Gene-specific reclassification patterns of variants in hypertrophic cardiomyopathy.

Likely pathogenic/pathogenic (LP/P) variants and variants of uncertain significance were re-evaluated using the ACMG/AMP framework in 2,154 hypertrophic cardiomyopathy (HCM) index cases, in genes selected from ClinGen gene-disease validity assessments. Overall, 12.8% of 1,355 variants were reclassified, 7.5% with clinical impact (3.5% upgraded from variant of uncertain significance to LP/P, 4% downgraded from LP/P to variant of uncertain significance). The genetic status of 86 individuals (4.0%) changed: 47 (2.2%) lost LP/P status and 39 (1.8%) received a new gene-positive diagnosis. MYBPC3 and MYH7 variants were largely unchanged (92.0% and 83.2%), TNNT2 showed the highest proportion of upgrades (28.6%), and the largest LP/P downgrades concerned ACTC1 (50.0%), MYL3 (42.9%), TPM1 (42.9%) and TNNI3 (20.0%).

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

The figure that matters for practice is the 47 individuals who lose an LP/P diagnosis, since it can affect family screening already started on the basis of these variants. The contrast between genes (MYBPC3 and MYH7 stable; ACTC1, MYL3 and TPM1 fragile) gives concrete priority to periodic re-evaluation. The abstract does not state the interval between initial classification and re-evaluation, which limits any estimate of a reanalysis schedule.

Analysis by Dr Thibaut Benquey