ClinVar Miner

Submissions for variant NM_000204.5(CFI):c.1420C>T (p.Arg474Ter)

gnomAD frequency: 0.00003  dbSNP: rs121964913
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001851811 SCV002239028 pathogenic not provided 2023-10-06 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg474*) in the CFI gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CFI are known to be pathogenic (PMID: 15917334, 16621965, 19065647, 20016463, 22710145). This variant is present in population databases (rs121964913, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with atypical hemolytic uremic syndrome (PMID: 20016463). This variant is also known as R456X. ClinVar contains an entry for this variant (Variation ID: 12121). For these reasons, this variant has been classified as Pathogenic.
PreventionGenetics, part of Exact Sciences RCV004532327 SCV004113684 likely pathogenic CFI-related disorder 2022-12-05 criteria provided, single submitter clinical testing The CFI c.1420C>T variant is predicted to result in premature protein termination (p.Arg474*). This variant has been reported in a patient with atypical hemolytic uremic syndrome (aHUS). In vitro functional characterization resulted in the absence of detectable recombinant FI in both the supernatant and the cell lysate (Patient 10, Bienaime et al. 2010. PubMed ID: 20016463). Another patient with aHUS had FI plasma levels below the lower limit of the normal range. However, the authors noted that natural variation in concentration was seen between carriers of the same variant and among samples from the same individual taken at different time points (de Jong et al. 2020. PubMed ID: 32510551). This variant was also detected in patients with advanced age-related macular degeneration (Seddon et al., 2013. PubMed ID: 24036952, Java et al. 2020. PubMed ID: 32908800). The variant was classified as a Type 1 variant which demonstrated low FI antigenic levels and low iC3b generation, but the iC3b generated per unit of FI (iC3b/FI) was normal when compared to controls (Java et al. 2020. PubMed ID: 32908800). This variant is reported in 0.0062% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/4-110667387-G-A). Nonsense variants in CFI are expected to be pathogenic. This variant is interpreted as likely pathogenic.
OMIM RCV000012904 SCV000033145 risk factor Atypical hemolytic-uremic syndrome with I factor anomaly 2004-06-01 no assertion criteria provided literature only

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