Submissions for variant NM_004333.6(BRAF):c.1787G>T (p.Gly596Val)

dbSNP: rs397507483

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen RASopathy Variant Curation Expert Panel	RCV000033332	SCV000616388	pathogenic	RASopathy	2017-04-03	reviewed by expert panel	curation	The c.1787G>T (p.Gly596Val) variant in BRAF has been reported in the literature in at least 2 unconfirmed de novo occurrences in patients with clinical features of a RASopathy (PM6_Strong; PMID 16439621, 25463315, Partners LMM and GeneDx internal data; GTR ID's: 21766, 26957; ClinVar SCV000197137, SCV000057237). In vitro functional studies provide some evidence that the p.Gly596Val variant may impact protein function (PS3; PMID 18413255). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is located in the BRAF gene, 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). Computational prediction tools and conservation analysis suggest that the p.Gly596Val variant may impact the protein (PP3). 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). 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): PM6_Strong, PS3, PM2, PP2, PP3, PM1.
GeneDx	RCV000077865	SCV000057237	pathogenic	not provided	2013-05-22	criteria provided, single submitter	clinical testing	p.Gly596Val (GGT>GTT): c.1787 G>T in exon 15 of the BRAF gene (NM_004333.4). The G596V mutation in the BRAF gene has been previously reported in at least 4 unrelated patients with Cardio-Facio-Cutaneous syndrome (Rodriguez-Viciana et al., 2006). This mutation falls within the activation loop located within the third conserved region of the BRAF protein. The G596V mutation was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The variant is found in NOONAN panel(s).
Eurofins Ntd Llc (ga)	RCV000077865	SCV000058306	pathogenic	not provided	2013-03-18	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000844615	SCV000197137	pathogenic	Noonan syndrome; Cardio-facio-cutaneous syndrome	2014-09-10	criteria provided, single submitter	clinical testing	The Gly596Val variant has been identified in 7 individuals with clinical feature s of Cardio-facio-cutaneous syndrome (CFC) and 3 individuals with clinical featu res of Noonan syndrome (Rodriguez-Viciana 2006, Yoon 2007, Rodriguez-Viciana 200 8, LMM unpublished data). It was absent from large population studies. In-vitro functional studies provide some evidence that the Gly596Val variant may impact p rotein function (Rodrigues-Viciana 2006). Furthermore, animal models in zebrafis h have shown that this variant causes severe developmental abnormalities (Anasta saki 2009). In summary, this variant meets our criteria to be classified as path ogenic (http://personalizedmedicine.partners.org/Laboratory-For-Molecular-Medici ne/).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000033332	SCV000936651	pathogenic	RASopathy	2022-07-01	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 596 of the BRAF protein (p.Gly596Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with cardio-facio-cutaneous syndrome (PMID: 16439621, 25463315). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 40387). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt BRAF protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on BRAF function (PMID: 16439621, 18413255, 19376813).
Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn	RCV000856749	SCV000999297	pathogenic	Cardiofaciocutaneous syndrome 1		criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000856749	SCV001369351	pathogenic	Cardiofaciocutaneous syndrome 1	2019-08-20	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PM1,PM2,PM6_Strong,PP2,PP3,PP4.
Ambry Genetics	RCV001265809	SCV001443981	likely pathogenic	Inborn genetic diseases	2018-01-10	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000856749	SCV005086841	pathogenic	Cardiofaciocutaneous syndrome 1	2023-07-16	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with cardiofaciocutaneous syndrome (MIM#115150), LEOPARD syndrome (MIM#3613707) and Noonan syndrome (MIM#7613706). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to valine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The germline variant has been reported multiple times as likely pathogenic and pathogenic in individuals with RASopathies, including Noonan syndrome (NS) and cardiofaciocutaneous (CFC) syndrome (ClinVar, PMID: 33040082). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) in a research setting (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Baylor Genetics	RCV000033332	SCV000196671	pathogenic	RASopathy		no assertion criteria provided	clinical testing	Variant classified using ACMG guidelines
GeneReviews	RCV000208758	SCV000264635	not provided	Cardio-facio-cutaneous syndrome		no assertion provided	literature only
GenomeConnect - CFC International	RCV000844615	SCV001156342	not provided	Noonan syndrome; Cardio-facio-cutaneous syndrome		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 12-03-2010 by Lab or GTR ID 21766. GenomeConnect-CFC International assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant.