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Systematic Reclassification of Variants of Uncertain Significance in a Clinical Nephrogenomics Program: Insights from the RAPIDS Collaboration

Tung-Lin Lee Yao-Chun Zhang Tina Si Ting Lim Chee Teck Koh Kay Yuan Chong Christina Titin Hui Z. Tan I. Mok J. L. Kwek C. Lim J. Choo J. Goh Sylvia Kam B. Cham J. Lim Ee-Shi-En Tan Esther Huimin Leow Yong H. Ng Jiamin Yap Sing-Ming Chao Siew Le Chong R. Lim S. Goh R. Lim S. Yeo Zi-Yin Wang C. Lim D. Chan David Lu Sharon Teo P. Lau Mya Than J. Ng Gek-Cher Chan Yi Da Bo-On W. Teo H. Yap Hui-Lin Chin K. Ng

Nov 2026 · Clinical Kidney Journal · 0 citations

Abstract

A nationwide nephrologist-led genetic testing program for suspected monogenic glomerular disease and unexplained chronic kidney disease was implemented across four tertiary hospitals in Singapore. Initial testing yielded a genetic diagnosis in 11.5% probands, while 77 (18.4%) harboured variants of uncertain significance (VUS) that could explain their kidney disease (VUS-congruent). We evaluated a structured pipeline for reclassifying VUS-congruent to likely pathogenic or pathogenic (LP/P) to improve diagnostic yield and clinical utility. Probands with VUS-congruent were reviewed at monthly multidisciplinary genomic board meetings. A stepwise framework incorporated genotype–phenotype correlations (Step 1), then re-appraisal of existing evidence (Step 2) through review of population databases, literature and in-silico prediction. For VUS with high suspicion of pathogenicity (VUS-High), resolution strategies were recommended (Step 3), including familial variant-specific testing, deeper phenotyping, and functional studies. Primary outcome was the proportion of VUS-congruent reclassified to LP/P; secondary outcomes were improvements in diagnostic yield and clinical utility. Among 418 probands tested over 28 months, 77 (18.4%) had VUS-congruent. Step 2 reclassified 26/77 VUS-congruent to LP/P, with another 22/77 VUS-congruent stratified as VUS-High. Among these 22 recommended for Step 3, completed strategies were functional studies (n=8), segregation analysis (n=1), deeper phenotyping (n=1), phase determination (n=1) and combination strategies (n=6). This enabled VUS-High reclassification to LP/P for 16 additional probands. Overall, 42/77 probands (54.5%) had VUS-congruent reclassified to LP/P, increasing diagnostic yield from 11.5% to 21.5%. Among these, 28 (66.7%) experienced clinically meaningful management changes. A structured, multidisciplinary VUS resolution workflow enabled considerable VUS reclassification, nearly doubling the diagnostic yield.

DOI Semantic Scholar

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