ClinVar Miner

Submissions for variant NM_000744.7(CHRNA4):c.1741G>A (p.Glu581Lys)

gnomAD frequency: 0.00001  dbSNP: rs752289948
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Baylor Genetics RCV001335437 SCV001528587 uncertain significance Autosomal dominant nocturnal frontal lobe epilepsy 1 2018-10-12 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
GeneDx RCV001575408 SCV001802395 uncertain significance not provided 2019-10-14 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 22873564)
New York Genome Center RCV001335437 SCV001815829 uncertain significance Autosomal dominant nocturnal frontal lobe epilepsy 1 2020-09-23 criteria provided, single submitter clinical testing The inherited c.1741G>A (p.Glu581Lys) variant identified in the CHRNA4 gene of this individual substitutes a well conserved Glutamic Acid for Lysine at amino acid 581/628 (exon 5/6). This variant is found with low frequency in gnomAD(v3.0) (1 heterozygote, 0 homozygotes; allele frequency: 6.57e-6), suggesting it is not a common benign variant in the populations represented in that database. In silico algorithms do not agree on the effect of this variant, as it is predicted both Tolerated (SIFT; score:0.269) and Pathogenic (REVEL; score:0.652) to the function of the canonical transcript. This variant is absent from ClinVar and to our current knowledge has not been reported in an individual with seizures in the literature. The p.Glu581 residue is not within a mapped domain of CHRNA4 (UniProtKB:P43681). Given the lack of compelling evidence for its pathogenicity, the inherited c.1741G>A (p.Glu581Lys) variant identified in the CHRNA4 gene is reported as a Variant of Uncertain Significance.
Labcorp Genetics (formerly Invitae), Labcorp RCV002546733 SCV002990637 likely benign Autosomal dominant nocturnal frontal lobe epilepsy 2023-05-16 criteria provided, single submitter clinical testing

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