The relationship between CFB and C3 glomerulopathy was evaluated on 7 March 2024 using the ClinGen Clinical Validity Framework. CFB codes for a single chain glycoprotein that is a component of the alternative complement pathway, is cleaved by Factor D, and where the C3bBb molecule represents the alternate pathway convertase. CFB was first reported associated with C3 glomerulopathy by Imamura et al (PMID: 25758434). Only three pathogenic variants associated with C3 glomerulonephritis have been reported, two of which have been described previously in atypical Haemolytic uremic syndrome. These variants are missense changes with functional data supporting pathogenicity and have been reported in different publications over time. The mechanism of pathogenicity is Gain of Function. This gene-disease association for CFB is also supported by biochemical function, protein interactions, altered biochemical function in affected individuals, and by functional alteration in a cell culture model.
In summary, CFB has a limited association with C3 glomerulopathy. The association has been demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. The Expert panel expect that the association will be confirmed more robustly with the demonstration of more CFB variants in patients with C3 glomerulopathy.
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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