JACC. Asia
September 18, 2026 · via Europe PMC
Gene-Tiered Interpretation of Sarcomere VUS Refines Risk Stratification in Hypertrophic Cardiomyopathy.
Choi HM, Seo SH, Hwang IC, +11 more, Kim HK
AI summary — for doctors, generated from the abstract only
In a Korean cohort of patients with hypertrophic cardiomyopathy, genetic variants of uncertain significance in genes with strong prior evidence for causing the disease were associated with intermediate disease severity and outcomes between clearly pathogenic variants and no variant at all, suggesting that how genes are classified could improve risk prediction even for uncertain genetic findings.
What was studied
A retrospective study of 438 Korean patients with hypertrophic cardiomyopathy (HCM) who underwent targeted genetic testing, categorizing patients by sarcomere variant status (no variant, variant of uncertain significance in genes with limited evidence for HCM, variant of uncertain significance in genes with definitive HCM evidence, or pathogenic/likely pathogenic variant), and comparing clinical/imaging phenotypes and a composite major adverse cardiovascular event endpoint across these groups using statistical modeling.
Key findings
- Pathogenic or likely pathogenic variants were identified in 163 of 438 patients (37.2%), while variants of uncertain significance in genes with definitive HCM evidence and in genes with limited evidence were found in 83 (18.9%) and 85 (19.4%) patients, respectively.
- Patients with uncertain-significance variants in genes with definitive HCM evidence showed intermediate phenotypic and prognostic features between those with clearly pathogenic variants and those with no variant at all, while those with uncertain variants in less-established genes resembled genotype-negative patients clinically.
- Over a median follow-up of 6.4 years, the primary composite endpoint occurred in 29 of 438 patients (6.6%); modeling the four-group classification as an ordinal variable showed a stepwise increase in risk (hazard ratio 1.62, 95% CI 1.08-2.63, p=0.019), which remained significant after adjusting for family history and maximum wall thickness.
Clinical relevance
These findings suggest that not all 'variants of uncertain significance' in hypertrophic cardiomyopathy carry the same clinical risk, and that classifying such variants by the strength of evidence linking their specific gene to the disease (gene-tiering) can meaningfully refine risk stratification, which could improve clinical management and genetic counseling, particularly for Asian populations underrepresented in current genetic variant databases.
Who should care
Limitations
This is a retrospective, single-country (Korean) cohort study, which may limit generalizability to other populations; the relatively small number of primary endpoint events (29 total) across four subgroups limits statistical precision for some comparisons.
Not all 'uncertain' genetic findings in hypertrophic cardiomyopathy carry the same risk; those in genes already strongly linked to the disease predicted intermediate outcomes between clearly disease-causing and no genetic findings at all, which could help refine how doctors interpret ambiguous genetic test results.
This is an AI-generated summary of the published abstract, not a clinical recommendation. It may not reflect the full text or subsequent updates — verify against the original source before acting on it.
Abstract
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.
DOI
10.1016/j.jacasi.2026.08.015
PMID
42799725
Research metadata (titles, abstracts, authors, publication dates) is sourced from Europe PMC, which aggregates content from PubMed/MEDLINE, PubMed Central, and other providers under the U.S. National Library of Medicine (NLM/NCBI). NLM does not claim copyright on abstracts; the original journal publishers or authors may hold rights to the full articles. AI-generated summaries are derived only from the abstract, never the full text, and are always labeled as AI-generated.
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