ClinVar Genomic variation as it relates to human health

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.

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).

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. 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. For these reasons, this variant has been classified as Pathogenic.

proposed classification - variant undergoing re-assessment, contact laboratory