ClinVar Miner

Submissions for variant NM_172107.4(KCNQ2):c.794C>T (p.Ala265Val) (rs587777219)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000187868 SCV000241468 pathogenic not provided 2018-08-22 criteria provided, single submitter clinical testing The A265V missense substitution has been previously reported as a variant in 2 individuals with Ohtahara syndrome (Kato et al., 2013; Saitsu et al., 2012). A265V has also been reported as a variant in an individual with early-onset epileptic encephalopathy (Kato et al., 2013). Additionally, different missense variant at the same position (A265P and A265T) have been reported as variants in association with neonatal epileptic encephalopathy (Milh et al., 2013; Weckhuysen et al., 2012). The A265V variant alters a highly conserved position in the pore loop between the 5th and 6th transmembrane domains of the protein.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000187868 SCV000575317 likely pathogenic not provided 2016-10-01 criteria provided, single submitter clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV000106299 SCV000803835 pathogenic Early infantile epileptic encephalopathy 7 2017-06-26 criteria provided, single submitter clinical testing
Ambry Genetics RCV000720048 SCV000850924 likely pathogenic Seizures 2017-05-01 criteria provided, single submitter clinical testing Rarity in general population databases (dbsnp, esp, 1000 genomes);In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Other strong data supporting pathogenic classification
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000768250 SCV000898776 likely pathogenic Benign familial neonatal seizures 1; Early infantile epileptic encephalopathy 7 2018-03-13 criteria provided, single submitter clinical testing KCNQ2 NM_172107.3 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 Early infantile epileptic encephalopathy 7 2019-04-27 criteria provided, single submitter clinical testing
Invitae RCV001056302 SCV001220740 pathogenic Early infantile epileptic encephalopathy 2019-07-26 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 265 of the KCNQ2 protein (p.Ala265Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in individuals affected with early onset epileptic encephalopathy (PMID: 22926866, 30185235). ClinVar contains an entry for this variant (Variation ID: 120176). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Ala265 amino acid residue in KCNQ2. Other variant(s) that disrupt this residue have been observed in individuals with KCNQ2-related conditions (PMID: 23692823, 27535030, 27602407, 27779742, 22275249), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000106299 SCV000143758 pathogenic Early infantile epileptic encephalopathy 7 2013-07-01 no assertion criteria provided literature only
GeneReviews RCV000106299 SCV000484579 pathogenic Early infantile epileptic encephalopathy 7 2016-03-31 no assertion criteria 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

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