ClinVar

Description

p.Cys1264Phe (TGT>TTT): c.3791 G>T in exon 33 of the MYBPC3 gene (NM_000256.3). A published missense variant that is likely pathogenic was identified in the MYBPC3 gene. The C1264F variant in the MYBPC3 gene has been reported previously in association with familial dilated cardiomyopathy (DCM) (Hershberger R et al, 2010). Hershberger et al. (2010) identified C1264F in two related individuals with cardiomyopathy, which was absent in 246 control samples, and classified this variant as likely disease-causing. Additionally, the C1264F variant was not observed in approximately 6,200 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Furthermore, C1264F results in 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. Mutations in surrounding residues (E1265V, C1266R, E1266Y) have been reported in association with cardiomyopathy, further supporting the functional importance of this region of the protein. Nevertheless, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, this variant is a strong candidate for a pathogenic mutation, however the possibility that it is a benign variant cannot be excluded. Mutations in the MYBPC3 gene have been reported in 20%-30% of patients with autosomal dominant familial hypertrophic cardiomyopathy, and have been reported less frequently in patients with autosomal dominant familial dilated cardiomyopathy (CirinoA et al., 2011; Hershberger R et al., 2009). The variant is found in HCM panel(s).