ClinVar Genomic variation as it relates to human health

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 474 of the CFI protein (p.Arg474Gln). This variant is present in population databases (rs765956155, gnomAD 0.03%). This missense change has been observed in individual(s) with CFI-related conditions (PMID: 26826462). ClinVar contains an entry for this variant (Variation ID: 2203558). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CFI protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CFI function (PMID: 32510551, 35069568). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Variant summary: CFI c.1421G>A (p.Arg474Gln) results in a conservative amino acid change located in the serine proteases, trypsin domain (IPR001254) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 251304 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CFI causing Complement Factor I Deficiency (4.8e-05 vs 0.0011), allowing no conclusion about variant significance. c.1421G>A has been reported in the literature in the heterozygous state in at least two individuals affected with Atypical Hemolytic Uremic Syndrome, however in one case the individual also had a pathogenic CFI variant in trans and it was unclear whether it alone may have been causative for the phenotype (e.g. Szarvas_2016, Zhang_2022). These reports do not provide unequivocal conclusions about association of the variant with CFI-related disorders. Functional studies evaluating an impact on protein function reported that the variant had no impact on FI expression versus the WT protein, but resulted in a moderately reduced ability to degrade C3b in vitro and in patient serum (e.g. de Jong_2020, de Jong_2022, Zhang_2022). The following publications have been ascertained in the context of this evaluation (PMID: 26826462, 35619721, 35069568, 32510551). ClinVar contains an entry for this variant (Variation ID: 2203558). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.