rs587777219
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_172107.4(KCNQ2):c.794C>T(p.Ala265Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A265T) has been classified as Pathogenic.
Frequency
Consequence
NM_172107.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 19 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
KCNQ2 | NM_172107.4 | c.794C>T | p.Ala265Val | missense_variant | 5/17 | ENST00000359125.7 | NP_742105.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
KCNQ2 | ENST00000359125.7 | c.794C>T | p.Ala265Val | missense_variant | 5/17 | 1 | NM_172107.4 | ENSP00000352035 | A1 |
Frequencies
GnomAD3 genomes Cov.: 29
GnomAD4 exome Cov.: 32
GnomAD4 genome Cov.: 29
ClinVar
Submissions by phenotype
Developmental and epileptic encephalopathy, 7 Pathogenic:4Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | Jun 26, 2017 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 01, 2013 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Apr 27, 2019 | - - |
not provided, no classification provided | literature only | GeneReviews | - | EE (epileptic encephalopathy) - |
Pathogenic, criteria provided, single submitter | clinical testing | Molecular Genetics, Royal Melbourne Hospital | Oct 01, 2021 | 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. - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | Feb 14, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 09, 2022 | 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) - |
KCNQ2-related disorder Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals | Jun 27, 2017 | - - |
Inborn genetic diseases Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 01, 2017 | 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. - |
Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jun 25, 2023 | 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). - |
Intellectual disability Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Strasbourg University Hospital | Dec 01, 2017 | - - |
Seizures, benign familial neonatal, 1;C3150986:Developmental and epileptic encephalopathy, 7 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Nov 11, 2021 | 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. - |
Seizure Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Génétique des Maladies du Développement, Hospices Civils de Lyon | Jan 26, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at