Pathogenic variants in MYBPC3, encoding cardiac MyBP-C (myosin binding protein C), are the most common cause of familial hypertrophic cardiomyopathy (HCM). Patients with MYBPC3 and HCM variants were screened from the Sarcomeric Human Cardiomyopathy Registry (SHaRe). The variant locations and types were analyzed, morphological severity was assessed, and time-event analysis was performed (the composite clinical outcome of sudden death, class III/IV heart failure, left ventricular assist device/transplant, atrial fibrillation).

Amongst the 4756 genotyped patients with HCM in SHaRe, 1316 patients were identified with adjudicated pathogenic non truncating (191 patients, N=22 unique variants) or truncating (1047 patients, N=234 unique variants) variants in MYBPC3. Non-truncating pathogenic variants clustered in the C10, C6, and C3 domains were associated with similar hypertrophy adverse and severity event rates observed with truncating variants. The results demonstrate that phenotypic severity and clinical outcomes are similar across the range of MYBPC3 pathogenic variant carriers, without prominent associations based on the location of truncating variants, founder or non-founder truncating variant carriers, or truncating versus non truncating variants.

In conclusion, we leverage the largest cohort of patients with MYBPC3 pathogenic variants to date to develop a compendium of benign, pathogenic, and uncertain MYBPC3 variants and identify genotype-phenotype correlations.