ClinVar Miner

Submissions for variant NM_004333.6(BRAF):c.1495A>G (p.Lys499Glu) (rs180177037)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000207517 SCV000057217 pathogenic not provided 2018-08-09 criteria provided, single submitter clinical testing The K499E missense variant in the BRAF gene has been reported previously in association with cardio-facio-cutaneous (CFC) syndrome (Niihori et al., 2006; Schulz et al., 2008). This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). K499E is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Functional in vitro studies demonstrate that K499E results in increased kinase activity (Rodriguez-Viciana et al., 2008). Additionally, missense variants in the same (K499N) and a nearby residue (E501K/G/V/A) have been reported in the Human Gene Mutation Database in association with cardio-facio-cutaneous syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein. Based on currently available evidence, K499E is interpreted as a pathogenic variant.
Integrated Genetics/Laboratory Corporation of America RCV000779848 SCV000916701 likely pathogenic Rasopathy 2018-04-09 criteria provided, single submitter clinical testing Variant summary: BRAF c.1495A>G (p.Lys499Glu) results in a conservative amino acid change located in the protein kinase domain (IPR000719) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 246384 control chromosomes (in gnomAD and publication data). c.1495A>G has been reported in the literature in individuals affected with Cardiofaciocutaneous Syndrome (Rodriguez-Viciana 2006, Niihori 2006, Schulz 2008). These data indicate that the variant may be associated with disease. Two publications report experimental evidence evaluating an impact on protein function, and both of them demonstrated an increased kinase activity for the variant protein (Rodriguez-Viciana 2006, Niihori 2006). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Molecular Diagnostics Lab,Nemours Alfred I. duPont Hospital for Children RCV000207517 SCV000263063 likely pathogenic not provided 2015-07-23 criteria provided, single submitter clinical testing
OMIM RCV000015010 SCV000035266 pathogenic Cardiofaciocutaneous syndrome 1 2006-03-01 no assertion criteria provided literature only

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