ClinVar Miner

Submissions for variant NM_000064.4(C3):c.3754G>A (p.Val1252Ile)

gnomAD frequency: 0.00001  dbSNP: rs537300095
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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 RCV001357738 SCV002236367 uncertain significance not provided 2024-08-31 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1252 of the C3 protein (p.Val1252Ile). This variant is present in population databases (rs537300095, gnomAD 0.2%). 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: 1050379). 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 RCV002499717 SCV002794283 uncertain significance Age related macular degeneration 9; Atypical hemolytic-uremic syndrome with C3 anomaly; Complement component 3 deficiency 2024-05-03 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV001357738 SCV005408681 uncertain significance not provided 2024-01-09 criteria provided, single submitter clinical testing BP4, PP2
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001357738 SCV001553298 uncertain significance not provided no assertion criteria provided clinical testing The C3 p.V1252I variant was not identified in the literature nor was it identified in Clinvar. The variant was identified in dbSNP (ID: rs537300095) and in control databases in 65 of 251496 chromosomes at a frequency of 0.0002585, and was observed at the highest frequency in the South Asian population in 59 of 30616 chromosomes (freq: 0.001927) (Genome Aggregation Database March 6, 2019, v2.1.1). The p.V1252 residue is conserved in mammals however computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a deleterious effect on splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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