Gene-specific reclassification patterns of variants in hypertrophic cardiomyopathy

Background

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, particularly in patient cohorts in which variants were originally classified before the establishment of a widely accepted set of pathogenicity criteria.

Methods

All reported pathogenic/likely pathogenic (LP/P) variants and variants of unknown significance (VUS) were re-evaluated in 2,154 adults with HCM. Analyses were restricted to genes with definitive, strong or moderate evidence for non-syndromic HCM according to ClinGen curation. Variant re-interpretation applied contemporary ACMG/AMP criteria with gene- and disease-specific ClinGen specifications. Re-classification was assessed at variant, unique-variant, gene and patient levels.

Purpose

The aim of this study was to assess the impact of contemporary ACMG/AMP criteria and ClinGen gene–disease validity frameworks on variant interpretation in a large HCM cohort.

Results

Overall, 12.8% of 1,356 variants in HCM genes were reclassified with 7.5% resulting in a significant clinical impact (3.5% upgrades from VUS to LP/P and 4% downgrades vice versa). Overall, variant re-classification affected the genetic status of 4.0% of individuals, including loss of LP/P status in 48 (2.2%) and new gene-positive diagnoses in 39 (1.8%).

Of 545 unique variants, 20 (3.7%) were upgraded from VUS to LP/P and 45 (8.3%) were downgraded from LP/P to VUS, while 294 (53.9%) retained LP/P status. Re-classification showed gene-dependent patterns. Variants in the predominant sarcomeric genes MYBPC3 and MYH7 largely maintained pathogenic classification, (93.4% and 82.2% stable, respectively). TNNT2 (5/28), CSRP3 (1/6) and JPH2 (1/6) displayed upgrades in approximately one-fifth of variants. The largest downward shifts were observed in MYL3 (3/12, 25.0%), TPM1 (3/14, 21.4%), and TNNI3 (4/25, 16.0%).

Conclusions

In this large HCM cohort, variant re-interpretation resulted in modest but clinically relevant diagnostic shifts. MYBPC3 and MYH7 classifications were largely unchanged. Upgrades in TNNT2 variants, the third more frequent gene in this cohort, are consistent with consolidation of locus-specific evidence and are important given its association with adverse outcomes, including sudden cardiac death and heart failure despite modest hypertrophy.Gene-specific reclassification patternsVariant reclassification Sankey diagram