Submissions for variant NM_000064.4(C3):c.1775G>A (p.Arg592Gln)

dbSNP: rs121909583

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Mayo Clinic Laboratories, Mayo Clinic	RCV001507917	SCV001713758	pathogenic	not provided	2024-03-20	criteria provided, single submitter	clinical testing	PM1, PM2_moderate, PM5, PS3, PS4
GeneDx	RCV001507917	SCV001764136	likely pathogenic	not provided	2020-12-10	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect on binding affinity and decreased co-factor activity (Fremeaux-Bacchi et al., 2008; Schramm et al., 2015); Not observed in large population cohorts (Lek et al., 2016); Identified in one patient in a Chinese cohort with C3 glomerulopathy (Zhao et al., 2018); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29566171, 19590060, 18796626, 21902819, 19775316, 24161037, 29450785, 25486517, 27013439, 23314101, 30046676, 25608561, 32950058, 21102542)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001844014	SCV002104095	likely pathogenic	Familial Atypical Hemolytic-Uremic Syndrome	2022-02-10	criteria provided, single submitter	clinical testing	Variant summary: C3 c.1775G>A (p.Arg592Gln) results in a conservative amino acid change located in the Alpha-2-macroglobulin, bait region domain (IPR011625) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251464 control chromosomes. c.1775G>A has been reported in the literature in individuals affected with Genetic Atypical Hemolytic Uremic Syndrome (example, Fremeaux-Bacchi_2008, Fidalgo_2017, Zhao_2018, Bahougne_2020). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 22% of WT activity in binding to complement regulators such as membrane coding factor (MCP), resulting in a resistance to cleavage by factor I and a decreased cofactor activity (example, Fremeaux-Bachhi_2008 and reproduced by Schramm_2015). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001507917	SCV002171265	pathogenic	not provided	2022-04-01	criteria provided, single submitter	clinical testing	Experimental studies have shown that this missense change affects C3 function (PMID: 18796626). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 592 of the C3 protein (p.Arg592Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant C3-related conditions (PMID: 18796626, 19590060, 29566171, 30046676). It has also been observed to segregate with disease in related individuals. This variant is also known as R570Q. ClinVar contains an entry for this variant (Variation ID: 17060). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002496404	SCV002809845	likely pathogenic	Age related macular degeneration 9; Atypical hemolytic-uremic syndrome with C3 anomaly; Complement component 3 deficiency	2024-03-28	criteria provided, single submitter	clinical testing
OMIM	RCV000018589	SCV000038872	risk factor	Atypical hemolytic-uremic syndrome with C3 anomaly	2008-12-15	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV004751217	SCV005349140	likely pathogenic	C3-related disorder	2024-07-31	no assertion criteria provided	clinical testing	The C3 c.1775G>A variant is predicted to result in the amino acid substitution p.Arg592Gln. This variant in heterozygous state was associated with atypical haemolytic uraemic syndrome (Reported as R570Q in Fremeaux-Bacchi et al 2008. PubMed ID: 18796626; Schramm et al 2015. PubMed ID: 25608561). Of note, another missense variant (p.Arg592Trp), affecting the same amino acid, was also associated with atypical haemolytic uraemic syndrome (reported as R570W in Fremeaux-Bacchi et al 2008. PubMed ID: 18796626). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as likely pathogenic.