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

Euyn Lim; Chloe Borden; Seysha Mehta; Mary-Beth Roberts; Sarah Mazzola; Fang Zhao; Xiangling Wang

doi:10.1016/j.ekir.2024.01.055

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

Kidney Int Rep. 2024 Feb 6;9(5):1441-1450. doi: 10.1016/j.ekir.2024.01.055. eCollection 2024 May.

Authors

Euyn Lim¹, Chloe Borden², Seysha Mehta², Mary-Beth Roberts³, Sarah Mazzola³, Fang Zhao⁴, Xiangling Wang^{1

2

3

5

6}

Affiliations

¹ Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
² Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio, USA.
³ Center for Personalized Genetic Healthcare, Medical Specialties Institute, Cleveland Clinic, Cleveland, Ohio, USA.
⁴ Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, Ohio, USA.
⁵ Department of Kidney Medicine, Medical Specialties Institute, Cleveland Clinic, Cleveland, Ohio, USA.
⁶ Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio, USA.

Abstract

Introduction: Genetic testing is increasingly utilized in nephrology practice, but limited real-world data exist on variant reclassification 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 significance (VUS) with or without concurrent pathogenic variant(s). Twenty amendments were issued across 19 pedigrees involving 19 variants in 17 genes. The overall variant reclassification rate was 5%, with 63% being upgrades and 32% downgrades. Of the reclassified variants, 79% were initially reported as VUS. The median time-to-amendments from initial reports was 8.4 (4-27) months. Following the variant reclassifications, 60% of the patients received a new diagnosis or a change in diagnosis. Among these, 67% of patients received significant changes in clinical management.

Conclusion: Variant reclassification following genetic testing is infrequent but important for diagnosis and management of patients with suspected genetic kidney disease. The majority of variant reclassifications involve VUS and are upgrades in clinically issued amended reports. Further studies are needed to investigate the predictors of such events.

Keywords: diagnosis and management; kidney disease; renal genetics; variant of uncertain significance; variant reclassification.