Submission Details

C3 was first reported in relation to autosomal dominant C3 Glomerulopathy (C3G) in 2010 (Martínez-Barricarte et al., PMID: 20852386). C3G is characterized by complement dysregulation occurring in the fluid phase and in the glomerular microenvironment (Smith et al., 2019, PMID: 30692664). The term C3G is inclusive of dense deposit disease (DDD) and C3 glomerulonephritis (C3GN). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in phenotypic variability. Therefore, the following disease entities have been split into multiple disease entities, atypical hemolytic uremic syndrome (aHUS) (OMIM:612925) and C3G. The split curation for autosomal dominant aHUS has been curated separately. Seventeen variants (missense) that have been reported in 17 probands in 7 publications (PMIDs: 20852386, 21784901, 26283675, 26471127, 26895476, 29566171, 37615951) are included in this curation. The mechanism of pathogenicity is known to be gain of function (GOF), causing the score of variants’ functional evidence to be upgraded when in support of this mechanism. This gene-disease association is also supported by protein interaction with CFH, functional alteration demonstrated on alternative pathway (AP) hemolysis assay, and biochemical function involving C3 nephritic factor (C3NeF) (PMIDs: 379217, 9291131, 21784901). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Complement-Mediated Kidney Diseases GCEP on the meeting date January 17, 2024 (SOP Version 10.1).