ClinVar Miner

Submissions for variant NM_000204.5(CFI):c.772G>A (p.Ala258Thr)

gnomAD frequency: 0.00014  dbSNP: rs199688124
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001993198 SCV002237176 pathogenic not provided 2024-01-09 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 258 of the CFI protein (p.Ala258Thr). RNA analysis indicates that this missense change induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs199688124, gnomAD 0.02%). This missense change has been observed in individual(s) with CFI-related conditions (PMID: 8613545, 18374984, 22710145, 26826462, 29888403). It has also been observed to segregate with disease in related individuals. This variant is also known as 801-A. ClinVar contains an entry for this variant (Variation ID: 1451295). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change results in skipping of exon 5, but is expected to preserve the integrity of the reading-frame (PMID: 8613545, 18374984). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics RCV002507693 SCV002809313 likely pathogenic Atypical hemolytic-uremic syndrome with I factor anomaly; Age related macular degeneration 13; Factor I deficiency 2022-03-31 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV001993198 SCV004226768 pathogenic not provided 2023-01-30 criteria provided, single submitter clinical testing PP4, PM3_strong, PVS1_strong
OMIM RCV002074443 SCV000033143 pathogenic Factor I deficiency 1996-02-15 no assertion criteria provided literature only
PreventionGenetics, part of Exact Sciences RCV004542199 SCV004779220 pathogenic CFI-related disorder 2024-02-13 no assertion criteria provided clinical testing The CFI c.772G>A variant is predicted to result in the amino acid substitution p.Ala258Thr. This variant was reported in individuals with complement factor I deficiency, aHUS, and age-related macular degeneration (see for example - Seddon et al. 2013. PubMed ID: 24036952; de Jong et al. 2020. PubMed ID: 32510551; Naesens et al. 2020. PubMed ID: 32853637; Java et al. 2020. PubMed ID: 32908800; Khan et al. 2021. PubMed ID: 34153144). This variant is the final nucleotide of the exon and functional studies found this variant causes exon skipping (Ponce-Castro et al. 2008. PubMed ID: 18374984). This variant is reported in 0.024% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.

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