Reclassification of Variants Following Renal Genetics Testing: Uncommon Yet Impactful for Diagnosis and Management

Introduction: Genetic testing is increasingly utilized in nephrology practice, but limited real -world data exist on variant reclassi fi cation following renal genetics testing. Methods: A cohort of patients at the Cleveland Clinic Renal Genetics Clinic who underwent genetic testing through clinical laboratories was assessed with their clinical and laboratory data analyzed. Results: Between January 2019 and June 2023, 425 new patients with variable kidney disorders from 413 pedigrees completed genetic testing through 10 clinical laboratories, including 255 (60%) females with median (25th, 75th percentiles) age of 36 (22-54) years. Multigene panel was the most frequently used modality followed by single -gene testing, exome sequencing (ES), chromosomal microarray (CMA), and genome sequencing (GS). At initial report, 52% of patients had $ 1 variants of uncertain signi fi cance (VUS) with or without concurrent pathogenic variant(s). Twenty amendments were issued across 19 pedigrees involving 19 variants in 17 genes. The overall variant reclassi fi cation rate was 5%, with 63% being upgrades and 32% downgrades. Of the reclassi fi ed variants, 79% were initially reported as VUS. The median time -to -amendments from initial reports was 8.4 (4-27) months. Following the variant reclassi fi cations, 60% of the patients received a new diagnosis or a change in diagnosis. Among these, 67% of patients received signi fi cant changes in clinical management. Conclusion: Variant reclassi fi cation following genetic testing is infrequent but important for diagnosis and management of patients with suspected genetic kidney disease. The majority of variant reclassi fi cations involve VUS and are upgrades in clinically issued amended reports. Further studies are needed to investigate the predictors of such events.