Abstract
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.