ClinVar Miner

Submissions for variant NM_000064.4(C3):c.1999G>A (p.Ala667Thr)

gnomAD frequency: 0.00001  dbSNP: rs199535288
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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 RCV001880190 SCV002214431 uncertain significance not provided 2024-01-01 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 667 of the C3 protein (p.Ala667Thr). This variant is present in population databases (rs199535288, gnomAD 0.006%). 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: 988244). 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) performed at Invitae 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 RCV002493460 SCV002782301 uncertain significance Age related macular degeneration 9; Atypical hemolytic-uremic syndrome with C3 anomaly; Complement component 3 deficiency 2022-02-05 criteria provided, single submitter clinical testing
Sydney Genome Diagnostics, Children's Hospital Westmead RCV001328275 SCV001449197 uncertain significance Atypical hemolytic-uremic syndrome 2018-05-31 no assertion criteria provided clinical testing This patient is heterozygous for a variant of uncertain significance (VOUS), c.1999G>A (p.Ala667Thr), in the C3 gene. To our knowledge, this variant has not been previously reported to be a disease causing variant and it has not been reported in the ExAC allele frequency database (http://exac.broadinstitute.org). In silico analysis (using Alamutv2.7.2) using Align GVGD; SIFT; Mutation Taster and PolyPhen2 all predict that this variant is likely to be benign

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