Submissions for variant NM_172107.4(KCNQ2):c.841G>A (p.Gly281Arg)

dbSNP: rs794727813

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000179560	SCV000231822	uncertain significance	not provided	2014-06-06	criteria provided, single submitter	clinical testing
GeneDx	RCV000179560	SCV000241482	pathogenic	not provided	2021-12-20	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports a deleterious effect on splicing; 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: 27602407, 25590979, 24107868, 28867141, 28133863, 29056246, 25533962, 28135719, 29186148, 28191890, 30109124, 20437616, 31785789, Vanoye2021[article])
Labcorp Genetics (formerly Invitae), Labcorp	RCV001063168	SCV001228003	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2024-04-27	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 281 of the KCNQ2 protein (p.Gly281Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with early onset epileptic encephalopathies (PMID: 24107868, 25590979, 28133863, 30109124). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 198284). 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%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic.
Illumina Laboratory Services, Illumina	RCV003985079	SCV004801521	pathogenic	KCNQ2-related disorder	2020-09-29	criteria provided, single submitter	clinical testing	The KCNQ2 c.841G>A (p.Gly281Arg) variant is a missense variant that has been reported in a heterozygous state in at least five individuals with early onset epileptic encephalopathy; in at least four of these cases, the variant arose de novo (Weckhuysen et al. 2013; Zhu et al. 2015; Olson et al. 2017; Butler et al. 2017; Ostrander et al. 2018). The p.Gly281Arg variant is not found in the Genome Aggregation Database. This variant alters a conserved residue within the pore-forming intramembrane domain between the S5 and S6 transmembrane domains and is also within a 6-residue span thought to function as the selectivity filter. Multiple missense changes within this region have been reported as pathogenic, including another nucleotide change resulting in the same amino acid change as well as two additional amino acid changes at the same position (Landrum et al. 2015). Based on the collective evidence, the c.841G>A (p.Gly281Arg) variant is classified a pathogenic for KCNQ2-related disorders.
GeneReviews	RCV000678143	SCV000484584	not provided	Developmental and epileptic encephalopathy, 7		no assertion provided	literature only	EE (epileptic encephalopathy)
Channelopathy-Associated Epilepsy Research Center	RCV003315310	SCV004015087	not provided	Complex neurodevelopmental disorder		no assertion provided	literature only