ClinVar Miner

Submissions for variant NM_172107.3(KCNQ2):c.1216A>G (p.Arg406Gly) (rs1240338507)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000522556 SCV000621725 uncertain significance not provided 2017-10-19 criteria provided, single submitter clinical testing The c.1216 A>G variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant is not observed in large population cohorts (Lek et al., 2016). Severalin-silico splice prediction models predict that c.1216 A>G may destroy or damage the natural splice donor site for exon 10 and lead to abnormal gene splicing; however, in the absence of RNA/functional studies, the actual effect of c.1216 A>G on splicing is unknown. If c.1216 A>G does not alter splicing, it will result in the R406G missense change, which is a non-conservative amino acid substitution that is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution alters a conserved position that is predicted to be within theC-terminal cytoplasmic domain. In silico analysis predicts this variant is probably damaging to theprotein structure/function. Therefore, based on the currently available information, it is unclearwhether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000702823 SCV000831694 uncertain significance Early infantile epileptic encephalopathy 2018-02-19 criteria provided, single submitter clinical testing This sequence change replaces arginine with glycine at codon 406 of the KCNQ2 protein (p.Arg406Gly). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and glycine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with KCNQ2-related disease. ClinVar contains an entry for this variant (Variation ID: 452880). 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. 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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