BRAF NM_001354609.1:c.770A>G, Gln257Arg

The p.Gln257Arg variant in BRAF is an established pathogenic variant for Cardiof aciocutaneous syndrome (CFC) and is absent from large population studies. The p. Gln257Arg variant is one of the most commonly identified variants in BRAF and ha s been reported in >30 individuals with CFC syndrome (Rodriguez-Viciana 2008, Sa rkozy 2009, Neumann 2009, Abe 2012 Luk 2013, Wong Ramsey 2014, LMM unpublished d ata) and in 1 individual with LEOPARD syndrome (Carcavilla 2013). De novo occurr ences have been described for several individuals (Gripp 2007, Sarkozy 2009, Luk 2013, Neumann 2009, Niihori 2006). In addition, in vitro and in vivo functional studies support that this variant impacts protein function (Anastaski 2009, Ana stasaki 2012, Wen 2013, Inoue 2014). In summary, this variant meets our criteria to be classified as pathogenic for CFC syndrome in an autosomal dominant manner based upon de novo occurrence, absence from controls, and functional evidence.

The p.Q257R pathogenic mutation (also known as c.770A>G), located in coding exon 6 of the BRAF gene, results from an A to G substitution at nucleotide position 770. The glutamine at codon 257 is replaced by arginine, an amino acid with highly similar properties. This variant has been reported in multiple individuals with features consistent with BRAF-related RASopathy, including several de novo occurrences (Niihori T et al. Nat Genet, 2006 Mar;38:294-6; Gripp KW et al. Am J Med Genet A, 2007 Jul;143A:1472-80; Wong Ramsey KN et al. Am J Med Genet A, 2014 Aug;164A:2036-42; Joyce S et al. Eur J Hum Genet, 2016 May;24:690-6; Mucciolo M et al. Int J Mol Sci, 2016 Jun;17; Mellis R et al. BJOG, 2022 Jan;129:52-61). In an assay testing BRAF function, this variant showed a functionally abnormal result (Rodriguez-Viciana P et al. Methods Enzymol, 2008;438:277-89). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

Variant summary: The BRAF c.770A>G (p.Gln257Arg) variant involves the alteration of a conserved nucleotide, is predicted to be damaging by 3/4 in silico tools (SNPs&GO not captured due to low reliability index) and is located in acylglycerol/phorbol-ester binding domain of the protein (InterPro). This variant is absent from 118580 control chromosomes from ExAC dataset. The variant is widely accepted to be pathogenic in the literature with concordant clinical and functional data. It is frequently reported in patients with CFC including evidence of de novo occurrences. In vitro as well as in vivo functional evidences are consistent with pathogenic outcome. Several clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic.