ClinVar Miner

Submissions for variant NM_000744.7(CHRNA4):c.1209_1210delinsTT (p.Pro404Ser)

dbSNP: rs1064795858
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000482601 SCV000572060 uncertain significance not specified 2016-10-24 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the CHRNA4 gene. The c.1209_1210delGCinsTT variant is caused by two nucleotide substitutions (c.1209 G>T and c.1210 C>T) on the same allele (in cis), resulting in an in-frame deletion of a single Proline residue and the insertion of a single Serine residue at amino acid position 404, denoted P404S. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. P404S is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is not conserved. In silico analysis predicts this variant likely does not alter the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV003746525 SCV004386821 uncertain significance Autosomal dominant nocturnal frontal lobe epilepsy 2023-12-02 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 404 of the CHRNA4 protein (p.Pro404Ser). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This variant has not been reported in the literature in individuals affected with CHRNA4-related conditions. This missense change has been observed in at least one individual who was not affected with CHRNA4-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 422561). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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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