ClinVar Miner

Submissions for variant NM_000064.4(C3):c.1273C>T (p.Arg425Cys)

gnomAD frequency: 0.00011  dbSNP: rs200967589
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000520102 SCV000617851 uncertain significance not provided 2017-06-30 criteria provided, single submitter clinical testing The R425C variant in the C3 gene has been reported previously as a heterozygous finding in at least 3 individuals of Asian ancestry with atypical hemolytic uremic syndrome (Fan et al., 2013; Matsukama et al., 2014; Cho et al., 2016). However, this variant is observed in 15/8620 (0.17%) alleles from individuals of East Asian background in the ExAC dataset (Lek et al., 2016). The R425C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is not conserved. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret R425C as a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp RCV000520102 SCV001542475 uncertain significance not provided 2024-10-11 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 425 of the C3 protein (p.Arg425Cys). This variant is present in population databases (rs200967589, gnomAD 0.3%). This missense change has been observed in individual(s) with atypical hemolytic uremic syndrome (PMID: 23314101, 25431709, 27722136, 33213850, 35685318). ClinVar contains an entry for this variant (Variation ID: 449567). 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 expected to disrupt C3 protein function with a positive 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.
Mayo Clinic Laboratories, Mayo Clinic RCV000520102 SCV001713759 uncertain significance not provided 2020-02-27 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002476054 SCV002790341 uncertain significance Age related macular degeneration 9; Atypical hemolytic-uremic syndrome with C3 anomaly; Complement component 3 deficiency 2024-04-26 criteria provided, single submitter clinical testing
Ambry Genetics RCV004023545 SCV004916113 uncertain significance Inborn genetic diseases 2023-11-06 criteria provided, single submitter clinical testing The c.1273C>T (p.R425C) alteration is located in exon 12 (coding exon 12) of the C3 gene. This alteration results from a C to T substitution at nucleotide position 1273, causing the arginine (R) at amino acid position 425 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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