Population and family data support TNNT2 p.Arg288Cys as an intermediate effect variant in hypertrophic cardiomyopathy

AbstractBackgroundThe TNNT2 (NM_001276345.2):c.862C>T, p.Arg288Cys variant has conflicting pathogenicity classifications. It is reported in individuals with severe hypertrophic cardiomyopathy (HCM) yet also occurs in the general population at a frequency challenging its presumed pathogenicity and creating uncertainty for genetic counseling. Therefore, the aim of this study was to evaluate its clinical relevance.MethodsWe analyzed 592 carriers, 3,096 matched non-carriers, and 641 individuals with HCM from the UK Biobank, assessing cardiac imaging, electrocardiography, and clinical data. In addition, we provide a detailed description of seven Dutch probands and their relatives.ResultsHCM prevalence was 0.5% (3/592) in carriers versus 0.1% (3/3,096) in non-carriers (p = 0.032). Carriers showed preserved cardiac structure but higher mitral and tricuspid annular plane systolic excursion, suggesting subtle functional differences. Dutch families demonstrated variable expressivity and incomplete HCM penetrance.Under TNNT2-specific ACMG/ClinGen criteria, the variant does not meet thresholds for pathogenicity because of its population frequency, limited segregation evidence, and only modest functional data. These findings highlight the challenge of applying traditional Mendelian frameworks to variants with low penetrance.ConclusionAlthough ACMG/ClinGen criteria classify TNNT2 p.Arg288Cys as likely benign, integrating population imaging, functional data, and family observations provides a more nuanced interpretation. Together, these findings support its classification as an intermediate-effect variant that modulates HCM risk in the presence of additional genetic or clinical factors.