Total submissions: 9
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Eurofins Ntd Llc |
RCV000187866 | SCV000230473 | pathogenic | not provided | 2015-02-18 | criteria provided, single submitter | clinical testing | |
Gene |
RCV000187866 | SCV000241466 | pathogenic | not provided | 2023-03-25 | criteria provided, single submitter | clinical testing | Published functional studies demonstrate that R213W decreases the stability of the ion channel and decreases voltage sensitivity (Miceli et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); The majority of missense variants in this gene are considered pathogenic; 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: 20437616, 24375629, 24318194, 22455920, 18353052, 29056246, 28038823, 27535030, 26993267, 25959266, 28717674, 27779742, 17765802, 22275249, 32139178, 31512412, 32917465, 32712949, 33726816, 31440721, 33659638, 31440733, 30440138, 23440208) |
Invitae | RCV000234346 | SCV000291572 | pathogenic | Early infantile epileptic encephalopathy with suppression bursts | 2023-11-24 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 213 of the KCNQ2 protein (p.Arg213Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with benign familial neonatal seizures or early-onset epilepsy (PMID: 18353052, 27779742, 29056246). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 21795). 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: 23440208). This variant disrupts the p.Arg213 amino acid residue in KCNQ2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22275249, 25982755). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |
Equipe Genetique des Anomalies du Developpement, |
RCV000178400 | SCV000700169 | pathogenic | Developmental and epileptic encephalopathy, 7 | 2017-02-02 | criteria provided, single submitter | clinical testing | |
Mendelics | RCV000990336 | SCV001141279 | pathogenic | Seizures, benign familial neonatal, 1 | 2019-05-28 | criteria provided, single submitter | clinical testing | |
Ce |
RCV000187866 | SCV001249239 | pathogenic | not provided | 2018-11-01 | criteria provided, single submitter | clinical testing | |
Institute of Human Genetics, |
RCV000178400 | SCV001934249 | pathogenic | Developmental and epileptic encephalopathy, 7 | 2020-10-19 | criteria provided, single submitter | clinical testing | This variant was identified as de novo (maternity and paternity confirmed). |
Ambry Genetics | RCV002354168 | SCV002655405 | pathogenic | Inborn genetic diseases | 2019-11-06 | criteria provided, single submitter | clinical testing | The p.R213W pathogenic mutation (also known as c.637C>T), located in coding exon 4 of the KCNQ2 gene, results from a C to T substitution at nucleotide position 637. The arginine at codon 213 is replaced by tryptophan, an amino acid with dissimilar properties. This mutation was detected in two siblings with BFNC (benign familial neonatal convulsions). Neither parent carried the mutation, and after parental relationships were confirmed, authors suspected germline mosaicism (Sadewa AH et al. Pediatr Int, 2008 Apr;50:167-71). In another study, this mutation was detected in an individual with EOEE (early onset epileptic encephalopathy) and was found to be mosaic in a parent (Milh M et al. Am. J. Med. Genet. A, 2015 Oct;167A:2314-8). In addition, this mutation has been detected in individuals with: non-specific epileptic encephalopathy, neonatal seizure disorder, congenital variant of Rett syndrome, and EIMFS (Epilepsy of Infancy with Migrating Focal Seizures) (Butler KM et al. Pediatr. Neurol., 2017 Dec;77:61-66; Zhang Q et al. Clin. Genet., 2017 May;91:717-724; Wang J et al. Mol Genet Genomic Med, 2019 Sep;:e968; Ware TL et al. Epilepsia Open, 2019 Sep;4:504-510). One functional study showed that this mutation destabilized the potassium ion channel and decreased voltage sensitivity (Miceli F et al. Proc. Natl. Acad. Sci. U.S.A., 2013 Mar;110:4386-91). In addition, a different alteration located at the same position, p.R213Q, has been detected in multiple individuals with epilepsy (Weckhuysen S et al. Ann. Neurol., 2012 Jan;71:15-25; Trump N et al. J. Med. Genet., 2016 May;53:310-7) and has been shown to result in a decrease in channel voltage sensitivity (Miceli F et al. Proc. Natl. Acad. Sci. U.S.A., 2013 Mar;110:4386-91; Orhan G et al. Ann. Neurol., 2014 Mar;75:382-94). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
Gene |
RCV000178400 | SCV000041649 | not provided | Developmental and epileptic encephalopathy, 7 | no assertion provided | literature only | BFNE (benign familial neonatal epilepsy), EE (epileptic encephalopathy) |