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Entry
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- *300138 - CHLORIDE INTRACELLULAR CHANNEL 2; CLIC2
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- OMIM
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<p>
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<span class="h4">*300138</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<a href="#title"><strong>Title</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<a href="#mapping">Mapping</a>
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<a href="#geneFunction">Gene Function</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/300138">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<a href="#editHistory"><strong>Edit History</strong></a>
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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<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=ENSG00000155962;t=ENST00000369449" 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=1193" 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=300138" 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="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 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=ENSG00000155962;t=ENST00000369449" 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_001289" 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_001289" 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=300138" 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=02139&isoform_id=02139_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/CLIC2" 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/2570009,2584785,18490162,28394755,57209092,66346733,85681058,119593030,119593031,151357901,158259031" 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/O15247" 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 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=1193" 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=ENSG00000155962;t=ENST00000369449" 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=CLIC2" 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=CLIC2" 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+1193" 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/CLIC2" 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:1193" 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/1193" 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=chrX&hgg_gene=ENST00000369449.7&hgg_start=155276211&hgg_end=155334614&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><a href="https://search.clinicalgenome.org/kb/genes/HGNC:2063" 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=300138[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 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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<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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<div><a href="https://www.ncbi.nlm.nih.gov/clinvar?term=300138[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000155962" 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=CLIC2" 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=CLIC2" 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=CLIC2" 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/CLIC2" 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=CLIC2&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/PA26589" 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 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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<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><a href="https://www.alliancegenome.org/gene/HGNC:2063" 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/FBgn0030529.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="http://v1.marrvel.org/search/gene/CLIC2#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="https://www.ncbi.nlm.nih.gov/gene/1193/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=1193" 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="mim#WormbaseGeneFold" id="mimWormbaseGeneToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes."><span id="mimWormbaseGeneToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Wormbase Gene</div>
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<div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00001365;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00001365 </a></div><div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00001371;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00001371 </a></div>
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<div><a href="https://zfin.org/ZDB-GENE-040718-299" 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 class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<div style="display: table-cell;">Cellular Pathways</div>
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<div><a href="https://reactome.org/content/query?q=CLIC2&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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<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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<a id="title" class="mim-anchor"></a>
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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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300138
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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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CHLORIDE INTRACELLULAR CHANNEL 2; CLIC2
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</h3>
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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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<span class="mim-font">
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XAP121
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<br />
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
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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=CLIC2" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">CLIC2</a></em></strong>
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<a id="cytogeneticLocation" class="mim-anchor"></a>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: <a href="/geneMap/X/887?start=-3&limit=10&highlight=887">Xq28</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chrX:155276211-155334614&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'})">X:155,276,211-155,334,614</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 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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</span>
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<a id="description" class="mim-anchor"></a>
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<span id="mimDescriptionToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<strong>Description</strong>
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<p>The CLIC2 gene encodes a protein that belongs to a class of soluble and membrane-bound proteins named because the first members of this family formed intracellular chloride channels. The CLIC2 protein is structurally similar to CLIC1 (<a href="/entry/602872">602872</a>) and to a form of glutathione transferase (GSTO1; <a href="/entry/605482">605482</a>), but has no transferase activity. CLIC2 functions as a regulator of calcium homeostasis in cardiac myocytes via interaction with the cardiac ryanodine receptor (RYR2; <a href="/entry/180902">180902</a>) (summary by <a href="#1" class="mim-tip-reference" title="Board, P. G., Coggan, M., Watson, S., Gage, P. W., Dulhunty, A. F. <strong>CLIC-2 modulates cardiac ryanodine receptor Ca(2+) release channels.</strong> Int. J. Biochem. Cell Biol. 36: 1599-1612, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15147738/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15147738</a>] [<a href="https://doi.org/10.1016/j.biocel.2004.01.026" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15147738">Board et al., 2004</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15147738" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<br />
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<span id="mimCloningToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<strong>Cloning and Expression</strong>
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<p>As part of an effort to produce a transcript map of the Xq28 chromosomal region, <a href="#5" class="mim-tip-reference" title="Rogner, U. C., Heiss, N. S., Kioschis, P., Wiemann, S., Korn, B., Poustka, A. <strong>Transcriptional analysis of the candidate region for incontinentia pigmenti (IP2) in Xq28.</strong> Genome Res. 6: 922-934, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8908511/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8908511</a>] [<a href="https://doi.org/10.1101/gr.6.10.922" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8908511">Rogner et al. (1996)</a> characterized a cDNA that they designated XAP121, or CLIC2. <a href="#4" class="mim-tip-reference" title="Heiss, N. S., Poustka, A. <strong>Genomic structure of a novel chloride channel gene, CLIC2, in Xq28.</strong> Genomics 45: 224-228, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9339381/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9339381</a>] [<a href="https://doi.org/10.1006/geno.1997.4922" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9339381">Heiss and Poustka (1997)</a> reported that the predicted 243-amino acid CLIC2 protein shares 60% identity with the CLIC1 protein, a nuclear chloride channel. Using RT-PCR, <a href="#5" class="mim-tip-reference" title="Rogner, U. C., Heiss, N. S., Kioschis, P., Wiemann, S., Korn, B., Poustka, A. <strong>Transcriptional analysis of the candidate region for incontinentia pigmenti (IP2) in Xq28.</strong> Genome Res. 6: 922-934, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8908511/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8908511</a>] [<a href="https://doi.org/10.1101/gr.6.10.922" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8908511">Rogner et al. (1996)</a> found that CLIC2 is expressed in fetal liver and adult skeletal muscle. No signal was detected on Northern blots. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9339381+8908511" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Board, P. G., Coggan, M., Watson, S., Gage, P. W., Dulhunty, A. F. <strong>CLIC-2 modulates cardiac ryanodine receptor Ca(2+) release channels.</strong> Int. J. Biochem. Cell Biol. 36: 1599-1612, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15147738/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15147738</a>] [<a href="https://doi.org/10.1016/j.biocel.2004.01.026" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15147738">Board et al. (2004)</a> stated that the predicted CLIC2 protein has a molecular mass of 27.8 kD. The protein sequence showed 58.8% identity to CLIC1 and 18.6% identity to GSTO1. Northern blot analysis detected 2 abundant mRNA species of 1.45 and 2.37 kb, and a third less abundant species of 0.8 kb. The 2 larger mRNA transcripts were widely distributed in human tissues, with highest expression in lung and spleen and lesser expression in heart, liver, and skeletal muscle. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15147738" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 RT-PCR, <a href="#6" class="mim-tip-reference" title="Takano, K., Liu, D., Tarpey, P., Gallant, E., Lam, A., Witham, S., Alexov, E., Chaubey, A., Stevenson, R. E., Schwartz, C. E., Board, P. G., Dulhunty, A. F. <strong>An X-linked channelopathy with cardiomegaly due to a CLIC2 mutation enhancing ryanodine receptor channel activity.</strong> Hum. Molec. Genet. 21: 4497-4507, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22814392/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22814392</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22814392[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/10.1093/hmg/dds292" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22814392">Takano et al. (2012)</a> found expression of the CLIC2 gene in all fetal tissues, including brain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22814392" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#4" class="mim-tip-reference" title="Heiss, N. S., Poustka, A. <strong>Genomic structure of a novel chloride channel gene, CLIC2, in Xq28.</strong> Genomics 45: 224-228, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9339381/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9339381</a>] [<a href="https://doi.org/10.1006/geno.1997.4922" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9339381">Heiss and Poustka (1997)</a> found that the CLIC2 gene contains 6 exons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9339381" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#5" class="mim-tip-reference" title="Rogner, U. C., Heiss, N. S., Kioschis, P., Wiemann, S., Korn, B., Poustka, A. <strong>Transcriptional analysis of the candidate region for incontinentia pigmenti (IP2) in Xq28.</strong> Genome Res. 6: 922-934, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8908511/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8908511</a>] [<a href="https://doi.org/10.1101/gr.6.10.922" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8908511">Rogner et al. (1996)</a> identified the CLIC2 gene on chromosome Xq28. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8908511" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#1" class="mim-tip-reference" title="Board, P. G., Coggan, M., Watson, S., Gage, P. W., Dulhunty, A. F. <strong>CLIC-2 modulates cardiac ryanodine receptor Ca(2+) release channels.</strong> Int. J. Biochem. Cell Biol. 36: 1599-1612, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15147738/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15147738</a>] [<a href="https://doi.org/10.1016/j.biocel.2004.01.026" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15147738">Board et al. (2004)</a> demonstrated that CLIC2 is a strong inhibitor of the cardiac ryanodine receptor (RYR2) calcium release channels in both lipid bilayers and in cardiac sarcoplasmic reticulum vesicles, suggesting that it contributes to intracellular calcium homeostasis by regulating its release from internal stores in the cell. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15147738" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Dulhunty, A. F., Pouliquin, P., Coggan, M., Gage, P. W., Board, P. G. <strong>A recently identified member of the glutathione transferase structural family modifies cardiac RyR2 substate activity, coupled gating and activation by Ca(2+) and ATP.</strong> Biochem. J. 390: 333-343, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15916532/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15916532</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15916532[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/10.1042/BJ20042113" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15916532">Dulhunty et al. (2005)</a> demonstrated that CLIC2 reduces activation of the RYR2 channel by its primary endogenous ligands ATP and calcium. When CLIC2 was added to the cytoplasmic side of RYR2 channels in lipid bilayers, RYR2 activity was depressed in a reversible, voltage-independent manner. The authors concluded that CLIC2 may act physiologically as a cytosolic inhibitor of RYR2 channels during diastole and during stress. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15916532" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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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The H101Q variant in the CLIC2 gene (<a href="#0001">300138.0001</a>) that was identified in 2 brothers (family K8015) with syndromic X-linked intellectual developmental disorder (see <a href="/entry/300886">300886</a>) by <a href="#6" class="mim-tip-reference" title="Takano, K., Liu, D., Tarpey, P., Gallant, E., Lam, A., Witham, S., Alexov, E., Chaubey, A., Stevenson, R. E., Schwartz, C. E., Board, P. G., Dulhunty, A. F. <strong>An X-linked channelopathy with cardiomegaly due to a CLIC2 mutation enhancing ryanodine receptor channel activity.</strong> Hum. Molec. Genet. 21: 4497-4507, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22814392/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22814392</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22814392[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/10.1093/hmg/dds292" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22814392">Takano et al. (2012)</a> has been reclassified as a variant of unknown significance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22814392" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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> rs398122917 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs398122917;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/rs398122917?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=rs398122917" 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=rs398122917" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>This variant, formerly titled INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED, SYNDROMIC 32 based on the report of <a href="#6" class="mim-tip-reference" title="Takano, K., Liu, D., Tarpey, P., Gallant, E., Lam, A., Witham, S., Alexov, E., Chaubey, A., Stevenson, R. E., Schwartz, C. E., Board, P. G., Dulhunty, A. F. <strong>An X-linked channelopathy with cardiomegaly due to a CLIC2 mutation enhancing ryanodine receptor channel activity.</strong> Hum. Molec. Genet. 21: 4497-4507, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22814392/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22814392</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22814392[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/10.1093/hmg/dds292" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22814392">Takano et al. (2012)</a>, has been reclassified based on a review of the gnomAD database by <a href="#3" class="mim-tip-reference" title="Hamosh, A. <strong>Personal Communication.</strong> Baltimore, Md. 5/20/2024."None>Hamosh (2024)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22814392" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 brothers (family K8015) with X-linked syndromic intellectual developmental disorder-32 (MRXS32; <a href="/entry/300886">300886</a>), <a href="#6" class="mim-tip-reference" title="Takano, K., Liu, D., Tarpey, P., Gallant, E., Lam, A., Witham, S., Alexov, E., Chaubey, A., Stevenson, R. E., Schwartz, C. E., Board, P. G., Dulhunty, A. F. <strong>An X-linked channelopathy with cardiomegaly due to a CLIC2 mutation enhancing ryanodine receptor channel activity.</strong> Hum. Molec. Genet. 21: 4497-4507, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22814392/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22814392</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22814392[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/10.1093/hmg/dds292" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22814392">Takano et al. (2012)</a> identified a hemizygous c.303C-G transversion in the CLIC2 gene, resulting in a his101-to-gln (H101Q) substitution at a highly conserved residue in the joint region. The mutation was not found in 1,059 normal individuals, but was inherited from the mother who had mild learning disabilities. The mutation was identified by exome capture and deep sequencing. COS-7 and PC-12 cells expressing the mutation showed normal cell morphology and neurite length, and there was normal localization of the mutant protein, which appeared to fold normally. However, the mutant protein had increased thermal stability compared to wildtype. In lipid bilayers, the mutant H101Q protein resulted in an increase in both the skeletal RYR1 (<a href="/entry/180901">180901</a>) and cardiac RYR2 (<a href="/entry/180902">180902</a>) channels being in the open probability states, which was a reversal of the effect of wildtype CLIC2. Three-dimensional predictions indicated that the H101Q mutation affected the binding affinity to RYR channels, resulting in stronger and more stable binding compared to wildtype. The authors noted that folding free energy calculations by <a href="#7" class="mim-tip-reference" title="Witham, S., Takano, K., Schwartz, C., Alexov, E. <strong>A missense mutation in CLIC2 associated with intellectual disability is predicted by in silico modeling to affect protein stability and dynamics.</strong> Proteins 79: 2444-2454, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21630357/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21630357</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21630357[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/prot.23065" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21630357">Witham et al. (2011)</a> had predicted that the H101Q mutant is more stable than wildtype. Overall, the data suggested that mutant CLIC2 would stimulate the release of calcium by keeping the RYR channels in the open state, resulting in overly active RYR2 in heart muscle with excess potential firing in those cells. There was also some evidence that the mutation may impair insertion of CLIC2 into the membrane to form a functioning ion channel. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=22814392+21630357" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Hamosh, A. <strong>Personal Communication.</strong> Baltimore, Md. 5/20/2024."None>Hamosh (2024)</a> noted that the c.303C-G variant was present in too many males in the gnomAD database (v4.1) to account for this phenotype.</p>
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<strong>REFERENCES</strong>
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<a id="Board2004" class="mim-anchor"></a>
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Board, P. G., Coggan, M., Watson, S., Gage, P. W., Dulhunty, A. F.
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<strong>CLIC-2 modulates cardiac ryanodine receptor Ca(2+) release channels.</strong>
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Int. J. Biochem. Cell Biol. 36: 1599-1612, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15147738/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15147738</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15147738" 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.biocel.2004.01.026" target="_blank">Full Text</a>]
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Dulhunty, A. F., Pouliquin, P., Coggan, M., Gage, P. W., Board, P. G.
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<strong>A recently identified member of the glutathione transferase structural family modifies cardiac RyR2 substate activity, coupled gating and activation by Ca(2+) and ATP.</strong>
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Biochem. J. 390: 333-343, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15916532/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15916532</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15916532[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=15916532" 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/10.1042/BJ20042113" target="_blank">Full Text</a>]
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<a id="Hamosh2024" class="mim-anchor"></a>
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Hamosh, A.
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<strong>Personal Communication.</strong>
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Baltimore, Md. 5/20/2024.
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Heiss, N. S., Poustka, A.
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<strong>Genomic structure of a novel chloride channel gene, CLIC2, in Xq28.</strong>
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Genomics 45: 224-228, 1997.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9339381/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9339381</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9339381" 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/geno.1997.4922" target="_blank">Full Text</a>]
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Rogner, U. C., Heiss, N. S., Kioschis, P., Wiemann, S., Korn, B., Poustka, A.
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<strong>Transcriptional analysis of the candidate region for incontinentia pigmenti (IP2) in Xq28.</strong>
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Genome Res. 6: 922-934, 1996.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8908511/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8908511</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8908511" 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/10.1101/gr.6.10.922" target="_blank">Full Text</a>]
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Takano, K., Liu, D., Tarpey, P., Gallant, E., Lam, A., Witham, S., Alexov, E., Chaubey, A., Stevenson, R. E., Schwartz, C. E., Board, P. G., Dulhunty, A. F.
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<strong>An X-linked channelopathy with cardiomegaly due to a CLIC2 mutation enhancing ryanodine receptor channel activity.</strong>
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Hum. Molec. Genet. 21: 4497-4507, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22814392/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22814392</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22814392[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=22814392" 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/dds292" target="_blank">Full Text</a>]
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Witham, S., Takano, K., Schwartz, C., Alexov, E.
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<strong>A missense mutation in CLIC2 associated with intellectual disability is predicted by in silico modeling to affect protein stability and dynamics.</strong>
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Proteins 79: 2444-2454, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21630357/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21630357</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21630357[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=21630357" 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/prot.23065" target="_blank">Full Text</a>]
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Ada Hamosh - updated : 05/21/2024
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Carol A. Bocchini - updated : 1/22/2015<br>Cassandra L. Kniffin - updated : 11/27/2012
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Rebekah S. Rasooly : 7/21/1998
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carol : 05/21/2024
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alopez : 08/20/2021<br>carol : 01/22/2015<br>carol : 1/21/2015<br>ckniffin : 1/20/2015<br>carol : 12/3/2012<br>ckniffin : 11/27/2012<br>carol : 8/20/2012<br>carol : 1/18/2001<br>alopez : 7/21/1998
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CHLORIDE INTRACELLULAR CHANNEL 2; CLIC2
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<p>The CLIC2 gene encodes a protein that belongs to a class of soluble and membrane-bound proteins named because the first members of this family formed intracellular chloride channels. The CLIC2 protein is structurally similar to CLIC1 (602872) and to a form of glutathione transferase (GSTO1; 605482), but has no transferase activity. CLIC2 functions as a regulator of calcium homeostasis in cardiac myocytes via interaction with the cardiac ryanodine receptor (RYR2; 180902) (summary by Board et al., 2004). </p>
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<strong>Cloning and Expression</strong>
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<p>As part of an effort to produce a transcript map of the Xq28 chromosomal region, Rogner et al. (1996) characterized a cDNA that they designated XAP121, or CLIC2. Heiss and Poustka (1997) reported that the predicted 243-amino acid CLIC2 protein shares 60% identity with the CLIC1 protein, a nuclear chloride channel. Using RT-PCR, Rogner et al. (1996) found that CLIC2 is expressed in fetal liver and adult skeletal muscle. No signal was detected on Northern blots. </p><p>Board et al. (2004) stated that the predicted CLIC2 protein has a molecular mass of 27.8 kD. The protein sequence showed 58.8% identity to CLIC1 and 18.6% identity to GSTO1. Northern blot analysis detected 2 abundant mRNA species of 1.45 and 2.37 kb, and a third less abundant species of 0.8 kb. The 2 larger mRNA transcripts were widely distributed in human tissues, with highest expression in lung and spleen and lesser expression in heart, liver, and skeletal muscle. </p><p>Using RT-PCR, Takano et al. (2012) found expression of the CLIC2 gene in all fetal tissues, including brain. </p>
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<strong>Gene Structure</strong>
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<span class="mim-text-font">
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<p>Heiss and Poustka (1997) found that the CLIC2 gene contains 6 exons. </p>
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<strong>Mapping</strong>
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<span class="mim-text-font">
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<p>Rogner et al. (1996) identified the CLIC2 gene on chromosome Xq28. </p>
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<strong>Gene Function</strong>
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<p>Board et al. (2004) demonstrated that CLIC2 is a strong inhibitor of the cardiac ryanodine receptor (RYR2) calcium release channels in both lipid bilayers and in cardiac sarcoplasmic reticulum vesicles, suggesting that it contributes to intracellular calcium homeostasis by regulating its release from internal stores in the cell. </p><p>Dulhunty et al. (2005) demonstrated that CLIC2 reduces activation of the RYR2 channel by its primary endogenous ligands ATP and calcium. When CLIC2 was added to the cytoplasmic side of RYR2 channels in lipid bilayers, RYR2 activity was depressed in a reversible, voltage-independent manner. The authors concluded that CLIC2 may act physiologically as a cytosolic inhibitor of RYR2 channels during diastole and during stress. </p>
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<strong>Molecular Genetics</strong>
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<p><strong><em>Reclassified Variants</em></strong></p><p>
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The H101Q variant in the CLIC2 gene (300138.0001) that was identified in 2 brothers (family K8015) with syndromic X-linked intellectual developmental disorder (see 300886) by Takano et al. (2012) has been reclassified as a variant of unknown significance. </p>
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>1 Selected Example):</strong>
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</h4>
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<p />
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<h4>
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<span class="mim-font">
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<strong>.0001 RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE</strong>
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</h4>
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<span class="mim-text-font">
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CLIC2, HIS101GLN
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<br />
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SNP: rs398122917,
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gnomAD: rs398122917,
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ClinVar: RCV000033043, RCV002247413
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<span class="mim-text-font">
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<p>This variant, formerly titled INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED, SYNDROMIC 32 based on the report of Takano et al. (2012), has been reclassified based on a review of the gnomAD database by Hamosh (2024). </p><p>In 2 brothers (family K8015) with X-linked syndromic intellectual developmental disorder-32 (MRXS32; 300886), Takano et al. (2012) identified a hemizygous c.303C-G transversion in the CLIC2 gene, resulting in a his101-to-gln (H101Q) substitution at a highly conserved residue in the joint region. The mutation was not found in 1,059 normal individuals, but was inherited from the mother who had mild learning disabilities. The mutation was identified by exome capture and deep sequencing. COS-7 and PC-12 cells expressing the mutation showed normal cell morphology and neurite length, and there was normal localization of the mutant protein, which appeared to fold normally. However, the mutant protein had increased thermal stability compared to wildtype. In lipid bilayers, the mutant H101Q protein resulted in an increase in both the skeletal RYR1 (180901) and cardiac RYR2 (180902) channels being in the open probability states, which was a reversal of the effect of wildtype CLIC2. Three-dimensional predictions indicated that the H101Q mutation affected the binding affinity to RYR channels, resulting in stronger and more stable binding compared to wildtype. The authors noted that folding free energy calculations by Witham et al. (2011) had predicted that the H101Q mutant is more stable than wildtype. Overall, the data suggested that mutant CLIC2 would stimulate the release of calcium by keeping the RYR channels in the open state, resulting in overly active RYR2 in heart muscle with excess potential firing in those cells. There was also some evidence that the mutation may impair insertion of CLIC2 into the membrane to form a functioning ion channel. </p><p>Hamosh (2024) noted that the c.303C-G variant was present in too many males in the gnomAD database (v4.1) to account for this phenotype.</p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
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Board, P. G., Coggan, M., Watson, S., Gage, P. W., Dulhunty, A. F.
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<strong>CLIC-2 modulates cardiac ryanodine receptor Ca(2+) release channels.</strong>
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Int. J. Biochem. Cell Biol. 36: 1599-1612, 2004.
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[PubMed: 15147738]
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[Full Text: https://doi.org/10.1016/j.biocel.2004.01.026]
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</li>
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<li>
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<p class="mim-text-font">
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Dulhunty, A. F., Pouliquin, P., Coggan, M., Gage, P. W., Board, P. G.
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<strong>A recently identified member of the glutathione transferase structural family modifies cardiac RyR2 substate activity, coupled gating and activation by Ca(2+) and ATP.</strong>
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Biochem. J. 390: 333-343, 2005.
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[PubMed: 15916532]
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[Full Text: https://doi.org/10.1042/BJ20042113]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Hamosh, A.
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<strong>Personal Communication.</strong>
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Baltimore, Md. 5/20/2024.
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Heiss, N. S., Poustka, A.
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<strong>Genomic structure of a novel chloride channel gene, CLIC2, in Xq28.</strong>
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Genomics 45: 224-228, 1997.
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[PubMed: 9339381]
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[Full Text: https://doi.org/10.1006/geno.1997.4922]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Rogner, U. C., Heiss, N. S., Kioschis, P., Wiemann, S., Korn, B., Poustka, A.
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<strong>Transcriptional analysis of the candidate region for incontinentia pigmenti (IP2) in Xq28.</strong>
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Genome Res. 6: 922-934, 1996.
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[PubMed: 8908511]
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[Full Text: https://doi.org/10.1101/gr.6.10.922]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Takano, K., Liu, D., Tarpey, P., Gallant, E., Lam, A., Witham, S., Alexov, E., Chaubey, A., Stevenson, R. E., Schwartz, C. E., Board, P. G., Dulhunty, A. F.
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|
<strong>An X-linked channelopathy with cardiomegaly due to a CLIC2 mutation enhancing ryanodine receptor channel activity.</strong>
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Hum. Molec. Genet. 21: 4497-4507, 2012.
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[PubMed: 22814392]
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[Full Text: https://doi.org/10.1093/hmg/dds292]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Witham, S., Takano, K., Schwartz, C., Alexov, E.
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<strong>A missense mutation in CLIC2 associated with intellectual disability is predicted by in silico modeling to affect protein stability and dynamics.</strong>
|
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Proteins 79: 2444-2454, 2011.
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[PubMed: 21630357]
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[Full Text: https://doi.org/10.1002/prot.23065]
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</p>
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</li>
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</ol>
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<div>
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<br />
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</div>
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Contributors:
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Ada Hamosh - updated : 05/21/2024<br>Carol A. Bocchini - updated : 1/22/2015<br>Cassandra L. Kniffin - updated : 11/27/2012
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Creation Date:
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Rebekah S. Rasooly : 7/21/1998
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carol : 05/21/2024<br>alopez : 08/20/2021<br>carol : 01/22/2015<br>carol : 1/21/2015<br>ckniffin : 1/20/2015<br>carol : 12/3/2012<br>ckniffin : 11/27/2012<br>carol : 8/20/2012<br>carol : 1/18/2001<br>alopez : 7/21/1998
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