Kidney Week

Abstract: FR-PO0120

Genotype-First Evaluation of COL4A3/4 Variants and Kidney Disease Risks

Session Information

• Hereditary Glomerular and Tubulointerstitial Kidney Diseases
  October 23, 2026 | Location: Exhibit Hall A, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1202 Genetic Diseases of the Kidneys: Non-Cystic (Complex and Non-Cystic Monogenic)

Authors

• Chang, Alexander R., Geisinger Health, Danville, Pennsylvania, United States

Alexander R. Chang, MD, MS

• Moore, Bryn S., Geisinger Health, Danville, Pennsylvania, United States

Bryn S. Moore, MS

• Urban, Gretchen M., Geisinger Health, Danville, Pennsylvania, United States

Gretchen M. Urban, MS

• Kirchner, H. Lester, Geisinger Health, Danville, Pennsylvania, United States

H. Lester Kirchner, PhD

• Wongboonsin, Janewit, Mahidol University Faculty of Medicine Siriraj Hospital, Bangkok, Thailand

Janewit Wongboonsin, MD, MS

• Savige, Judith A., Melbourne Health, Melbourne, Victoria, Australia

Judith A. Savige, MBBS, PhD

Background

Pathogenic heterozygous variants in COL4A3/4 have been linked to kidney phenotypes ranging from hematuria, proteinuria, impaired kidney function to kidney failure. Missense variants in position 1 glycine residues in Gly-X-Y repeats in collagenous domains often cause disease though many remain classified as variants of uncertain significance (VUS).

Methods

We used data from MyCode DiscovEHR (175k freeze), an exome sequencing study linked to electronic health records (EHR) to improve categorization of COL4A3/4 variants. Phenotype data included hematuria, proteinuria, most recent eGFR <60 ml/min/1.73m², and kidney failure (eGFR <15, dialysis, kidney transplant). We included rare COL4A3/4 variants (allele frequency <0.01), protein truncating variants (excluding those in last exon and last 50 nucleotides of penultimate exon), and glycine collagenous domain variants. ClinVar, REVEL score (≥0.7), alpha missense (≥0.564), and SpliceAI (≥0.5) were used to categorize variants. Prevalence ratios (PRs) of kidney phenotypes were evaluated comparing genotype groups vs. those without rare COL4A3/4/5 variants, using generalized linear models with a log-link Poisson model with robust standard errors, adjusting for age and sex.

Results

Risk of hematuria was higher for glycine P/LP variants (PR 3.06, 95% CI: 2.81, 3.35) and splice variants (PR 3.27, 95% CI: 2.80, 3.81) than null variants (PR 1.95, 95% CI: 1.63, 2.33). Risk of kidney failure followed a similar pattern with prevalences for glycine P/LP, splice, and null variants of 6.8%, 6.4%, and 3.5% (Table). Glycine variants classified as VUS or P/LP with VUS categorization were significantly associated with dipstick hematuria. Classifying glycine collagenous domain using REVEL score or alpha missense resulted in similar associations.

Conclusion

Heterozygous COL4A3/4 glycine collagenous domain and splice variants are associated with more severe kidney disease phenotypes than frameshift and stop-gain variants, possibly due to dominant negative effects.

Acknowledgment

We are grateful to the many participants who contributed to the MyCode Community Health Initiative by providing genomic and electronic health information. We thank the Regeneron Genetics Center for providing funding for participant enrollment and exome sequencing for the DiscovEHR study, and we would like to acknowledge the Geisinger-Regeneron DiscovEHR Collaboration for the genotypic and phenotypic data.