ClinVar Miner

Submissions for variant NM_000742.4(CHRNA2):c.1099C>T (p.Arg367Trp) (rs751699392)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000344505 SCV000473186 benign Epilepsy, nocturnal frontal lobe, type 4 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
GeneDx RCV000486437 SCV000569182 uncertain significance not provided 2018-12-12 criteria provided, single submitter clinical testing The R367W variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R367W variant is observed in 13/34402 (0.04%) alleles from individuals of Latino background in large population cohorts (Lek et al., 2016). The R367W variant 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. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. However, this amino acid substitution is not predicted to occur within the transmembrane region of the protein, where the vast majority of pathogenic missense variants have been identified in association with epilepsy (Steinlein et al., 2010). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000535541 SCV000658045 uncertain significance Autosomal dominant nocturnal frontal lobe epilepsy 2019-12-12 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 367 of the CHRNA2 protein (p.Arg367Trp). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs751699392, ExAC 0.03%). This variant has not been reported in the literature in individuals with CHRNA2-related disease. ClinVar contains an entry for this variant (Variation ID: 362695). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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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