ClinVar

Description

The T241M pathogenic variant in the BRAF gene has been reported as de novo in an individual with a clinical diagnosis of Noonan syndrome (Sarkozy et al., 2009). Additionally, it has been confirmed de novo in a patient with features of a RASopathy at GeneDx. Other missense variants at the same codon (T241R and T241P) have been reported in association with Noonan syndrome and NSML/Costello syndrome, respectively (Sarkozy et al., 2009; Nava et al., 2007), and missense variants in nearby residues (T244P, L245F, A246P) have been reported in the Human Gene Mutation Database in association with cardio-facio-cutaneous syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein. The T241M variant 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 T241M variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function.