ClinVar Miner

Submissions for variant NM_000064.4(C3):c.3023C>T (p.Ser1008Leu)

gnomAD frequency: 0.00004  dbSNP: rs746172422
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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 RCV001874798 SCV002146156 uncertain significance not provided 2023-05-12 criteria provided, single submitter clinical testing 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. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on C3 protein function. ClinVar contains an entry for this variant (Variation ID: 1372748). This missense change has been observed in individual(s) with atypical hemolytic uremic syndrome (PMID: 26559391). This variant is present in population databases (rs746172422, gnomAD 0.007%). This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 1008 of the C3 protein (p.Ser1008Leu).
Johns Hopkins Genomics, Johns Hopkins University RCV002282624 SCV002570349 uncertain significance Atypical hemolytic-uremic syndrome with C3 anomaly 2022-08-22 criteria provided, single submitter clinical testing This C3 missense variant has been reported in an individual with atypical hemolytic uremic syndrome (aHUS). The variant (rs746172422) is rare (<0.1%) in a large population dataset (gnomAD: 9/251364 total alleles; 0.0036%; no homozygotes), and has been reported in ClinVar (Variation ID 1372748). Of two bioinformatic tools queried, one predicts that the substitution would be possibly damaging, while the other predicts that it would be tolerated, and the serine residue at this position is evolutionarily conserved across many of the species assessed6. We consider the clinical significance of c.3023C>T in C3 to be uncertain at this time.
PreventionGenetics, part of Exact Sciences RCV003913432 SCV004728634 uncertain significance C3-related disorder 2023-12-05 criteria provided, single submitter clinical testing The C3 c.3023C>T variant is predicted to result in the amino acid substitution p.Ser1008Leu. This variant was reported in an individual with atypical hemolytic uremic syndrome (Patient ID 9, Phillips et al. 2016. PubMed ID: 26559391). This variant is reported in 0.0062% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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