Reassessment and reclassification of variants of unknown significance in patients with cardiomyopathy in a specialist department

Background: The utility of diagnostic genetic testing in cardiomyopathy has grown significantly, due to the discovery of novel genes and greater awareness among healthcare professionals. However, a substantial proportion of cases (around 50%) yield no causative genetic variants or have variants of unknown significance (VUS), limiting their use in clinical management and familial screening. The increase in data quantity and quality in reference databases, coupled with variant interpretation guidelines, allows for periodic reanalysis of VUS, potentially reducing diagnostic gaps.

Methods: This study presents a review of VUS results identified in hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM) and arrhythmogenic cardiomyopathy (ACM) probands over a 5-year period, using American College of Medical Genetics and Genomics criteria. A total of 248 VUS from 233 reports were reviewed, with the majority of patients with a diagnosis of HCM (n=112), followed by DCM (n=99) and ACM (n=22).

Results: Four (1.6%) VUS showed sufficient evidence to upgrade to likely pathogenic/pathogenic status, while 8 (3.2%) were downgraded to benign. The majority 236 (95.2%) remained VUS after reanalysis, of which 12 (4.7%) had potential to reclassification to benign or likely pathogenic/pathogenic depending on further data.

Conclusion: The study emphasises the importance of periodic re-evaluation of VUS results for clinical management of probands as well as cascade testing. We show feasibility of conducting reclassification analysis in a referral centre, but highlight the need for ongoing collaboration between clinical and laboratory experts. Our work supports the current recommendation of reclassification every 3-5 years to keep pace with evolving evidence.