ClinVar Miner

Submissions for variant NM_000744.6(CHRNA4):c.1360G>A (p.Gly454Ser) (rs78306886)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000716299 SCV000847139 uncertain significance Seizures 2016-07-26 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx RCV000186905 SCV000240476 likely benign not specified 2018-02-18 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae RCV000464341 SCV000553240 uncertain significance Autosomal dominant nocturnal frontal lobe epilepsy 2018-12-24 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 454 of the CHRNA4 protein (p.Gly454Ser). The glycine residue is weakly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs78306886, ExAC 0.09%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in reported in 4/718 patients and 1/1300 controls in a case-control study of ALS, and identified in an individual affected with ALS in another study (PMID: 22873564, 19628474). It has not been reported in individuals affected with autosomal dominant nocturnal frontal lobe epilepsy. ClinVar contains an entry for this variant (Variation ID: 204998). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). The serine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. 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.

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