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

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