ClinVar Genomic variation as it relates to human health

The c.1454T>C (p.Leu485Ser) variant in BRAF is absent from gnomAD (PM2). It has been identified in at least 4 patients clinically diagnosed with Cardiofaciocutaneous syndrome (CFC) (PS4_Moderate; 18039235, 21871821, 20395089, SCV000197150.4). 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). Additionally, computational prediction tools and conservation analysis suggest that p.Leu485Ser may affect the protein (PP3). Two different pathogenic missense variants have been previously identified at this codon of BRAF, each resulting in p.Leu485Phe, which supports that this residue may be critical to the function of the protein (PM5; ClinVar 177844, 13975). A functional assay has been performed on this variant, but given that it is not currently an approved assay outlined by the RASopathy VCEP, it has not been assessed for PS3 at this time (PMID:16474404). In summary, this variant meets criteria to be classified as likely pathogenic for RASopathies in an autosomal dominant manner. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PM2, PS4_Moderate, PP2, PP3, PM5.

The Leu485Ser variant in BRAF has been reported in 3 individuals with Cardio-fac io-cutaneous syndrome. All of these individuals had severe seizure disorders (Yo on 2007, Aizaki 2011, Adachi, 2012). It was absent from large population studies . In addition, another variant (Leu485Phe) at this position was identified in > 5 individuals with a RASopathy suggesting that changes at this position are not tolerated. Computational prediction tools and conservation analysis suggest that the Leu485Ser variant may impact the protein, though this information is not pr edictive enough to determine pathogenicity. In summary, although additional stud ies are required to fully establish its clinical significance, the Leu485Ser var iant is likely pathogenic.

Variant summary: BRAF c.1454T>C (p.Leu485Ser) results in a non-conservative amino acid change located in the catalytic domain (IPR001245) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251326 control chromosomes (gnomAD). c.1454T>C has been reported in the literature in individuals affected with Cardio-facio-cutaneous syndrome (Yoon_2007, Aizaki_2011, Adachi_2012); of note, all of these reported individuals had severe seizure disorders. These data indicate that the variant may be associated with disease. Other missense variants affecting this residue (Leu485Phe, Leu485del) has been reported in patients (HGMD and PMID: 30842599), supporting the functional importance of this amino acid. Publications reported experimental evidence and demonstrated that the variant altered gene expression signatures similar to KRAS activation (Berger_2016), and also modified the synaptic signal transduction cascade (Lim_2017). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 16474404, 18039235, 21871821, 18413255, 24803665, 20395089)