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

Talitha C F Spanjersberg1, Fahima Hassanzada2, Jan D H Jongbloed3

  • 1Division Heart & Lungs, Department of Cardiology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.

International Journal of Cardiology
|March 4, 2026
PubMed

Insights

The TNNT2 p.Arg288Cys variant, associated with hypertrophic cardiomyopathy (HCM), shows conflicting classifications. This study suggests it is an intermediate-effect variant modulating HCM risk, not a definitively pathogenic one.

Area of Science:

  • Cardiovascular Genetics
  • Genetic Variant Interpretation
  • Population Genomics

Background:

  • Conflicting classifications exist for the TNNT2 p.Arg288Cys variant, reported in hypertrophic cardiomyopathy (HCM) cases but also found in the general population.
  • This frequency discrepancy creates uncertainty for genetic counseling regarding its clinical relevance.

Purpose of the Study:

  • To evaluate the clinical relevance and pathogenicity of the TNNT2 p.Arg288Cys variant.
  • To clarify the variant's role in hypertrophic cardiomyopathy (HCM) risk.

Main Methods:

  • Analysis of 592 carriers and 3096 non-carriers from UK Biobank, including cardiac imaging, ECG, and clinical data.
  • Assessment of seven Dutch families with detailed proband and relative data.
  • Application of ACMG/ClinGen criteria for variant pathogenicity assessment.

Main Results:

  • HCM prevalence was slightly higher in carriers (0.5%) versus non-carriers (0.1%) (p=0.032).
  • Carriers exhibited preserved cardiac structure but enhanced systolic excursion, indicating subtle functional impacts.
  • Dutch families showed incomplete penetrance and variable expressivity of HCM.
  • Under ACMG/ClinGen criteria, the variant did not meet pathogenicity thresholds due to population frequency and limited evidence.

Conclusions:

  • The TNNT2 p.Arg288Cys variant does not meet criteria for pathogenicity, despite its association with HCM.
  • Integrating population data, functional evidence, and family studies suggests an intermediate effect on HCM risk.
  • This variant may modulate HCM risk in conjunction with other genetic or clinical factors, highlighting challenges in applying traditional Mendelian frameworks to low-penetrance variants.
Abstract

Keywords:
Hypertrophic cardiomyopathyPopulation geneticsTNNT2

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