Reclassification of genetic variants in patients with hypertrophic cardiomyopathy from the Sarcomeric Human Cardiomyopathy Registry (SHaRe)

Variant classification evolves with publicly available case data, improved classification rules and reassessment of gene-disease validity, exposing reports to changes of class over time.

Genetic testing is a Class I recommendation in hypertrophic cardiomyopathy, but variant classifications may change as case data, classification rules and gene-disease validity evolve. The authors reevaluated variants from the international multicentre SHaRe registry: of 12,187 patients, 8,054 (66%) had undergone genetic testing between 1989 and 2020 and 4,923 of them (61%) carried a variant in one of 29 hypertrophic cardiomyopathy genes, amounting to 1,606 unique variants, all computationally reannotated and then curated either in expedited form (704 variants, 44%) or by full manual curation (902, 56%). In total, 1,275 variants (79%) retained their classification — 146 benign or likely benign, 660 VUS, 468 pathogenic or likely pathogenic — and 276 (17%, involving 672 patients) were reclassified: 73 upgrades, including 61 from VUS to pathogenic or likely pathogenic (199 patients) and 12 from benign to VUS, against 203 downgrades, including 108 from pathogenic or likely pathogenic to VUS (196 patients) and 95 to benign or likely benign. Subclassification of VUS into VUS-High (90), VUS-Mid (129) and VUS-Low (115) placed 369 variants (40.6%) in the VUS-Low or benign categories, with a very strong probability of not being disease associated. The authors conclude that clinically meaningful reclassification affects 10% of variants identified in probands and that periodic reevaluation is essential.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The figure to remember is not the upgrades but the downgrades: 108 variants moved from pathogenic or likely pathogenic to VUS, affecting 196 patients whose result had served as the basis for cascade family screening and surveillance decisions. This turns periodic reevaluation into an organisational obligation, with the question — not addressed here — of who recontacts families and how often. VUS subclassification is practically useful but remains a probability scale specific to the authors rather than an enforceable standard, and the work has not yet been peer reviewed.

Analysis by Dr Thibaut Benquey