Submissions for variant NM_172107.4(KCNQ2):c.881C>T (p.Ala294Val)

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000187883	SCV000241485	pathogenic	not provided	2018-04-27	criteria provided, single submitter	clinical testing	The A294V variant in the KCNQ2 gene has been reported previously as a de novo pathogenic variant in multiple unrelated individuals with early-onset epileptic encephalopathy (Milh et al., 2013; Kato et al., 2013, Allen et al., 2014). Additionally, the A294V variant has been observed as a de novo variant with confirmed parentage in a patient previously tested at GeneDx, and has been reported as a de novo variant in patients reported in other databases including ClinVar and LOVD. Functional studies of A294V indicate that the variant alters protein expression and function (Abidi et al., 2015). The A294V variant is not observed in large population cohorts (Lek et al., 2016). The A294V variant is a conservative amino acid substitution; however, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. A different pathogenic missense variant at the same position (A294G) and other variants nearby residues have been reported in individuals with KCNQ2-related disorders (Steinlein et al., 2007; Stenson et al., 2014). Therefore, the presence of A294V is consistent with the diagnosis of a KCNQ2-related disorder in this individual.
NeuroMeGen, Hospital Clinico Santiago de Compostela	RCV000203604	SCV000258966	pathogenic	Developmental and epileptic encephalopathy, 7		criteria provided, single submitter	clinical testing
Neurogenetics Laboratory - MEYER, AOU Meyer	RCV000417034	SCV000494522	pathogenic	Epileptic encephalopathy	2016-11-16	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000473067	SCV000543200	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2023-11-08	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 294 of the KCNQ2 protein (p.Ala294Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with early-onset epileptic encephalopathy (PMID: 23692823, 25052858, 25880994, 26007637, 27602407). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 205886). 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%. Experimental studies have shown that this missense change affects KCNQ2 function (PMID: 26007637, 27905566). For these reasons, this variant has been classified as Pathogenic.
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000187883	SCV000610764	pathogenic	not provided	2017-03-28	criteria provided, single submitter	clinical testing
Génétique des Maladies du Développement, Hospices Civils de Lyon	RCV000203604	SCV001164190	pathogenic	Developmental and epileptic encephalopathy, 7	2017-11-02	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000187883	SCV001247383	pathogenic	not provided	2017-03-01	criteria provided, single submitter	clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV001265545	SCV001443695	pathogenic	KCNQ2-related disorder	2019-12-20	criteria provided, single submitter	clinical testing	This variant has been previously reported as a de novo change in multiple unrelated individuals with early-onset epileptic encephalopathy (PMID: 23692823, 23621294, 25052858). Functional studies indicate that this variant alters subcellular localization of the encoded potassium channel (PMID: 26007637). It is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. The c.881C>T (p.Ala294Val) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. 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, the c.881C>T (p.Ala294Val) variant is classified as Pathogenic.
Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	RCV000203604	SCV002499561	pathogenic	Developmental and epileptic encephalopathy, 7	2022-04-18	criteria provided, single submitter	clinical testing	PS3, PS4, PP3
Neuberg Centre For Genomic Medicine, NCGM	RCV000203604	SCV002820256	pathogenic	Developmental and epileptic encephalopathy, 7		criteria provided, single submitter	clinical testing	The missense variant p.A294V in KCNQ2 (NM_172107.3) has been previously reported as a de novo variant in multiple affected individuals with early onset epileptic encephalopathy (Pisano et al, 2015; Allen et al, 2014; Epi4K Consortium et al, 2013). Functional studies indicate that variant alters protein expression and function (Abidi et al, 2015). The variant has been submitted to ClinVar as a Pathogenic variant. The p.A294V variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.A294V missense variant is predicted to be damaging by both SIFT and PolyPhen2. The alanine residue at codon 294 of KCNQ2 is conserved in all mammalian species. The nucleotide c.881 in KCNQ2 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic
Revvity Omics, Revvity	RCV000187883	SCV003818777	pathogenic	not provided	2021-12-02	criteria provided, single submitter	clinical testing
Génétique des Maladies du Développement, Hospices Civils de Lyon	RCV004577325	SCV005061432	pathogenic	Seizure	2024-06-16	criteria provided, single submitter	clinical testing
GeneReviews	RCV000203604	SCV000484590	not provided	Developmental and epileptic encephalopathy, 7		no assertion provided	literature only	EE (epileptic encephalopathy)
Center of Excellence for Medical Genomics, Chulalongkorn University	RCV000203604	SCV002564403	pathogenic	Developmental and epileptic encephalopathy, 7	2022-08-19	no assertion criteria provided	research
Center of Excellence for Medical Genomics, Chulalongkorn University	RCV002281568	SCV002570029	pathogenic	Seizures, benign familial neonatal, 1	2002-09-08	no assertion criteria provided	research
Channelopathy-Associated Epilepsy Research Center	RCV003315318	SCV004015100	not provided	Complex neurodevelopmental disorder		no assertion provided	literature only