CFH was first reported in relation to autosomal recessive C3 glomerulopathy (C3G) in 1997 (Ault et al., PMID: 9312129). 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 inheritance patterns. Therefore, autosomal recessive cases and autosomal dominant cases were reviewed separately. Following review of autosomal dominant C3G, it was determined by expert consensus that heterozygous variation in CFH is a risk factor of C3G, but not associated with Mendelian disease. Eight variants (missense and in-frame indel) that have been reported in 7 probands in 4 publications (PMIDs: 9312129, 14978182, 16612335, 37615951) are included in this curation. Of note, the score of missense variants at cysteine residues have been upgraded to reflect the equivalent score of truncating variants based on their structural impact to factor H, per expert consensus (Ault et al., 1997, PMID: 9312129). The mechanism of pathogenicity is known to be LOF. This gene-disease association is also supported by a mouse and pig model as well as biochemical function (PMIDs: 7883953, 12091909, 16612335). In summary, CFH is definitively associated with autosomal recessive C3G. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Complement-Mediated Kidney Diseases GCEP on the meeting date February 21, 2024 (SOP Version 10.1).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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