Impact of variant reclassification on genetic testing yield and clinical outlook in patients with…

Cohort studyInternational journal of cardiology· Aug 2026

Impact of variant reclassification on genetic testing yield and clinical outlook in patients with hypertrophic cardiomyopathy.

Annamaria Del Franco, Valeria Setti, Federica Colio … Francesca Girolami

Clinical GeneticsCohort studyPrognosisQ1IF 2.5

22.1% of hypertrophic cardiomyopathy gene variants were reclassified on reinterpretation.

Impact of variant reclassification on genetic testing yield and clinical outlook in patients with hypertrophic cardiomyopathy.

Annamaria Del Franco … Francesca Girolami

International journal of cardiology · Aug 2026

Background

Periodic reinterpretation of variants associated with hypertrophic cardiomyopathy (hypertrophic cardiomyopathy) is recommended in the light of evolving knowledge, but it requires considerable resources, and its clinical impact is unresolved.

Purpose

We here report the results of a systematic variant reclassification of hypertrophic cardiomyopathy-associated variants identified at a national referral center, and the impact on clinical profiling.

Methods

A total of 805 consecutive probands with a definite hypertrophic cardiomyopathy diagnosis genotyped in 1998-2023 (overall 276 variants: 162 pathogenic/likely pathogenic -P/LP-, 109 variants of uncertain significance -VUS-, and 5 benign/likely benign - B/LB) underwent variant reclassification.

n = 69 patients

Results

over a fifth of variants were reclassified, mostly resolving uncertain results

More results

The overall yield of genetic testing (% with P/LP) changed from 58.7 to 55.4%.

At survival analysis, HRs associated with P/LP status improved after reclassification for both all-cause death and ventricular arrhythmia.

No changes were observed for the other outcomes.

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Conclusion · 1 of 2

Systematic reclassification of genetic variants led to a refinement of variant classification accuracy due to downgrading of 5.5% of P/LP variants, although 18.3%VUS/B/LB were upgraded to P/LP.

Conclusion · 2 of 2

Reclassification more accurately identified risks associated with P/LP status, compared to the initial adjudication.

Impact of variant reclassification on genetic testing yield and clinical outlook in patients with hypertrophic cardiomyopathy.

Impact of variant reclassification on genetic testing yield and clinical outlook in patients with hypertrophic cardiomyopathy.

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