ClinVar Miner

Submissions for variant NM_172107.3(KCNQ2):c.619C>T (p.Arg207Trp) (rs74315391)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000623725 SCV000741598 pathogenic Inborn genetic diseases 2016-07-22 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
GeneDx RCV000187862 SCV000241462 pathogenic not provided 2018-02-06 criteria provided, single submitter clinical testing The R207W pathogenic variant has been previously reported in several unrelated families withneonatal seizures (Dedek et al., 2001; Blumkin et al., 2012). In addition to seizures, some individualswith the R207W variant were reported to have myoclonus, myokymia, intellectual disability orlearning disabilities, developmental delay, or ataxia. The R207W pathogenic variant is anon-conservative amino acid substitution, which is likely to impact secondary protein structure asthese residues differ in polarity, charge, size and/or other properties. This substitution alters a highlyconserved position in the S4 segment of the transmembrane domain of the KCNQ2 protein, andfunctional studies indicate it alters voltage-dependent gating and activation (Dedek et al., 2001).
GeneReviews RCV000678084 SCV000041645 pathogenic Benign familial neonatal seizures 1 2016-03-31 no assertion criteria provided literature only BFNE (benign familial neonatal epilepsy), Myokymia, EE (epileptic encephalopathy)
Invitae RCV000636312 SCV000757751 pathogenic Early infantile epileptic encephalopathy 2017-11-10 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 207 of the KCNQ2 protein (p.Arg207Trp). 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 individuals affected with Myokymia (PMID: 11572947). This variant has also been reported to segregate with Myokymia and neonatal epilepsy, persistent seizures and intellectual deficiency, and severe dyskinesia in several families (PMID: 11572947, 24375629, 22169383). ClinVar contains an entry for this variant (Variation ID: 7386). Experimental studies have shown that this missense change causes a shift of voltage-dependent activation of KCNQ2 and a dramatic slowing of activation upon depolarization (PMID: 11572947, 22455920). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000007811 SCV000028012 pathogenic Seizures, benign familial neonatal, 1, and/or myokymia 2007-11-27 no assertion criteria provided literature only

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