ClinVar Miner

Submissions for variant NM_000064.4(C3):c.4348A>C (p.Lys1450Gln)

gnomAD frequency: 0.00001  dbSNP: rs191489530
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Fulgent Genetics, Fulgent Genetics RCV002486017 SCV002778492 uncertain significance Age related macular degeneration 9; Atypical hemolytic-uremic syndrome with C3 anomaly; Complement component 3 deficiency 2022-03-02 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV003770406 SCV004652770 uncertain significance not provided 2024-10-03 criteria provided, single submitter clinical testing This sequence change replaces lysine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1450 of the C3 protein (p.Lys1450Gln). This variant is present in population databases (rs191489530, gnomAD 0.003%). 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: 988195). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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.
Sydney Genome Diagnostics, Children's Hospital Westmead RCV001328209 SCV001449358 uncertain significance Atypical hemolytic-uremic syndrome 2019-05-08 no assertion criteria provided clinical testing This individual is heterozygous for the c.4348A>C variant in the C3 gene, which results in the amino acid substitution of lysine to glutamine at residue 1450, p.(Lys1450Gln). This variant is listed in the gnomAD browser (http://gnomad.broadinstitute.org) with a very low allele frequency of 0.001% (3 out of 282,864 alleles). To our knowledge, this variant has not been previously reported in the literature or any disease specific databases to be a disease causing variant. In silico analysis of pathogenicity (through Alamut Visual v2.8.1) is inconclusive regarding this variant, PolyPhen2 and MutationTaster predicts it to be likely pathogenic whereas SIFT predicts it to be likely benign. This variant is considered to be a variant of uncertain clinical significance (VOUS) according to the ACMG guidelines (Evidence used: PM2)

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