Carriage of TNNT2 p.Arg288Cys variant was associated with a low prevalence of HCM (0.5% vs 0.1% in non-carriers, p=0.032) and an estimated cumulative HCM penetrance of 0.82% by age 80, indicating an intermediate effect variant with subtle functional cardiac alterations but incomplete penetrance.
Observational (n=592)
Yes
Does the TNNT2 p.Arg288Cys variant increase the risk of hypertrophic cardiomyopathy and alter cardiac structure or function in the general population?
The TNNT2 p.Arg288Cys variant acts as an intermediate-effect variant with low penetrance for overt HCM but is associated with subtle functional contractile differences in the general population.
Effect estimate: OR 5 (approximate from prevalence difference but exact OR not provided)
Absolute Event Rate: 0.5% vs 0.1%
p-value: p=0.032 (not significant after multiple testing correction: adjusted p=0.413)
AbstractBackground The TNNT2 (NM₀01276345. 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. Methods We analyzed 592 carriers, 3096 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. Results HCM prevalence was 0. 5% (3/592) in carriers versus 0. 1% (3/3096) 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. Conclusion Although 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.
Spanjersberg et al. (2026) conducted an observational in Adults carrying the TNNT2 p.Arg288Cys variant from the UK Biobank population (n=592). Carriage of TNNT2 p.Arg288Cys genetic variant vs. Non-carrier controls without TNNT2 p.Arg288Cys variant or other pathogenic cardiomyopathy variants was evaluated on Prevalence and penetrance of hypertrophic cardiomyopathy (HCM) diagnosis (OR 5 (approximate from prevalence difference but exact OR not provided), p=0.032 (not significant after multiple testing correction: adjusted p=0.413)). Carriage of TNNT2 p.Arg288Cys variant was associated with a low prevalence of HCM (0.5% vs 0.1% in non-carriers, p=0.032) and an estimated cumulative HCM penetrance of 0.82% by age 80, indicating an intermediate effect variant with subtle functional cardiac alterations but incomplete penetrance.