ClinVar Miner

Submissions for variant NM_172107.4(KCNQ2):c.1657C>T (p.Arg553Trp) (rs759584387)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000187912 SCV000241514 pathogenic not provided 2017-02-15 criteria provided, single submitter clinical testing The R553W pathogenic variant in the KCNQ2 gene has been reported previously as a de novo change in an individual with early-onset epileptic encephalopathy (Kato et al., 2013). It has also been reported as a de novo change in an individual with benign neonatal seizures (Hortiguela et al., 2016). The R553W variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R553W 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 occurs at a conserved position predicted to be within the C-terminal cytoplasmic domain, and different missense variants in the same residue (R553L, R553Q) as well as missense variants in nearby residues (K552T, K554N, K556E) have been reported in the Human Gene Mutation Database in association with KCNQ2-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. In silico analysis predicts this variant is probably damaging to the protein structure/function.
GeneReviews RCV000678185 SCV000484634 pathogenic Early infantile epileptic encephalopathy 7 2016-03-31 no assertion criteria provided literature only EE (epileptic encephalopathy)
Invitae RCV000706752 SCV000835821 pathogenic Early infantile epileptic encephalopathy 2018-07-04 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 553 of the KCNQ2 protein (p.Arg553Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs759584387, ExAC 0.002%). This variant has been reported to be de novo in individuals affected with early infantile epileptic encephalopathy and benign neonatal seizures (PMID: 23621294, 27535030). ClinVar contains an entry for this variant (Variation ID: 205913). 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"). A different missense substitution at this codon (p.Arg553Leu) has been determined to be pathogenic (PMID: 23621294). This suggests that the arginine residue is critical for KCNQ2 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
NeuroMeGen,Hospital Clinico Santiago de Compostela RCV000203596 SCV000258979 pathogenic Benign familial neonatal seizures 1 criteria provided, single submitter clinical testing

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