ClinVar Miner

Submissions for variant NM_000742.4(CHRNA2):c.401G>A (p.Arg134Lys) (rs150112824)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000186894 SCV000240465 uncertain significance not provided 2014-10-02 criteria provided, single submitter clinical testing p.Arg134Lys (AGG>AAG): c.401 G>A in exon 5 of the CHRNA2 gene (NM_000742.3). A variant of unknown significance has been identified in the CHRNA2 gene. The R134K variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The R134K substitution occurs at a position that is conserved across species. However, it is not predicted to be within the transmembrane region of the protein, where the vast majority of pathogenic missense mutations have been identified in association with epilepsy (Steinlein et al., 2010). In addition, R134K is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in CHILD-EPI panel(s).
Ambry Genetics RCV000720357 SCV000851234 likely benign Seizures 2018-02-01 criteria provided, single submitter clinical testing
Invitae RCV001068668 SCV001233793 uncertain significance Autosomal dominant nocturnal frontal lobe epilepsy 2019-11-25 criteria provided, single submitter clinical testing This sequence change replaces arginine with lysine at codon 134 of the CHRNA2 protein (p.Arg134Lys). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and lysine. This variant is present in population databases (rs150112824, ExAC 0.04%). This variant has not been reported in the literature in individuals with CHRNA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 204988). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a 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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