ClinVar Miner

Submissions for variant NM_004333.6(BRAF):c.1390G>A (p.Gly464Arg) (rs121913349)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Database of Curated Mutations (DoCM) RCV000429423 SCV000505052 likely pathogenic Cutaneous melanoma 2015-07-14 no assertion criteria provided literature only
GeneDx RCV000413557 SCV000490914 pathogenic not provided 2015-09-24 criteria provided, single submitter clinical testing While the nucleotide substitution c.1390 G>A in the BRAF gene has not been reported previously, another nucleotide substitution at the same position, c.1390 G>C, has been published in association with Cardio-Facio-Cutaneous (CFC) Syndrome (Cave et al., 2008). Both nucleotide changes result in a non-conservative amino acid substitution of a highly conserved neutral, non-polar Glycine with a positively charged Arginine, designated G464R. The NHLBI ESP Exome Variant Server reports G464R was not observed in approximately 6,500 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. Additionally, in silico algorithms predict that G464R is not tolerated. Although this mutation has not been reported previously to our knowledge, its presence is consistent with a diagnosis of a Noonan spectrum disorder
Invitae RCV000694211 SCV000822645 pathogenic Rasopathy 2018-11-05 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 464 of the BRAF protein (p.Gly464Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with BRAF-related syndromes  (PMID: 17704260, Invitae). ClinVar contains an entry for this variant (Variation ID: 372572). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Gly464 amino acid residue in BRAF. Another variant that disrupts this residue, p.Gly464Val, has been observed in affected individuals (PMID: 18413255, 18039235, 23907581, 19376813), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Service de Génétique Moléculaire,Hôpital Robert Debré RCV000824916 SCV000965948 likely pathogenic Cardio-facio-cutaneous syndrome no assertion criteria provided clinical testing

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