001052798, RCV001091493
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of a German family with autosomal dominant myofibrillar myopathy-5 (MFM5; 609524), Vorgerd et al. (2005) identified a heterozygous c.8130G-A transition in exon 48 of the FLNC gene, resulting in a trp2710-to-ter (W2710X) substitution. The mutation leads to a truncation of the filamin C immunoglobulin domain that is responsible for dimerization. Functional expression studies showed that the W2710X protein had improper folding, was unable to form dimers, and showed abnormal aggregation. The findings implied that dimer formation is essential for the biologic function of filamin. The mutation was not identified in 220 control chromosomes. </p><p><strong><em>Variant Function</em></strong></p><p>
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By in vitro functional expression studies, Lowe et al. (2007) showed that W2710X-mutant protein was less stable and more susceptible to proteolysis compared to wildtype. The mutant protein did not dimerize properly and formed filamin aggregates in cultured cells. Aggregation of mutant protein did not affect dimerization of wildtype filamin C, and the mutant protein still showed normal binding to actin and sarcoglycans. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 MYOPATHY, MYOFIBRILLAR, 5</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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FLNC, 12-BP DEL, NT2997
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<br />
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SNP: rs1562995872,
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ClinVar: RCV000019979, RCV003144109
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a German mother and daughter with autosomal dominant myofibrillar myopathy-5 (MFM5; 609524), Shatunov et al. (2009) identified a heterozygous 12-bp deletion (c.2997_3008del, NM_001458.4) in exon 18 of the FLNC gene, predicted to result in an in-frame deletion of 4 residues (val930 to thr933) in the seventh repeat and confirmed by RT-PCR analysis of muscle tissue from the affected daughter. The phenotype was characterized by adult-onset muscle weakness initially involving proximal muscles of the lower limbs and spreading to the upper limbs and distal muscles of lower extremities. Both had paraspinal and abdominal muscle involvement and winging of the scapula. Cardiac and respiratory muscles were not affected. Skeletal muscle biopsy from the daughter showed marked variation in fiber size, some fibers with internal nuclei, and type 1 fiber predominance. Several fibers showed polymorphous hyaline and nonhyaline myofibrillary FLNC-positive inclusions with a convoluted, serpentine appearance. Ultrastructural examination showed major myofibrillar abnormalities, with accumulation of Z disc debris, granulofilamentous material, and nemaline rods. There were also mitochondrial aggregates. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 MYOPATHY, DISTAL, 4</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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FLNC, MET251THR
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<br />
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SNP: rs387906586,
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ClinVar: RCV000022428, RCV001781296
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of a large Australian family with autosomal dominant distal myopathy-4 (MPD4; 614065) originally reported by Williams et al. (2005), Duff et al. (2011) identified a heterozygous c.752T-C transition (c.752T-C, NM_001127487.1) in exon 4 of the FLNC gene, resulting in a met251-to-thr (M251T) substitution in a highly conserved residue in the CH2 domain in the actin-binding domain. The mutation was not found in 400 control chromosomes. The mutant protein had slightly decreased thermal stability and showed increased actin-binding activity compared to the wildtype protein. Transfection of the mutant M251T protein into cells showed significantly decreased nuclear localization compared to wildtype and resulted in the formation of intracellular protein aggregates. Duff et al. (2011) concluded that the disease mechanism somehow involves increased affinity for actin. The phenotype was characterized by adult onset of distal muscle weakness and atrophy affecting the upper and lower limbs, with nonspecific findings on muscle biopsy. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0004 MYOPATHY, DISTAL, 4</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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FLNC, ALA193THR
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<br />
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SNP: rs387906587,
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gnomAD: rs387906587,
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ClinVar: RCV000022429, RCV000442836, RCV000600715, RCV001384941, RCV001535684, RCV004555848
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|
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In affected members of an Italian family with autosomal dominant distal myopathy-4 (MPD4; 614065), Duff et al. (2011) identified a heterozygous c.577G-A transition (c.577G-A, NM_001127487.1) in exon 2 of the FLNC gene, resulting in an ala193-to-thr (A193T) substitution in a highly conserved residue in the CH2 domain in the actin-binding domain. The mutation was not found in 204 control chromosomes. The mutant protein had slightly decreased thermal stability and showed increased actin-binding activity compared to the wildtype protein. Nuclear localization was unaltered, but transfection resulted in the formation of intracellular protein aggregates. Duff et al. (2011) concluded that the disease mechanism somehow involves increased affinity for actin. The phenotype was characterized by adult onset of distal muscle weakness and atrophy affecting the upper and lower limbs, with nonspecific findings on muscle biopsy. </p>
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|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 26</strong>
|
|
</span>
|
|
</h4>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
FLNC, ALA1539THR
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|
<br />
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|
|
SNP: rs1562999443,
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|
|
ClinVar: RCV000239536, RCV001854932
|
|
|
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|
|
</span>
|
|
</div>
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In all affected members of 2 Spanish families with hypertrophic cardiomyopathy (CMH26; 617047) and a history of sudden death, Valdes-Mas et al. (2014) identified heterozygosity for a G-A transition (chr7.128,488,649G-A, GRCh37) in the FLNC gene, resulting in an ala1539-to-thr (A1539T) substitution at a highly conserved residue within a C-terminal rod repeat. The mutation showed reduced penetrance, being detected in 2 asymptomatic family members from 1 of the families, a 12-year-old girl and a 52-year-old man, both of whom had normal electrocardiography and echocardiogram. The variant was not found in more than 400 Spanish controls, or the 1000 Genomes Project or Exome Sequencing Project databases. Cardiac muscle histology from 1 family member who underwent heart transplantation showed marked sarcomeric abnormalities, including myofibrillar disarray, sarcomeric aggregates, and fibrosis; immunohistochemical staining confirmed the presence of filamin C in the sarcomeric aggregates. In contrast, skeletal muscle biopsy from an affected individual showed intact sarcomeric structures and normal ATPase, SDH, and NADH staining, as well as the absence of the characteristic small aggregates of myofibrillar myopathy. When the A1539T mutant was expressed in rat neonatal cardiac myocytes, large perinuclear filamin-C aggregates were observed. Overexpression of A1539T in C2C12 mouse skeletal muscle myoblasts also resulted in formation of protein aggregates, although they were smaller than those observed in cardiac myocytes, supporting a model in which interaction of these mutants with tissue-specific proteins contributes to the predominant cardiac phenotype. </p>
|
|
</span>
|
|
</div>
|
|
|
|
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|
|
<div>
|
|
<br />
|
|
</div>
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|
|
</div>
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|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 26</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FLNC, HIS2315ASN
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|
|
|
|
|
<br />
|
|
|
|
SNP: rs1563003848,
|
|
|
|
|
|
|
|
ClinVar: RCV000239587
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 3 affected sibs from a Spanish family with hypertrophic cardiomyopathy (CMH26; 617047), Valdes-Mas et al. (2014) identified heterozygosity for a C-A transversion (chr7.128,494,682C-A, GRCh37) in the FLNC gene, resulting in a his2315-to-asn (H2315N) substitution at a highly conserved residue within a C-terminal rod repeat. The mutation showed reduced penetrance, being detected in 1 asymptomatic family member, a 29-year-old man with normal electrocardiography and echocardiogram. </p>
|
|
</span>
|
|
</div>
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<div>
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<br />
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|
</div>
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|
|
</div>
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|
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|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 26</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
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|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FLNC, VAL123ALA
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|
|
|
|
|
<br />
|
|
|
|
SNP: rs1562991002,
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|
|
|
|
|
|
|
ClinVar: RCV000239505
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Spanish father and son with hypertrophic cardiomyopathy (CMH26; 617047), Valdes-Mas et al. (2014) identified heterozygosity for a T-C transition (chr7.128,475,395T-C, GRCh37) in the FLNC gene, resulting in a val123-to-ala (V123A) substitution at a highly conserved residue within the N-terminal actin-binding domain. Western blot analysis of transiently transfected H9C2 rat cardiomyocytes showed that the V123A mutant was detected in the insoluble fraction, with formation of actin aggregates, whereas wildtype FLNC was exclusively present in the insoluble fraction. </p>
|
|
</span>
|
|
</div>
|
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<div>
|
|
<br />
|
|
</div>
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|
|
|
</div>
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<div>
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 CARDIOMYOPATHY, FAMILIAL RESTRICTIVE, 5</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 26, INCLUDED
|
|
</span>
|
|
</div>
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
FLNC, SER1624LEU
|
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<br />
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|
|
|
SNP: rs879255639,
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|
|
|
gnomAD: rs879255639,
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|
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ClinVar: RCV000239540, RCV001223109, RCV002255096, RCV003150143, RCV003372670, RCV004547624
|
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|
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</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p />
|
|
<p><strong><em>Familial Restrictive Cardiomyopathy 5</em></strong></p><p>
|
|
In a 4-generation Canadian family with restrictive cardiomyopathy (RCM5; see 617047), Brodehl et al. (2016) identified heterozygosity for a c.4871C-T transition (c.4871C-T, NM_001458.4) in the FLNC gene, resulting in a ser1624-to-leu (S1624L) substitution at a highly conserved residue within the 14th immunoglobulin-like domain. The mutation segregated with disease and was not found in public variant databases, including the ExAC database. Immunohistochemical analysis of explanted cardiac tissue from the left ventricular wall and septum of the proband showed filamin-C aggregates and disturbed Z-disc staining, and did not show the normal intercalated disc localization of desmin (DES; 125660). Functional analysis in H9C2 rat cardiac myoblasts and C2C12 mouse skeletal myoblasts demonstrated that the S1624L mutant failed to show the wildtype cytoplasmic distribution, instead forming protein aggregates. The proband in this family presented at age 13 years with congestive heart failure and severe biatrial enlargement, and underwent cardiac transplantation at age 14; she later had dizygotic twin daughters, 1 of whom was affected and underwent cardiac transplantation before age 2 years. </p><p><strong><em>Familial Hypertrophic Cardiomyopathy 26</em></strong></p><p>
|
|
In a sister and brother with hypertrophic cardiomyopathy (CMH26; 617047), Ader et al. (2019) identified heterozygosity for the S1624L mutation in the FLNC gene. DNA was not available from their affected mother, who had died at age 42 years during heart transplantation. All 3 patients presented an atypical CMH phenotype with a restrictive profile. The proband (patient 12), who was diagnosed with CMH at age 42 years and had congestive heart failure, exhibited a maximum wall thickness of 18 mm but a preserved interventricular septum (11 mm), with normal systolic function. Her brother was diagnosed with CMH at age 45 years and underwent cardiac transplantation at age 54. The authors suggested that this family presented a mixed phenotype of CMH and RCM, and noted similarities to the Canadian family reported by Brodehl et al. (2016). </p>
|
|
</span>
|
|
</div>
|
|
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<div>
|
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<br />
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</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 CARDIOMYOPATHY, FAMILIAL RESTRICTIVE, 5</strong>
|
|
</span>
|
|
</h4>
|
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</div>
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<div>
|
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<span class="mim-text-font">
|
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FLNC, ILE2160PHE
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<br />
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|
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SNP: rs879255640,
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|
|
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|
|
ClinVar: RCV000239590, RCV003765487
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</span>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 4-generation Canadian family with restrictive cardiomyopathy (RCM5; see 617047), Brodehl et al. (2016) identified heterozygosity for a c.6478A-T transversion (c.6478A-T, NM_001458.4) in the FLNC gene, resulting in an ile2160-to-phe (I2160F) substitution at a highly conserved residue within the 19th immunoglobulin-like domain. The mutation segregated with disease and was not found in public variant databases, including the ExAC database. Immunohistochemical analysis of explanted cardiac tissue from the proband revealed that the normal intercalated disc localization of desmin (DES; 125660) was absent, but no obvious filamin-C aggregates were present. This family was evaluated after the asymptomatic 15-year-old female proband was diagnosed with severe diastolic dysfunction, enlarged atria, and elevated pulmonary pressure, suggesting RCM. Her brother, father, and paternal uncle were known to have cardiomyopathy, with features of RCM on echocardiography. In addition, 2 paternal first cousins had RCM. </p>
|
|
</span>
|
|
</div>
|
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<div>
|
|
<br />
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</div>
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</div>
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<div>
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 MYOPATHY, MYOFIBRILLAR, 5</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
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|
FLNC, TRP2710TER, c.8129G-A
|
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|
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<br />
|
|
|
|
SNP: rs1585173340,
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|
|
ClinVar: RCV000855733, RCV001038999, RCV001267920, RCV001290001
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 34 Chinese individuals with autosomal dominant myofibrillar myopathy-5 (MFM5; 609524) from 9 apparently unrelated families in Hong Kong, Lee et al. (2020) identified a heterozygous c.8129G-A transition (c.8129G-A, NM_001458.4) in the FLNC gene, resulting in a trp2710-to-ter (W2710X) substitution. The mutation, which was found by Sanger sequencing of the FLNC gene, was not present in the Exome Sequencing Project, 1000 Genomes Project, gnomAD, ethnic-specific Chinese Millionome, and Virtual Chinese Genome databases. The mutation affects the same amino acid residue as that in a German family with MFM5 with a different basepair substitution in the same codon (c.8130G-A, 102565.0001). The mutation is predicted to eliminate the last 16 amino acids at the C terminus, resulting in reduced stability of the dimerization domain. Functional studies were not performed. Polymorphic marker analysis on the 9 probands identified a distinct haplotype that was not detected among 20 ethnically matched control chromosomes. The mutation was estimated to have occurred 42 to 71 generations previously, dating it to 844 to 1,315 years earlier. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0011 MYOPATHY, DISTAL, 4</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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FLNC, MET222THR
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<br />
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ClinVar: RCV002284052
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a 53-year-old Italian man (patient 1) with distal myopathy-4 (MPD4; 614065), Velardo et al. (2022) identified a novel de novo heterozygous T-to-C transition (c.665T-C, NM_001458) in exon 3 of the FLNC gene, resulting in met222-to-thr (M222T) substitution at an evolutionarily conserved position. The mutation was identified by trio exome sequencing. No other family members were affected, and the patient's asymptomatic sibs did not carry the mutation. Functional studies of the mutation were not performed. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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|
<strong>.0012 MYOPATHY, DISTAL, 4</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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FLNC, VAL245MET
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<br />
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ClinVar: RCV002284053, RCV002290862, RCV002382502
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a 33-year-old Italian man (patient 2) with distal myopathy-4 (MPD4; 614065), Velardo et al. (2022) identified a novel heterozygous G-to-A transition (c.733G-A, NM_001458) in exon 4 of the FLNC gene, resulting in a val245-to-met (V245M) substitution at an evolutionarily conserved position. The mutation was identified by sequencing with a panel of genes involved in muscle disorders. Functional studies were not performed. The mutation was inherited from the patient's 65-year-old clinically asymptomatic father, who on testing had abnormal muscle MRI findings. The proband also had 2 affected maternal uncles who carried the mutation: one, age 60, was unable to lift on his toes, and the other, age 57, had a dilated cardiomyopathy without apparent skeletal muscle involvement. Velardo et al. (2022) stated that this family emphasized the extreme intrafamilial variability in clinical manifestations, necessitating testing of asymptomatic relatives. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0013 CARDIOMYOPATHY, FAMILIAL DILATED, 1PP</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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FLNC, IVS43, G-A, +1
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<br />
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SNP: rs1554401581,
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ClinVar: RCV000649067, RCV003235326
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In affected members of 2 Italian families (TSFDC029 and TSFDC031) segregating autosomal dominant dilated cardiomyopathy (CMD1PP; see 617047), Begay et al. (2016) identified heterozygosity for the same splice site mutation in intron 43 (c.7251+1G-A, NM_001458) of the FLNC gene. The mutation segregated with disease in both families, but was also present in the 34-year-old sister of the proband from family TSFDC029, who had a history of palpitations and an unremarkable echocardiogram, and declined further clinical follow-up. The authors noted that the splice site mutation was thus 83% penetrant. Analysis of nearby genotypes in the 2 families, who lived in the same region of Italy, was consistent with a shared ancestral haplotype. Sanger sequencing of patient transcripts confirmed the absence of FLNC exon 43, causing a frameshift predicted to result in premature truncation of the protein 21 amino acids downstream of the mutation site. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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|
<span class="mim-font">
|
|
<strong>.0014 CARDIOMYOPATHY, FAMILIAL DILATED, 1PP</strong>
|
|
</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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FLNC, 1-BP DEL, 5669-1delG
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<br />
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|
|
SNP: rs1563001548,
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|
|
ClinVar: RCV000686980, RCV003235349
|
|
|
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|
|
</span>
|
|
</div>
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|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a sister and brother (family DNFDC057) with dilated cardiomyopathy (CMD1PP; see 617047), Begay et al. (2016) identified heterozygosity for a splice site mutation (c.5669-1delG, NM_001458) in the FLNC gene. Mutation status was not reported for their deceased parents. Cardiac tissue from the sister's explanted heart showed decreased FLNC mRNA expression, as well as reduced FLNC protein, compared to control. </p>
|
|
</span>
|
|
</div>
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<div>
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|
<br />
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</div>
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</div>
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<div>
|
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|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0015 CARDIOMYOPATHY, FAMILIAL DILATED, 1PP</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
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<div>
|
|
<span class="mim-text-font">
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|
|
FLNC, IVS23, 1-BP DEL, 4127+1delG
|
|
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|
|
|
<br />
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|
|
|
|
|
|
|
ClinVar: RCV003236956
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 8 affected members of 2 families (33319 and 29876) segregating autosomal dominant dilated cardiomyopathy (CMD1PP; see 617047), Ortiz-Genga et al. (2016) identified heterozygosity for a 1-bp deletion (c.4127+1delG, NM_001458.4) in intron 23 of the FLNC gene, abolishing the splice donor site and predicted to cause a frameshift resulting in premature termination. The mutation was also present in the asymptomatic 32-year-old daughter of the proband in family 33319, for whom no cardiac studies were available. Among the 8 symptomatic individuals, 3 were designated as having a phenotype of dilated cardiomyopathy, and 5 as having left-dominant arrhythmogenic cardiomyopathy (LDACM); patients with either designation exhibited frequent ventricular ectopy as well as ventricular tachycardia, sustained or nonsustained. In addition, palmoplantar keratoderma was observed in 4 of the 6 affected individuals in family 29876. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0016 CARDIOMYOPATHY, FAMILIAL RESTRICTIVE, 5</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FLNC, IVS28, 1-BP DEL, 4927+1delG
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV003236957
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 55-year-old woman (family 31277) with restrictive cardiomyopathy and first-degree atrioventricular block (RCM5; see 617047), Ortiz-Genga et al. (2016) identified heterozygosity for a 1-bp deletion (c.4927+1delG, NM_001458.4) in intron 28 of the FLNC gene, abolishing the splice donor site and predicted to cause a frameshift resulting in premature termination. Familial segregation was not reported. The patient was diagnosed with RCM at age 29 years and underwent cardiac transplantation at age 45. She showed muscle weakness of the lower extremities during follow-up, and electromyography showed moderate myopathic changes; however, those changes were attributed to her treatment with simvastatin and corticosteroids. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0017 ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA, FAMILIAL, 15</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FLNC, GLU2189TER
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV003236958
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 66-year-old woman and her 45-year-old nephew (family TSRVD029) with arrhythmogenic right ventricular cardiomyopathy (ARVD15; see 617047), Brun et al. (2020) identified heterozygosity for a c.6565G-T transversion (c.6565G-T, NM_001458) in exon 40 of the FLNC gene, resulting in a glu2189-to-ter (E2189X) substitution. The proband's sister had refractory supraventricular arrhythmias, and a male cousin died of progressive heart failure while awaiting heart transplantation; their mutation status was not reported. The mutation was not found in the gnomAD database. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0018 ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA, FAMILIAL, 15</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FLNC, 1-BP DEL, 8107G
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1563006160,
|
|
|
|
|
|
|
|
ClinVar: RCV000685726, RCV003226966, RCV003237321, RCV004026209
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 37-year-old woman (family JHRVD0001) with arrhythmogenic right ventricular cardiomyopathy (ARVD15; see 617047), Brun et al. (2020) identified heterozygosity for a de novo 1-bp deletion (c.8107delG, NM_001458) in exon 48 of the FLNC gene, causing a frameshift predicted to result in a premature termination codon (Asp2703ThrfsTer69). The mutation was not found in her unaffected parents or in the gnomAD database. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
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|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
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|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
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<p />
|
|
</div>
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<div>
|
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<ol>
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<li>
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<p class="mim-text-font">
|
|
Ader, F., De Groote, P., Reant, P., Rooryck-Thambo, C., Dupin-Deguine, D., Rambaud, C., Khraiche, D., Perret, C., Pruny, J. F., Mathieu-Dramard, M., Gerard, M., Troadec, Y., Gouya, L., Jeunemaitre, X., Van Maldergem, L., Hagege, A., Villard, E., Charron, P., Richard, P.
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|
<strong>FLNC pathogenic variants in patients with cardiomyopathies: prevalence and genotype-phenotype correlations.</strong>
|
|
Clin. Genet. 96: 317-329, 2019.
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|
[PubMed: 31245841]
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[Full Text: https://doi.org/10.1111/cge.13594]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Beatham, J., Romero, R., Townsend, S. K. M., Hacker, T., van der Ven, P. F. M., Blanco, G.
|
|
<strong>Filamin C interacts with the muscular dystrophy KY protein and is abnormally distributed in mouse KY deficient muscle fibres.</strong>
|
|
Hum. Molec. Genet. 13: 2863-2874, 2004.
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[PubMed: 15385448]
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[Full Text: https://doi.org/10.1093/hmg/ddh308]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Begay, R. L., Tharp, C. A., Martin, A., Graw, S. L., Sinagra, G., Miani, D., Sweet, M. E., Slavov, D. B., Stafford, N., Zeller, M. J., Alnefaie, R., Rowland, T. J., Brun, F., Jones, K. L., Gowan, K., Mestroni, L., Garrity, D. M., Taylor, M. R.
|
|
<strong>FLNC gene splice mutations cause dilated cardiomyopathy.</strong>
|
|
JACC Basic Transl. Sci. 1: 344-359, 2016.
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|
[PubMed: 28008423]
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[Full Text: https://doi.org/10.1016/j.jacbts.2016.05.004]
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</p>
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<li>
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<p class="mim-text-font">
|
|
Brodehl, A., Ferrier, R. A., Hamilton, S. J., Greenway, S. C., Brundler, M.-A., Yu, W., Gibson, W. T., McKinnon, M. L., McGillivray, B., Alvarez, N., Giuffre, M., Schwartzentruber, J., FORGE Canada Consortium, Gerull, B.
|
|
<strong>Mutations in FLNC are associated with familial restrictive cardiomyopathy.</strong>
|
|
Hum. Mutat. 37: 269-279, 2016.
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[PubMed: 26666891]
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[Full Text: https://doi.org/10.1002/humu.22942]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Brun, F., Gigli, M., Graw, S. L., Judge, D. P., Merlo, M., Murray, B., Calkins, H., Sinagra, G., Taylor, M. R. G., Mestroni, L., James, C. A.
|
|
<strong>FLNC truncations cause arrhythmogenic right ventricular cardiomyopathy.</strong>
|
|
J. Med. Genet. 57: 254-257, 2020.
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[PubMed: 31924696]
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[Full Text: https://doi.org/10.1136/jmedgenet-2019-106394]
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</p>
|
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Chakarova, C., Wehnert, M. S., Uhl, K., Sakthivel, S., Vosberg, H.-P., van der Ven, P. F. M., Furst, D. O.
|
|
<strong>Genomic structure and fine mapping of the two human filamin gene paralogues FLNB and FLNC and comparative analysis of the filamin gene family.</strong>
|
|
Hum. Genet. 107: 597-611, 2000.
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|
[PubMed: 11153914]
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|
|
[Full Text: https://doi.org/10.1007/s004390000414]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Chevessier, F., Schuld, J., Orfanos, Z., Plank, A.-C., Wolf, L., Maerkens, A., Unger, A., Schlotzer-Schrehardt, U., Kley, R. A., Von Horsten, S., Marcus, K., Linke, W. A., Vorgerd, M., van der Ven, P. F. M., Furst, D. O., Schroder, R.
|
|
<strong>Myofibrillar instability exacerbated by acute exercise in filaminopathy.</strong>
|
|
Hum. Molec. Genet. 24: 7207-7220, 2015.
|
|
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|
|
[PubMed: 26472074]
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[Full Text: https://doi.org/10.1093/hmg/ddv421]
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</p>
|
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Duff, R. M., Tay, V., Hackman, P., Ravenscroft, G., McLean, C., Kennedy, P., Steinbach, A., Schoffler, W., van der Ven, P. F., Furst, D. O., Song, J., Djinovic-Carugo, K., and 12 others.
|
|
<strong>Mutations in the N-terminal actin-binding domain of filamin C cause a distal myopathy.</strong>
|
|
Am. J. Hum. Genet. 88: 729-740, 2011.
|
|
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|
|
[PubMed: 21620354]
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|
[Full Text: https://doi.org/10.1016/j.ajhg.2011.04.021]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Gariboldi, M., Maestrini, E., Canzian, F., Manenti, G., De Gregorio, L., Rivella, S., Chatterjee, A., Herman, G. E., Archidiacono, N., Antonacci, R., Pierotti, M. A., Dragani, T. A., Toniolo, D.
|
|
<strong>Comparative mapping of the actin-binding protein 280 genes in human and mouse.</strong>
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