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

Authors

Annamaria Del Franco, Valeria Setti, Federica Colio, Carlotta Mazzoni, Giacomo Bonacchi, Giulia Biagioni, Francesca Bonanni, Sara Giovani, Eleonora Insinna, Adelaide Ballerini, Alessia Gozzini, Mattia Zampieri, Maurizio Pieroni, Francesco Cappelli, Iacopo Olivotto, Francesca Girolami

Published in

International journal of cardiology. Pages 134718. Aug 09, 2026. Epub Aug 09, 2026.

Abstract

Periodic reinterpretation of variants associated with hypertrophic cardiomyopathy (HCM) is recommended in the light of evolving knowledge, but it requires considerable resources, and its clinical impact is unresolved.
We here report the results of a systematic variant reclassification of HCM-associated variants identified at a national referral center, and the impact on clinical profiling.
A total of 805 consecutive probands with a definite HCM 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. All were analyzed for all-cause death, ventricular arrhythmia composite (sudden death, cardiac arrest, appropriate implantable cardioverter-defibrillator therapy), atrial fibrillation or cerebrovascular events, heart failure composite (NYHA class III/IV, left ventricular ejection fraction <35%, cardiac transplantation).
After a median follow-up of 8.8 [6.1-11.8] years, among the 276 variants, 61 (22.1%) were reclassified: 29 variants from P/LP to VUS or B/LB, 21 from VUS to P/LP, and 11 from VUS to B/LB, affecting 69 patients overall. 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.
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. Reclassification more accurately identified risks associated with P/LP status, compared to the initial adjudication.

PMID:
42571822
Bibliographic data and abstract were imported from PubMed on 10 Aug 2026.

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