Reclassifying genetic variants in inherited retinal diseases
Reviewed by Ian Reekie

The authors present a retrospective study of 142 gene sequence variants from 28 patients with vitreoretinal dystrophies which were re-interpreted based on American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP) guidelines. Overall, there was good agreement between the original classification and the reclassification. 31/142 variants had discordant results between the original and the updated classification, and the majority of discordant results were ‘downgrades’; 11 from pathogenic to variant of unknown significance and 15 from variant of unknown significance to benign. One variant was reclassified from pathogenic to benign. The authors also give an in-depth discussion on subjectivity within the application of the ACMG and AMP classification guidelines, and touch on how modifications to the guidelines may be beneficial when considering gene variants in inherited retinal diseases. The emergence of effective gene therapies for inherited retinal diseases means that accurate and reproducible classification of disease-causing gene variants is now vital. Inclusion in trials and eligibility for licenced treatments depends heavily on patients having known pathogenic mutations in genes of interest. This study demonstrates the need for improved classification of variants in inherited retinal diseases.

Measuring historical variant reclassification in inherited retinal disease and its impact on clinical genetic testing.
Kern K, Gordon A, Drackley A, et al.
OPHTHALMIC GENETICS 
2026;47(1):35–42.