Submissions for variant NM_172107.4(KCNQ2):c.794C>T (p.Ala265Val)

dbSNP: rs587777219

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000187868	SCV000241468	pathogenic	not provided	2022-03-09	criteria provided, single submitter	clinical testing	The majority of missense variants in this gene are considered pathogenic (HGMD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22926866, 23621294, 28867141, 30185235, 31036916, 31418850, 32362866, 32139178, 32917465, 33098118, 32712949, 31785789, 27602407)
CeGaT Center for Human Genetics Tuebingen	RCV000187868	SCV000575317	pathogenic	not provided	2020-08-01	criteria provided, single submitter	clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000106299	SCV000803835	pathogenic	Developmental and epileptic encephalopathy, 7	2017-06-26	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002316289	SCV000850924	likely pathogenic	Inborn genetic diseases	2017-05-01	criteria provided, single submitter	clinical testing	The p.A265V variant (also known as c.794C>T), located in coding exon 5 of the KCNQ2 gene, results from a C to T substitution at nucleotide position 794. The alanine at codon 265 is replaced by valine, an amino acid with similar properties. This variant as been observed de novo in unrelated patients with early onset epileptic encephalopathy (Saitsu H et al. Ann. Neurol., 2012 Aug;72:298-300; Milh M et al. Am. J. Med. Genet. A, 2015 Oct;167A:2314-8). 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.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000768250	SCV000898776	likely pathogenic	Seizures, benign familial neonatal, 1; Developmental and epileptic encephalopathy, 7	2021-11-11	criteria provided, single submitter	clinical testing	KCNQ2 NM_172107 exon 5 p.Ala265Val (c.794C>T): This variant has been reported in the literature in at least 2 individuals (1 with early onset epileptic encephalopathy and 1 with Ohtahara syndrome), both of whom were reported as de novo (Saitsu 2012 PMID:2292866, Kato 2013 PMID:23621294). This variant is not present in large control databases. This variant is present in ClinVar (Variation ID:120176). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. Of note, other variants at this position (p.Ala265Thr, p.Ala265Pro) have been reported in association with disease, suggesting that this codon has functional significance. In summary, data on this variant is highly suspicious for disease, but requires further evidence for pathogenicity. Therefore, this variant classified as likely pathogenic.
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000106299	SCV000930365	likely pathogenic	Developmental and epileptic encephalopathy, 7	2019-04-27	criteria provided, single submitter	clinical testing
Invitae	RCV001056302	SCV001220740	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2023-06-25	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ala265 amino acid residue in KCNQ2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22275249, 23692823, 27535030, 27602407, 27779742). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 120176). This missense change has been observed in individual(s) with early onset epileptic encephalopathy (PMID: 22926866, 30185235). 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 alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 265 of the KCNQ2 protein (p.Ala265Val).
Molecular Genetics, Royal Melbourne Hospital	RCV000106299	SCV002498638	pathogenic	Developmental and epileptic encephalopathy, 7	2021-10-01	criteria provided, single submitter	clinical testing	This sequence change in KCNQ2 is predicted to replace alanine with valine at codon 265 (p.(Ala265Val)). The alanine residue is highly conserved (100 vertebrates, UCSC), and is located in the transmembrane ion transport domain in a region, amino acids 1-369, that is highly constrained. There is a moderate physicochemical difference between alanine and valine. This variant is absent from gnomAD v2.1 and v3.1. This variant has been identified as a de novo occurrence with confirmed parental relationships in 3 individuals and as a de novo occurrence with unconfirmed parental relationships in 2 individuals with Ohtahara syndrome or undetermined neonatal epileptic encephalopathy (NEE; PMID: 22926866, 23621294, 25959266, 32362866, 34354098). It has also been identified in 2 individuals with NEE and unknown de novo status (PMID: 25959266, 34395220). Multiple lines of computational evidence have conflicting predictions for the missense substitution (4/6 algorithms predict deleterious). Another missense variant c.793G>A, p.Ala265Thr in the same codon has been classified as pathogenic for NEE (ClinVar Variation ID: 197891). Based on the classification scheme RMH Modified ACMG Guidelines v1.4.0, this variant is classified as PATHOGENIC. Following criteria are met: PS2/PM6_Strong, PM1, PM5, PS4_Supporting, PM2_Supporting.
OMIM	RCV000106299	SCV000143758	pathogenic	Developmental and epileptic encephalopathy, 7	2013-07-01	no assertion criteria provided	literature only
GeneReviews	RCV000106299	SCV000484579	not provided	Developmental and epileptic encephalopathy, 7		no assertion provided	literature only	EE (epileptic encephalopathy)
Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	RCV000578260	SCV000680117	pathogenic	KCNQ2-Related Disorders	2017-06-27	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Strasbourg University Hospital	RCV001089803	SCV001244215	pathogenic	Intellectual disability	2017-12-01	no assertion criteria provided	clinical testing