ClinVar Miner

Submissions for variant NM_000744.7(CHRNA4):c.1535C>G (p.Ser512Cys)

gnomAD frequency: 0.00006  dbSNP: rs754133410
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000688432 SCV000816042 uncertain significance Autosomal dominant nocturnal frontal lobe epilepsy 2023-03-31 criteria provided, single submitter clinical testing This variant has not been reported in the literature in individuals affected with CHRNA4-related conditions. 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. 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 CHRNA4 protein function. ClinVar contains an entry for this variant (Variation ID: 568165). This variant is present in population databases (rs754133410, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 512 of the CHRNA4 protein (p.Ser512Cys).
Ambry Genetics RCV002397379 SCV002706694 likely benign Inborn genetic diseases 2018-12-14 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

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