Submissions for variant NM_000204.5(CFI):c.781G>A (p.Gly261Ser)

gnomAD frequency: 0.00001  dbSNP: rs547901965

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001148813	SCV001309724	uncertain significance	Atypical hemolytic-uremic syndrome with I factor anomaly	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
PreventionGenetics, part of Exact Sciences	RCV004538373	SCV004121305	uncertain significance	CFI-related disorder	2022-12-01	criteria provided, single submitter	clinical testing	The CFI c.781G>A variant is predicted to result in the amino acid substitution p.Gly261Ser. This variant was reported in an individual with both atypical hemolytic uremic syndrome and C3 glomerulopathy (Supplemental Table S3, CFI tab, Geerlings et al. 2018. PubMed ID: 29888403). Functional studies showed that this variant lead to FI expression similar to that of wildtype in the supernatant (99%) and in the lysate (90.5%) (Supplemental Table 1, de Jong et al. 2020. PubMed ID: 32510551). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/4-110681528-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003727915	SCV004540340	uncertain significance	not provided	2023-02-28	criteria provided, single submitter	clinical testing	Experimental studies have shown that this missense change does not substantially affect CFI function (PMID: 32510551). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 261 of the CFI protein (p.Gly261Ser). This variant is present in population databases (rs547901965, gnomAD 0.0009%). This missense change has been observed in individual(s) with clinical features of CFI-related conditions (PMID: 29888403). ClinVar contains an entry for this variant (Variation ID: 902336). 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. 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.