Description of a Cohort with a New Truncating MYBPC3 Variant for Hypertrophic Cardiomyopathy in Northern Spain

The pathogenicity of the different genetic variants causing hypertrophic cardiomyopathy (HCM) and the genotype/phenotype correlations are difficult to assess in clinical practice, as most mutations are unique or identified in non-informative families. Pathogenic variants in the sarcomeric gene inherited with an autosomal dominant pattern, whereas incomplete and age-dependent penetrance are the most common causes of HCM. We describe the clinical characteristics of a new truncating variant, p.Val931Glyfs*120, in 75 subjects from 18 different families from northern Spain with the p.Val931Glyfs*120 variant. Our cohort allows us to estimate the penetrance and prognosis of this variant. The penetrance of the disease increases with age, whereas 50% of males in our sample developed HCM by the age of 36 years old, and 50% of women developed the disease by the time they reached 48 years of age ( = 0.104). Men have more documented arrhythmias with potential risk of sudden death ( = 0.018), requiring implantation of cardioverter defibrillators ( = 0.024). Semi-professional/competitive sport among males is related to earlier onset of HCM ( = 0.004). The p.Val931Glyfs*120 truncating variant in is associated with a moderate phenotype of HCM, with a high penetrance, onset in middle age, and a worse outcome in males due to higher risk of sudden death due to arrhythmias.