ClinVar Miner

Submissions for variant NM_172107.3(KCNQ2):c.997C>T (p.Arg333Trp) (rs118192215)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000187879 SCV000241479 pathogenic not provided 2016-06-03 criteria provided, single submitter clinical testing The R333W pathogenic variant in the KCNQ2 gene has been reported previously as a de novo variant in association with seizures (Schmitt et al., 2005; Kato et al., 2013; Milh et al., 2013). Additionally, a different amino acid substitution at the same codon (R333Q) was reported in association with benign familial neonatal seizures (Singh et al., 2003). The R333W variant 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. The R333W 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. This substitution is predicted to be within the C-terminal cytoplasmic domain and occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret R333W as a pathogenic variant .
GeneReviews RCV000678101 SCV000041667 pathogenic Early infantile epileptic encephalopathy 7 2016-03-31 no assertion criteria provided literature only EE (epileptic encephalopathy)
Invitae RCV000636293 SCV000757732 pathogenic Early infantile epileptic encephalopathy 2017-10-27 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 333 of the KCNQ2 protein (p.Arg333Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been reported to be de novo in multiple individuals affected with neonatal seizures (PMID: 16039833, 23621294, 23692823). ClinVar contains an entry for this variant (Variation ID: 21809). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this is a rare missense change that has been reported as de novo in multiple affected individuals.  For these reasons, this variant has been classified as Pathogenic.

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