Unmasking the Unknown: Tracing C3 Glomerulonephritis to a C3 Gene Variant of Unknown Significance

Introduction: C3 glomerulonephritis(C3GN) is a rare form of kidney disease characterized by glomerular complement deposition, resulting from dysregulation of alternate complement pathway. Complement activation can be induced by circulating factors or genetic defect in the pathway. We present a case of biopsy-proven C3GN in a patient with a variant of unknown significance(VUS) in the C3 gene, also detected in his mother, suggesting a possible hereditary component. Case Description: A 22-year-old male with no medical history was referred to nephrology clinic for hematuria and proteinuria found during routine health screening. He had grade 1 hypertension, >300mg/dl proteinuria, hematuria but no active complaints. He denied use of OTC supplements or recreational drug use. Workup revealed preserved kidney function, hypoalbuminemia (3.2 g/dl), persistent proteinuria (UACR:1099) and hematuria with dysmorphic RBCs. Serological evaluation for autoimmune disease, infection, hemolysis, and monoclonal gammopathy was negative but he had low complement C3(8 mg/dl), normal C4(22 mg/dl). Kidney imaging was unremarkable. Kidney biopsy demonstrated membranoproliferative GN pattern with C3 granular deposit in mesangium and glomerular basement membrane on IF consistent with C3GN. Complement testing showed reduced factor B(9.2 mg/dl), elevated C3 nephritic factor(72 U/ml) and sMAC terminal complement component Sc 5b-9: 1965(N<244 ng/ml). Genetic testing revealed a VUS in the C3 gene (c 2837C>T). Parental screening showed that his mother carried the same VUS and had mild kidney disease with low C3 levels. His siblings are undergoing genetic evaluation. Patient was initially treated with eculizumab, which improved proteinuria and is now maintained on ravulizumab with improved complement levels. Discussion: Identifying genetic defects leading to C3GN is a growing area of interest due to its rare occurrence. Our patient had a C3 gene VUS causing biopsy-proven C3GN with preserved kidney function, while his mother carried the same gene variant with mild kidney disease and low complement levels suggesting a possible familial link. Increased awareness and investigation of VUS may enhance our understanding of their clinical implications. This case highlights a potential hereditary component of C3GN and emphasizes the importance of genetic testing in patient with C3GN.