ClinVar Miner

Submissions for variant NM_000064.4(C3):c.4667A>G (p.Asn1556Ser)

gnomAD frequency: 0.00014  dbSNP: rs139381845
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001312779 SCV001503247 uncertain significance not provided 2025-02-02 criteria provided, single submitter clinical testing This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 1556 of the C3 protein (p.Asn1556Ser). This variant is present in population databases (rs139381845, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with C3-related conditions. ClinVar contains an entry for this variant (Variation ID: 1014094). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt C3 protein function with a negative predictive value of 80%. 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.
Fulgent Genetics, Fulgent Genetics RCV002476444 SCV002775934 uncertain significance Age related macular degeneration 9; Atypical hemolytic-uremic syndrome with C3 anomaly; Complement component 3 deficiency 2024-03-28 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004782703 SCV005395869 uncertain significance not specified 2024-09-16 criteria provided, single submitter clinical testing Variant summary: C3 c.4667A>G (p.Asn1556Ser) results in a conservative amino acid change located in the Netrin domain (IPR001134) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.4e-05 in 250774 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in C3 causing Age-Related Macular Degeneration, allowing no conclusion about variant significance. To our knowledge, no occurrence of c.4667A>G in individuals affected with Age-Related Macular Degeneration and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 1014094). Based on the evidence outlined above, the variant was classified as uncertain significance.
PreventionGenetics, part of Exact Sciences RCV003945990 SCV004760135 uncertain significance C3-related disorder 2024-01-24 no assertion criteria provided clinical testing The C3 c.4667A>G variant is predicted to result in the amino acid substitution p.Asn1556Ser. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.013% 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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