ClinVar Miner

Submissions for variant NM_000744.6(CHRNA4):c.274G>C (p.Glu92Gln) (rs146651027)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000718190 SCV000849052 uncertain significance Seizures 2017-02-14 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000767933 SCV000898609 uncertain significance Epilepsy, nocturnal frontal lobe, type 1 2018-08-27 criteria provided, single submitter clinical testing CHRNA4 NM_000744.6 exon 4 c.274G>A (p.Glu92Gln): This variant has not been reported in the literature and is present in 0.06% (75/119670) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/20-61987436-C-G). This variant is present in ClinVar (Variation ID:205043). Evolutionary conservation of this residue suggests that this may impact the protein, but computational predictive tools for this variant are conflicting. Of note, computational tools designed to predict splicing suggest a potential effect from this variant. However, further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Division of Human Genetics,Children's Hospital of Philadelphia RCV000477750 SCV000536811 uncertain significance Epilepsy, nocturnal frontal lobe, type 1; Tobacco addiction, susceptibility to 2016-07-03 no assertion criteria provided research
GeneDx RCV000186963 SCV000240534 benign not specified 2017-10-03 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 RCV000654308 SCV000776198 uncertain significance Autosomal dominant nocturnal frontal lobe epilepsy 2018-05-09 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with glutamine at codon 92 of the CHRNA4 protein (p.Glu92Gln). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and glutamine. This variant is present in population databases (rs146651027, ExAC 0.07%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with CHRNA4-related disease. ClinVar contains an entry for this variant (Variation ID: 205043). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, 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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