4036 lines
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Entry
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- *609831 - METABOLISM OF COBALAMIN ASSOCIATED C; MMACHC
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*609831</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<li role="presentation">
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<li role="presentation">
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</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/609831">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</ul>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000132763;t=ENST00000401061" 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=25974" 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=609831" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000132763;t=ENST00000401061" 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_001330540,NM_015506" 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_015506" 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=609831" 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=18585&isoform_id=18585_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/MMACHC" 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/31455227,52545527,85681045,119627388,153070822,1060099294" 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/Q9Y4U1" 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=25974" 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=ENSG00000132763;t=ENST00000401061" 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=MMACHC" 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=MMACHC" 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+25974" 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/MMACHC" 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:25974" 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/25974" 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=chr1&hgg_gene=ENST00000401061.9&hgg_start=45500300&hgg_end=45513382&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:24525" 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:24525" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/mmachc" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=609831[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=609831[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://www.deciphergenomics.org/gene/MMACHC/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000132763" 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=MMACHC" 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=MMACHC" 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=MMACHC" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="http://databases.lovd.nl/genomed/home.php?select_db=MMACHC" class="mim-tip-hint" title="A gene-specific database of variation." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Locus Specific DBs</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=MMACHC&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/PA142671348" 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:24525" 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://www.mousephenotype.org/data/genes/MGI:1914346" 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/MMACHC#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:1914346" 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/25974/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=25974" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00022766;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-030131-3167" 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:25974" 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=MMACHC&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 74653006<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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609831
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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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METABOLISM OF COBALAMIN ASSOCIATED C; MMACHC
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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=MMACHC" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">MMACHC</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/1/557?start=-3&limit=10&highlight=557">1p34.1</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr1:45500300-45513382&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'})">1:45,500,300-45,513,382</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/1/557?start=-3&limit=10&highlight=557">
|
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1p34.1
|
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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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Methylmalonic aciduria and homocystinuria, cblC type
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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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|
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<a href="/entry/277400"> 277400 </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">
|
|
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/609831" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/609831" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
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</ul>
|
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</div>
|
|
<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="cloning" class="mim-anchor"></a>
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<p><a href="#9" class="mim-tip-reference" title="Lerner-Ellis, J. P., Tirone, J. C., Pawelek, P. D., Dore, C., Atkinson, J. L., Watkins, D., Morel, C. F., Fujiwara, T. M., Moras, E., Hosack, A. R., Dunbar, G. V., Antonicka, H., and 10 others. <strong>Identification of the gene responsible for methylmalonic aciduria and homocystinuria, cblC type.</strong> Nature Genet. 38: 93-100, 2006. Note: Erratum: Nature Genet. 38: 957 only, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16311595/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16311595</a>] [<a href="https://doi.org/10.1038/ng1683" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16311595">Lerner-Ellis et al. (2006)</a> identified a gene, designated MMACHC, within the critical interval on chromosome 1p34-p32 for methylmalonic aciduria and homocystinuria cblC type (MAHCC; <a href="/entry/277400">277400</a>). The cDNA had an 846-basepair open reading frame encoding a 282-amino acid polypeptide with a predicted molecular weight of 31.7 kD. Northern blot analysis detected expression of 1.9-, 3.0-, and 5.4-kb transcripts in most human tissues examined, with higher levels in fetal liver and lower levels in spleen, lymph node, thymus, and bone marrow. The 3.0-kb message predominated, followed by the 5.4- and 1.9-kb messages. <a href="#9" class="mim-tip-reference" title="Lerner-Ellis, J. P., Tirone, J. C., Pawelek, P. D., Dore, C., Atkinson, J. L., Watkins, D., Morel, C. F., Fujiwara, T. M., Moras, E., Hosack, A. R., Dunbar, G. V., Antonicka, H., and 10 others. <strong>Identification of the gene responsible for methylmalonic aciduria and homocystinuria, cblC type.</strong> Nature Genet. 38: 93-100, 2006. Note: Erratum: Nature Genet. 38: 957 only, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16311595/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16311595</a>] [<a href="https://doi.org/10.1038/ng1683" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16311595">Lerner-Ellis et al. (2006)</a> stated that MMACHC is not a member of any previously identified gene family. The protein is well conserved among mammals, although the C-terminal end does not seem to be conserved in eukaryotes outside Mammalia. While no homologous protein was identified in prokaryotes, motifs homologous to those found in bacterial genes with cobalamin-related functions were identified. Transduction of wildtype MMACHC into immortalized cblC fibroblast cell lines corrected the cellular phenotype. Molecular modeling predicted that the C-terminal region of the product of the MMACHC gene folds similarly to TonB, a bacterial protein involved in energy transduction for cobalamin uptake. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16311595" 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>The MMACHC gene contains 5 exons (<a href="#9" class="mim-tip-reference" title="Lerner-Ellis, J. P., Tirone, J. C., Pawelek, P. D., Dore, C., Atkinson, J. L., Watkins, D., Morel, C. F., Fujiwara, T. M., Moras, E., Hosack, A. R., Dunbar, G. V., Antonicka, H., and 10 others. <strong>Identification of the gene responsible for methylmalonic aciduria and homocystinuria, cblC type.</strong> Nature Genet. 38: 93-100, 2006. Note: Erratum: Nature Genet. 38: 957 only, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16311595/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16311595</a>] [<a href="https://doi.org/10.1038/ng1683" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16311595">Lerner-Ellis et al., 2006</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16311595" 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="Lerner-Ellis, J. P., Tirone, J. C., Pawelek, P. D., Dore, C., Atkinson, J. L., Watkins, D., Morel, C. F., Fujiwara, T. M., Moras, E., Hosack, A. R., Dunbar, G. V., Antonicka, H., and 10 others. <strong>Identification of the gene responsible for methylmalonic aciduria and homocystinuria, cblC type.</strong> Nature Genet. 38: 93-100, 2006. Note: Erratum: Nature Genet. 38: 957 only, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16311595/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16311595</a>] [<a href="https://doi.org/10.1038/ng1683" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16311595">Lerner-Ellis et al. (2006)</a> identified the MMACHC gene on chromosome 1p34.1, within the locus for methylmalonic aciduria and homocystinuria cblC type. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16311595" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In 204 individuals with methylmalonic aciduria (MMA) and homocystinuria cblC type (MAHCC; <a href="/entry/277400">277400</a>), <a href="#9" class="mim-tip-reference" title="Lerner-Ellis, J. P., Tirone, J. C., Pawelek, P. D., Dore, C., Atkinson, J. L., Watkins, D., Morel, C. F., Fujiwara, T. M., Moras, E., Hosack, A. R., Dunbar, G. V., Antonicka, H., and 10 others. <strong>Identification of the gene responsible for methylmalonic aciduria and homocystinuria, cblC type.</strong> Nature Genet. 38: 93-100, 2006. Note: Erratum: Nature Genet. 38: 957 only, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16311595/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16311595</a>] [<a href="https://doi.org/10.1038/ng1683" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16311595">Lerner-Ellis et al. (2006)</a> found 42 different mutations, many consistent with loss of function of the protein product. One mutation, 271dupA (<a href="#0001">609831.0001</a>), accounted for 40% of all disease alleles. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16311595" 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>Among 79 unrelated Chinese patients with combined methylmalonic aciduria and homocystinuria cblC type, <a href="#10" class="mim-tip-reference" title="Liu, M.-Y., Yang, Y.-L., Chang, Y.-C., Chiang, S.-H., Lin, S.-P., Han, L.-S., Qi, Y., Hsiao, K.-J., Liu, T.-T. <strong>Mutation spectrum of MMACHC in Chinese patients with combined methylmalonic aciduria and homocystinuria.</strong> J. Hum. Genet. 55: 621-626, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20631720/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20631720</a>] [<a href="https://doi.org/10.1038/jhg.2010.81" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20631720">Liu et al. (2010)</a> identified 24 different mutations in the MMACHC gene, including 7 novel mutations. All patients had 2 mutations, except for 3 patients in whom only 1 mutation was identified. The 2 most common alleles were W203X (<a href="#0006">609831.0006</a>) and 658delAAG (<a href="#0007">609831.0007</a>), which accounted for 48.1% and 13.9% of mutant alleles, respectively. Haplotype analysis indicated a different founder effect for each mutation, but the major mutation profile did not differ between patients from northern and southern China. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20631720" 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 4 patients with combined pulmonary arterial hypertension and renal thrombotic microangiopathy, <a href="#7" class="mim-tip-reference" title="Komhoff, M., Roofthooft, M. T., Westra, D., Teertstra, T. K., Losito, A., van de Kar, N. C. A. J., Berger, R. M. F. <strong>Combined pulmonary hypertension and renal thrombotic microangiopathy in cobalamin C deficiency.</strong> Pediatrics 132: e540-e544, 2013. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23837176/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23837176</a>] [<a href="https://doi.org/10.1542/peds.2012-2581" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23837176">Komhoff et al. (2013)</a> detected 1 of 2 basepair substitutions at nucleotide 276 of the MMACHC gene (see <a href="#0008">609831.0008</a> and <a href="#0009">609831.0009</a>). These patients were compound heterozygous for various frameshift mutations. A fifth patient had a homozygous missense mutation in MMACHC (<a href="#0010">609831.0010</a>). <a href="#7" class="mim-tip-reference" title="Komhoff, M., Roofthooft, M. T., Westra, D., Teertstra, T. K., Losito, A., van de Kar, N. C. A. J., Berger, R. M. F. <strong>Combined pulmonary hypertension and renal thrombotic microangiopathy in cobalamin C deficiency.</strong> Pediatrics 132: e540-e544, 2013. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23837176/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23837176</a>] [<a href="https://doi.org/10.1542/peds.2012-2581" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23837176">Komhoff et al. (2013)</a> identified cblC deficiency as the cause of the rare combination of pulmonary arterial hypertension and renal thrombotic microangiopathy in these patients. The authors proposed that early recognition of cblC deficiency and vigorous treatment with hydroxocobalamin may ameliorate the devastating course of this condition. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23837176" 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 3 unrelated patients with autosomal recessive cblC vitamin B12 deficiency, <a href="#5" class="mim-tip-reference" title="Gueant, J.-L., Chery, C., Oussalah, A., Nadaf, J., Coelho, D., Josse, T., Flayac, J., Robert, A., Koscinski, I., Gastin, I., Filhine-Tresarrieu, P., Pupavac, M., and 19 others. <strong>A PRDX1 mutant allele causes a MMACHC secondary epimutation in cblC patients.</strong> Nature Commun. 9: 67, 2018. Note: Electronic Article. Erratum: Nature Commun. 9: 554, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29302025/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29302025</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29302025[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41467-017-02306-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29302025">Gueant et al. (2018)</a> identified compound heterozygous mutations in the MMACHC gene: a different coding mutation on 1 allele in all 3 patients (<a href="#0011">609831.0011</a>-<a href="#0013">609831.0013</a>), combined with the same 'secondary epimutation' on the other allele. The epimutation, 32 hypermethylated CpG sites detected by bisulfite sequencing, was a consequence of a heterozygous mutation in the adjacent, reverse-oriented PRDX1 gene: c.515-1G-T (<a href="/entry/176763#0001">176763.0001</a>) or c.515-2A-T (<a href="/entry/176763#0002">176763.0002</a>). The PRDX1 mutations were also found in unaffected relatives who carried the secondary epimutation. In all instances, the PRDX1 mutations affected a canonical splice acceptor site of intron 5 and caused skipping of exon 6 and the polyA termination signal of PRDX1. The resulting read-through transcript extended through the adjacent MMACHC locus in the antisense orientation. The authors proposed that the antisense transcript leads to the formation of triplexes in the promoter of MMACHC and generates CpG methylation resulting in reduced expression of the normal message. This was confirmed experimentally by growing fibroblasts from an affected proband in 5-azacytidine, which reduced promoter methylation, and by silencing PRDX1 with an siRNA, both of which increased expression of MMACHC. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29302025" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By Sanger or next-generation sequencing in 70 Chinese individuals with MAHCC and hydrocephalus, <a href="#6" class="mim-tip-reference" title="He, R., Zhang, H., Kang, L., Li, H., Shen, M., Zhang, Y., Mo, R., Liu, Y., Song, J., Chen, Z., Liu, Y., Jin, Y., and 11 others. <strong>Analysis of 70 patients with hydrocephalus due to cobalamin C deficiency.</strong> Neurology 95: e3129-e3137, 2020. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32943488/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32943488</a>] [<a href="https://doi.org/10.1212/WNL.0000000000010912" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32943488">He et al. (2020)</a> identified homozygous or compound heterozygous mutations in the MMACHC gene. The parents in each case were carriers of the mutation. Eighteen individual mutations were identified, including 4 novel mutations (Q143X, W200X, Y205X, and c.568insT) that were predicted to cause loss of function and were not present in the Exome Sequencing Project, 1000 Genomes Project, or ExAC databases. The most frequent mutation was W209X (<a href="#0006">609831.0006</a>), accounting for 62.9% of the mutations, followed by c.658delAAG (<a href="#0007">609831.0007</a>), R73X, and c.567dupT, seen at a frequency of 12.1%, 5%, and 5%, respectively. The findings were consistent with a previous study in the Chinese population by <a href="#10" class="mim-tip-reference" title="Liu, M.-Y., Yang, Y.-L., Chang, Y.-C., Chiang, S.-H., Lin, S.-P., Han, L.-S., Qi, Y., Hsiao, K.-J., Liu, T.-T. <strong>Mutation spectrum of MMACHC in Chinese patients with combined methylmalonic aciduria and homocystinuria.</strong> J. Hum. Genet. 55: 621-626, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20631720/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20631720</a>] [<a href="https://doi.org/10.1038/jhg.2010.81" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20631720">Liu et al. (2010)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=32943488+20631720" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a 28-year-old woman with nonsyndromic bull's eye maculopathy who was subsequently diagnosed with cblC, <a href="#3" class="mim-tip-reference" title="Collison, F. T., Xie, Y., Gambin, T., Jhangiani, S., Muzny, D., Gibbs, R., Lupski, J. R., Fishman, G. A., Allikmets, R. <strong>Whole exome sequencing identifies an adult-onset case of methylmalonic aciduria and homocystinuria type C (cblC) with non-syndromic bull's eye maculopathy.</strong> Ophthal. Genet. 36: 270-275, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25687216/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25687216</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25687216[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/10.3109/13816810.2015.1010736" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25687216">Collison et al. (2015)</a> identified compound heterozygous mutations in the MMACHC gene (<a href="#0005">609831.0005</a> and <a href="#0011">609831.0011</a>). The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. The parents were shown to be mutation carriers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25687216" 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="#11" class="mim-tip-reference" title="Morel, C. F., Lerner-Ellis, J. P., Rosenblatt, D. S. <strong>Combined methylmalonic aciduria and homocystinuria (cblC): phenotype-genotype correlations and ethnic-specific observations.</strong> Molec. Genet. Metab. 88: 315-321, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16714133/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16714133</a>] [<a href="https://doi.org/10.1016/j.ymgme.2006.04.001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16714133">Morel et al. (2006)</a> reported genotype-phenotype correlations in 37 patients from published case reports, representing most of the landmark descriptions of cobalamin C deficiency. Twenty-five of 37 had early-onset disease, presenting in the first 6 months of life. Seventeen of these 25 were found to be either homozygous for the 271dupA mutation (<a href="#0001">609831.0001</a>) (n = 9) or for the 331C-T (R111X; <a href="#0004">609831.0004</a>) mutation (n = 3) or compound heterozygous for these 2 mutations (n = 5). Nine of 12 late-onset cases presented with acute neurologic symptoms; 4 of 9 were homozygous for the 347T-C mutation (<a href="#0002">609831.0002</a>), 2 of 9 were compound heterozygous for the 271dupA and 394C-T (R132X; <a href="#0003">609831.0003</a>) mutations, and 3 of 9 for the 271dupA mutation and a missense mutation. The 394C-T mutation is common in the Asiatic-Indian/Pakistani/Middle Eastern populations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16714133" 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>Among 118 patients with cblC deficiency, <a href="#8" class="mim-tip-reference" title="Lerner-Ellis, J. P., Anastasio, N., Liu, J., Coelho, D., Suormala, T., Stucki, M., Loewy, A. D., Gurd, S., Grundberg, E., Morel, C. F., Watkins, D., Baumgartner, M. R., Pastinen, T., Rosenblatt, D. S., Fowler, B. <strong>Spectrum of mutations in MMACHC, allelic expression, and evidence for genotype-phenotype correlations.</strong> Hum. Mutat. 30: 1072-1081, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19370762/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19370762</a>] [<a href="https://doi.org/10.1002/humu.21001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19370762">Lerner-Ellis et al. (2009)</a> identified 34 different MMACHC mutations, including 11 novel mutations. The 271dupA mutation was the most common, accounting for 42% of pathogenic alleles, followed by the R132X (20%) and R111X (5%) mutations. Six variants defined specific haplotypes that varied with ethnicity. Genotype/phenotype correlations were apparent. Individuals with the R132X and R161Q (<a href="#0005">609831.0005</a>) mutations tended to present with late-onset disease, whereas patients with R111X and 271dupA mutations tended to present in infancy. Functional expression analyses on cblC fibroblasts showed that the early-onset 271dupA mutation was consistently underexpressed compared to control alleles and the late-onset R132X and R161Q mutations. The early-onset R111X mutation was also underexpressed when compared to control alleles and the R132X mutation. Quantitative RT-PCR studies showed that the late-onset R132X mutation had significantly higher levels of transcript compared to cell lines homozygous for the early-onset mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19370762" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Demaret, T., Bedard, K., Soucy, J. F., Watkins, D., Allard, P., Levtova, A., O'Brien, A., Brunel-Guitton, C., Rosenblatt, D. S., Mitchell, G. A. <strong>The MMACHC variant c.158T>C: Mild clinical and biochemical phenotypes and marked hydroxocobalamin response in cblC patients.</strong> Molec. Genet. Metab. 142: 108345, 2024.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/38387306/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">38387306</a>] [<a href="https://doi.org/10.1016/j.ymgme.2024.108345" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="38387306">Demaret et al. (2024)</a> compared the phenotypes of 3 patients who were compound heterozygous for mutations in the MMACHC gene, c.271dupA (<a href="#0001">609831.0001</a>) and L53P (<a href="#0013">609831.0013</a>), and 4 patients who were homozygous for the c.271dupA mutation. The patients with compound heterozygous mutations had milder disease manifestations compared to the patients with the homozygous mutations. The patients with compound heterozygous mutations had normalization of homocysteine and methylmalonic acid levels with hydroxocobalamin treatment, age-appropriate cognitive development, and normal eye examinations, whereas the patients with homozygosity for the c.271dupA mutation had psychomotor retardation, ophthalmologic abnormalities, and feeding difficulties. Fibroblasts from the patients with compound heterozygous mutations exhibited higher propionate incorporation compared to fibroblasts from the patients with the homozygous mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=38387306" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=609831[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs398124292 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs398124292;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/rs398124292?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=rs398124292" 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=rs398124292" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In individuals from several different ethnic groups, <a href="#9" class="mim-tip-reference" title="Lerner-Ellis, J. P., Tirone, J. C., Pawelek, P. D., Dore, C., Atkinson, J. L., Watkins, D., Morel, C. F., Fujiwara, T. M., Moras, E., Hosack, A. R., Dunbar, G. V., Antonicka, H., and 10 others. <strong>Identification of the gene responsible for methylmalonic aciduria and homocystinuria, cblC type.</strong> Nature Genet. 38: 93-100, 2006. Note: Erratum: Nature Genet. 38: 957 only, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16311595/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16311595</a>] [<a href="https://doi.org/10.1038/ng1683" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16311595">Lerner-Ellis et al. (2006)</a> found that methylmalonic aciduria and homocystinuria cblC type (MAHCC; <a href="/entry/277400">277400</a>) was associated with a 271dupA mutation in the MMACHC gene. The 271dupA mutation predicts a change of amino acid residue 91 from arginine to lysine followed by frameshift with a premature termination 14 codons downstream (Arg91LysfsTer14). The mutation was present in homozygous state in 46 individuals, in whom the diagnosis was made under the age of 1 year in 44. In 2 individuals in whom the diagnosis was made after the age of 20 years, the 271dupA mutation was in compound heterozygous state with a 347T-C transition (<a href="#0002">609831.0002</a>). The 271dupA mutation accounted for 40% of all disease alleles among the 204 patients studied. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16311595" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Lerner-Ellis, J. P., Anastasio, N., Liu, J., Coelho, D., Suormala, T., Stucki, M., Loewy, A. D., Gurd, S., Grundberg, E., Morel, C. F., Watkins, D., Baumgartner, M. R., Pastinen, T., Rosenblatt, D. S., Fowler, B. <strong>Spectrum of mutations in MMACHC, allelic expression, and evidence for genotype-phenotype correlations.</strong> Hum. Mutat. 30: 1072-1081, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19370762/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19370762</a>] [<a href="https://doi.org/10.1002/humu.21001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19370762">Lerner-Ellis et al. (2009)</a> identified the 271dupA allele in 42% of pathogenic alleles from 118 patients with cblC. Patients with the 271dupA mutation tended to present in infancy. Transcript analysis on cblC fibroblasts showed that the early-onset 271dupA mutation was consistently underexpressed compared to control alleles and to MMACHC alleles associated with later-onset disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19370762" 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 METHYLMALONIC ACIDURIA AND HOMOCYSTINURIA, cblC TYPE</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121918240 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918240;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/rs121918240?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=rs121918240" 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=rs121918240" 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=RCV000001487 OR RCV002512644" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000001487, RCV002512644" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000001487...</a>
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<p>In 2 patients in whom the diagnosis of methylmalonic aciduria and homocystinuria cblC type (MAHCC; <a href="/entry/277400">277400</a>) was made after the age of 20 years, <a href="#9" class="mim-tip-reference" title="Lerner-Ellis, J. P., Tirone, J. C., Pawelek, P. D., Dore, C., Atkinson, J. L., Watkins, D., Morel, C. F., Fujiwara, T. M., Moras, E., Hosack, A. R., Dunbar, G. V., Antonicka, H., and 10 others. <strong>Identification of the gene responsible for methylmalonic aciduria and homocystinuria, cblC type.</strong> Nature Genet. 38: 93-100, 2006. Note: Erratum: Nature Genet. 38: 957 only, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16311595/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16311595</a>] [<a href="https://doi.org/10.1038/ng1683" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16311595">Lerner-Ellis et al. (2006)</a> found compound heterozygosity in the MMACHC gene for the most common mutation, 271dupA (<a href="#0001">609831.0001</a>), which in homozygous state causes early-onset disease, and a 347T-C transition, which was predicted to result in a leu116-to-pro (L116P) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16311595" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121918241 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918241;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/rs121918241?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=rs121918241" 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=rs121918241" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a survey of 204 individuals with methylmalonic aciduria and homocystinuria cblC type (MAHCC; <a href="/entry/277400">277400</a>), <a href="#9" class="mim-tip-reference" title="Lerner-Ellis, J. P., Tirone, J. C., Pawelek, P. D., Dore, C., Atkinson, J. L., Watkins, D., Morel, C. F., Fujiwara, T. M., Moras, E., Hosack, A. R., Dunbar, G. V., Antonicka, H., and 10 others. <strong>Identification of the gene responsible for methylmalonic aciduria and homocystinuria, cblC type.</strong> Nature Genet. 38: 93-100, 2006. Note: Erratum: Nature Genet. 38: 957 only, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16311595/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16311595</a>] [<a href="https://doi.org/10.1038/ng1683" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16311595">Lerner-Ellis et al. (2006)</a> found 34 examples of the 394C-T mutant allele of the MMACHC gene, predicted to result in an arg132-to-ter mutation (R132X). The R132X mutation was primarily associated with late-onset disease and was noted in the homozygous state among published individuals in Asiatic-Indian, Pakistani, or Middle Eastern descent and reported by <a href="#11" class="mim-tip-reference" title="Morel, C. F., Lerner-Ellis, J. P., Rosenblatt, D. S. <strong>Combined methylmalonic aciduria and homocystinuria (cblC): phenotype-genotype correlations and ethnic-specific observations.</strong> Molec. Genet. Metab. 88: 315-321, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16714133/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16714133</a>] [<a href="https://doi.org/10.1016/j.ymgme.2006.04.001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16714133">Morel et al. (2006)</a> in an additional 9 unpublished patients from their database who were either of Asiatic-Indian, Pakistani, or Middle Eastern descent. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16714133+16311595" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Ben-Omran, T. I., Wong, H., Blaser, S., Feigenbaum, A. <strong>Late-onset cobalamin-C disorder: a challenging diagnosis.</strong> Am. J. Med. Genet. 143A: 979-984, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17431913/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17431913</a>] [<a href="https://doi.org/10.1002/ajmg.a.31671" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17431913">Ben-Omran et al. (2007)</a> reported 2 unrelated girls of Pakistani and Bengali origin, respectively, with cblC disease caused by a homozygous R132X mutation. The girls presented with neuropsychiatric symptoms at ages 14 and 10 years, respectively. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17431913" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a study of 118 patients with cblC disease, <a href="#8" class="mim-tip-reference" title="Lerner-Ellis, J. P., Anastasio, N., Liu, J., Coelho, D., Suormala, T., Stucki, M., Loewy, A. D., Gurd, S., Grundberg, E., Morel, C. F., Watkins, D., Baumgartner, M. R., Pastinen, T., Rosenblatt, D. S., Fowler, B. <strong>Spectrum of mutations in MMACHC, allelic expression, and evidence for genotype-phenotype correlations.</strong> Hum. Mutat. 30: 1072-1081, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19370762/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19370762</a>] [<a href="https://doi.org/10.1002/humu.21001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19370762">Lerner-Ellis et al. (2009)</a> found that individuals with the R132X mutation tended to present with late-onset disease. Transcript and RT-PCR analysis of cblC fibroblasts showed that the R132X mutation resulted in significantly higher levels of transcript compared to cell lines homozygous for the early-onset mutations. The authors postulated that nonsense-mediated decay may not occur with this mutation, or that it may occur to a lesser extent. Alternatively, the mutation may result in a truncated protein with residual function. <a href="#8" class="mim-tip-reference" title="Lerner-Ellis, J. P., Anastasio, N., Liu, J., Coelho, D., Suormala, T., Stucki, M., Loewy, A. D., Gurd, S., Grundberg, E., Morel, C. F., Watkins, D., Baumgartner, M. R., Pastinen, T., Rosenblatt, D. S., Fowler, B. <strong>Spectrum of mutations in MMACHC, allelic expression, and evidence for genotype-phenotype correlations.</strong> Hum. Mutat. 30: 1072-1081, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19370762/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19370762</a>] [<a href="https://doi.org/10.1002/humu.21001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19370762">Lerner-Ellis et al. (2009)</a> identified the R132X mutation in 20% of pathogenic alleles from 118 patients with cblC. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19370762" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121918242 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918242;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/rs121918242?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=rs121918242" 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=rs121918242" 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=RCV000001489 OR RCV000186026 OR RCV001273220 OR RCV002512646 OR RCV004755697" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000001489, RCV000186026, RCV001273220, RCV002512646, RCV004755697" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000001489...</a>
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<p>In a review of 37 published cases of methylmalonic aciduria and homocystinuria cblC type (MAHCC; <a href="/entry/277400">277400</a>), <a href="#11" class="mim-tip-reference" title="Morel, C. F., Lerner-Ellis, J. P., Rosenblatt, D. S. <strong>Combined methylmalonic aciduria and homocystinuria (cblC): phenotype-genotype correlations and ethnic-specific observations.</strong> Molec. Genet. Metab. 88: 315-321, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16714133/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16714133</a>] [<a href="https://doi.org/10.1016/j.ymgme.2006.04.001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16714133">Morel et al. (2006)</a> identified 3 Cajun patients who were homozygous for a 331C-T transition in the MMACHC gene, resulting in an arg111-to-ter (R111X) substitution. They also reported 3 unpublished patients of French Canadian background who were homozygous for this mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16714133" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Lerner-Ellis, J. P., Anastasio, N., Liu, J., Coelho, D., Suormala, T., Stucki, M., Loewy, A. D., Gurd, S., Grundberg, E., Morel, C. F., Watkins, D., Baumgartner, M. R., Pastinen, T., Rosenblatt, D. S., Fowler, B. <strong>Spectrum of mutations in MMACHC, allelic expression, and evidence for genotype-phenotype correlations.</strong> Hum. Mutat. 30: 1072-1081, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19370762/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19370762</a>] [<a href="https://doi.org/10.1002/humu.21001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19370762">Lerner-Ellis et al. (2009)</a> identified the R111X mutation in 5% of pathogenic alleles from 118 patients with cblC. Patients with the R111X mutation tended to present in infancy. Functional expression analyses on cblC fibroblasts showed that the early-onset R111X mutation was underexpressed when compared to control alleles or to alleles associated with late-onset disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19370762" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121918243 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918243;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/rs121918243?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=rs121918243" 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=rs121918243" 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=RCV000001490 OR RCV000081740 OR RCV000624532 OR RCV000721969 OR RCV001273229 OR RCV002512647 OR RCV003894782" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000001490, RCV000081740, RCV000624532, RCV000721969, RCV001273229, RCV002512647, RCV003894782" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000001490...</a>
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<p>In a male with late-onset methylmalonic aciduria and homocystinuria cblC type (MAHCC; <a href="/entry/277400">277400</a>), originally reported by <a href="#2" class="mim-tip-reference" title="Bodamer, O. A. F., Rosenblatt, D. S., Appel, S. H., Beaudet, A. L. <strong>Adult-onset combined methylmalonic aciduria and homocystinuria (cblC).</strong> Neurology 56: 1113 only, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11320193/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11320193</a>] [<a href="https://doi.org/10.1212/wnl.56.8.1113" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11320193">Bodamer et al. (2001)</a>, <a href="#11" class="mim-tip-reference" title="Morel, C. F., Lerner-Ellis, J. P., Rosenblatt, D. S. <strong>Combined methylmalonic aciduria and homocystinuria (cblC): phenotype-genotype correlations and ethnic-specific observations.</strong> Molec. Genet. Metab. 88: 315-321, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16714133/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16714133</a>] [<a href="https://doi.org/10.1016/j.ymgme.2006.04.001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16714133">Morel et al. (2006)</a> identified compound heterozygosity for 2 mutations in the MMACHC gene: the 271dupA (<a href="#0001">609831.0001</a>) mutation and a 482G-A transition resulting in an arg161-to-gln (R161Q) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16714133+11320193" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#12" class="mim-tip-reference" title="Tsai, A. C.-H., Morel, C. F., Scharer, G., Yang, M., Lerner-Ellis, J. P., Rosenblatt, D. S., Thomas, J. A. <strong>Late-onset combined homocystinuria and methylmalonic aciduria (cblC) and neuropsychiatric disturbance.</strong> Am. J. Med. Genet. 143A: 2430-2434, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17853453/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17853453</a>] [<a href="https://doi.org/10.1002/ajmg.a.31932" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17853453">Tsai et al. (2007)</a> described a 36-year-old woman with a psychiatric history and a spinal cord infarct who was subsequently diagnosed with methylmalonic aciduria and homocystinuria cblC type. Molecular analysis of the MMACHC gene revealed compound heterozygosity for the 271dupA and R161Q mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17853453" 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>Among 118 patients with cblC, <a href="#8" class="mim-tip-reference" title="Lerner-Ellis, J. P., Anastasio, N., Liu, J., Coelho, D., Suormala, T., Stucki, M., Loewy, A. D., Gurd, S., Grundberg, E., Morel, C. F., Watkins, D., Baumgartner, M. R., Pastinen, T., Rosenblatt, D. S., Fowler, B. <strong>Spectrum of mutations in MMACHC, allelic expression, and evidence for genotype-phenotype correlations.</strong> Hum. Mutat. 30: 1072-1081, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19370762/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19370762</a>] [<a href="https://doi.org/10.1002/humu.21001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19370762">Lerner-Ellis et al. (2009)</a> found that those with the R161Q mutation tended to present with late-onset disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19370762" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Liu, M.-Y., Yang, Y.-L., Chang, Y.-C., Chiang, S.-H., Lin, S.-P., Han, L.-S., Qi, Y., Hsiao, K.-J., Liu, T.-T. <strong>Mutation spectrum of MMACHC in Chinese patients with combined methylmalonic aciduria and homocystinuria.</strong> J. Hum. Genet. 55: 621-626, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20631720/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20631720</a>] [<a href="https://doi.org/10.1038/jhg.2010.81" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20631720">Liu et al. (2010)</a> also found that the R161Q mutation was associated with a late onset and relatively mild phenotype among Chinese patients with cblC carrying this mutation. This allele was the third most common mutation found among 79 unrelated patients, accounting for 7% of mutant alleles. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20631720" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a 28-year-old woman with nonsyndromic bull's eye maculopathy who was subsequently diagnosed with cblC, <a href="#3" class="mim-tip-reference" title="Collison, F. T., Xie, Y., Gambin, T., Jhangiani, S., Muzny, D., Gibbs, R., Lupski, J. R., Fishman, G. A., Allikmets, R. <strong>Whole exome sequencing identifies an adult-onset case of methylmalonic aciduria and homocystinuria type C (cblC) with non-syndromic bull's eye maculopathy.</strong> Ophthal. Genet. 36: 270-275, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25687216/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25687216</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25687216[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/10.3109/13816810.2015.1010736" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25687216">Collison et al. (2015)</a> identified compound heterozygous mutations in the MMACHC gene: R161Q and a 1-bp insertion (c.270_271insA; <a href="#0011">609831.0011</a>), predicted to result in a frameshift and a premature termination codon (Arg91LysfsTer14). The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. The parents were shown to be mutation carriers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25687216" 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 METHYLMALONIC ACIDURIA AND HOMOCYSTINURIA, cblC TYPE</strong>
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MMACHC, TRP203TER
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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> rs587776889 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587776889;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/rs587776889?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=rs587776889" 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=rs587776889" 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=RCV000023785 OR RCV000756343 OR RCV001275215 OR RCV002513204" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023785, RCV000756343, RCV001275215, RCV002513204" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023785...</a>
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<p>In Chinese patients with methylmalonic aciduria and homocystinuria cblC type (MAHCC; <a href="/entry/277400">277400</a>), <a href="#10" class="mim-tip-reference" title="Liu, M.-Y., Yang, Y.-L., Chang, Y.-C., Chiang, S.-H., Lin, S.-P., Han, L.-S., Qi, Y., Hsiao, K.-J., Liu, T.-T. <strong>Mutation spectrum of MMACHC in Chinese patients with combined methylmalonic aciduria and homocystinuria.</strong> J. Hum. Genet. 55: 621-626, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20631720/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20631720</a>] [<a href="https://doi.org/10.1038/jhg.2010.81" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20631720">Liu et al. (2010)</a> identified a 609G-A transition in exon 4 of the MMACHC gene, resulting in a trp203-to-ter (W203X) substitution. This allele was the most common mutation found among 79 unrelated patients, accounting for 48.1% of mutant alleles. Fifteen patients who were homozygous for the mutation showed an early-onset phenotype, with 3 showing onset before age 4 years. Haplotype analysis suggested a founder effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20631720" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a molecular analysis of 70 Chinese individuals with MAHCC, <a href="#6" class="mim-tip-reference" title="He, R., Zhang, H., Kang, L., Li, H., Shen, M., Zhang, Y., Mo, R., Liu, Y., Song, J., Chen, Z., Liu, Y., Jin, Y., and 11 others. <strong>Analysis of 70 patients with hydrocephalus due to cobalamin C deficiency.</strong> Neurology 95: e3129-e3137, 2020. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32943488/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32943488</a>] [<a href="https://doi.org/10.1212/WNL.0000000000010912" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32943488">He et al. (2020)</a> found that the W203X mutation accounted for 62.9% of the identified mutations. Twenty-nine patients were homozygous for the mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32943488" 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="0007" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0007 METHYLMALONIC ACIDURIA AND HOMOCYSTINURIA, cblC TYPE</strong>
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</span>
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</h4>
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</div>
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MMACHC, 3-BP DEL, 658AAG
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs398124296 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs398124296;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=rs398124296" 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=rs398124296" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000081744 OR RCV000272939 OR RCV001275218 OR RCV004755765" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000081744, RCV000272939, RCV001275218, RCV004755765" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000081744...</a>
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<span class="mim-text-font">
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<p>In Chinese patients with methylmalonic aciduria and homocystinuria cblC type (MAHCC; <a href="/entry/277400">277400</a>), <a href="#10" class="mim-tip-reference" title="Liu, M.-Y., Yang, Y.-L., Chang, Y.-C., Chiang, S.-H., Lin, S.-P., Han, L.-S., Qi, Y., Hsiao, K.-J., Liu, T.-T. <strong>Mutation spectrum of MMACHC in Chinese patients with combined methylmalonic aciduria and homocystinuria.</strong> J. Hum. Genet. 55: 621-626, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20631720/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20631720</a>] [<a href="https://doi.org/10.1038/jhg.2010.81" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20631720">Liu et al. (2010)</a> identified a 3-bp deletion (658delAAG) in exon 4 of the MMACHC gene, resulting in an in-frame deletion of lys220. This allele was the second most common found among 79 unrelated patients, accounting for 13.9% of mutant alleles. Haplotype analysis suggested a founder effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20631720" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a molecular analysis of 70 Chinese individuals with MAHCC, <a href="#6" class="mim-tip-reference" title="He, R., Zhang, H., Kang, L., Li, H., Shen, M., Zhang, Y., Mo, R., Liu, Y., Song, J., Chen, Z., Liu, Y., Jin, Y., and 11 others. <strong>Analysis of 70 patients with hydrocephalus due to cobalamin C deficiency.</strong> Neurology 95: e3129-e3137, 2020. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32943488/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32943488</a>] [<a href="https://doi.org/10.1212/WNL.0000000000010912" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32943488">He et al. (2020)</a> found that the 658delAAG mutation accounted for 12.1% of the identified mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32943488" 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="0008" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0008 METHYLMALONIC ACIDURIA AND HOMOCYSTINURIA, cblC TYPE</strong>
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</span>
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</h4>
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</div>
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MMACHC, GLU92ASP
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</span>
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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> rs556977618 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs556977618;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/rs556977618?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=rs556977618" 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=rs556977618" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000148298" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000148298" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000148298</a>
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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 with combined pulmonary arterial hypertension and renal thrombotic microangiopathy caused by cblC deficiency (MAHCC; <a href="/entry/277400">277400</a>), <a href="#7" class="mim-tip-reference" title="Komhoff, M., Roofthooft, M. T., Westra, D., Teertstra, T. K., Losito, A., van de Kar, N. C. A. J., Berger, R. M. F. <strong>Combined pulmonary hypertension and renal thrombotic microangiopathy in cobalamin C deficiency.</strong> Pediatrics 132: e540-e544, 2013. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23837176/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23837176</a>] [<a href="https://doi.org/10.1542/peds.2012-2581" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23837176">Komhoff et al. (2013)</a> identified compound heterozygosity for a c.276G-T transversion in the MMACHC gene, resulting in a glu92-to-asp (E92D) substitution. Two patients also carried the common 271dupA (<a href="#0001">609831.0001</a>) mutation on the other allele; the third patient was compound heterozygous for a different frameshift mutation. The patients were of Spanish/Turkish or Dutch ethnicity. Because another patient with a synonymous change at that position was identified (see <a href="#0009">609831.0009</a>), the authors concluded that the actual effect of the mutation, which affects the last nucleotide of exon 2, is aberrant splicing and ultimately deletion of the erroneous pre-mRNA via nonsense-mediated decay. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23837176" 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>
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<div>
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<a id="0009" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0009 METHYLMALONIC ACIDURIA AND HOMOCYSTINURIA, cblC TYPE</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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MMACHC, GLU92GLU
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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> rs556977618 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs556977618;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/rs556977618?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=rs556977618" 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=rs556977618" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000148299" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000148299" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000148299</a>
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In an Italian patient with combined renal thrombotic microangiopathy and pulmonary arterial hypertension caused by cblC deficiency (MAHCC; <a href="/entry/277400">277400</a>), <a href="#7" class="mim-tip-reference" title="Komhoff, M., Roofthooft, M. T., Westra, D., Teertstra, T. K., Losito, A., van de Kar, N. C. A. J., Berger, R. M. F. <strong>Combined pulmonary hypertension and renal thrombotic microangiopathy in cobalamin C deficiency.</strong> Pediatrics 132: e540-e544, 2013. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23837176/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23837176</a>] [<a href="https://doi.org/10.1542/peds.2012-2581" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23837176">Komhoff et al. (2013)</a> identified heterozygosity for a c.276G-A transition in the MMACHC gene, resulting in a synonymous glu92-to-glu (E92E) substitution. Because this mutation occurred in the last nucleotide of exon 2, the authors suggested that the actual effect of the mutation is an aberrantly spliced pre-mRNA that undergoes nonsense-mediated decay. The patient was heterozygous for a frameshift mutation on the other allele. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23837176" 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="0010" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0010 METHYLMALONIC ACIDURIA AND HOMOCYSTINURIA, cblC TYPE</strong>
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</span>
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</h4>
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MMACHC, GLY155GLU
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs606231425 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs606231425;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=rs606231425" 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=rs606231425" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000148300" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000148300" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000148300</a>
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<div>
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<span class="mim-text-font">
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<p><a href="#7" class="mim-tip-reference" title="Komhoff, M., Roofthooft, M. T., Westra, D., Teertstra, T. K., Losito, A., van de Kar, N. C. A. J., Berger, R. M. F. <strong>Combined pulmonary hypertension and renal thrombotic microangiopathy in cobalamin C deficiency.</strong> Pediatrics 132: e540-e544, 2013. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23837176/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23837176</a>] [<a href="https://doi.org/10.1542/peds.2012-2581" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23837176">Komhoff et al. (2013)</a> reported a patient of Dutch ancestry with combined renal thrombotic microangiopathy and pulmonary arterial hypertension caused by cblC deficiency (MAHCC; <a href="/entry/277400">277400</a>) who had a homozygous c.464G-A transition in the MMACHC gene, resulting in a gly155-to-glu (G155E) substitution. The patient presented at 2.5 years of age and died from right ventricular failure 2 weeks after diagnosis. Homocysteine level was 123 micromol/L; methylmalonic acid (MMA) was 14,424 nmol/L. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23837176" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0011 METHYLMALONIC ACIDURIA AND HOMOCYSTINURIA, cblC TYPE, DIGENIC</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000001486 OR RCV000081737 OR RCV000203236 OR RCV000308836 OR RCV000507720 OR RCV000585799 OR RCV001273215 OR RCV001328208 OR RCV002251853 OR RCV003421892 OR RCV004018537 OR RCV004798712" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000001486, RCV000081737, RCV000203236, RCV000308836, RCV000507720, RCV000585799, RCV001273215, RCV001328208, RCV002251853, RCV003421892, RCV004018537, RCV004798712" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000001486...</a>
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<p>In a Caucasian female (CHU-12122) with cbl-type methylmalonic aciduria and homocystinuria (MAHCC; <a href="/entry/277400">277400</a>), who died at 1 month of age, <a href="#5" class="mim-tip-reference" title="Gueant, J.-L., Chery, C., Oussalah, A., Nadaf, J., Coelho, D., Josse, T., Flayac, J., Robert, A., Koscinski, I., Gastin, I., Filhine-Tresarrieu, P., Pupavac, M., and 19 others. <strong>A PRDX1 mutant allele causes a MMACHC secondary epimutation in cblC patients.</strong> Nature Commun. 9: 67, 2018. Note: Electronic Article. Erratum: Nature Commun. 9: 554, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29302025/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29302025</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29302025[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41467-017-02306-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29302025">Gueant et al. (2018)</a> identified compound heterozygous mutations in the MMACHC gene: a 1-bp insertion (c.270_271insA), resulting in a frameshift and a premature termination codon (Arg91LysfsTer14), inherited from the mother, and a secondary epimutation causing promoter hypermethylation and MMACHC silencing inherited from the father. The secondary epimutation was triggered by a heterozygous mutation in the adjacent, reverse-oriented PRDX1 gene (<a href="/entry/176763#0001">176763.0001</a>). The patient's paternal grandfather also carried the epimutation, which was present in her father's sperm. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29302025" 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>For discussion of the c.270_271insA mutation that was found in compound heterozygous state in the MMACHC gene in a patient with MAHCC by <a href="#3" class="mim-tip-reference" title="Collison, F. T., Xie, Y., Gambin, T., Jhangiani, S., Muzny, D., Gibbs, R., Lupski, J. R., Fishman, G. A., Allikmets, R. <strong>Whole exome sequencing identifies an adult-onset case of methylmalonic aciduria and homocystinuria type C (cblC) with non-syndromic bull's eye maculopathy.</strong> Ophthal. Genet. 36: 270-275, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25687216/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25687216</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25687216[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/10.3109/13816810.2015.1010736" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25687216">Collison et al. (2015)</a>, see <a href="#0005">609831.0005</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25687216" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1553162317 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1553162317;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=rs1553162317" 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=rs1553162317" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a female (WG-3838) of Japanese and Korean ancestry, who died at 2 months of age, with cbl-type methylmalonic aciduria and homocystinuria (MAHCC; <a href="/entry/277400">277400</a>), <a href="#5" class="mim-tip-reference" title="Gueant, J.-L., Chery, C., Oussalah, A., Nadaf, J., Coelho, D., Josse, T., Flayac, J., Robert, A., Koscinski, I., Gastin, I., Filhine-Tresarrieu, P., Pupavac, M., and 19 others. <strong>A PRDX1 mutant allele causes a MMACHC secondary epimutation in cblC patients.</strong> Nature Commun. 9: 67, 2018. Note: Electronic Article. Erratum: Nature Commun. 9: 554, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29302025/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29302025</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29302025[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41467-017-02306-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29302025">Gueant et al. (2018)</a> identified compound heterozygous mutations in the MMACHC gene: a splice site mutation (c.81G-A) inherited from the mother, and a secondary epimutation causing promoter hypermethylation and MMACHC silencing inherited from the father. The secondary epimutation was triggered by a heterozygous mutation in the adjacent, reverse-oriented PRDX1 gene (<a href="/entry/176763#0002">176763.0002</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29302025" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs756980496 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs756980496;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/rs756980496?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=rs756980496" 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=rs756980496" 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=RCV000585794 OR RCV003323623 OR RCV003465319" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000585794, RCV003323623, RCV003465319" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000585794...</a>
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<p>In a 59-year-old Caucasian man (WG-4152) with cbl-type methylmalonic aciduria and homocystinuria (MAHCC; <a href="/entry/277400">277400</a>), <a href="#5" class="mim-tip-reference" title="Gueant, J.-L., Chery, C., Oussalah, A., Nadaf, J., Coelho, D., Josse, T., Flayac, J., Robert, A., Koscinski, I., Gastin, I., Filhine-Tresarrieu, P., Pupavac, M., and 19 others. <strong>A PRDX1 mutant allele causes a MMACHC secondary epimutation in cblC patients.</strong> Nature Commun. 9: 67, 2018. Note: Electronic Article. Erratum: Nature Commun. 9: 554, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29302025/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29302025</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29302025[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41467-017-02306-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29302025">Gueant et al. (2018)</a> identified compound heterozygous mutations in the MMACHC gene: a c.158T-C transition, resulting in a leu53-to-pro (L53P) substitution, and a secondary epimutation causing promoter hypermethylation and MMACHC silencing. The secondary epimutation was triggered by a heterozygous mutation in the adjacent, reverse-oriented PRDX1 gene (<a href="/entry/176763#0001">176763.0001</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29302025" 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>Late-onset cobalamin-C disorder: a challenging diagnosis.</strong>
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Am. J. Med. Genet. 143A: 979-984, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17431913/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17431913</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17431913" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.31671" target="_blank">Full Text</a>]
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Bodamer, O. A. F., Rosenblatt, D. S., Appel, S. H., Beaudet, A. L.
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<strong>Adult-onset combined methylmalonic aciduria and homocystinuria (cblC).</strong>
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Neurology 56: 1113 only, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11320193/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11320193</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11320193" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Collison, F. T., Xie, Y., Gambin, T., Jhangiani, S., Muzny, D., Gibbs, R., Lupski, J. R., Fishman, G. A., Allikmets, R.
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<strong>Whole exome sequencing identifies an adult-onset case of methylmalonic aciduria and homocystinuria type C (cblC) with non-syndromic bull's eye maculopathy.</strong>
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Ophthal. Genet. 36: 270-275, 2015.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25687216/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25687216</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25687216[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=25687216" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Demaret, T., Bedard, K., Soucy, J. F., Watkins, D., Allard, P., Levtova, A., O'Brien, A., Brunel-Guitton, C., Rosenblatt, D. S., Mitchell, G. A.
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<strong>The MMACHC variant c.158T>C: Mild clinical and biochemical phenotypes and marked hydroxocobalamin response in cblC patients.</strong>
|
|
Molec. Genet. Metab. 142: 108345, 2024.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/38387306/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">38387306</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=38387306" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ymgme.2024.108345" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="5" class="mim-anchor"></a>
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<a id="Gueant2018" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Gueant, J.-L., Chery, C., Oussalah, A., Nadaf, J., Coelho, D., Josse, T., Flayac, J., Robert, A., Koscinski, I., Gastin, I., Filhine-Tresarrieu, P., Pupavac, M., and 19 others.
|
|
<strong>A PRDX1 mutant allele causes a MMACHC secondary epimutation in cblC patients.</strong>
|
|
Nature Commun. 9: 67, 2018. Note: Electronic Article. Erratum: Nature Commun. 9: 554, 2018.
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|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29302025/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29302025</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29302025[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=29302025" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/s41467-017-02306-5" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="6" class="mim-anchor"></a>
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<a id="He2020" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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He, R., Zhang, H., Kang, L., Li, H., Shen, M., Zhang, Y., Mo, R., Liu, Y., Song, J., Chen, Z., Liu, Y., Jin, Y., and 11 others.
|
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<strong>Analysis of 70 patients with hydrocephalus due to cobalamin C deficiency.</strong>
|
|
Neurology 95: e3129-e3137, 2020. Note: Electronic Article.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32943488/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32943488</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32943488" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1212/WNL.0000000000010912" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="7" class="mim-anchor"></a>
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<a id="Komhoff2013" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Komhoff, M., Roofthooft, M. T., Westra, D., Teertstra, T. K., Losito, A., van de Kar, N. C. A. J., Berger, R. M. F.
|
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<strong>Combined pulmonary hypertension and renal thrombotic microangiopathy in cobalamin C deficiency.</strong>
|
|
Pediatrics 132: e540-e544, 2013. Note: Electronic Article.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23837176/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23837176</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23837176" 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/10.1542/peds.2012-2581" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="8" class="mim-anchor"></a>
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<a id="Lerner-Ellis2009" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Lerner-Ellis, J. P., Anastasio, N., Liu, J., Coelho, D., Suormala, T., Stucki, M., Loewy, A. D., Gurd, S., Grundberg, E., Morel, C. F., Watkins, D., Baumgartner, M. R., Pastinen, T., Rosenblatt, D. S., Fowler, B.
|
|
<strong>Spectrum of mutations in MMACHC, allelic expression, and evidence for genotype-phenotype correlations.</strong>
|
|
Hum. Mutat. 30: 1072-1081, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19370762/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19370762</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19370762" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/humu.21001" target="_blank">Full Text</a>]
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<li>
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<a id="9" class="mim-anchor"></a>
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<a id="Lerner-Ellis2006" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Lerner-Ellis, J. P., Tirone, J. C., Pawelek, P. D., Dore, C., Atkinson, J. L., Watkins, D., Morel, C. F., Fujiwara, T. M., Moras, E., Hosack, A. R., Dunbar, G. V., Antonicka, H., and 10 others.
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<strong>Identification of the gene responsible for methylmalonic aciduria and homocystinuria, cblC type.</strong>
|
|
Nature Genet. 38: 93-100, 2006. Note: Erratum: Nature Genet. 38: 957 only, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16311595/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16311595</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16311595" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ng1683" target="_blank">Full Text</a>]
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</p>
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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="Liu2010" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Liu, M.-Y., Yang, Y.-L., Chang, Y.-C., Chiang, S.-H., Lin, S.-P., Han, L.-S., Qi, Y., Hsiao, K.-J., Liu, T.-T.
|
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<strong>Mutation spectrum of MMACHC in Chinese patients with combined methylmalonic aciduria and homocystinuria.</strong>
|
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J. Hum. Genet. 55: 621-626, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20631720/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20631720</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20631720" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/jhg.2010.81" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="11" class="mim-anchor"></a>
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<a id="Morel2006" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Morel, C. F., Lerner-Ellis, J. P., Rosenblatt, D. S.
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<strong>Combined methylmalonic aciduria and homocystinuria (cblC): phenotype-genotype correlations and ethnic-specific observations.</strong>
|
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Molec. Genet. Metab. 88: 315-321, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16714133/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16714133</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16714133" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ymgme.2006.04.001" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="12" class="mim-anchor"></a>
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<a id="Tsai2007" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Tsai, A. C.-H., Morel, C. F., Scharer, G., Yang, M., Lerner-Ellis, J. P., Rosenblatt, D. S., Thomas, J. A.
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<strong>Late-onset combined homocystinuria and methylmalonic aciduria (cblC) and neuropsychiatric disturbance.</strong>
|
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Am. J. Med. Genet. 143A: 2430-2434, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17853453/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17853453</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17853453" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.31932" target="_blank">Full Text</a>]
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</ol>
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<br />
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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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<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 : 07/05/2024
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</span>
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</div>
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</div>
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<div class="row collapse" id="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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Hilary J. Vernon - updated : 11/19/2021<br>Hilary J. Vernon - updated : 04/06/2021<br>Alan F. Scott - updated : 03/06/2018<br>Ada Hamosh - updated : 12/1/2014<br>Cassandra L. Kniffin - updated : 10/11/2010<br>Cassandra L. Kniffin - updated : 11/10/2009<br>Kelly A. Przylepa - updated : 4/1/2008<br>Cassandra L. Kniffin - updated : 7/17/2007<br>Ada Hamosh - updated : 6/28/2007<br>Anne M. Stumpf - updated : 1/18/2006
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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="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 : 1/18/2006
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</span>
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</div>
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</div>
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<div>
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<a id="editHistory" class="mim-anchor"></a>
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<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 : 07/05/2024
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</span>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 11/19/2021<br>carol : 04/07/2021<br>carol : 04/06/2021<br>carol : 10/31/2019<br>carol : 09/27/2018<br>carol : 03/06/2018<br>carol : 01/12/2018<br>carol : 05/11/2016<br>alopez : 12/1/2014<br>alopez : 12/1/2014<br>alopez : 4/11/2011<br>wwang : 4/8/2011<br>ckniffin : 10/11/2010<br>wwang : 12/3/2009<br>ckniffin : 11/10/2009<br>carol : 4/4/2008<br>terry : 4/1/2008<br>wwang : 7/19/2007<br>ckniffin : 7/17/2007<br>alopez : 7/6/2007<br>terry : 6/28/2007<br>ckniffin : 3/16/2007<br>alopez : 1/18/2006
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</span>
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</div>
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</div>
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<div class="container visible-print-block">
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<h3>
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<span class="mim-font">
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<strong>*</strong> 609831
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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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METABOLISM OF COBALAMIN ASSOCIATED C; MMACHC
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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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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: MMACHC</em></strong>
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</span>
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</p>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 74653006;
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</span>
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</p>
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<div>
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<br />
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: 1p34.1
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Genomic coordinates <span class="small">(GRCh38)</span> : 1:45,500,300-45,513,382 </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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1p34.1
|
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</span>
|
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</td>
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<td>
|
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<span class="mim-font">
|
|
Methylmalonic aciduria and homocystinuria, cblC type
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
277400
|
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</span>
|
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</td>
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<td>
|
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<span class="mim-font">
|
|
Autosomal recessive
|
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</span>
|
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</td>
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<td>
|
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<span class="mim-font">
|
|
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>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>Lerner-Ellis et al. (2006) identified a gene, designated MMACHC, within the critical interval on chromosome 1p34-p32 for methylmalonic aciduria and homocystinuria cblC type (MAHCC; 277400). The cDNA had an 846-basepair open reading frame encoding a 282-amino acid polypeptide with a predicted molecular weight of 31.7 kD. Northern blot analysis detected expression of 1.9-, 3.0-, and 5.4-kb transcripts in most human tissues examined, with higher levels in fetal liver and lower levels in spleen, lymph node, thymus, and bone marrow. The 3.0-kb message predominated, followed by the 5.4- and 1.9-kb messages. Lerner-Ellis et al. (2006) stated that MMACHC is not a member of any previously identified gene family. The protein is well conserved among mammals, although the C-terminal end does not seem to be conserved in eukaryotes outside Mammalia. While no homologous protein was identified in prokaryotes, motifs homologous to those found in bacterial genes with cobalamin-related functions were identified. Transduction of wildtype MMACHC into immortalized cblC fibroblast cell lines corrected the cellular phenotype. Molecular modeling predicted that the C-terminal region of the product of the MMACHC gene folds similarly to TonB, a bacterial protein involved in energy transduction for cobalamin uptake. </p>
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</span>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene 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>The MMACHC gene contains 5 exons (Lerner-Ellis et al., 2006). </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>Lerner-Ellis et al. (2006) identified the MMACHC gene on chromosome 1p34.1, within the locus for methylmalonic aciduria and homocystinuria cblC type. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>In 204 individuals with methylmalonic aciduria (MMA) and homocystinuria cblC type (MAHCC; 277400), Lerner-Ellis et al. (2006) found 42 different mutations, many consistent with loss of function of the protein product. One mutation, 271dupA (609831.0001), accounted for 40% of all disease alleles. </p><p>Among 79 unrelated Chinese patients with combined methylmalonic aciduria and homocystinuria cblC type, Liu et al. (2010) identified 24 different mutations in the MMACHC gene, including 7 novel mutations. All patients had 2 mutations, except for 3 patients in whom only 1 mutation was identified. The 2 most common alleles were W203X (609831.0006) and 658delAAG (609831.0007), which accounted for 48.1% and 13.9% of mutant alleles, respectively. Haplotype analysis indicated a different founder effect for each mutation, but the major mutation profile did not differ between patients from northern and southern China. </p><p>In 4 patients with combined pulmonary arterial hypertension and renal thrombotic microangiopathy, Komhoff et al. (2013) detected 1 of 2 basepair substitutions at nucleotide 276 of the MMACHC gene (see 609831.0008 and 609831.0009). These patients were compound heterozygous for various frameshift mutations. A fifth patient had a homozygous missense mutation in MMACHC (609831.0010). Komhoff et al. (2013) identified cblC deficiency as the cause of the rare combination of pulmonary arterial hypertension and renal thrombotic microangiopathy in these patients. The authors proposed that early recognition of cblC deficiency and vigorous treatment with hydroxocobalamin may ameliorate the devastating course of this condition. </p><p>In 3 unrelated patients with autosomal recessive cblC vitamin B12 deficiency, Gueant et al. (2018) identified compound heterozygous mutations in the MMACHC gene: a different coding mutation on 1 allele in all 3 patients (609831.0011-609831.0013), combined with the same 'secondary epimutation' on the other allele. The epimutation, 32 hypermethylated CpG sites detected by bisulfite sequencing, was a consequence of a heterozygous mutation in the adjacent, reverse-oriented PRDX1 gene: c.515-1G-T (176763.0001) or c.515-2A-T (176763.0002). The PRDX1 mutations were also found in unaffected relatives who carried the secondary epimutation. In all instances, the PRDX1 mutations affected a canonical splice acceptor site of intron 5 and caused skipping of exon 6 and the polyA termination signal of PRDX1. The resulting read-through transcript extended through the adjacent MMACHC locus in the antisense orientation. The authors proposed that the antisense transcript leads to the formation of triplexes in the promoter of MMACHC and generates CpG methylation resulting in reduced expression of the normal message. This was confirmed experimentally by growing fibroblasts from an affected proband in 5-azacytidine, which reduced promoter methylation, and by silencing PRDX1 with an siRNA, both of which increased expression of MMACHC. </p><p>By Sanger or next-generation sequencing in 70 Chinese individuals with MAHCC and hydrocephalus, He et al. (2020) identified homozygous or compound heterozygous mutations in the MMACHC gene. The parents in each case were carriers of the mutation. Eighteen individual mutations were identified, including 4 novel mutations (Q143X, W200X, Y205X, and c.568insT) that were predicted to cause loss of function and were not present in the Exome Sequencing Project, 1000 Genomes Project, or ExAC databases. The most frequent mutation was W209X (609831.0006), accounting for 62.9% of the mutations, followed by c.658delAAG (609831.0007), R73X, and c.567dupT, seen at a frequency of 12.1%, 5%, and 5%, respectively. The findings were consistent with a previous study in the Chinese population by Liu et al. (2010). </p><p>In a 28-year-old woman with nonsyndromic bull's eye maculopathy who was subsequently diagnosed with cblC, Collison et al. (2015) identified compound heterozygous mutations in the MMACHC gene (609831.0005 and 609831.0011). The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. The parents were shown to be mutation carriers. </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>Genotype/Phenotype Correlations</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>Morel et al. (2006) reported genotype-phenotype correlations in 37 patients from published case reports, representing most of the landmark descriptions of cobalamin C deficiency. Twenty-five of 37 had early-onset disease, presenting in the first 6 months of life. Seventeen of these 25 were found to be either homozygous for the 271dupA mutation (609831.0001) (n = 9) or for the 331C-T (R111X; 609831.0004) mutation (n = 3) or compound heterozygous for these 2 mutations (n = 5). Nine of 12 late-onset cases presented with acute neurologic symptoms; 4 of 9 were homozygous for the 347T-C mutation (609831.0002), 2 of 9 were compound heterozygous for the 271dupA and 394C-T (R132X; 609831.0003) mutations, and 3 of 9 for the 271dupA mutation and a missense mutation. The 394C-T mutation is common in the Asiatic-Indian/Pakistani/Middle Eastern populations. </p><p>Among 118 patients with cblC deficiency, Lerner-Ellis et al. (2009) identified 34 different MMACHC mutations, including 11 novel mutations. The 271dupA mutation was the most common, accounting for 42% of pathogenic alleles, followed by the R132X (20%) and R111X (5%) mutations. Six variants defined specific haplotypes that varied with ethnicity. Genotype/phenotype correlations were apparent. Individuals with the R132X and R161Q (609831.0005) mutations tended to present with late-onset disease, whereas patients with R111X and 271dupA mutations tended to present in infancy. Functional expression analyses on cblC fibroblasts showed that the early-onset 271dupA mutation was consistently underexpressed compared to control alleles and the late-onset R132X and R161Q mutations. The early-onset R111X mutation was also underexpressed when compared to control alleles and the R132X mutation. Quantitative RT-PCR studies showed that the late-onset R132X mutation had significantly higher levels of transcript compared to cell lines homozygous for the early-onset mutations. </p><p>Demaret et al. (2024) compared the phenotypes of 3 patients who were compound heterozygous for mutations in the MMACHC gene, c.271dupA (609831.0001) and L53P (609831.0013), and 4 patients who were homozygous for the c.271dupA mutation. The patients with compound heterozygous mutations had milder disease manifestations compared to the patients with the homozygous mutations. The patients with compound heterozygous mutations had normalization of homocysteine and methylmalonic acid levels with hydroxocobalamin treatment, age-appropriate cognitive development, and normal eye examinations, whereas the patients with homozygosity for the c.271dupA mutation had psychomotor retardation, ophthalmologic abnormalities, and feeding difficulties. Fibroblasts from the patients with compound heterozygous mutations exhibited higher propionate incorporation compared to fibroblasts from the patients with the homozygous mutation. </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>13 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 METHYLMALONIC ACIDURIA AND HOMOCYSTINURIA, cblC TYPE</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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MMACHC, 1-BP DUP, 271A
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<br />
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SNP: rs398124292,
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gnomAD: rs398124292,
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ClinVar: RCV000001486, RCV000081737, RCV000203236, RCV000308836, RCV000507720, RCV000585799, RCV001273215, RCV001328208, RCV002251853, RCV003421892, RCV004018537, RCV004798712
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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 individuals from several different ethnic groups, Lerner-Ellis et al. (2006) found that methylmalonic aciduria and homocystinuria cblC type (MAHCC; 277400) was associated with a 271dupA mutation in the MMACHC gene. The 271dupA mutation predicts a change of amino acid residue 91 from arginine to lysine followed by frameshift with a premature termination 14 codons downstream (Arg91LysfsTer14). The mutation was present in homozygous state in 46 individuals, in whom the diagnosis was made under the age of 1 year in 44. In 2 individuals in whom the diagnosis was made after the age of 20 years, the 271dupA mutation was in compound heterozygous state with a 347T-C transition (609831.0002). The 271dupA mutation accounted for 40% of all disease alleles among the 204 patients studied. </p><p>Lerner-Ellis et al. (2009) identified the 271dupA allele in 42% of pathogenic alleles from 118 patients with cblC. Patients with the 271dupA mutation tended to present in infancy. Transcript analysis on cblC fibroblasts showed that the early-onset 271dupA mutation was consistently underexpressed compared to control alleles and to MMACHC alleles associated with later-onset disease. </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 METHYLMALONIC ACIDURIA AND HOMOCYSTINURIA, cblC TYPE</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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MMACHC, LEU116PRO
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<br />
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SNP: rs121918240,
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gnomAD: rs121918240,
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ClinVar: RCV000001487, RCV002512644
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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 2 patients in whom the diagnosis of methylmalonic aciduria and homocystinuria cblC type (MAHCC; 277400) was made after the age of 20 years, Lerner-Ellis et al. (2006) found compound heterozygosity in the MMACHC gene for the most common mutation, 271dupA (609831.0001), which in homozygous state causes early-onset disease, and a 347T-C transition, which was predicted to result in a leu116-to-pro (L116P) substitution. </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 METHYLMALONIC ACIDURIA AND HOMOCYSTINURIA, cblC TYPE</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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MMACHC, ARG132TER
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<br />
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SNP: rs121918241,
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gnomAD: rs121918241,
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ClinVar: RCV000001488, RCV000153508, RCV000721968, RCV001250251, RCV001273221, RCV001813934, RCV002512645, RCV004794321
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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 survey of 204 individuals with methylmalonic aciduria and homocystinuria cblC type (MAHCC; 277400), Lerner-Ellis et al. (2006) found 34 examples of the 394C-T mutant allele of the MMACHC gene, predicted to result in an arg132-to-ter mutation (R132X). The R132X mutation was primarily associated with late-onset disease and was noted in the homozygous state among published individuals in Asiatic-Indian, Pakistani, or Middle Eastern descent and reported by Morel et al. (2006) in an additional 9 unpublished patients from their database who were either of Asiatic-Indian, Pakistani, or Middle Eastern descent. </p><p>Ben-Omran et al. (2007) reported 2 unrelated girls of Pakistani and Bengali origin, respectively, with cblC disease caused by a homozygous R132X mutation. The girls presented with neuropsychiatric symptoms at ages 14 and 10 years, respectively. </p><p>In a study of 118 patients with cblC disease, Lerner-Ellis et al. (2009) found that individuals with the R132X mutation tended to present with late-onset disease. Transcript and RT-PCR analysis of cblC fibroblasts showed that the R132X mutation resulted in significantly higher levels of transcript compared to cell lines homozygous for the early-onset mutations. The authors postulated that nonsense-mediated decay may not occur with this mutation, or that it may occur to a lesser extent. Alternatively, the mutation may result in a truncated protein with residual function. Lerner-Ellis et al. (2009) identified the R132X mutation in 20% of pathogenic alleles from 118 patients with cblC. </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 METHYLMALONIC ACIDURIA AND HOMOCYSTINURIA, cblC TYPE</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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MMACHC, ARG111TER
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<br />
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SNP: rs121918242,
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gnomAD: rs121918242,
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ClinVar: RCV000001489, RCV000186026, RCV001273220, RCV002512646, RCV004755697
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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 review of 37 published cases of methylmalonic aciduria and homocystinuria cblC type (MAHCC; 277400), Morel et al. (2006) identified 3 Cajun patients who were homozygous for a 331C-T transition in the MMACHC gene, resulting in an arg111-to-ter (R111X) substitution. They also reported 3 unpublished patients of French Canadian background who were homozygous for this mutation. </p><p>Lerner-Ellis et al. (2009) identified the R111X mutation in 5% of pathogenic alleles from 118 patients with cblC. Patients with the R111X mutation tended to present in infancy. Functional expression analyses on cblC fibroblasts showed that the early-onset R111X mutation was underexpressed when compared to control alleles or to alleles associated with late-onset disease. </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 METHYLMALONIC ACIDURIA AND HOMOCYSTINURIA, cblC TYPE</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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MMACHC, ARG161GLN
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<br />
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SNP: rs121918243,
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gnomAD: rs121918243,
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ClinVar: RCV000001490, RCV000081740, RCV000624532, RCV000721969, RCV001273229, RCV002512647, RCV003894782
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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 male with late-onset methylmalonic aciduria and homocystinuria cblC type (MAHCC; 277400), originally reported by Bodamer et al. (2001), Morel et al. (2006) identified compound heterozygosity for 2 mutations in the MMACHC gene: the 271dupA (609831.0001) mutation and a 482G-A transition resulting in an arg161-to-gln (R161Q) substitution. </p><p>Tsai et al. (2007) described a 36-year-old woman with a psychiatric history and a spinal cord infarct who was subsequently diagnosed with methylmalonic aciduria and homocystinuria cblC type. Molecular analysis of the MMACHC gene revealed compound heterozygosity for the 271dupA and R161Q mutations. </p><p>Among 118 patients with cblC, Lerner-Ellis et al. (2009) found that those with the R161Q mutation tended to present with late-onset disease. </p><p>Liu et al. (2010) also found that the R161Q mutation was associated with a late onset and relatively mild phenotype among Chinese patients with cblC carrying this mutation. This allele was the third most common mutation found among 79 unrelated patients, accounting for 7% of mutant alleles. </p><p>In a 28-year-old woman with nonsyndromic bull's eye maculopathy who was subsequently diagnosed with cblC, Collison et al. (2015) identified compound heterozygous mutations in the MMACHC gene: R161Q and a 1-bp insertion (c.270_271insA; 609831.0011), predicted to result in a frameshift and a premature termination codon (Arg91LysfsTer14). The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. The parents were shown to be mutation carriers. </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 METHYLMALONIC ACIDURIA AND HOMOCYSTINURIA, cblC TYPE</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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MMACHC, TRP203TER
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<br />
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SNP: rs587776889,
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gnomAD: rs587776889,
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ClinVar: RCV000023785, RCV000756343, RCV001275215, RCV002513204
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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 Chinese patients with methylmalonic aciduria and homocystinuria cblC type (MAHCC; 277400), Liu et al. (2010) identified a 609G-A transition in exon 4 of the MMACHC gene, resulting in a trp203-to-ter (W203X) substitution. This allele was the most common mutation found among 79 unrelated patients, accounting for 48.1% of mutant alleles. Fifteen patients who were homozygous for the mutation showed an early-onset phenotype, with 3 showing onset before age 4 years. Haplotype analysis suggested a founder effect. </p><p>In a molecular analysis of 70 Chinese individuals with MAHCC, He et al. (2020) found that the W203X mutation accounted for 62.9% of the identified mutations. Twenty-nine patients were homozygous for the mutation. </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>.0007 METHYLMALONIC ACIDURIA AND HOMOCYSTINURIA, cblC TYPE</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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MMACHC, 3-BP DEL, 658AAG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs398124296,
|
|
|
|
|
|
|
|
ClinVar: RCV000081744, RCV000272939, RCV001275218, RCV004755765
|
|
|
|
|
|
</span>
|
|
</div>
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|
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<div>
|
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<span class="mim-text-font">
|
|
<p>In Chinese patients with methylmalonic aciduria and homocystinuria cblC type (MAHCC; 277400), Liu et al. (2010) identified a 3-bp deletion (658delAAG) in exon 4 of the MMACHC gene, resulting in an in-frame deletion of lys220. This allele was the second most common found among 79 unrelated patients, accounting for 13.9% of mutant alleles. Haplotype analysis suggested a founder effect. </p><p>In a molecular analysis of 70 Chinese individuals with MAHCC, He et al. (2020) found that the 658delAAG mutation accounted for 12.1% of the identified mutations. </p>
|
|
</span>
|
|
</div>
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<div>
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|
<br />
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|
</div>
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</div>
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<div>
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|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 METHYLMALONIC ACIDURIA AND HOMOCYSTINURIA, cblC TYPE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
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|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
MMACHC, GLU92ASP
|
|
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|
|
|
<br />
|
|
|
|
SNP: rs556977618,
|
|
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|
|
|
gnomAD: rs556977618,
|
|
|
|
|
|
ClinVar: RCV000148298
|
|
|
|
|
|
</span>
|
|
</div>
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|
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|
|
<div>
|
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<span class="mim-text-font">
|
|
<p>In 3 patients with combined pulmonary arterial hypertension and renal thrombotic microangiopathy caused by cblC deficiency (MAHCC; 277400), Komhoff et al. (2013) identified compound heterozygosity for a c.276G-T transversion in the MMACHC gene, resulting in a glu92-to-asp (E92D) substitution. Two patients also carried the common 271dupA (609831.0001) mutation on the other allele; the third patient was compound heterozygous for a different frameshift mutation. The patients were of Spanish/Turkish or Dutch ethnicity. Because another patient with a synonymous change at that position was identified (see 609831.0009), the authors concluded that the actual effect of the mutation, which affects the last nucleotide of exon 2, is aberrant splicing and ultimately deletion of the erroneous pre-mRNA via nonsense-mediated decay. </p>
|
|
</span>
|
|
</div>
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<div>
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<br />
|
|
</div>
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</div>
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|
<div>
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|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 METHYLMALONIC ACIDURIA AND HOMOCYSTINURIA, cblC TYPE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MMACHC, GLU92GLU
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs556977618,
|
|
|
|
|
|
gnomAD: rs556977618,
|
|
|
|
|
|
ClinVar: RCV000148299
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In an Italian patient with combined renal thrombotic microangiopathy and pulmonary arterial hypertension caused by cblC deficiency (MAHCC; 277400), Komhoff et al. (2013) identified heterozygosity for a c.276G-A transition in the MMACHC gene, resulting in a synonymous glu92-to-glu (E92E) substitution. Because this mutation occurred in the last nucleotide of exon 2, the authors suggested that the actual effect of the mutation is an aberrantly spliced pre-mRNA that undergoes nonsense-mediated decay. The patient was heterozygous for a frameshift mutation on the other allele. </p>
|
|
</span>
|
|
</div>
|
|
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|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 METHYLMALONIC ACIDURIA AND HOMOCYSTINURIA, cblC TYPE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MMACHC, GLY155GLU
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs606231425,
|
|
|
|
|
|
|
|
ClinVar: RCV000148300
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Komhoff et al. (2013) reported a patient of Dutch ancestry with combined renal thrombotic microangiopathy and pulmonary arterial hypertension caused by cblC deficiency (MAHCC; 277400) who had a homozygous c.464G-A transition in the MMACHC gene, resulting in a gly155-to-glu (G155E) substitution. The patient presented at 2.5 years of age and died from right ventricular failure 2 weeks after diagnosis. Homocysteine level was 123 micromol/L; methylmalonic acid (MMA) was 14,424 nmol/L. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 METHYLMALONIC ACIDURIA AND HOMOCYSTINURIA, cblC TYPE, DIGENIC</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
METHYLMALONIC ACIDURIA AND HOMOCYSTINURIA, cblC TYPE, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MMACHC, 1-BP INS, 270A
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000001486, RCV000081737, RCV000203236, RCV000308836, RCV000507720, RCV000585799, RCV001273215, RCV001328208, RCV002251853, RCV003421892, RCV004018537, RCV004798712
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Caucasian female (CHU-12122) with cbl-type methylmalonic aciduria and homocystinuria (MAHCC; 277400), who died at 1 month of age, Gueant et al. (2018) identified compound heterozygous mutations in the MMACHC gene: a 1-bp insertion (c.270_271insA), resulting in a frameshift and a premature termination codon (Arg91LysfsTer14), inherited from the mother, and a secondary epimutation causing promoter hypermethylation and MMACHC silencing inherited from the father. The secondary epimutation was triggered by a heterozygous mutation in the adjacent, reverse-oriented PRDX1 gene (176763.0001). The patient's paternal grandfather also carried the epimutation, which was present in her father's sperm. </p><p>For discussion of the c.270_271insA mutation that was found in compound heterozygous state in the MMACHC gene in a patient with MAHCC by Collison et al. (2015), see 609831.0005. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 METHYLMALONIC ACIDURIA AND HOMOCYSTINURIA, cblC TYPE, DIGENIC</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MMACHC, 81G-A
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1553162317,
|
|
|
|
|
|
|
|
ClinVar: RCV000585803
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a female (WG-3838) of Japanese and Korean ancestry, who died at 2 months of age, with cbl-type methylmalonic aciduria and homocystinuria (MAHCC; 277400), Gueant et al. (2018) identified compound heterozygous mutations in the MMACHC gene: a splice site mutation (c.81G-A) inherited from the mother, and a secondary epimutation causing promoter hypermethylation and MMACHC silencing inherited from the father. The secondary epimutation was triggered by a heterozygous mutation in the adjacent, reverse-oriented PRDX1 gene (176763.0002). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 METHYLMALONIC ACIDURIA AND HOMOCYSTINURIA, cblC TYPE, DIGENIC</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MMACHC, LEU53PRO
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs756980496,
|
|
|
|
|
|
gnomAD: rs756980496,
|
|
|
|
|
|
ClinVar: RCV000585794, RCV003323623, RCV003465319
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 59-year-old Caucasian man (WG-4152) with cbl-type methylmalonic aciduria and homocystinuria (MAHCC; 277400), Gueant et al. (2018) identified compound heterozygous mutations in the MMACHC gene: a c.158T-C transition, resulting in a leu53-to-pro (L53P) substitution, and a secondary epimutation causing promoter hypermethylation and MMACHC silencing. The secondary epimutation was triggered by a heterozygous mutation in the adjacent, reverse-oriented PRDX1 gene (176763.0001). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
<div>
|
|
<ol>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Ben-Omran, T. I., Wong, H., Blaser, S., Feigenbaum, A.
|
|
<strong>Late-onset cobalamin-C disorder: a challenging diagnosis.</strong>
|
|
Am. J. Med. Genet. 143A: 979-984, 2007.
|
|
|
|
|
|
[PubMed: 17431913]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1002/ajmg.a.31671]
|
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|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Bodamer, O. A. F., Rosenblatt, D. S., Appel, S. H., Beaudet, A. L.
|
|
<strong>Adult-onset combined methylmalonic aciduria and homocystinuria (cblC).</strong>
|
|
Neurology 56: 1113 only, 2001.
|
|
|
|
|
|
[PubMed: 11320193]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1212/wnl.56.8.1113]
|
|
|
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|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Collison, F. T., Xie, Y., Gambin, T., Jhangiani, S., Muzny, D., Gibbs, R., Lupski, J. R., Fishman, G. A., Allikmets, R.
|
|
<strong>Whole exome sequencing identifies an adult-onset case of methylmalonic aciduria and homocystinuria type C (cblC) with non-syndromic bull's eye maculopathy.</strong>
|
|
Ophthal. Genet. 36: 270-275, 2015.
|
|
|
|
|
|
[PubMed: 25687216]
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|
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|
|
[Full Text: https://doi.org/10.3109/13816810.2015.1010736]
|
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|
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</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Demaret, T., Bedard, K., Soucy, J. F., Watkins, D., Allard, P., Levtova, A., O'Brien, A., Brunel-Guitton, C., Rosenblatt, D. S., Mitchell, G. A.
|
|
<strong>The MMACHC variant c.158T>C: Mild clinical and biochemical phenotypes and marked hydroxocobalamin response in cblC patients.</strong>
|
|
Molec. Genet. Metab. 142: 108345, 2024.
|
|
|
|
|
|
[PubMed: 38387306]
|
|
|
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|
|
[Full Text: https://doi.org/10.1016/j.ymgme.2024.108345]
|
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|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Gueant, J.-L., Chery, C., Oussalah, A., Nadaf, J., Coelho, D., Josse, T., Flayac, J., Robert, A., Koscinski, I., Gastin, I., Filhine-Tresarrieu, P., Pupavac, M., and 19 others.
|
|
<strong>A PRDX1 mutant allele causes a MMACHC secondary epimutation in cblC patients.</strong>
|
|
Nature Commun. 9: 67, 2018. Note: Electronic Article. Erratum: Nature Commun. 9: 554, 2018.
|
|
|
|
|
|
[PubMed: 29302025]
|
|
|
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|
|
[Full Text: https://doi.org/10.1038/s41467-017-02306-5]
|
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|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
He, R., Zhang, H., Kang, L., Li, H., Shen, M., Zhang, Y., Mo, R., Liu, Y., Song, J., Chen, Z., Liu, Y., Jin, Y., and 11 others.
|
|
<strong>Analysis of 70 patients with hydrocephalus due to cobalamin C deficiency.</strong>
|
|
Neurology 95: e3129-e3137, 2020. Note: Electronic Article.
|
|
|
|
|
|
[PubMed: 32943488]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1212/WNL.0000000000010912]
|
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|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Komhoff, M., Roofthooft, M. T., Westra, D., Teertstra, T. K., Losito, A., van de Kar, N. C. A. J., Berger, R. M. F.
|
|
<strong>Combined pulmonary hypertension and renal thrombotic microangiopathy in cobalamin C deficiency.</strong>
|
|
Pediatrics 132: e540-e544, 2013. Note: Electronic Article.
|
|
|
|
|
|
[PubMed: 23837176]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1542/peds.2012-2581]
|
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|
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</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Lerner-Ellis, J. P., Anastasio, N., Liu, J., Coelho, D., Suormala, T., Stucki, M., Loewy, A. D., Gurd, S., Grundberg, E., Morel, C. F., Watkins, D., Baumgartner, M. R., Pastinen, T., Rosenblatt, D. S., Fowler, B.
|
|
<strong>Spectrum of mutations in MMACHC, allelic expression, and evidence for genotype-phenotype correlations.</strong>
|
|
Hum. Mutat. 30: 1072-1081, 2009.
|
|
|
|
|
|
[PubMed: 19370762]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1002/humu.21001]
|
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|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Lerner-Ellis, J. P., Tirone, J. C., Pawelek, P. D., Dore, C., Atkinson, J. L., Watkins, D., Morel, C. F., Fujiwara, T. M., Moras, E., Hosack, A. R., Dunbar, G. V., Antonicka, H., and 10 others.
|
|
<strong>Identification of the gene responsible for methylmalonic aciduria and homocystinuria, cblC type.</strong>
|
|
Nature Genet. 38: 93-100, 2006. Note: Erratum: Nature Genet. 38: 957 only, 2006.
|
|
|
|
|
|
[PubMed: 16311595]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/ng1683]
|
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|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Liu, M.-Y., Yang, Y.-L., Chang, Y.-C., Chiang, S.-H., Lin, S.-P., Han, L.-S., Qi, Y., Hsiao, K.-J., Liu, T.-T.
|
|
<strong>Mutation spectrum of MMACHC in Chinese patients with combined methylmalonic aciduria and homocystinuria.</strong>
|
|
J. Hum. Genet. 55: 621-626, 2010.
|
|
|
|
|
|
[PubMed: 20631720]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/jhg.2010.81]
|
|
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|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Morel, C. F., Lerner-Ellis, J. P., Rosenblatt, D. S.
|
|
<strong>Combined methylmalonic aciduria and homocystinuria (cblC): phenotype-genotype correlations and ethnic-specific observations.</strong>
|
|
Molec. Genet. Metab. 88: 315-321, 2006.
|
|
|
|
|
|
[PubMed: 16714133]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1016/j.ymgme.2006.04.001]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Tsai, A. C.-H., Morel, C. F., Scharer, G., Yang, M., Lerner-Ellis, J. P., Rosenblatt, D. S., Thomas, J. A.
|
|
<strong>Late-onset combined homocystinuria and methylmalonic aciduria (cblC) and neuropsychiatric disturbance.</strong>
|
|
Am. J. Med. Genet. 143A: 2430-2434, 2007.
|
|
|
|
|
|
[PubMed: 17853453]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1002/ajmg.a.31932]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
</ol>
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
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|
|
|
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|
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|
|
<div>
|
|
<div class="row">
|
|
<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
|
|
<span class="text-nowrap mim-text-font">
|
|
Contributors:
|
|
</span>
|
|
</div>
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Hilary J. Vernon - updated : 07/05/2024<br>Hilary J. Vernon - updated : 11/19/2021<br>Hilary J. Vernon - updated : 04/06/2021<br>Alan F. Scott - updated : 03/06/2018<br>Ada Hamosh - updated : 12/1/2014<br>Cassandra L. Kniffin - updated : 10/11/2010<br>Cassandra L. Kniffin - updated : 11/10/2009<br>Kelly A. Przylepa - updated : 4/1/2008<br>Cassandra L. Kniffin - updated : 7/17/2007<br>Ada Hamosh - updated : 6/28/2007<br>Anne M. Stumpf - updated : 1/18/2006
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