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

Background: 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. Objectives: 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. Methods: 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). Results: 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. Conclusion: 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.