Gene-specific reclassification patterns of variants in hypertrophic cardiomyopathy

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Abstract
Genetic variant interpretation in hypertrophic cardiomyopathy (HCM) evolves as population reference datasets expand, gene–disease validity assessments examine new candidate genes and additional functional and segregation evidence accumulates. Periodic re-interpretation is, therefore, necessary. Likely pathogenic/pathogenic (LP/P) variants and variants of unknown significance (VUS) were re-evaluated in 2154 HCM index cases using the ACMG/AMP framework. Gene selection was based on ClinGen gene-disease validity assessments. Overall, 12.8% of 1355 variants in HCM genes were reclassified, with 7.5% resulting in clinically meaningful impact (3.5% upgrading from VUS to LP/P and 4% downgrading from LP/P to VUS). Variant reclassification affected the genetic status of 86 individuals (4.0%), including loss of LP/P status in 47 (2.2%) and new gene-positive diagnoses in 39 (1.8%). Of 536 unique variants, 19 (3.5%) were upgraded from VUS to LP/P, 44 (8.2%) were downgraded from LP/P to VUS and 287 (53.5%) maintained LP/P status. Variants in MYBPC3 and MYH7 largely retained pathogenic classification (92.0% and 83.2% unchanged). TNNT2 showed the highest proportion of VUS upgrades (28.6%) alongside high retention of pathogenic variants. The largest LP/P to VUS shifts were noted in ACTC1 (50.0%), MYL3 (42.9%), TPM1 (42.9%) and TNNI3 (20.0%). In this large HCM cohort, variant re-evaluation resulted in a modest but clinically relevant reclassification of genetic variants. MYBPC3 and MYH7 classifications were largely unaltered, showing limited net change. Upgrades in TNNT2 variants, the third most frequent gene in this cohort, are consistent with consolidation of locus-specific evidence and are important given their association with adverse outcomes, despite modest hypertrophy.

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