Submission Details

CFI was first reported in relation to autosomal dominant C3 glomerulopathy (C3G) in 2012 (Servais et al., PMID: 22456601). 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:612923) and C3G. The split curation for autosomal dominant aHUS has been curated separately. Seven variants (missense, nonsense, and frameshift) that have been reported in 7 probands in 3 publications (PMIDs: 22456601, 35619721, 37615951) are included in this curation. The mechanism of pathogenicity is known to be loss of function, causing dysregulation of the complement-mediated immune pathway. This gene-disease relationship is also supported by biochemical function in the complement-mediated immune pathway, protein interaction with factor H, functional alteration demonstrated by reduced in vitro expression in HEK293T cells and low FI plasma levels caused by variants observed in patients, and a mouse model recapitulating C3G as seen in human patients (PMIDs: 28671664, 32510551, 34149444). 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 April 17, 2024 (SOP Version 10).