ClinVar Miner

Submissions for variant NM_004333.6(BRAF):c.1799T>G (p.Val600Gly) (rs113488022)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen RASopathy Variant Curation Expert Panel RCV000798913 SCV001424737 pathogenic Rasopathy 2020-06-25 reviewed by expert panel curation The c.1799T>G (p.Val600Gly) variant in BRAF is absent from gnomAD (PM2). It has been identified in one individual with Cardiofaciocutaneous syndrome (PS4_Supporting; PMID: 20735442). It has also been reported in the literature as an unconfirmed de novo occurrence (PM6; GeneDx internal communication). In vitro functional studies provide some evidence that the p.Val600Gly variant may impact protein function (PS3; PMID: 20735442). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of BRAF (PM1; PMID 29493581). Computational prediction tools and conservation analysis suggest that the p.Val600Gly variant may impact the protein (PP3). Finally, the variant is located in BRAF, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS3, PM1, PM2, PM6, PS4_Supporting, PP3, PP2.
Invitae RCV000798913 SCV000938556 uncertain significance Rasopathy 2018-10-19 criteria provided, single submitter clinical testing This sequence change replaces valine with glycine at codon 600 of the BRAF protein (p.Val600Gly). The valine residue is highly conserved and there is a moderate physicochemical difference between valine and glycine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in an individual affected with cardio-facio-cutaneous syndrome (PMID: 20735442). ClinVar contains an entry for this variant (Variation ID: 40389). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneReviews RCV000208774 SCV000264637 pathogenic Cardio-facio-cutaneous syndrome 2016-03-03 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000433794 SCV000504247 pathogenic Cutaneous melanoma 2014-10-02 no assertion criteria provided literature only

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