Measuring historical variant reclassification in inherited retinal disease and its impact on clinical genetic testing

Inherited retinal diseases (IRDs) are clinically and genetically diverse conditions whose heterogeneity makes molecular diagnosis challenging. These challenges can lead to interpretation discordance which has a particular impact on gene-targeted therapies for IRD.

Discordance was evaluated in a clinical testing cohort and in ClinVar. 140 sequence variants identified through genetic testing in a cohort of pediatric participations with IRD were reclassified using the American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP) guidelines for variant interpretation. ClinVar datasets from December 2, 2019 and January 3, 2022 for the gene RPE65 were analyzed for discordance.

The discordance rate in the pediatric cohort was 22.2%. Discordance in ClinVar increased from 23.6% to 36.6%.

Discordance in the pediatric cohort may have been impacted by subjective application of the ACMG/AMP guidelines and heterogeneity in IRD. Subjectivity in the guidelines, laboratory differences, and lack of interpretation review may have contributed to discordance in ClinVar. Work to improve interpretation for IRD should include better understanding of the genetic influences of IRD and optimization of the ACMG/AMP guidelines for this field.