C3 was first reported in relation to autosomal dominant atypical hemolytic uremic syndrome (aHUS) in 2008 (Frémeaux-Bacchi et al., PMID: 18796626). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in phenotypic variability. Therefore, the following diseases have been split into separate entities, aHUS (OMIM: 612925) and C3 glomerulopathy (C3G) (OMIM: 613779). The split curation for semidominant C3G will be conducted separately. Thirteen variants (missense) that have been reported in thirteen probands in three publications (PMIDs: 18796626, 25608561, 26826462) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is reported to be gain of function. This gene-disease relationship is also supported by biochemical function in the complement mediated immune response, protein interaction with CFH and CFI, and a mouse model phenocopying disease in humans (PMIDs: 9291131, 21285368, 30714990). In summary, there is definitive evidence supporting the relationship between C3 and autosomal dominant aHUS. 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 August 3, 2023 (SOP Version 9).
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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