ClinVar Genomic variation as it relates to human health

Published functional studies demonstrate reduced expression and activity (van de Ven et al., 2013); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20513133, 23685748, 26767664, 28637922, 28282489, 27939104, 27380463, 29398083, 29410599, 31528764, 31614353, 32510551, 32832254, 25352734, 24036952, 26691988, 29087762, 27918759, 29700787, 29888403, 29392637, 20203157, 32516404, 32195675, 33610747, 34153144, 34945728, 34169201)

Variant summary: CFI c.355G>A (p.Gly119Arg) results in a non-conservative amino acid change located in the SRCR domain (IPR001190) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00076 in 1613848 control chromosomes, predominantly at a frequency of 0.001 within the Non-Finnish European subpopulation in the gnomAD database, including 3 homozygotes. This frequency is approximately equal to the maximum estimated frequency for a pathogenic variant in CFI causing Complement Factor I Deficiency ( 0.001 vs 0.0011) and is much higher than estimated for a pathogenic variant causing an autosomal dominant condition such as Atypical Hemolytic Uremic Syndrome, suggesting this variant may be benign. c.355G>A has been reported in the literature in the heterozygous state in multiple individuals affected with Atypical Hemolytic Uremic Syndrome and Age-related Macular Degeneration, without strong evidence for pathogenicity (i.e. segregation data) and has also been reported in healthy controls (e.g. Maga_2010, van de Ven_2013, de Jong_2020, Zhang_2022). It has been reported in at least two presumably compound heterozygous individuals (phase unspecified) with Atypical Hemolytic Uremic Syndrome/C3 glomerulopathy who were not described as having clinical features of Complement Factor I Deficiency (e.g. Maga_2010, Zhang_2022) and to our knowledge, this variant has not been reported in individuals with this condition. These reports do not provide unequivocal conclusions about association of the variant with disease. At least two publications report experimental evidence evaluating an impact on protein function (van de Ven_2013, de Jong_2020). The variant results in decreased expression and secretion in vitro, but has a higher efficiency versus the WT protein. Heterozygous carriers of the variant have been found to have reduced FI plasma levels, at approximately 55-60% of normal, however the clinical significance of this with respect to disease manifestation is unclear (de Jong_2020). The following publications have been ascertained in the context of this evaluation (PMID: 20513133, 35619721, 32510551, 23685748). ClinVar contains an entry for this variant (Variation ID: 66014). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.

PS3, PS4, PP3

Evidence in support of status as susceptibility allele: - Variant is present in gnomAD (v2) <0.001 for a dominant condition (120 heterozygotes, 0 homozygotes). - This variant has been reported as a susceptibility factor for aHUS and has been reported in patients with aHUS (PMIDs: 27177491, 20513133 and ClinVar). Additional information: - Loss of function in this gene is associated with susceptibility to atypical haemolytic uraemic syndrome (aHUS) 3 (MIM#612923). - This gene is associated with autosomal recessive complement factor I deficiency (MIM#610984). Monoallelic variants in this gene are associated with susceptibility to aHUS 3 (MIM#612923). - Variant is predicted to result in a missense amino acid change from glycine to arginine. - This variant is heterozygous. - Missense variant with conflicting in silico predictions and uninformative conservation. - Variant is located in the annotated CD5 domain (PMID: 20513133). - This variant has been shown to be maternally inherited (by trio analysis).

This individual is heterozygous for the c.355G>A variant in the CFI gene, which results in the amino acid substitution of glycine to arginine at residue 119, p.(Gly119Arg). This variant has been reported in the gnomAD browser (http://gnomad.broadinstitute.org) with an allele frequency of 0.09% (110 out of 129,124 alleles) in the European non-Finnish population. This variant has been reported in the Database of complement gene variants (https://www.complement-db.org/home.php) as a VOUS in 16 individuals with aHUS with and without a second variant in CFI or another complement gene. p.Gly119Arg has been reported in ClinVar as a VOUS (variation ID 66014). p.Gly119Arg has also been reported to confer high risk of developing age-related macular degeneration (ARMD) (van de Ven et al 2013 Nat Genet 45:813-817 and Fritsche et al 2016 Nat Genet. 48:134-143). In vitro functional studies were performed by van de Ven et al 2013 and showed that the Gly119Arg mutant protein resulted in lower levels of expression and secretion compared to wild-type protein. This variant is considered to be a variant of uncertain clinical significance (VOUS) according to the ACMG guidelines (Evidence used: PS3).