Reclassification of Genetic Variants in Patients with Hypertrophic Cardiomyopathy from the Sarcomeric Human Cardiomyopathy Registry (SHaRe)

Abstract

BackgroundGenetic testing is a Class I recommendation for patients with hypertrophic cardiomyopathy (HCM). Variant classification relies on evidence from publicly available case data, evolving classification rules, and gene-disease associations. Thus, as knowledge increases, genetic variant classifications change over time. We evaluated the occurrence and reasons for variant reclassification from a large multi-center international HCM registry (Sarcomeric Human Cardiomyopathy Registry; SHaRe), with the goal to minimize uncertainty for patients and clinicians. MethodsParticipants receive clinical care at specialized HCM centres. Baseline classifications were derived from the clinical genetic test report (original or updated) or prior further adjudication by SHaRe geneticists. All variants were then computationally reannotated and reevaluated during 2024-2025. Variants underwent expedited curation if no new evidence was present. The remainder underwent full manual curation using accepted criteria and classified as pathogenic/likely pathogenic (P/LP), variant of uncertain significance (VUS) and benign/likely benign (B/LB). VUS were sub-classified to high, mid or low. ResultsOf 12,187 HCM patients, 8,054 (66%) had genetic testing between 1990-2024, and 4,923 (61%) had a variant identified in one of 29 ClinGen-validated HCM genes (1606 unique variants). Expedited curation was performed for 704 (44%) variants and 902 (56%) underwent manual curation. There were 1279 (79%) variants that retained their classification: 148 B/LB, 663 VUS, and 468 P/LP. While 276 (17%) variants (n=557 patients) were reclassified, including 73 upgrades: 61 from VUS to P/LP (199 patients), and 12 from B/LB to VUS. There were 203 downgrades: 108 from P/LP to VUS (196 patients), and 95 from P/LP or VUS to B/LB. VUS were additionally subclassified: 90 VUS-High, 129 VUS-Mid, 115 VUS-Low. Sub-classification of VUS resulted in less uncertainty, with 369 (40.6%) variants reclassified as VUS-Low or B/LB, indicating a very strong probability of not being HCM associated. ConclusionsClinically meaningful reclassification occurred in 10% of variants identified in HCM probands. Most VUS were unlikely to be causal, and sub-classification has potential to reduce their burden on clinicians and families. Contemporary approaches to classification can minimize uncertainty of genetic results and highlight the need for periodic reevaluation.