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Entry
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- *238330 - GLYCINE CLEAVAGE SYSTEM H PROTEIN; GCSH
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- OMIM
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<p>
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<span class="h4">*238330</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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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#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="#geneFunction">Gene Function</a>
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<a href="#mapping">Mapping</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<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/238330">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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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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<div id="mimFloatingLinksMenu">
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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 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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<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=ENSG00000140905;t=ENST00000315467" 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=2653" 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=238330" 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 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=ENSG00000140905;t=ENST00000315467" 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_004483,NR_033249,XM_017023136,XM_017023137,XM_047433900" 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_004483" 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=238330" 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=01998&isoform_id=01998_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/GCSH" 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/184348,219671,12653985,18089221,31559180,32879997,45386061,48146261,49574537,119615951,119615952,189065194,311033385,1034594275,1034594277,2217305422,2462498819,2462498821,2462498823,2462548387,2462548389,2462548391" 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/P23434" 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=2653" 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=ENSG00000140905;t=ENST00000315467" 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=GCSH" 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=GCSH" 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+2653" 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/GCSH" 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:2653" 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/2653" 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=chr16&hgg_gene=ENST00000564536.2&hgg_start=81081945&hgg_end=81096395&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:4208" 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:4208" 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=238330[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=238330[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/ENSG00000140905" 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=GCSH" 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=GCSH" 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=GCSH" 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="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=GCSH&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/PA28621" 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:4208" 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/FBgn0027945.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:1915383" 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/GCSH#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:1915383" 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/2653/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=2653" 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 id="mimWormbaseGeneFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00008354;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00008354 </a></div><div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00009918;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00009918 </a></div>
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</div>
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<div><a href="https://zfin.org/ZDB-GENE-040718-319" 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:2653" 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=GCSH&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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238330
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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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GLYCINE CLEAVAGE SYSTEM H PROTEIN; GCSH
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<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=GCSH" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">GCSH</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>
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Cytogenetic location: <a href="/geneMap/16/674?start=-3&limit=10&highlight=674">16q23.2</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr16:81081945-81096395&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'})">16:81,081,945-81,096,395</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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</span>
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</div>
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<div>
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="1">
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<span class="mim-font">
|
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<a href="/geneMap/16/674?start=-3&limit=10&highlight=674">
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16q23.2
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</a>
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
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Multiple mitochondrial dysfunctions syndrome 7
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/620423"> 620423 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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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>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<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/238330" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<li><a href="/graph/radial/238330" 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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</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="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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</span>
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</span>
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</h4>
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<div>
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<a id="description" class="mim-anchor"></a>
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<p>The enzyme system for cleavage of glycine (glycine cleavage system; <a href="https://enzyme.expasy.org/EC/2.1.2.10" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'EC\', \'domain\': \'expasy.org\'})">EC 2.1.2.10</a>), which is confined to the mitochondria, is composed of 4 protein components: P protein (a pyridoxal phosphate-dependent glycine decarboxylase; <a href="/entry/238300">238300</a>), H protein (a lipoic acid-containing protein), T protein (a tetrahydrofolate-requiring enzyme; <a href="/entry/238310">238310</a>), and L protein (a lipoamide dehydrogenase; <a href="/entry/238331">238331</a>).</p>
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<p><a href="#4" class="mim-tip-reference" title="Hiraga, K., Kure, S., Yamamoto, M., Ishiguro, Y., Suzuki, T. <strong>Cloning of cDNA encoding human H-protein, a constituent of the glycine cleavage system.</strong> Biochem. Biophys. Res. Commun. 151: 758-762, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3348809/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3348809</a>] [<a href="https://doi.org/10.1016/s0006-291x(88)80345-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3348809">Hiraga et al. (1988)</a> cloned a cDNA encoding H protein from a human liver cDNA library. <a href="#5" class="mim-tip-reference" title="Koyata, H., Hiraga, K. <strong>The glycine cleavage system: structure of a cDNA encoding human H-protein, and partial characterization of its gene in patients with hyperglycinemias.</strong> Am. J. Hum. Genet. 48: 351-361, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1671321/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1671321</a>]" pmid="1671321">Koyata and Hiraga (1991)</a> isolated a 1,192-bp cDNA that encodes the entire precursor of human H protein. <a href="#2" class="mim-tip-reference" title="Fujiwara, K., Okamura-Ikeda, K., Hayasaka, K., Motokawa, Y. <strong>The primary structure of human H-protein of the glycine cleavage system deduced by cDNA cloning.</strong> Biochem. Biophys. Res. Commun. 176: 711-716, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2025283/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2025283</a>] [<a href="https://doi.org/10.1016/s0006-291x(05)80242-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2025283">Fujiwara et al. (1991)</a> isolated a full-length GCSH cDNA encoding a precursor protein of 173 amino acids and a mature protein of 125 amino acids. By dot-blot analysis, <a href="#6" class="mim-tip-reference" title="Kure, S., Kojima, K., Kudo, T., Kanno, K., Aoki, Y., Suzuki, Y., Shinka, T., Sakata, Y., Narisawa, K., Matsubara, Y. <strong>Chromosomal localization, structure, single-nucleotide polymorphisms, and expression of the human H-protein gene of the glycine cleavage system (GCSH), a candidate gene for nonketotic hyperglycinemia.</strong> J. Hum. Genet. 46: 378-384, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11450847/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11450847</a>] [<a href="https://doi.org/10.1007/s100380170057" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11450847">Kure et al. (2001)</a> found that GCSH was expressed in all 29 tissues examined. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2025283+3348809+11450847+1671321" 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="#6" class="mim-tip-reference" title="Kure, S., Kojima, K., Kudo, T., Kanno, K., Aoki, Y., Suzuki, Y., Shinka, T., Sakata, Y., Narisawa, K., Matsubara, Y. <strong>Chromosomal localization, structure, single-nucleotide polymorphisms, and expression of the human H-protein gene of the glycine cleavage system (GCSH), a candidate gene for nonketotic hyperglycinemia.</strong> J. Hum. Genet. 46: 378-384, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11450847/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11450847</a>] [<a href="https://doi.org/10.1007/s100380170057" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11450847">Kure et al. (2001)</a> isolated and characterized a human PAC clone encoding GCSH. They found that GCSH spans 13.5 kb and contains 5 exons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11450847" 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="#9" class="mim-tip-reference" title="Sakata, Y., Owada, Y., Sato, K., Kojima, K., Hisanaga, K., Shinka, T., Suzuki, Y., Aoki, Y., Satoh, J., Kondo, H., Matsubara, Y., Kure, S. <strong>Structure and expression of the glycine cleavage system in rat central nervous system.</strong> Molec. Brain Res. 94: 119-130, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11597772/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11597772</a>] [<a href="https://doi.org/10.1016/s0169-328x(01)00225-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11597772">Sakata et al. (2001)</a> reported the structure and expression of the glycine cleavage system in rat central nervous system. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11597772" 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 fluorescence in situ hybridization, <a href="#6" class="mim-tip-reference" title="Kure, S., Kojima, K., Kudo, T., Kanno, K., Aoki, Y., Suzuki, Y., Shinka, T., Sakata, Y., Narisawa, K., Matsubara, Y. <strong>Chromosomal localization, structure, single-nucleotide polymorphisms, and expression of the human H-protein gene of the glycine cleavage system (GCSH), a candidate gene for nonketotic hyperglycinemia.</strong> J. Hum. Genet. 46: 378-384, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11450847/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11450847</a>] [<a href="https://doi.org/10.1007/s100380170057" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11450847">Kure et al. (2001)</a> mapped the GCSH gene to chromosome 16q24. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11450847" 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>Multiple Mitochondrial Dysfunctions Syndrome 7</em></strong></p><p>
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In 3 patients from 2 Indian families with multiple mitochondrial dysfunctions syndrome-7 (MMDS7; <a href="/entry/620423">620423</a>) <a href="#8" class="mim-tip-reference" title="Majethia, P., Somashekar, P. H., Hebbar, M., Kadavigere, R., Praveen, B. K., Girisha, K. M., Shukla, A. <strong>Biallelic start loss variant, c.1A > G in GCSH is associated with variant nonketotic hyperglycinemia.</strong> Clin. Genet. 100: 201-205, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33890291/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33890291</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=33890291[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1111/cge.13970" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33890291">Majethia et al. (2021)</a> identified a homozygous mutation (c.1A-G; <a href="#0002">238330.0002</a>) in the GCSH gene predicted to disrupt the methionine start site. Homozygosity mapping demonstrated a shared 490-kb region of homozygosity on chromosome 16 shared by the 2 families. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33890291" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 5 unrelated patients with MMDS7, <a href="#1" class="mim-tip-reference" title="Arribas-Carreira, L., Dallabona, C., Swanson, M. A., Farris, J., Ostergaard, E., Tsiakas, K., Hempel, M., Aquaviva-Bourdain, C., Koutsoukos, S., Stence, N. V., Magistrati, M., Spector, E. B., and 19 others. <strong>Pathogenic variants in GCSH encoding the moonlighting H-protein cause combined nonketotic hyperglycinemia and lipoate deficiency.</strong> Hum. Molec. Genet. 32: 917-933, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36190515/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36190515</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=36190515[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/ddac246" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="36190515">Arribas-Carreira et al. (2023)</a> identified biallelic mutations in the GCSH gene (<a href="#0002">238330.0002</a>-<a href="#0008">238330.0008</a>). Analysis of the mutations in patient cells, COS7 cells, and/or yeast cells showed that the mutations had variable effects in glycine exchange and protein lipoylation. Most of the mutations resulted in hypomorphic effects on both glycine exchange and lipoylation, whereas some mutations affected only 1 function. Patient phenotypes showed some correlation to the enzyme defect in either of the 2 GCSH enzyme functions (glycine exchange or lipoylation). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=36190515" 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>Reclassified Variants</em></strong></p><p>
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The complex rearrangement (<a href="#0001">238330.0001</a>) identified in a patient with glycine encephalopathy by <a href="#5" class="mim-tip-reference" title="Koyata, H., Hiraga, K. <strong>The glycine cleavage system: structure of a cDNA encoding human H-protein, and partial characterization of its gene in patients with hyperglycinemias.</strong> Am. J. Hum. Genet. 48: 351-361, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1671321/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1671321</a>]" pmid="1671321">Koyata and Hiraga (1991)</a> has been reclassified as a variant of unknown significance. <a href="#3" class="mim-tip-reference" title="Hiraga, K., Kochi, H., Hayasaka, K., Kikuchi, G., Nyhan, W. L. <strong>Defective glycine cleavage system in non-ketotic hyperglycinemia: occurrence of a less active glycine decarboxylase and an abnormal aminomethyl carrier protein.</strong> J. Clin. Invest. 68: 525-534, 1981.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6790577/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6790577</a>] [<a href="https://doi.org/10.1172/jci110284" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6790577">Hiraga et al. (1981)</a> found low activity for both P protein and H protein and a structural abnormality of H protein in the liver and brain of a patient with glycine encephalopathy. This patient was also reported to have progressive degeneration of the central nervous system (<a href="#10" class="mim-tip-reference" title="Trauner, D. A., Page, T., Greco, C., Sweetman, L., Kulovich, S., Nyhan, W. L. <strong>Progressive neurodegenerative disorder in a patient with nonketotic hyperglycinemia.</strong> J. Pediat. 98: 272-275, 1981.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6780675/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6780675</a>] [<a href="https://doi.org/10.1016/s0022-3476(81)80659-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6780675">Trauner et al., 1981</a>). By Southern analysis using an H protein cDNA probe, <a href="#5" class="mim-tip-reference" title="Koyata, H., Hiraga, K. <strong>The glycine cleavage system: structure of a cDNA encoding human H-protein, and partial characterization of its gene in patients with hyperglycinemias.</strong> Am. J. Hum. Genet. 48: 351-361, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1671321/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1671321</a>]" pmid="1671321">Koyata and Hiraga (1991)</a> found a deletion of one SacI fragment in the GCSH gene (<a href="#0001">238330.0001</a>) in this patient. The same fragment was deleted in 1 of 7 patients with GCE resulting from deficiency of glycine decarboxylase (GCE1; <a href="/entry/605899">605899</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6780675+1671321+6790577" 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>Polymorphisms</em></strong></p><p>
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By direct sequencing analysis, <a href="#6" class="mim-tip-reference" title="Kure, S., Kojima, K., Kudo, T., Kanno, K., Aoki, Y., Suzuki, Y., Shinka, T., Sakata, Y., Narisawa, K., Matsubara, Y. <strong>Chromosomal localization, structure, single-nucleotide polymorphisms, and expression of the human H-protein gene of the glycine cleavage system (GCSH), a candidate gene for nonketotic hyperglycinemia.</strong> J. Hum. Genet. 46: 378-384, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11450847/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11450847</a>] [<a href="https://doi.org/10.1007/s100380170057" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11450847">Kure et al. (2001)</a> identified 5 single-nucleotide polymorphisms in the GCSH gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11450847" 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="Leung, K.-Y., De Castro, S. C. P., Galea, G. L., Copp, A. J., Greene, N. D. E. <strong>Glycine cleavage system H protein is essential for embryonic viability, implying additional function beyond the glycine cleavage system.</strong> Front. Genet. 12: 625120, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33569080/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33569080</a>] [<a href="https://doi.org/10.3389/fgene.2021.625120" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33569080">Leung et al. (2021)</a> found that Gcsh homozygous null genotype resulted in embryonic death prior to gestational day 10.5. Maternal formate supplementation did not rescue the embryonic lethality, suggesting that the lethality did not result from defective 1-carbon metabolism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33569080" 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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<span id="mimAllelicVariantsToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<strong>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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<strong>8 Selected Examples</a>):</strong>
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<a href="/allelicVariants/238330" class="btn btn-default" role="button"> Table View </a>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=238330[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<strong>.0001 RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE</strong>
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GCSH, COMPLEX REARRANGEMENT
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012753" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012753" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012753</a>
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<p>This variant, formerly titled GLYCINE ENCEPHALOPATHY, has been reclassified as a variant of unknown significance because its contribution to the disorder has not been confirmed.</p><p>By Southern analysis using an H protein cDNA probe, <a href="#5" class="mim-tip-reference" title="Koyata, H., Hiraga, K. <strong>The glycine cleavage system: structure of a cDNA encoding human H-protein, and partial characterization of its gene in patients with hyperglycinemias.</strong> Am. J. Hum. Genet. 48: 351-361, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1671321/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1671321</a>]" pmid="1671321">Koyata and Hiraga (1991)</a> found a deletion of one SacI fragment in a patient with glycine encephalopathy (see <a href="/entry/605899">605899</a>) reported by <a href="#3" class="mim-tip-reference" title="Hiraga, K., Kochi, H., Hayasaka, K., Kikuchi, G., Nyhan, W. L. <strong>Defective glycine cleavage system in non-ketotic hyperglycinemia: occurrence of a less active glycine decarboxylase and an abnormal aminomethyl carrier protein.</strong> J. Clin. Invest. 68: 525-534, 1981.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6790577/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6790577</a>] [<a href="https://doi.org/10.1172/jci110284" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6790577">Hiraga et al. (1981)</a>. The same fragment was deleted in 1 of 7 patients with glycine encephalopathy resulting from deficiency of glycine decarboxylase (GLDC; <a href="/entry/238300">238300</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1671321+6790577" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0002 MULTIPLE MITOCHONDRIAL DYSFUNCTIONS SYNDROME 7</strong>
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GCSH, MET1?
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs886039730 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs886039730;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=rs886039730" 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=rs886039730" 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=RCV000255962 OR RCV001804993 OR RCV003236578 OR RCV003401220" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000255962, RCV001804993, RCV003236578, RCV003401220" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000255962...</a>
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<p>In 3 patients, including a sib pair, from 2 Indian families with multiple mitochondrial dysfunctions syndrome-7 (MMDS7; <a href="/entry/620423">620423</a>), <a href="#8" class="mim-tip-reference" title="Majethia, P., Somashekar, P. H., Hebbar, M., Kadavigere, R., Praveen, B. K., Girisha, K. M., Shukla, A. <strong>Biallelic start loss variant, c.1A > G in GCSH is associated with variant nonketotic hyperglycinemia.</strong> Clin. Genet. 100: 201-205, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33890291/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33890291</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=33890291[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1111/cge.13970" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33890291">Majethia et al. (2021)</a> identified homozygosity for a c.1A-G transition (c.1A-G, NM_004483.5) in the GCSH gene, predicted to disrupt the methionine initiation site. The mutations were identified by whole-exome sequencing and confirmed by Sanger sequencing, and the parents were shown to be mutation carriers. The variant was present in gnomAD in 2 individuals in heterozygosity only. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33890291" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 unrelated patients (patients 2 and 3) with MMDS7 <a href="#1" class="mim-tip-reference" title="Arribas-Carreira, L., Dallabona, C., Swanson, M. A., Farris, J., Ostergaard, E., Tsiakas, K., Hempel, M., Aquaviva-Bourdain, C., Koutsoukos, S., Stence, N. V., Magistrati, M., Spector, E. B., and 19 others. <strong>Pathogenic variants in GCSH encoding the moonlighting H-protein cause combined nonketotic hyperglycinemia and lipoate deficiency.</strong> Hum. Molec. Genet. 32: 917-933, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36190515/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36190515</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=36190515[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/ddac246" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="36190515">Arribas-Carreira et al. (2023)</a> identified compound heterozygosity for the c.1A-G mutation and a 1-bp insertion (c.293-2_293-1insT, <a href="#0003">238330.0003</a>) or a nonsense mutation (Q76X; <a href="#0004">238330.0004</a>), respectively. The mutations were identified by whole-exome sequencing. Expression of GCSH with the c.1A-G mutation in COS7 cells resulted in near absence of normal-sized H protein and lipoylated H protein, with decreased mitochondrial localization. Functional studies showed decreased glycine exchange activity and decreased lipoylation activity. RNA analysis of the c.293-2_293-1insT mutation, carried by the father of patient 2, showed that it resulted in skipping of exon 4 and in-frame deletion of 44 amino acids (Asp98_Asp141del). Western blot analysis in chorionic villus cells (CVS) cells from patient 2 demonstrated reduced H protein expression and near absence of lipoylated proteins in the mitochondria. Both patients 2 and 3 had a severe presentation, and died at ages 7 days and 11 months. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=36190515" 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="0003" class="mim-anchor"></a>
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<span class="mim-font">
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<strong>.0003 MULTIPLE MITOCHONDRIAL DYSFUNCTIONS SYNDROME 7</strong>
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GCSH, IVS3, 1-BP INS, NT293-2
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV003236610" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV003236610" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV003236610</a>
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<p>For discussion of the c.293-2_293-1insT (c.293-2_293-1insT, NM_004483.5) mutation in the GCSH gene, resulting in skipping of exon 4, that was identified in patient 2 with multiple mitochondrial dysfunctions syndrome-7 (MMDS7; <a href="/entry/620423">620423</a>) by <a href="#1" class="mim-tip-reference" title="Arribas-Carreira, L., Dallabona, C., Swanson, M. A., Farris, J., Ostergaard, E., Tsiakas, K., Hempel, M., Aquaviva-Bourdain, C., Koutsoukos, S., Stence, N. V., Magistrati, M., Spector, E. B., and 19 others. <strong>Pathogenic variants in GCSH encoding the moonlighting H-protein cause combined nonketotic hyperglycinemia and lipoate deficiency.</strong> Hum. Molec. Genet. 32: 917-933, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36190515/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36190515</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=36190515[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/ddac246" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="36190515">Arribas-Carreira et al. (2023)</a>, see <a href="#0002">238330.0002</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=36190515" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0004 MULTIPLE MITOCHONDRIAL DYSFUNCTIONS SYNDROME 7</strong>
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GCSH, GLN76TER
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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> rs769222264 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs769222264;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/rs769222264?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=rs769222264" 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=rs769222264" 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=RCV000254729 OR RCV001359426 OR RCV003236577 OR RCV003417868" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000254729, RCV001359426, RCV003236577, RCV003417868" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000254729...</a>
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<p>For discussion of the c.226C-T transition (c.226C-T, NM_004483.5) in the GCSH gene, resulting in a gln76-to-ter (Q76X) substitution, that was identified in patient 3 with multiple mitochondrial dysfunctions syndrome-7 (MMDS7; <a href="/entry/620423">620423</a>) by <a href="#1" class="mim-tip-reference" title="Arribas-Carreira, L., Dallabona, C., Swanson, M. A., Farris, J., Ostergaard, E., Tsiakas, K., Hempel, M., Aquaviva-Bourdain, C., Koutsoukos, S., Stence, N. V., Magistrati, M., Spector, E. B., and 19 others. <strong>Pathogenic variants in GCSH encoding the moonlighting H-protein cause combined nonketotic hyperglycinemia and lipoate deficiency.</strong> Hum. Molec. Genet. 32: 917-933, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36190515/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36190515</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=36190515[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/ddac246" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="36190515">Arribas-Carreira et al. (2023)</a>, see <a href="#0002">238330.0002</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=36190515" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0005 MULTIPLE MITOCHONDRIAL DYSFUNCTIONS SYNDROME 7</strong>
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<p>In a patient (patient 1) with multiple mitochondrial dysfunctions syndrome-7 (MMDS7; <a href="/entry/620423">620423</a>), <a href="#1" class="mim-tip-reference" title="Arribas-Carreira, L., Dallabona, C., Swanson, M. A., Farris, J., Ostergaard, E., Tsiakas, K., Hempel, M., Aquaviva-Bourdain, C., Koutsoukos, S., Stence, N. V., Magistrati, M., Spector, E. B., and 19 others. <strong>Pathogenic variants in GCSH encoding the moonlighting H-protein cause combined nonketotic hyperglycinemia and lipoate deficiency.</strong> Hum. Molec. Genet. 32: 917-933, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36190515/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36190515</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=36190515[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/ddac246" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="36190515">Arribas-Carreira et al. (2023)</a> identified compound heterozygosity for 2 mutations in the GCSH gene: a c.170A-G transition (c.170A-G, NM_004483.5), resulting in a his57-to-arg (H57R) substitution, and a deletion of exon 2 (<a href="#0006">238330.0006</a>). The mutations were identified by sequencing of a custom exome panel and multiplex ligation-dependent probe amplification. Expression of GCSH with the H57R mutation in COS7 cells resulted in increased levels of H protein and mitochondrial colocalization. Functional studies showed increased glycine exchange activity and decreased lipoylation activity. A yeast model of the mutation demonstrated impaired mitochondrial respiration and cell growth. The patient had a severe presentation and died at age 18 days. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=36190515" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0006 MULTIPLE MITOCHONDRIAL DYSFUNCTIONS SYNDROME 7</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV003236612" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV003236612" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV003236612</a>
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<p>For discussion of the deletion of exon 2 in the GCSH gene that was identified in patient 1 with multiple mitochondrial dysfunctions syndrome-7 (MMDS7; <a href="/entry/620423">620423</a>) by <a href="#1" class="mim-tip-reference" title="Arribas-Carreira, L., Dallabona, C., Swanson, M. A., Farris, J., Ostergaard, E., Tsiakas, K., Hempel, M., Aquaviva-Bourdain, C., Koutsoukos, S., Stence, N. V., Magistrati, M., Spector, E. B., and 19 others. <strong>Pathogenic variants in GCSH encoding the moonlighting H-protein cause combined nonketotic hyperglycinemia and lipoate deficiency.</strong> Hum. Molec. Genet. 32: 917-933, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36190515/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36190515</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=36190515[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/ddac246" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="36190515">Arribas-Carreira et al. (2023)</a>, see <a href="#0005">238330.0005</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=36190515" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0007 MULTIPLE MITOCHONDRIAL DYSFUNCTIONS SYNDROME 7</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV003236613" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV003236613" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV003236613</a>
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<p>In a patient (patient 5) with multiple mitochondrial dysfunctions syndrome-7 (MMDS7; <a href="/entry/620423">620423</a>), <a href="#1" class="mim-tip-reference" title="Arribas-Carreira, L., Dallabona, C., Swanson, M. A., Farris, J., Ostergaard, E., Tsiakas, K., Hempel, M., Aquaviva-Bourdain, C., Koutsoukos, S., Stence, N. V., Magistrati, M., Spector, E. B., and 19 others. <strong>Pathogenic variants in GCSH encoding the moonlighting H-protein cause combined nonketotic hyperglycinemia and lipoate deficiency.</strong> Hum. Molec. Genet. 32: 917-933, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36190515/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36190515</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=36190515[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/ddac246" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="36190515">Arribas-Carreira et al. (2023)</a> identified homozygosity for a duplication of exons 4 and 5 (c.292+1_293-1_*919_?dup, NM_004483.5) of the GCSH gene. The genomic coordinates of the deletion were given as chr16:81,116,399-81,118,259. The mutation was identified by whole-exome sequencing. Western blot analysis of patient fibroblasts demonstrated reduced H protein expression and decreased lipoylated proteins in the mitochondria. The patient had an attenuated phenotype and was 20 months of age at the time of the report. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=36190515" 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 MULTIPLE MITOCHONDRIAL DYSFUNCTIONS SYNDROME 7</strong>
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GCSH, PRO115LEU
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV003236614" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV003236614" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV003236614</a>
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<p>In a patient (patient 6) with multiple mitochondrial dysfunctions syndrome-7 (MMDS7; <a href="/entry/620423">620423</a>), <a href="#1" class="mim-tip-reference" title="Arribas-Carreira, L., Dallabona, C., Swanson, M. A., Farris, J., Ostergaard, E., Tsiakas, K., Hempel, M., Aquaviva-Bourdain, C., Koutsoukos, S., Stence, N. V., Magistrati, M., Spector, E. B., and 19 others. <strong>Pathogenic variants in GCSH encoding the moonlighting H-protein cause combined nonketotic hyperglycinemia and lipoate deficiency.</strong> Hum. Molec. Genet. 32: 917-933, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36190515/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36190515</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=36190515[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/ddac246" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="36190515">Arribas-Carreira et al. (2023)</a> identified homozygosity for a c.344C-T transition (c.344C-T, NM_004483.5) in the GCSH gene, resulting in a pro115-to-leu (P115L) substitution. The mutation was identified by sequencing of a custom exome panel. Western blot analysis of patient fibroblasts demonstrated reduced H protein expression and decreased lipoylated proteins in the mitochondria. Expression of the mutant protein in COS7 cells resulted in almost normal amounts of H protein correctly localized to mitochondria, decreased glycine exchange activity, and decreased lipoylation activity. This patient had an attenuated phenotype with severe global developmental delays at age 4.5 years. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=36190515" 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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<span id="mimReferencesToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<strong>REFERENCES</strong>
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<a id="Arribas-Carreira2023" class="mim-anchor"></a>
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Arribas-Carreira, L., Dallabona, C., Swanson, M. A., Farris, J., Ostergaard, E., Tsiakas, K., Hempel, M., Aquaviva-Bourdain, C., Koutsoukos, S., Stence, N. V., Magistrati, M., Spector, E. B., and 19 others.
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<strong>Pathogenic variants in GCSH encoding the moonlighting H-protein cause combined nonketotic hyperglycinemia and lipoate deficiency.</strong>
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Hum. Molec. Genet. 32: 917-933, 2023.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36190515/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36190515</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=36190515[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=36190515" 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/ddac246" target="_blank">Full Text</a>]
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Fujiwara, K., Okamura-Ikeda, K., Hayasaka, K., Motokawa, Y.
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<strong>The primary structure of human H-protein of the glycine cleavage system deduced by cDNA cloning.</strong>
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Biochem. Biophys. Res. Commun. 176: 711-716, 1991.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2025283/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2025283</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2025283" 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/s0006-291x(05)80242-6" target="_blank">Full Text</a>]
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Hiraga, K., Kochi, H., Hayasaka, K., Kikuchi, G., Nyhan, W. L.
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<strong>Defective glycine cleavage system in non-ketotic hyperglycinemia: occurrence of a less active glycine decarboxylase and an abnormal aminomethyl carrier protein.</strong>
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J. Clin. Invest. 68: 525-534, 1981.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6790577/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6790577</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6790577" 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/10.1172/jci110284" target="_blank">Full Text</a>]
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Hiraga, K., Kure, S., Yamamoto, M., Ishiguro, Y., Suzuki, T.
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<strong>Cloning of cDNA encoding human H-protein, a constituent of the glycine cleavage system.</strong>
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Biochem. Biophys. Res. Commun. 151: 758-762, 1988.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3348809/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3348809</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3348809" 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/s0006-291x(88)80345-0" target="_blank">Full Text</a>]
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<a id="Koyata1991" class="mim-anchor"></a>
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Koyata, H., Hiraga, K.
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<strong>The glycine cleavage system: structure of a cDNA encoding human H-protein, and partial characterization of its gene in patients with hyperglycinemias.</strong>
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Am. J. Hum. Genet. 48: 351-361, 1991.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1671321/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1671321</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1671321" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<a id="Kure2001" class="mim-anchor"></a>
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Kure, S., Kojima, K., Kudo, T., Kanno, K., Aoki, Y., Suzuki, Y., Shinka, T., Sakata, Y., Narisawa, K., Matsubara, Y.
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<strong>Chromosomal localization, structure, single-nucleotide polymorphisms, and expression of the human H-protein gene of the glycine cleavage system (GCSH), a candidate gene for nonketotic hyperglycinemia.</strong>
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J. Hum. Genet. 46: 378-384, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11450847/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11450847</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11450847" 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/s100380170057" target="_blank">Full Text</a>]
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<a id="Leung2021" class="mim-anchor"></a>
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Leung, K.-Y., De Castro, S. C. P., Galea, G. L., Copp, A. J., Greene, N. D. E.
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<strong>Glycine cleavage system H protein is essential for embryonic viability, implying additional function beyond the glycine cleavage system.</strong>
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Front. Genet. 12: 625120, 2021.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33569080/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33569080</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33569080" 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/fgene.2021.625120" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="8" class="mim-anchor"></a>
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<a id="Majethia2021" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Majethia, P., Somashekar, P. H., Hebbar, M., Kadavigere, R., Praveen, B. K., Girisha, K. M., Shukla, A.
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<strong>Biallelic start loss variant, c.1A > G in GCSH is associated with variant nonketotic hyperglycinemia.</strong>
|
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Clin. Genet. 100: 201-205, 2021.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33890291/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33890291</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=33890291[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=33890291" 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.13970" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="9" class="mim-anchor"></a>
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<a id="Sakata2001" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Sakata, Y., Owada, Y., Sato, K., Kojima, K., Hisanaga, K., Shinka, T., Suzuki, Y., Aoki, Y., Satoh, J., Kondo, H., Matsubara, Y., Kure, S.
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<strong>Structure and expression of the glycine cleavage system in rat central nervous system.</strong>
|
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Molec. Brain Res. 94: 119-130, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11597772/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11597772</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11597772" 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/s0169-328x(01)00225-x" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="10" class="mim-anchor"></a>
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<a id="Trauner1981" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Trauner, D. A., Page, T., Greco, C., Sweetman, L., Kulovich, S., Nyhan, W. L.
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<strong>Progressive neurodegenerative disorder in a patient with nonketotic hyperglycinemia.</strong>
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J. Pediat. 98: 272-275, 1981.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6780675/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6780675</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6780675" 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/s0022-3476(81)80659-2" target="_blank">Full Text</a>]
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</p>
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</div>
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</ol>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Hilary J. Vernon - updated : 06/21/2023
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Ada Hamosh - updated : 05/31/2023<br>Cassandra L. Kniffin - updated : 12/20/2002<br>Ada Hamosh - updated : 2/20/2002<br>Victor A. McKusick - updated : 7/18/2001<br>Joanna S. Amberger - updated : 5/4/2001
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 10/16/1986
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 09/05/2023
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 06/21/2023<br>alopez : 06/21/2023<br>carol : 05/31/2023<br>joanna : 04/27/2018<br>carol : 08/04/2010<br>ckniffin : 1/10/2003<br>ckniffin : 12/20/2002<br>alopez : 2/25/2002<br>terry : 2/20/2002<br>mcapotos : 8/10/2001<br>mcapotos : 8/10/2001<br>mcapotos : 7/27/2001<br>terry : 7/18/2001<br>carol : 6/22/2001<br>joanna : 5/4/2001<br>carol : 5/3/2001<br>carol : 4/17/2000<br>carol : 4/4/2000<br>carol : 4/4/2000<br>carol : 7/16/1998<br>joanna : 1/27/1997<br>mimadm : 2/19/1994<br>carol : 8/17/1992<br>supermim : 3/16/1992<br>carol : 6/25/1991<br>carol : 3/1/1991<br>supermim : 3/20/1990
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</span>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<div class="container visible-print-block">
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<div class="row">
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<div class="col-md-8 col-md-offset-1">
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<div>
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<div>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 238330
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</span>
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</h3>
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</div>
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<div>
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<h3>
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<span class="mim-font">
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GLYCINE CLEAVAGE SYSTEM H PROTEIN; GCSH
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: GCSH</em></strong>
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</span>
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</p>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: 16q23.2
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Genomic coordinates <span class="small">(GRCh38)</span> : 16:81,081,945-81,096,395 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="1">
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<span class="mim-font">
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16q23.2
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</span>
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</td>
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<td>
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<span class="mim-font">
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Multiple mitochondrial dysfunctions syndrome 7
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</span>
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</td>
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<td>
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<span class="mim-font">
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620423
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The enzyme system for cleavage of glycine (glycine cleavage system; EC 2.1.2.10), which is confined to the mitochondria, is composed of 4 protein components: P protein (a pyridoxal phosphate-dependent glycine decarboxylase; 238300), H protein (a lipoic acid-containing protein), T protein (a tetrahydrofolate-requiring enzyme; 238310), and L protein (a lipoamide dehydrogenase; 238331).</p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Hiraga et al. (1988) cloned a cDNA encoding H protein from a human liver cDNA library. Koyata and Hiraga (1991) isolated a 1,192-bp cDNA that encodes the entire precursor of human H protein. Fujiwara et al. (1991) isolated a full-length GCSH cDNA encoding a precursor protein of 173 amino acids and a mature protein of 125 amino acids. By dot-blot analysis, Kure et al. (2001) found that GCSH was expressed in all 29 tissues examined. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Structure</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Kure et al. (2001) isolated and characterized a human PAC clone encoding GCSH. They found that GCSH spans 13.5 kb and contains 5 exons. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Sakata et al. (2001) reported the structure and expression of the glycine cleavage system in rat central nervous system. </p>
|
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</span>
|
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<div>
|
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<br />
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>Mapping</strong>
|
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By fluorescence in situ hybridization, Kure et al. (2001) mapped the GCSH gene to chromosome 16q24. </p>
|
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</span>
|
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<div>
|
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<br />
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>Molecular Genetics</strong>
|
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</span>
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</h4>
|
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</div>
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<span class="mim-text-font">
|
|
<p><strong><em>Multiple Mitochondrial Dysfunctions Syndrome 7</em></strong></p><p>
|
|
In 3 patients from 2 Indian families with multiple mitochondrial dysfunctions syndrome-7 (MMDS7; 620423) Majethia et al. (2021) identified a homozygous mutation (c.1A-G; 238330.0002) in the GCSH gene predicted to disrupt the methionine start site. Homozygosity mapping demonstrated a shared 490-kb region of homozygosity on chromosome 16 shared by the 2 families. </p><p>In 5 unrelated patients with MMDS7, Arribas-Carreira et al. (2023) identified biallelic mutations in the GCSH gene (238330.0002-238330.0008). Analysis of the mutations in patient cells, COS7 cells, and/or yeast cells showed that the mutations had variable effects in glycine exchange and protein lipoylation. Most of the mutations resulted in hypomorphic effects on both glycine exchange and lipoylation, whereas some mutations affected only 1 function. Patient phenotypes showed some correlation to the enzyme defect in either of the 2 GCSH enzyme functions (glycine exchange or lipoylation). </p><p><strong><em>Reclassified Variants</em></strong></p><p>
|
|
The complex rearrangement (238330.0001) identified in a patient with glycine encephalopathy by Koyata and Hiraga (1991) has been reclassified as a variant of unknown significance. Hiraga et al. (1981) found low activity for both P protein and H protein and a structural abnormality of H protein in the liver and brain of a patient with glycine encephalopathy. This patient was also reported to have progressive degeneration of the central nervous system (Trauner et al., 1981). By Southern analysis using an H protein cDNA probe, Koyata and Hiraga (1991) found a deletion of one SacI fragment in the GCSH gene (238330.0001) in this patient. The same fragment was deleted in 1 of 7 patients with GCE resulting from deficiency of glycine decarboxylase (GCE1; 605899). </p><p><strong><em>Polymorphisms</em></strong></p><p>
|
|
By direct sequencing analysis, Kure et al. (2001) identified 5 single-nucleotide polymorphisms in the GCSH gene. </p>
|
|
</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>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">
|
|
<p>Leung et al. (2021) found that Gcsh homozygous null genotype resulted in embryonic death prior to gestational day 10.5. Maternal formate supplementation did not rescue the embryonic lethality, suggesting that the lethality did not result from defective 1-carbon metabolism. </p>
|
|
</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>
|
|
<span class="mim-font">
|
|
<strong>ALLELIC VARIANTS</strong>
|
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</span>
|
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<strong>8 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>
|
|
<span class="mim-font">
|
|
<strong>.0001 RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE</strong>
|
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</span>
|
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</h4>
|
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</div>
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<div>
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<span class="mim-text-font">
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|
GCSH, COMPLEX REARRANGEMENT
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<br />
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|
ClinVar: RCV000012753
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>This variant, formerly titled GLYCINE ENCEPHALOPATHY, has been reclassified as a variant of unknown significance because its contribution to the disorder has not been confirmed.</p><p>By Southern analysis using an H protein cDNA probe, Koyata and Hiraga (1991) found a deletion of one SacI fragment in a patient with glycine encephalopathy (see 605899) reported by Hiraga et al. (1981). The same fragment was deleted in 1 of 7 patients with glycine encephalopathy resulting from deficiency of glycine decarboxylase (GLDC; 238300). </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 MULTIPLE MITOCHONDRIAL DYSFUNCTIONS SYNDROME 7</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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GCSH, MET1?
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<br />
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SNP: rs886039730,
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ClinVar: RCV000255962, RCV001804993, RCV003236578, RCV003401220
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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 3 patients, including a sib pair, from 2 Indian families with multiple mitochondrial dysfunctions syndrome-7 (MMDS7; 620423), Majethia et al. (2021) identified homozygosity for a c.1A-G transition (c.1A-G, NM_004483.5) in the GCSH gene, predicted to disrupt the methionine initiation site. The mutations were identified by whole-exome sequencing and confirmed by Sanger sequencing, and the parents were shown to be mutation carriers. The variant was present in gnomAD in 2 individuals in heterozygosity only. </p><p>In 2 unrelated patients (patients 2 and 3) with MMDS7 Arribas-Carreira et al. (2023) identified compound heterozygosity for the c.1A-G mutation and a 1-bp insertion (c.293-2_293-1insT, 238330.0003) or a nonsense mutation (Q76X; 238330.0004), respectively. The mutations were identified by whole-exome sequencing. Expression of GCSH with the c.1A-G mutation in COS7 cells resulted in near absence of normal-sized H protein and lipoylated H protein, with decreased mitochondrial localization. Functional studies showed decreased glycine exchange activity and decreased lipoylation activity. RNA analysis of the c.293-2_293-1insT mutation, carried by the father of patient 2, showed that it resulted in skipping of exon 4 and in-frame deletion of 44 amino acids (Asp98_Asp141del). Western blot analysis in chorionic villus cells (CVS) cells from patient 2 demonstrated reduced H protein expression and near absence of lipoylated proteins in the mitochondria. Both patients 2 and 3 had a severe presentation, and died at ages 7 days and 11 months. </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 MULTIPLE MITOCHONDRIAL DYSFUNCTIONS SYNDROME 7</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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GCSH, IVS3, 1-BP INS, NT293-2
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<br />
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ClinVar: RCV003236610
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>For discussion of the c.293-2_293-1insT (c.293-2_293-1insT, NM_004483.5) mutation in the GCSH gene, resulting in skipping of exon 4, that was identified in patient 2 with multiple mitochondrial dysfunctions syndrome-7 (MMDS7; 620423) by Arribas-Carreira et al. (2023), see 238330.0002. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0004 MULTIPLE MITOCHONDRIAL DYSFUNCTIONS SYNDROME 7</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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GCSH, GLN76TER
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<br />
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SNP: rs769222264,
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gnomAD: rs769222264,
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ClinVar: RCV000254729, RCV001359426, RCV003236577, RCV003417868
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>For discussion of the c.226C-T transition (c.226C-T, NM_004483.5) in the GCSH gene, resulting in a gln76-to-ter (Q76X) substitution, that was identified in patient 3 with multiple mitochondrial dysfunctions syndrome-7 (MMDS7; 620423) by Arribas-Carreira et al. (2023), see 238330.0002. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0005 MULTIPLE MITOCHONDRIAL DYSFUNCTIONS SYNDROME 7</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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GCSH, HIS57ARG
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<br />
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ClinVar: RCV003236611
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a patient (patient 1) with multiple mitochondrial dysfunctions syndrome-7 (MMDS7; 620423), Arribas-Carreira et al. (2023) identified compound heterozygosity for 2 mutations in the GCSH gene: a c.170A-G transition (c.170A-G, NM_004483.5), resulting in a his57-to-arg (H57R) substitution, and a deletion of exon 2 (238330.0006). The mutations were identified by sequencing of a custom exome panel and multiplex ligation-dependent probe amplification. Expression of GCSH with the H57R mutation in COS7 cells resulted in increased levels of H protein and mitochondrial colocalization. Functional studies showed increased glycine exchange activity and decreased lipoylation activity. A yeast model of the mutation demonstrated impaired mitochondrial respiration and cell growth. The patient had a severe presentation and died at age 18 days. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0006 MULTIPLE MITOCHONDRIAL DYSFUNCTIONS SYNDROME 7</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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GCSH, EX2DEL
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<br />
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ClinVar: RCV003236612
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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>For discussion of the deletion of exon 2 in the GCSH gene that was identified in patient 1 with multiple mitochondrial dysfunctions syndrome-7 (MMDS7; 620423) by Arribas-Carreira et al. (2023), see 238330.0005. </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>.0007 MULTIPLE MITOCHONDRIAL DYSFUNCTIONS SYNDROME 7</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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GCSH, EX4-5DUP
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<br />
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ClinVar: RCV003236613
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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 a patient (patient 5) with multiple mitochondrial dysfunctions syndrome-7 (MMDS7; 620423), Arribas-Carreira et al. (2023) identified homozygosity for a duplication of exons 4 and 5 (c.292+1_293-1_*919_?dup, NM_004483.5) of the GCSH gene. The genomic coordinates of the deletion were given as chr16:81,116,399-81,118,259. The mutation was identified by whole-exome sequencing. Western blot analysis of patient fibroblasts demonstrated reduced H protein expression and decreased lipoylated proteins in the mitochondria. The patient had an attenuated phenotype and was 20 months of age at the time of the report. </p>
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|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 MULTIPLE MITOCHONDRIAL DYSFUNCTIONS SYNDROME 7</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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|
|
GCSH, PRO115LEU
|
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<br />
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|
|
ClinVar: RCV003236614
|
|
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</span>
|
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</div>
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|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient (patient 6) with multiple mitochondrial dysfunctions syndrome-7 (MMDS7; 620423), Arribas-Carreira et al. (2023) identified homozygosity for a c.344C-T transition (c.344C-T, NM_004483.5) in the GCSH gene, resulting in a pro115-to-leu (P115L) substitution. The mutation was identified by sequencing of a custom exome panel. Western blot analysis of patient fibroblasts demonstrated reduced H protein expression and decreased lipoylated proteins in the mitochondria. Expression of the mutant protein in COS7 cells resulted in almost normal amounts of H protein correctly localized to mitochondria, decreased glycine exchange activity, and decreased lipoylation activity. This patient had an attenuated phenotype with severe global developmental delays at age 4.5 years. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<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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Arribas-Carreira, L., Dallabona, C., Swanson, M. A., Farris, J., Ostergaard, E., Tsiakas, K., Hempel, M., Aquaviva-Bourdain, C., Koutsoukos, S., Stence, N. V., Magistrati, M., Spector, E. B., and 19 others.
|
|
<strong>Pathogenic variants in GCSH encoding the moonlighting H-protein cause combined nonketotic hyperglycinemia and lipoate deficiency.</strong>
|
|
Hum. Molec. Genet. 32: 917-933, 2023.
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[PubMed: 36190515]
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[Full Text: https://doi.org/10.1093/hmg/ddac246]
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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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Fujiwara, K., Okamura-Ikeda, K., Hayasaka, K., Motokawa, Y.
|
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<strong>The primary structure of human H-protein of the glycine cleavage system deduced by cDNA cloning.</strong>
|
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Biochem. Biophys. Res. Commun. 176: 711-716, 1991.
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[PubMed: 2025283]
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[Full Text: https://doi.org/10.1016/s0006-291x(05)80242-6]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Hiraga, K., Kochi, H., Hayasaka, K., Kikuchi, G., Nyhan, W. L.
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|
<strong>Defective glycine cleavage system in non-ketotic hyperglycinemia: occurrence of a less active glycine decarboxylase and an abnormal aminomethyl carrier protein.</strong>
|
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J. Clin. Invest. 68: 525-534, 1981.
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[PubMed: 6790577]
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[Full Text: https://doi.org/10.1172/jci110284]
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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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Hiraga, K., Kure, S., Yamamoto, M., Ishiguro, Y., Suzuki, T.
|
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<strong>Cloning of cDNA encoding human H-protein, a constituent of the glycine cleavage system.</strong>
|
|
Biochem. Biophys. Res. Commun. 151: 758-762, 1988.
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[PubMed: 3348809]
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[Full Text: https://doi.org/10.1016/s0006-291x(88)80345-0]
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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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Koyata, H., Hiraga, K.
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<strong>The glycine cleavage system: structure of a cDNA encoding human H-protein, and partial characterization of its gene in patients with hyperglycinemias.</strong>
|
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Am. J. Hum. Genet. 48: 351-361, 1991.
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[PubMed: 1671321]
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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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Kure, S., Kojima, K., Kudo, T., Kanno, K., Aoki, Y., Suzuki, Y., Shinka, T., Sakata, Y., Narisawa, K., Matsubara, Y.
|
|
<strong>Chromosomal localization, structure, single-nucleotide polymorphisms, and expression of the human H-protein gene of the glycine cleavage system (GCSH), a candidate gene for nonketotic hyperglycinemia.</strong>
|
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J. Hum. Genet. 46: 378-384, 2001.
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[PubMed: 11450847]
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[Full Text: https://doi.org/10.1007/s100380170057]
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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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Leung, K.-Y., De Castro, S. C. P., Galea, G. L., Copp, A. J., Greene, N. D. E.
|
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<strong>Glycine cleavage system H protein is essential for embryonic viability, implying additional function beyond the glycine cleavage system.</strong>
|
|
Front. Genet. 12: 625120, 2021.
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[PubMed: 33569080]
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[Full Text: https://doi.org/10.3389/fgene.2021.625120]
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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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Majethia, P., Somashekar, P. H., Hebbar, M., Kadavigere, R., Praveen, B. K., Girisha, K. M., Shukla, A.
|
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<strong>Biallelic start loss variant, c.1A > G in GCSH is associated with variant nonketotic hyperglycinemia.</strong>
|
|
Clin. Genet. 100: 201-205, 2021.
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[PubMed: 33890291]
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[Full Text: https://doi.org/10.1111/cge.13970]
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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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Sakata, Y., Owada, Y., Sato, K., Kojima, K., Hisanaga, K., Shinka, T., Suzuki, Y., Aoki, Y., Satoh, J., Kondo, H., Matsubara, Y., Kure, S.
|
|
<strong>Structure and expression of the glycine cleavage system in rat central nervous system.</strong>
|
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Molec. Brain Res. 94: 119-130, 2001.
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[PubMed: 11597772]
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[Full Text: https://doi.org/10.1016/s0169-328x(01)00225-x]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Trauner, D. A., Page, T., Greco, C., Sweetman, L., Kulovich, S., Nyhan, W. L.
|
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<strong>Progressive neurodegenerative disorder in a patient with nonketotic hyperglycinemia.</strong>
|
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J. Pediat. 98: 272-275, 1981.
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[PubMed: 6780675]
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[Full Text: https://doi.org/10.1016/s0022-3476(81)80659-2]
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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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</div>
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</div>
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<div>
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<div class="row">
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<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
|
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<span class="text-nowrap mim-text-font">
|
|
Contributors:
|
|
</span>
|
|
</div>
|
|
<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
|
<span class="mim-text-font">
|
|
Hilary J. Vernon - updated : 06/21/2023<br>Ada Hamosh - updated : 05/31/2023<br>Cassandra L. Kniffin - updated : 12/20/2002<br>Ada Hamosh - updated : 2/20/2002<br>Victor A. McKusick - updated : 7/18/2001<br>Joanna S. Amberger - updated : 5/4/2001
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|
</span>
|
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</div>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<div class="row">
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<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
|
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<span class="text-nowrap mim-text-font">
|
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Creation Date:
|
|
</span>
|
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</div>
|
|
<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
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<span class="mim-text-font">
|
|
Victor A. McKusick : 10/16/1986
|
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</span>
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</div>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<div class="row">
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carol : 09/05/2023<br>alopez : 06/21/2023<br>alopez : 06/21/2023<br>carol : 05/31/2023<br>joanna : 04/27/2018<br>carol : 08/04/2010<br>ckniffin : 1/10/2003<br>ckniffin : 12/20/2002<br>alopez : 2/25/2002<br>terry : 2/20/2002<br>mcapotos : 8/10/2001<br>mcapotos : 8/10/2001<br>mcapotos : 7/27/2001<br>terry : 7/18/2001<br>carol : 6/22/2001<br>joanna : 5/4/2001<br>carol : 5/3/2001<br>carol : 4/17/2000<br>carol : 4/4/2000<br>carol : 4/4/2000<br>carol : 7/16/1998<br>joanna : 1/27/1997<br>mimadm : 2/19/1994<br>carol : 8/17/1992<br>supermim : 3/16/1992<br>carol : 6/25/1991<br>carol : 3/1/1991<br>supermim : 3/20/1990
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