Gene-Tiered Interpretation of Sarcomere VUS Refines Risk Stratification in Hypertrophic Cardiomyopathy

The clinical significance of sarcomere variants of uncertain significance (VUS) in hypertrophic cardiomyopathy (HCM) remains unclear. Despite their increasing prevalence, VUS are often regarded as clinically nonactionable.

The authors evaluated genotype-phenotype and genotype-outcome associations by variant pathogenicity, focusing on gene-tiered sarcomere VUS in an Asian HCM cohort.

We retrospectively analyzed 438 Korean patients with HCM undergoing targeted genetic testing. Patients were categorized by sarcomere variant status: no sarcomere variant, VUS in genes with limited evidence (nondef9), VUS in genes with definitive HCM evidence (def9), and pathogenic or likely pathogenic (P/LP) in the sarcomere panel. We compared clinical and imaging phenotypes, and a composite endpoint of major adverse cardiovascular events, using Firth-penalized Cox models.

P/LP variants were identified in 163 of 438 patients (37.2%), and def9 and nondef9 VUS in 83 (18.9%) and 85 (19.4%) patients, respectively. def9 VUS carriers exhibited intermediate phenotypic and prognostic features between P/LP and genotype-negative patients, whereas nondef9 VUS carriers clinically resembled genotype-negative HCM. During a median follow-up of 6.4 years (IQR: 2.7-10.7 years), the primary endpoint occurred in 29 of 438 patients (6.6%). Modeled as an ordinal variable across these 4 groups, the classification showed a stepwise increase in risk of the primary endpoint (HR: 1.62; 95% CI: 1.08-2.63; P = 0.019), which was unchanged after adjustment for family history of HCM and maximum left ventricular wall thickness.

Sarcomere VUS do not represent a homogeneous category. Gene-tier stratification may refine variant interpretation and clinical management in HCM, particularly in populations under-represented in current variant databases.