2871 lines
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- *600098 - RELATED RAS VIRAL ONCOGENE HOMOLOG 2; RRAS2
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- OMIM
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<p>
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<span class="h4">*600098</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<a href="#title"><strong>Title</strong></a>
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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 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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<a href="#animalModel">Animal Model</a>
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/600098">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 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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<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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<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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</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=ENSG00000133818;t=ENST00000256196" 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=22800" 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=600098" 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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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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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=ENSG00000133818;t=ENST00000256196" 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_001102669,NM_001177314,NM_001177315,NM_012250,XM_017017363,XM_047426567,XM_047426568" 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_012250" 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=600098" 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=02518&isoform_id=02518_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/RRAS2" 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/190877,15341857,20147741,21361416,49065833,119588892,119588893,156713451,189054170,221042802,221043066,221043870,293597519,293597521,1034572487,2217281705,2217281707,2462523708,2462523710,2462523712" 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/P62070" class="mim-tip-hint" title="Comprehensive protein sequence and functional information, including supporting data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UniProt', 'domain': 'uniprot.org'})">UniProt</a></div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGeneInfo">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGeneInfoLinksFold" id="mimGeneInfoLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimGeneInfoLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Gene Info</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimGeneInfoLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="http://biogps.org/#goto=genereport&id=22800" 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=ENSG00000133818;t=ENST00000256196" 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=RRAS2" 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=RRAS2" 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+22800" 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/RRAS2" 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:22800" 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/22800" 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=chr11&hgg_gene=ENST00000256196.9&hgg_start=14277920&hgg_end=14364506&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 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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</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/genes/HGNC:17271" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=600098[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=600098[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/RRAS2/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/ENSG00000133818" 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=RRAS2" 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=RRAS2" 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=RRAS2" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=RRAS2&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/PA34862" 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:17271" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://flybase.org/reports/FBgn0003206.html" class="mim-tip-hint" title="A Database of Drosophila Genes and Genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'FlyBase', 'domain': 'flybase.org'})">FlyBase</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:1914172" 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/RRAS2#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:1914172" 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/22800/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=22800" 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=WBGene00004310;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-050417-352" 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:22800" 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=RRAS2&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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600098
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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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RELATED RAS VIRAL ONCOGENE HOMOLOG 2; RRAS2
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</span>
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</h3>
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</div>
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<div>
|
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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ONCOGENE RRAS2<br />
|
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TERATOCARCINOMA ONCOGENE TC21; TC21
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=RRAS2" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">RRAS2</a></em></strong>
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</span>
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</p>
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</div>
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<div>
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<a id="cytogeneticLocation" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
|
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<strong>
|
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<em>
|
|
Cytogenetic location: <a href="/geneMap/11/193?start=-3&limit=10&highlight=193">11p15.2</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr11:14277920-14364506&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'})">11:14,277,920-14,364,506</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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<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=618624," class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
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</a>
|
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</span>
|
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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="2">
|
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<span class="mim-font">
|
|
<a href="/geneMap/11/193?start=-3&limit=10&highlight=193">
|
|
11p15.2
|
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</a>
|
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</span>
|
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</td>
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|
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<td>
|
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<span class="mim-font">
|
|
Noonan syndrome 12
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</span>
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
|
|
<a href="/entry/618624"> 618624 </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 dominant">AD</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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<tr>
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<td>
|
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<span class="mim-font">
|
|
Ovarian carcinoma
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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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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
|
|
|
<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">
|
|
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
|
</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/600098" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/600098" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
|
</ul>
|
|
</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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<p>The TC21 oncogene, a member of the RAS superfamily, was initially cloned from a human teratocarcinoma cDNA library by PCR methods using degenerate oligonucleotides corresponding to the conserved region of the RAS genes (<a href="#3" class="mim-tip-reference" title="Drivas, G. T., Shih, A., Coutavas, E., Rush, M. G., D'Eustachio, P. <strong>Characterization of four novel ras-like genes expressed in a human teratocarcinoma cell line.</strong> Molec. Cell. Biol. 10: 1793-1798, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2108320/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2108320</a>] [<a href="https://doi.org/10.1128/mcb.10.4.1793-1798.1990" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2108320">Drivas et al., 1990</a>). <a href="#2" class="mim-tip-reference" title="Chan, A. M.-L., Miki, T., Meyers, K. A., Aaronson, S. A. <strong>A human oncogene of the RAS superfamily unmasked by expression cDNA cloning.</strong> Proc. Nat. Acad. Sci. 91: 7558-7562, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8052619/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8052619</a>] [<a href="https://doi.org/10.1073/pnas.91.16.7558" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8052619">Chan et al. (1994)</a> found the same oncogene when they generated an expression cDNA library from an ovarian carcinoma (<a href="/entry/167000">167000</a>) line. They found, furthermore, that a single point mutation (see MOLECULAR GENETICS) was responsible for activation of transforming properties. While the cDNA clone possessed high transforming activity, the ovarian tumor genomic DNA, which contained the mutated TC21 allele, failed to induce transformed foci. Thus, expression cDNA cloning made it possible to identify and isolate a human oncogene that had evaded detection by conventional approaches. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8052619+2108320" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using X-gal staining and RT-PCR analyses, <a href="#5" class="mim-tip-reference" title="Larive, R. M., Abad, A., Cardaba, C. M., Hernandez, T., Canamero, M., de Alva, E., Santos, E., Alarcon, B., Bustelo, X. R. <strong>The Ras-like protein R-Ras2/TC21 is important.</strong> Molec. Biol. Cell 23: 2373-2387, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22535521/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22535521</a>] [<a href="https://doi.org/10.1091/mbc.E12-01-0060" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22535521">Larive et al. (2012)</a> showed that Rras2 was expressed from early developmental stages to adulthood in mice. In adult mice, highest expression was in lung and testis, and lowest expression was in tongue, liver, skeletal muscle, and brown adipose. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22535521" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#4" class="mim-tip-reference" title="Gross, M. B. <strong>Personal Communication.</strong> Baltimore, Md. 1/3/2020."None>Gross (2020)</a> mapped the RRAS2 gene to chromosome 11p15.2 based on an alignment of the RRAS2 sequence (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=AF493924" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">AF493924</a>) with the genomic sequence (GRCh38).</p>
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In 9 patients from 6 unrelated families with Noonan syndrome (NS12; <a href="/entry/618624">618624</a>), <a href="#1" class="mim-tip-reference" title="Capri, Y., Flex, E., Krumbach, O. H. F., Carpentieri, G., Cecchetti, S., Lissewski, C., Adariani, S. R., Schanze, D., Brinkmann, J., Piard, J., Pantaleoni, F., Lepri, F. R., and 21 others. <strong>Activating mutations of RRAS2 are a rare cause of Noonan syndrome.</strong> Am. J. Hum. Genet. 104: 1223-1232, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31130282/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31130282</a>] [<a href="https://doi.org/10.1016/j.ajhg.2019.04.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31130282">Capri et al. (2019)</a> identified heterozygous germline mutations in the RRAS2 gene (see, e.g., <a href="#0001">600098.0001</a>-<a href="#0003">600098.0003</a>). The mutations arose de novo in the probands from 5 of the families. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31130282" 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 of 219 individuals suspected of having Noonan syndrome (NS) or NS-related disorders, <a href="#7" class="mim-tip-reference" title="Niihori, T., Nagai, K., Fujita, A., Ohashi, H., Okamoto, N., Okada, S., Harada, A., Kihara, H., Arbogast, T., Funayama, R., Shirota, M., Nakayama, K., Abe, T., Inoue, S., Tsai, I.-C., Matsumoto, N., Davis, E. E., Katsanis, N., Aoki, Y. <strong>Germline-activating RRAS2 mutations cause Noonan syndrome.</strong> Am. J. Hum. Genet. 104: 1233-1240, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31130285/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31130285</a>] [<a href="https://doi.org/10.1016/j.ajhg.2019.04.014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31130285">Niihori et al. (2019)</a> identified heterozygosity for de novo mutations in the RRAS2 gene (see, e.g., <a href="#0001">600098.0001</a> and <a href="#0003">600098.0003</a>). Functional analysis suggested that the mutations cause hyperactivation of the RAS/MAPK (see <a href="/entry/176948">176948</a>) pathway. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31130285" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Somatic Mutation</em></strong></p><p>
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In epithelial ovarian tumor tissue (<a href="/entry/167000">167000</a>), <a href="#2" class="mim-tip-reference" title="Chan, A. M.-L., Miki, T., Meyers, K. A., Aaronson, S. A. <strong>A human oncogene of the RAS superfamily unmasked by expression cDNA cloning.</strong> Proc. Nat. Acad. Sci. 91: 7558-7562, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8052619/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8052619</a>] [<a href="https://doi.org/10.1073/pnas.91.16.7558" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8052619">Chan et al. (1994)</a> identified a somatic missense mutation in the TC21 gene (Q72L; <a href="#0001">600098.0001</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8052619" 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>Using Rras2 -/- mice, <a href="#5" class="mim-tip-reference" title="Larive, R. M., Abad, A., Cardaba, C. M., Hernandez, T., Canamero, M., de Alva, E., Santos, E., Alarcon, B., Bustelo, X. R. <strong>The Ras-like protein R-Ras2/TC21 is important.</strong> Molec. Biol. Cell 23: 2373-2387, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22535521/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22535521</a>] [<a href="https://doi.org/10.1091/mbc.E12-01-0060" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22535521">Larive et al. (2012)</a> found that Rras2 was dispensable for proper development and function of mouse organs, despite its widespread expression in wildtype mice. However, Rras2 was necessary for proper mammary gland development during the pubertal period, as full development of mammary gland was not achieved until the adult period in Rras2 -/- mice. Double- and triple-knockout experiments showed that Rras2, Hras (<a href="/entry/190020">190020</a>), and Nras (<a href="/entry/164790">164790</a>) were all important for kinetics of mammary gland development during the pubertal phase, but not for the overall developmental program of mammary gland, and that they did not act redundantly or additively. In vivo and in vitro analyses showed that Rras2 was expressed in both cap and epithelial cells of terminal end buds during pubertal development of mammary gland and was specifically involved in proliferation of mammary epithelial cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22535521" 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="#6" class="mim-tip-reference" title="Martinez-Riano, A., Bovolenta, E. R., Boccasavia, V. L., Ponomarenko, J., Abia, D., Oeste, C. L., Fresno, M., van Santen, H. M., Alarcon, B. <strong>RRAS2 shapes the TCR repertoire by setting the threshold for negative selection.</strong> J. Exp. Med. 216: 2427-2447, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31324740/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31324740</a>] [<a href="https://doi.org/10.1084/jem.20181959" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31324740">Martinez-Riano et al. (2019)</a> found that Rras2 -/- mice showed a reduction in the percentage of Cd4 (<a href="/entry/186940">186940</a>)-positive/Cd8 (see <a href="/entry/186910">186910</a>)-positive (i.e., double-positive) thymocytes compared with wildtype due to enhanced negative selection in thymocytes. Negative selection in thymocytes was due to defective Pi3k (see <a href="/entry/601232">601232</a>)-Akt (<a href="/entry/164730">164730</a>) pathway activation, resulting in reduced T-cell receptor (TCR; see <a href="/entry/186880">186880</a>) expression and resistance to autoimmune disorders, including a model of inflammatory bowel disease (IBD; see <a href="/entry/266600">266600</a>) and experimental autoimmune encephalomyelitis (EAE). Analysis of the TCR repertoire in Rras2 -/- mice identified Trav4n3 and Trav4d3 (see <a href="/entry/615442">615442</a>) as V-alpha variable sequences biased toward autoimmunity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31324740" 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">rs113954997 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs113954997;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=rs113954997" 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=rs113954997" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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In an Indian boy (patient 4) who died at age 2 weeks with Noonan syndrome (NS12; <a href="/entry/618624">618624</a>), <a href="#1" class="mim-tip-reference" title="Capri, Y., Flex, E., Krumbach, O. H. F., Carpentieri, G., Cecchetti, S., Lissewski, C., Adariani, S. R., Schanze, D., Brinkmann, J., Piard, J., Pantaleoni, F., Lepri, F. R., and 21 others. <strong>Activating mutations of RRAS2 are a rare cause of Noonan syndrome.</strong> Am. J. Hum. Genet. 104: 1223-1232, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31130282/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31130282</a>] [<a href="https://doi.org/10.1016/j.ajhg.2019.04.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31130282">Capri et al. (2019)</a> identified heterozygosity for a de novo germline c.215A-T transversion (c.215A-T, NM_012250.5) in the RRAS2 gene, resulting in a gln72-to-leu (Q72L) substitution within the switch II region. The mutation was not present in general population genetic databases. Functional analysis in HEK293T cells showed constitutively enhanced ERK (see <a href="/entry/601795">601795</a>) phosphorylation with the Q72L mutant compared to wildtype protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31130282" 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 boy (patient HU1) with severe failure to thrive and features of Noonan syndrome, who died at age 3 years, <a href="#7" class="mim-tip-reference" title="Niihori, T., Nagai, K., Fujita, A., Ohashi, H., Okamoto, N., Okada, S., Harada, A., Kihara, H., Arbogast, T., Funayama, R., Shirota, M., Nakayama, K., Abe, T., Inoue, S., Tsai, I.-C., Matsumoto, N., Davis, E. E., Katsanis, N., Aoki, Y. <strong>Germline-activating RRAS2 mutations cause Noonan syndrome.</strong> Am. J. Hum. Genet. 104: 1233-1240, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31130285/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31130285</a>] [<a href="https://doi.org/10.1016/j.ajhg.2019.04.014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31130285">Niihori et al. (2019)</a> identified heterozygosity for the Q72L mutation (c.215A-T, NM_012250.6) in the RRAS2 gene. The mutation was shown to have arisen de novo. Functional analysis in HEK293T cells showed elevated association of RAF1 (<a href="/entry/164760">164760</a>) and activation of ERK1/2 (see <a href="/entry/176948">176948</a>) and ELK1 (<a href="/entry/311040">311040</a>). Low-dose overexpression of the Q72L variant in zebrafish larvae resulted in a significantly increased ceratohyal angle compared to wildtype larvae; overexpression at higher dose caused lethal developmental impairments. Noting the severe phenotype present in patient HU1 compared to other RRAS2-mutated patients, as well as the more potent effects with the Q72L variant compared to other Noonan-associated RRAS2 variants in their in vitro and in vivo assays, the authors suggested a possible genotype/phenotype correlation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31130285" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Somatic Mutation in Ovarian Cancer</em></strong></p><p>
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<a href="#2" class="mim-tip-reference" title="Chan, A. M.-L., Miki, T., Meyers, K. A., Aaronson, S. A. <strong>A human oncogene of the RAS superfamily unmasked by expression cDNA cloning.</strong> Proc. Nat. Acad. Sci. 91: 7558-7562, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8052619/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8052619</a>] [<a href="https://doi.org/10.1073/pnas.91.16.7558" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8052619">Chan et al. (1994)</a> identified a somatic gln72-to-leu (Q72L) mutation in the TC21 gene in epithelial ovarian tumor tissue (<a href="/entry/167000">167000</a>) and demonstrated that the mutation was associated with high transforming activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8052619" 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> rs782457908 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs782457908;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/rs782457908?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=rs782457908" 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=rs782457908" 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=RCV000852397 OR RCV000853183 OR RCV003411705 OR RCV004760768" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000852397, RCV000853183, RCV003411705, RCV004760768" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000852397...</a>
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<p>In 4 affected members over 3 generations of a German family (family 3) with Noonan syndrome (NS12; <a href="/entry/618624">618624</a>), <a href="#1" class="mim-tip-reference" title="Capri, Y., Flex, E., Krumbach, O. H. F., Carpentieri, G., Cecchetti, S., Lissewski, C., Adariani, S. R., Schanze, D., Brinkmann, J., Piard, J., Pantaleoni, F., Lepri, F. R., and 21 others. <strong>Activating mutations of RRAS2 are a rare cause of Noonan syndrome.</strong> Am. J. Hum. Genet. 104: 1223-1232, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31130282/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31130282</a>] [<a href="https://doi.org/10.1016/j.ajhg.2019.04.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31130282">Capri et al. (2019)</a> identified heterozygosity for a c.208G-A transition (c.208G-A, NM_012250.5) in the RRAS2 gene, resulting in an ala70-to-thr (A70T) substitution within the switch II region. The mutation, which was also identified in an 8-year-old Serbian girl (subject 5) with Noonan syndrome, was present in the gnomAD database in heterozygous state in 2 individuals (minor allele frequency, less than 0.00001). Biochemical analysis of the A70T mutant showed a significantly increased response to guanine nucleotide exchange factor (see <a href="/entry/610215">610215</a>) compared to wildtype RRAS2, whereas the GTP hydrolysis reactions of the mutant were reduced compared to wildtype protein. In addition, binding to a RRAS2 effector, RASSF5 (<a href="/entry/607020">607020</a>), was abolished by the mutation. Functional analysis in HEK293T cells showed constitutively enhanced ERK (see <a href="/entry/601795">601795</a>) phosphorylation with the A70T mutant compared to wildtype RRAS2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31130282" 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">rs1591495767 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1591495767;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=rs1591495767" 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=rs1591495767" 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=RCV000852399 OR RCV000853184 OR RCV001265738 OR RCV003117554" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000852399, RCV000853184, RCV001265738, RCV003117554" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000852399...</a>
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<p>In a 22-month-old male infant of South American and Ashkenazi ancestry (patient 6) with Noonan syndrome (NS12; <a href="/entry/618624">618624</a>), <a href="#1" class="mim-tip-reference" title="Capri, Y., Flex, E., Krumbach, O. H. F., Carpentieri, G., Cecchetti, S., Lissewski, C., Adariani, S. R., Schanze, D., Brinkmann, J., Piard, J., Pantaleoni, F., Lepri, F. R., and 21 others. <strong>Activating mutations of RRAS2 are a rare cause of Noonan syndrome.</strong> Am. J. Hum. Genet. 104: 1223-1232, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31130282/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31130282</a>] [<a href="https://doi.org/10.1016/j.ajhg.2019.04.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31130282">Capri et al. (2019)</a> identified heterozygosity for a de novo 9-bp duplication (c.70_78dup, NM_012250.5) in the RRAS2 gene, resulting in an in-frame duplication (Gly24_Gly26dup) within the phosphate-binding loop. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31130282" 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 6-year-old girl with Noonan syndrome (patient NS462), <a href="#7" class="mim-tip-reference" title="Niihori, T., Nagai, K., Fujita, A., Ohashi, H., Okamoto, N., Okada, S., Harada, A., Kihara, H., Arbogast, T., Funayama, R., Shirota, M., Nakayama, K., Abe, T., Inoue, S., Tsai, I.-C., Matsumoto, N., Davis, E. E., Katsanis, N., Aoki, Y. <strong>Germline-activating RRAS2 mutations cause Noonan syndrome.</strong> Am. J. Hum. Genet. 104: 1233-1240, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31130285/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31130285</a>] [<a href="https://doi.org/10.1016/j.ajhg.2019.04.014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31130285">Niihori et al. (2019)</a> identified heterozygosity for the c.70_78 duplication (c.70_78dup, NM_012250.6) in the RRAS2 gene, which was shown to have arisen de novo and was confirmed in hair and fingernails, consistent with a germline mutation. The authors noted that the duplication previously had been identified in a human uterine leiomyosarcoma cell line (SK-UT-1). Zebrafish larvae expressing the 9-bp duplication showed reduced body length, greater relative head length, and increased ceratohyal angle compared to wildtype larvae. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31130285" 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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Am. J. Hum. Genet. 104: 1223-1232, 2019.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31130282/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31130282</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31130282" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Chan, A. M.-L., Miki, T., Meyers, K. A., Aaronson, S. A.
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<strong>A human oncogene of the RAS superfamily unmasked by expression cDNA cloning.</strong>
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Proc. Nat. Acad. Sci. 91: 7558-7562, 1994.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8052619/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8052619</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8052619" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Drivas, G. T., Shih, A., Coutavas, E., Rush, M. G., D'Eustachio, P.
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<strong>Characterization of four novel ras-like genes expressed in a human teratocarcinoma cell line.</strong>
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Molec. Cell. Biol. 10: 1793-1798, 1990.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2108320/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2108320</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2108320" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Baltimore, Md. 1/3/2020.
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Larive, R. M., Abad, A., Cardaba, C. M., Hernandez, T., Canamero, M., de Alva, E., Santos, E., Alarcon, B., Bustelo, X. R.
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<strong>The Ras-like protein R-Ras2/TC21 is important.</strong>
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Molec. Biol. Cell 23: 2373-2387, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22535521/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22535521</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22535521" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<a id="6" class="mim-anchor"></a>
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<a id="Martinez-Riano2019" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Martinez-Riano, A., Bovolenta, E. R., Boccasavia, V. L., Ponomarenko, J., Abia, D., Oeste, C. L., Fresno, M., van Santen, H. M., Alarcon, B.
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<strong>RRAS2 shapes the TCR repertoire by setting the threshold for negative selection.</strong>
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J. Exp. Med. 216: 2427-2447, 2019.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31324740/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31324740</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31324740" 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/10.1084/jem.20181959" 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="Niihori2019" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Niihori, T., Nagai, K., Fujita, A., Ohashi, H., Okamoto, N., Okada, S., Harada, A., Kihara, H., Arbogast, T., Funayama, R., Shirota, M., Nakayama, K., Abe, T., Inoue, S., Tsai, I.-C., Matsumoto, N., Davis, E. E., Katsanis, N., Aoki, Y.
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<strong>Germline-activating RRAS2 mutations cause Noonan syndrome.</strong>
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Am. J. Hum. Genet. 104: 1233-1240, 2019.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31130285/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31130285</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31130285" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ajhg.2019.04.014" target="_blank">Full Text</a>]
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</p>
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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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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Bao Lige - updated : 04/13/2020
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</span>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<span class="mim-text-font">
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Matthew B. Gross - updated : 01/03/2020<br>Bao Lige - updated : 01/03/2020<br>Marla J. F. O'Neill - updated : 10/15/2019
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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 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 : 8/31/1994
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</span>
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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 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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mgross : 04/13/2020
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<div class="row collapse" id="mimCollapseEditHistory">
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<span class="mim-text-font">
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carol : 01/21/2020<br>mgross : 01/03/2020<br>mgross : 01/03/2020<br>alopez : 10/15/2019<br>ckniffin : 01/30/2009<br>carol : 12/6/2001<br>carol : 12/6/2001<br>alopez : 4/18/2001<br>mimadm : 9/23/1995<br>carol : 8/31/1994
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</span>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 600098
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<div>
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<h3>
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<span class="mim-font">
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RELATED RAS VIRAL ONCOGENE HOMOLOG 2; RRAS2
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</h3>
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</div>
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<div>
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<br />
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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<div>
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<h4>
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<span class="mim-font">
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ONCOGENE RRAS2<br />
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TERATOCARCINOMA ONCOGENE TC21; TC21
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</h4>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: RRAS2</em></strong>
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</span>
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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: 11p15.2
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Genomic coordinates <span class="small">(GRCh38)</span> : 11:14,277,920-14,364,506 </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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<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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<tbody>
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<td rowspan="2">
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<span class="mim-font">
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11p15.2
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<td>
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<span class="mim-font">
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Noonan syndrome 12
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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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618624
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</td>
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<span class="mim-font">
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Ovarian carcinoma
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<td>
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<span class="mim-font">
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<span class="mim-font">
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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<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>The TC21 oncogene, a member of the RAS superfamily, was initially cloned from a human teratocarcinoma cDNA library by PCR methods using degenerate oligonucleotides corresponding to the conserved region of the RAS genes (Drivas et al., 1990). Chan et al. (1994) found the same oncogene when they generated an expression cDNA library from an ovarian carcinoma (167000) line. They found, furthermore, that a single point mutation (see MOLECULAR GENETICS) was responsible for activation of transforming properties. While the cDNA clone possessed high transforming activity, the ovarian tumor genomic DNA, which contained the mutated TC21 allele, failed to induce transformed foci. Thus, expression cDNA cloning made it possible to identify and isolate a human oncogene that had evaded detection by conventional approaches. </p><p>Using X-gal staining and RT-PCR analyses, Larive et al. (2012) showed that Rras2 was expressed from early developmental stages to adulthood in mice. In adult mice, highest expression was in lung and testis, and lowest expression was in tongue, liver, skeletal muscle, and brown adipose. </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>Gross (2020) mapped the RRAS2 gene to chromosome 11p15.2 based on an alignment of the RRAS2 sequence (GenBank AF493924) with the genomic sequence (GRCh38).</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><strong><em>Noonan Syndrome 12</em></strong></p><p>
|
|
In 9 patients from 6 unrelated families with Noonan syndrome (NS12; 618624), Capri et al. (2019) identified heterozygous germline mutations in the RRAS2 gene (see, e.g., 600098.0001-600098.0003). The mutations arose de novo in the probands from 5 of the families. </p><p>In 3 of 219 individuals suspected of having Noonan syndrome (NS) or NS-related disorders, Niihori et al. (2019) identified heterozygosity for de novo mutations in the RRAS2 gene (see, e.g., 600098.0001 and 600098.0003). Functional analysis suggested that the mutations cause hyperactivation of the RAS/MAPK (see 176948) pathway. </p><p><strong><em>Somatic Mutation</em></strong></p><p>
|
|
In epithelial ovarian tumor tissue (167000), Chan et al. (1994) identified a somatic missense mutation in the TC21 gene (Q72L; 600098.0001). </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>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Using Rras2 -/- mice, Larive et al. (2012) found that Rras2 was dispensable for proper development and function of mouse organs, despite its widespread expression in wildtype mice. However, Rras2 was necessary for proper mammary gland development during the pubertal period, as full development of mammary gland was not achieved until the adult period in Rras2 -/- mice. Double- and triple-knockout experiments showed that Rras2, Hras (190020), and Nras (164790) were all important for kinetics of mammary gland development during the pubertal phase, but not for the overall developmental program of mammary gland, and that they did not act redundantly or additively. In vivo and in vitro analyses showed that Rras2 was expressed in both cap and epithelial cells of terminal end buds during pubertal development of mammary gland and was specifically involved in proliferation of mammary epithelial cells. </p><p>Martinez-Riano et al. (2019) found that Rras2 -/- mice showed a reduction in the percentage of Cd4 (186940)-positive/Cd8 (see 186910)-positive (i.e., double-positive) thymocytes compared with wildtype due to enhanced negative selection in thymocytes. Negative selection in thymocytes was due to defective Pi3k (see 601232)-Akt (164730) pathway activation, resulting in reduced T-cell receptor (TCR; see 186880) expression and resistance to autoimmune disorders, including a model of inflammatory bowel disease (IBD; see 266600) and experimental autoimmune encephalomyelitis (EAE). Analysis of the TCR repertoire in Rras2 -/- mice identified Trav4n3 and Trav4d3 (see 615442) as V-alpha variable sequences biased toward autoimmunity. </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>3 Selected Examples):</strong>
|
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</span>
|
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</h4>
|
|
<div>
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<p />
|
|
</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0001 NOONAN SYNDROME 12</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<div>
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<span class="mim-text-font">
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|
OVARIAN CANCER, SOMATIC, INCLUDED
|
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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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RRAS2, GLN72LEU
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<br />
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SNP: rs113954997,
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|
|
ClinVar: RCV000010054, RCV000852398, RCV001072115
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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 />
|
|
<p><strong><em>Noonan Syndrome 12</em></strong></p><p>
|
|
In an Indian boy (patient 4) who died at age 2 weeks with Noonan syndrome (NS12; 618624), Capri et al. (2019) identified heterozygosity for a de novo germline c.215A-T transversion (c.215A-T, NM_012250.5) in the RRAS2 gene, resulting in a gln72-to-leu (Q72L) substitution within the switch II region. The mutation was not present in general population genetic databases. Functional analysis in HEK293T cells showed constitutively enhanced ERK (see 601795) phosphorylation with the Q72L mutant compared to wildtype protein. </p><p>In a boy (patient HU1) with severe failure to thrive and features of Noonan syndrome, who died at age 3 years, Niihori et al. (2019) identified heterozygosity for the Q72L mutation (c.215A-T, NM_012250.6) in the RRAS2 gene. The mutation was shown to have arisen de novo. Functional analysis in HEK293T cells showed elevated association of RAF1 (164760) and activation of ERK1/2 (see 176948) and ELK1 (311040). Low-dose overexpression of the Q72L variant in zebrafish larvae resulted in a significantly increased ceratohyal angle compared to wildtype larvae; overexpression at higher dose caused lethal developmental impairments. Noting the severe phenotype present in patient HU1 compared to other RRAS2-mutated patients, as well as the more potent effects with the Q72L variant compared to other Noonan-associated RRAS2 variants in their in vitro and in vivo assays, the authors suggested a possible genotype/phenotype correlation. </p><p><strong><em>Somatic Mutation in Ovarian Cancer</em></strong></p><p>
|
|
Chan et al. (1994) identified a somatic gln72-to-leu (Q72L) mutation in the TC21 gene in epithelial ovarian tumor tissue (167000) and demonstrated that the mutation was associated with high transforming activity. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0002 NOONAN SYNDROME 12</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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RRAS2, ALA70THR
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<br />
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SNP: rs782457908,
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gnomAD: rs782457908,
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ClinVar: RCV000852397, RCV000853183, RCV003411705, RCV004760768
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<p>In 4 affected members over 3 generations of a German family (family 3) with Noonan syndrome (NS12; 618624), Capri et al. (2019) identified heterozygosity for a c.208G-A transition (c.208G-A, NM_012250.5) in the RRAS2 gene, resulting in an ala70-to-thr (A70T) substitution within the switch II region. The mutation, which was also identified in an 8-year-old Serbian girl (subject 5) with Noonan syndrome, was present in the gnomAD database in heterozygous state in 2 individuals (minor allele frequency, less than 0.00001). Biochemical analysis of the A70T mutant showed a significantly increased response to guanine nucleotide exchange factor (see 610215) compared to wildtype RRAS2, whereas the GTP hydrolysis reactions of the mutant were reduced compared to wildtype protein. In addition, binding to a RRAS2 effector, RASSF5 (607020), was abolished by the mutation. Functional analysis in HEK293T cells showed constitutively enhanced ERK (see 601795) phosphorylation with the A70T mutant compared to wildtype RRAS2. </p>
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<h4>
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<span class="mim-font">
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<strong>.0003 NOONAN SYNDROME 12</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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RRAS2, 9-BP DUP, NT70
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<br />
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SNP: rs1591495767,
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ClinVar: RCV000852399, RCV000853184, RCV001265738, RCV003117554
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</span>
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<p>In a 22-month-old male infant of South American and Ashkenazi ancestry (patient 6) with Noonan syndrome (NS12; 618624), Capri et al. (2019) identified heterozygosity for a de novo 9-bp duplication (c.70_78dup, NM_012250.5) in the RRAS2 gene, resulting in an in-frame duplication (Gly24_Gly26dup) within the phosphate-binding loop. </p><p>In a 6-year-old girl with Noonan syndrome (patient NS462), Niihori et al. (2019) identified heterozygosity for the c.70_78 duplication (c.70_78dup, NM_012250.6) in the RRAS2 gene, which was shown to have arisen de novo and was confirmed in hair and fingernails, consistent with a germline mutation. The authors noted that the duplication previously had been identified in a human uterine leiomyosarcoma cell line (SK-UT-1). Zebrafish larvae expressing the 9-bp duplication showed reduced body length, greater relative head length, and increased ceratohyal angle compared to wildtype larvae. </p>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<p />
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</div>
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<ol>
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<li>
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<p class="mim-text-font">
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Capri, Y., Flex, E., Krumbach, O. H. F., Carpentieri, G., Cecchetti, S., Lissewski, C., Adariani, S. R., Schanze, D., Brinkmann, J., Piard, J., Pantaleoni, F., Lepri, F. R., and 21 others.
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<strong>Activating mutations of RRAS2 are a rare cause of Noonan syndrome.</strong>
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Am. J. Hum. Genet. 104: 1223-1232, 2019.
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[PubMed: 31130282]
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[Full Text: https://doi.org/10.1016/j.ajhg.2019.04.013]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Chan, A. M.-L., Miki, T., Meyers, K. A., Aaronson, S. A.
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<strong>A human oncogene of the RAS superfamily unmasked by expression cDNA cloning.</strong>
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Proc. Nat. Acad. Sci. 91: 7558-7562, 1994.
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[PubMed: 8052619]
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[Full Text: https://doi.org/10.1073/pnas.91.16.7558]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Drivas, G. T., Shih, A., Coutavas, E., Rush, M. G., D'Eustachio, P.
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<strong>Characterization of four novel ras-like genes expressed in a human teratocarcinoma cell line.</strong>
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Molec. Cell. Biol. 10: 1793-1798, 1990.
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[PubMed: 2108320]
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[Full Text: https://doi.org/10.1128/mcb.10.4.1793-1798.1990]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Gross, M. B.
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<strong>Personal Communication.</strong>
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Baltimore, Md. 1/3/2020.
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Larive, R. M., Abad, A., Cardaba, C. M., Hernandez, T., Canamero, M., de Alva, E., Santos, E., Alarcon, B., Bustelo, X. R.
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<strong>The Ras-like protein R-Ras2/TC21 is important.</strong>
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Molec. Biol. Cell 23: 2373-2387, 2012.
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[PubMed: 22535521]
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[Full Text: https://doi.org/10.1091/mbc.E12-01-0060]
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<li>
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<p class="mim-text-font">
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Martinez-Riano, A., Bovolenta, E. R., Boccasavia, V. L., Ponomarenko, J., Abia, D., Oeste, C. L., Fresno, M., van Santen, H. M., Alarcon, B.
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<strong>RRAS2 shapes the TCR repertoire by setting the threshold for negative selection.</strong>
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J. Exp. Med. 216: 2427-2447, 2019.
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[PubMed: 31324740]
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[Full Text: https://doi.org/10.1084/jem.20181959]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Niihori, T., Nagai, K., Fujita, A., Ohashi, H., Okamoto, N., Okada, S., Harada, A., Kihara, H., Arbogast, T., Funayama, R., Shirota, M., Nakayama, K., Abe, T., Inoue, S., Tsai, I.-C., Matsumoto, N., Davis, E. E., Katsanis, N., Aoki, Y.
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<strong>Germline-activating RRAS2 mutations cause Noonan syndrome.</strong>
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Am. J. Hum. Genet. 104: 1233-1240, 2019.
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[PubMed: 31130285]
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[Full Text: https://doi.org/10.1016/j.ajhg.2019.04.014]
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</p>
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</li>
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<span class="mim-text-font">
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Bao Lige - updated : 04/13/2020<br>Matthew B. Gross - updated : 01/03/2020<br>Bao Lige - updated : 01/03/2020<br>Marla J. F. O'Neill - updated : 10/15/2019
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<span class="mim-text-font">
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Victor A. McKusick : 8/31/1994
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