ClinVar Miner

Submissions for variant NM_000204.5(CFI):c.559C>T (p.Arg187Ter)

gnomAD frequency: 0.00004  dbSNP: rs368615806
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services, Illumina RCV000778715 SCV000915070 likely pathogenic Atypical hemolytic-uremic syndrome with I factor anomaly 2018-12-10 criteria provided, single submitter clinical testing The CFI c.559C>T (p.Arg187Ter) is a stop-gained variant that is predicted to result in premature truncation of the protein. The p.Arg187Ter variant has been reported in a compound heterozygous state in three individuals from two unrelated families affected with CFI deficiency (Alba-Dominguez et al. 2012). The variant in each of the affected individuals was inherited from an unaffected heterozygous parent. Control data are unavailable for this variant, which is reported at a frequency of 0.000014 in the Total population of the Genome Aggregation Database. Based on the collective evidence and the potential impact of stop-gained variants, the p.Arg187Ter variant is classified as likely pathogenic for CFI-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000778715 SCV001448853 pathogenic Atypical hemolytic-uremic syndrome with I factor anomaly 2019-11-15 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001856163 SCV002240563 pathogenic not provided 2023-10-05 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg187*) 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 (rs368615806, gnomAD 0.008%). This premature translational stop signal has been observed in individual(s) with autosomal recessive complement factor I deficiency (PMID: 22710145, 31231365). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 631934). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV001856163 SCV002587929 likely pathogenic not provided 2022-04-07 criteria provided, single submitter clinical testing Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 31231365, 22710145)
Fulgent Genetics, Fulgent Genetics RCV002507347 SCV002807406 pathogenic Atypical hemolytic-uremic syndrome with I factor anomaly; Age related macular degeneration 13; Factor I deficiency 2021-11-10 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV001856163 SCV004226769 pathogenic not provided 2022-06-29 criteria provided, single submitter clinical testing PP1, PM3, PVS1

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