Submissions for variant NM_172107.4(KCNQ2):c.1742G>A (p.Arg581Gln)

dbSNP: rs118192235

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000187921	SCV000241523	pathogenic	not provided	2020-09-04	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20437616, 29186148, 25262651, 27864847, 28973083, 29141310, 28133863)
Neurogenetics Laboratory - MEYER, AOU Meyer	RCV000416983	SCV000494518	likely pathogenic	Epileptic encephalopathy	2016-11-16	criteria provided, single submitter	clinical testing
Invitae	RCV000792605	SCV000931911	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2022-10-18	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 21769). This missense change has been observed in individual(s) with early onset epileptic encephalopathy (PMID: 27864847, 28133863, 28973083; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 581 of the KCNQ2 protein (p.Arg581Gln). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg581 amino acid residue in KCNQ2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25262651, 29186148). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing.
Baylor Genetics	RCV000678062	SCV001530616	pathogenic	Seizures, benign familial neonatal, 1	2018-04-04	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Ambry Genetics	RCV002399331	SCV002711335	likely pathogenic	Inborn genetic diseases	2018-03-06	criteria provided, single submitter	clinical testing	The p.R581Q variant (also known as c.1742G>A), located in coding exon 15 of the KCNQ2 gene, results from a G to A substitution at nucleotide position 1742. The arginine at codon 581 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been detected as de novo in several individuals with early onset encephalopathy and/or clonic spasms and focal seizures (Olson HE et al. Ann. Neurol., 2017 Mar;81:419-429; Meng L et al. JAMA Pediatr, 2017 Dec;171:e173438; Parrini E et al. Hum. Mutat., 2017 Feb;38:216-225). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
GeneReviews	RCV000678062	SCV000041621	not provided	Seizures, benign familial neonatal, 1		no assertion provided	literature only
Channelopathy-Associated Epilepsy Research Center	RCV003315296	SCV004015029	not provided	Complex neurodevelopmental disorder		no assertion provided	literature only