ClinVar

Description

The c.1235_1236delTT pathogenic variant in the MYBPC3 gene has previously been reported in association with HCM (also reported as del TT[10512-10513] and I411 fs/0) (Richard et al., 2003; Van Driest et al., 2004; Ehlermann et al., 2008; Berge et al., 2014; Kapplinger et al., 2014). Ehlermann et al. (2008) observed segregation of the c.1235_1236delTT variant with disease in a mother and son with HCM diagnosed at age 69 and 35, respectively. In addition, this variant is classified in ClinVar as a pathogenic variant by two other clinical laboratories (ClinVar SCV000059027.3; SCV000219019.2; Landrum et al., 2016). This variant was absent from more than 2,700 control alleles, collectively (Richard et al., 2003; Van Driest et al., 2004; Ehlermann et al., 2008; Kapplinger et al., 2014) and 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. The c.1235_1236delTT variant causes a shift in reading frame starting at codon Phenylalanine 412, changing this amino acid to a premature stop codon, denoted p.Phe412Stop. This variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Furthermore, other downstream frameshift variants in the MYBPC3 gene have been reported in HGMD in association with cardiomyopathy (Stenson P et al., 2014).