Submissions for variant NM_004333.6(BRAF):c.1391G>A (p.Gly464Glu)

dbSNP: rs121913348

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen RASopathy Variant Curation Expert Panel	RCV000033304	SCV001335316	pathogenic	RASopathy	2020-03-09	reviewed by expert panel	curation	The c.1391G>A (p.Gly464Glu) variant in BRAF has been observed in 2 probands with phenotypes consistent with cardiofaciocutaneous syndrome (PS4_Supporting; LMM internal data, SCV000197160.4; GeneDx internal data, SCV000057209.13). One of these cases was de novo with maternity and paternity confirmed, while the other was de novo without confirmation of maternity or paternity (PS2, PM6). The p.Gly464Glu variant was absent from large population studies (PM2; gnomad.broadinstitute.org). In vitro functional assays indicate that this variant may impact protein function (PS3; PMID: 25155755). It occurs in the P-loop domain of the protein, which has been identified as an important region for protein function (PM1; 29493581). Computational prediction tools and conservation analyses also suggest that this variant may impact the protein (PP3). 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 variants are common (PP2; PMID: 29493581). Of note, this variant has also been observed in association with somatic malignancies; however, analysis and classification of somatic variation is currently not used to inform germline classifications for the RASopathies. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant RASopathy. RASopathy-specific ACMG/AMP criteria applied: PS2, PS3, PS4_Supporting, PM1, PM2, PM6, PP2, PP3.
GeneDx	RCV000207512	SCV000057209	pathogenic	not provided	2015-10-30	criteria provided, single submitter	clinical testing	The G464E missense mutation has not been reported as a mutation, but neither has it been published as a benign polymorphism. The position at which this mutation occurs is highly conserved across species and other missense mutations at this position (G464V, G464R) have been previously reported in the literature (Rodriguez-Viciana et al., 2008, Cave et al., 2008).
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000844618	SCV000197160	likely pathogenic	Noonan syndrome; Cardio-facio-cutaneous syndrome	2018-02-15	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
Molecular Diagnostics Lab, Nemours Children's Health, Delaware	RCV000207512	SCV000263062	likely pathogenic	not provided	2015-07-23	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000033304	SCV000943342	pathogenic	RASopathy	2021-04-09	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly464 amino acid residue in BRAF. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18413255, 18039235, 21062266, 19376813, 23680146). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. This variant has been observed in individual(s) with clinical features of Noonan syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 13964). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with glutamic acid at codon 464 of the BRAF protein (p.Gly464Glu). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and glutamic acid.
OMIM	RCV000014997	SCV000035253	pathogenic	Carcinoma of colon	2003-08-15	no assertion criteria provided	literature only
Service de Génétique Moléculaire, Hôpital Robert Debré	RCV001261044	SCV001438445	uncertain significance	Cardio-facio-cutaneous syndrome		no assertion criteria provided	clinical testing