ClinVar

In 115 members of 3 families with hypertrophic cardiomyopathy (CMH4; 115197), Niimura et al. (1998) identified a 1-bp insertion in codon 791 (791insG, or 2405insG) in exon 25 of the MYBPC3 gene. Of mutation-positive individuals who underwent examination, only 1 of 19 less than 20 years of age had cardiac hypertrophy, whereas 44 of 72 mutation-positive individuals 20 years old or older had cardiac hypertrophy.

Moolman et al. (2000) reported a large family segregating CMH4 caused by a single base insertion (G) in exon 25 of the MYBPC3 gene. This created a 5-prime splice donor site (AGGTGGG). Moolman et al. (2000) demonstrated that this mutation resulted in the loss of 40 basepairs at the 3-prime end of exon 25 in mRNA extracted from affected myocardium. This in turn led to a premature translation stop and a truncated protein in which the C-terminal binding sites for myosin heavy chain and titin were lost. This study also examined the phenotypic consequences of this mutation in 27 carriers within the same family. Overall, only 15 (56%) showed features of hypertrophic cardiomyopathy. Age of onset of symptoms varied from 29 to 68, with most individuals developing their first symptoms from the fourth decade onwards. The Kaplan-Meier survival curve for this group was similar to that of carriers of the asp175-to-asn tropomyosin-1 mutation (191010.0002) and significantly better than that of carriers of cardiac troponin T2 (191045) or cardiac beta-myosin heavy chain (160760) mutations. Twelve mutation carriers were entirely asymptomatic and had no changes on echocardiography or ECG at the time of the study. This mutation was therefore considered to have considerably reduced penetrance and delayed onset.