Submissions for variant NM_172107.4(KCNQ2):c.997C>T (p.Arg333Trp)

dbSNP: rs118192215

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000187879	SCV000241479	pathogenic	not provided	2021-08-27	criteria provided, single submitter	clinical testing	The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 27602407, 32593896, 20437616, 30182498, 28191890, 28135719, 28867141, 16039833, 23692823, 23621294)
Invitae	RCV000636293	SCV000757732	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2023-12-23	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 333 of the KCNQ2 protein (p.Arg333Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with neonatal seizures (PMID: 16039833, 23621294, 23692823). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 21809). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KCNQ2 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV003315224	SCV004014873	pathogenic	KCNQ2-Related Disorders		criteria provided, single submitter	clinical testing	The c.997C>T (p.Arg333Trp) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. This variant has been previously reported as a de novo and heterozygous change in patients with early onset epileptic encephalopathies (PMID: 16039833, 23621294, 23692823, 30182498, 31440721, 32593896). The c.997C>T (p.Arg333Trp) variant is located in a mutational hotspot for pathogenic variations associated with KCNQ2-related disorders (PMID: 30008368). A different amino acid change at the same residue, KCNQ2 c.998G>A (p.Arg333Gln), has been previously reported in individuals with benign neonatal seizures (PMID: 14534157, 29215089, 31152295, 31832524, 33897753). Functional studies indicate that the p.Arg333Trp variant reduced axonal surface expression of potassium voltage-gated channels, reduced the sensitivity of the channels to phosphatidylinositol-4,5-bisphosphate (PIP2) stimulation, and disrupted the ability to inhibit excitability in hippocampal neurons (PMID: 30008368). The c.997C>T (p.Arg333Trp) variant is absent from the gnomAD population database and thus is presumed to be rare. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, c.997C>T (p.Arg333Trp) is classified as Pathogenic.
GeneReviews	RCV000678101	SCV000041667	not provided	Developmental and epileptic encephalopathy, 7		no assertion provided	literature only	EE (epileptic encephalopathy)
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000187879	SCV001928866	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000187879	SCV001956937	pathogenic	not provided		no assertion criteria provided	clinical testing
Channelopathy-Associated Epilepsy Research Center	RCV003315305	SCV004015106	not provided	Complex neurodevelopmental disorder		no assertion provided	literature only