ClinVar

Description

p.Ser408Arg (AGC>CGC): c.1222 A>C in exon 13 of the MYBPC3 gene (NM_000256.3)A variant of unknown significance has been identified in the MYBPC3 gene. The S408R variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The S408R variant was not observed in approximately 6,000 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 S408R variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Splice prediction algorithms predict that this substitution may have a damaging effect on the splice donor site. A missense mutation affecting the same residue (S408N) and a neighboring residue (G407S) have been reported in association with cardiomyopathy, supporting the functional importance of this residue and this region of the protein. However, S408N was reported in only one HCM patient with no segregation analysis, and in silico predictors were noted to be discordant for this variant (Waldmuller et al., 2011). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. Mutations in the MYBPC3 gene have been reported in 20%-30% of patients with autosomal dominant familial hypertrophic cardiomyopathy (HCM), and have been reported less frequently in patients with autosomal dominant familial dilated cardiomyopathy (DCM) (Cirino A et al., 2011; Hershberger R et al., 2009). The variant is found in HCM panel(s).