ClinVar Miner

Submissions for variant NM_172107.4(KCNQ2):c.629G>A (p.Arg210His) (rs886041262)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000408715 SCV000928334 pathogenic Early infantile epileptic encephalopathy 7 2019-07-17 criteria provided, single submitter clinical testing
GeneDx RCV000267864 SCV000329586 pathogenic not provided 2018-04-13 criteria provided, single submitter clinical testing The R210H pathogenic variant has been reported multiple times as a de novo change in individuals with epileptic encephalopathy (Weckhuysen et al., 2013; Pisano et al., 2015; Reid et al., 2016). The R210H variant is not observed in large population cohorts (Lek et al., 2016). The R210H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution is predicted to be within the transmembrane segment S4 voltage sensor. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. In addition, a different missense variant in the same residue (R210C) as well as multiple missense variants in nearby residues 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. Therefore, we consider R210H to be a pathogenic variant.
GeneReviews RCV000408715 SCV000484546 pathogenic Early infantile epileptic encephalopathy 7 2016-03-31 no assertion criteria provided literature only EE (epileptic encephalopathy)
Invitae RCV000699430 SCV000828141 pathogenic Early infantile epileptic encephalopathy 2018-03-20 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 210 of the KCNQ2 protein (p.Arg210His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to be de novo in individuals affected with early infantile epileptic encephalopathy (PMID: 24371303, 26446091, 24107868, 25880994 ). ClinVar contains an entry for this variant (Variation ID: 279931). Experimental studies have shown that this missense change disrupts the normal channel conductance activity of the KCNQ2 protein (PMID: 28283543). For these reasons, this variant has been classified as Pathogenic.

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