Submissions for variant NM_172107.4(KCNQ2):c.587C>T (p.Ala196Val)

dbSNP: rs118192199

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Molecular Medicine, Children’s Hospital of Fudan University	RCV001030036	SCV001190554	pathogenic	Developmental and epileptic encephalopathy, 7	2019-05-10	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001066784	SCV001231804	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2024-11-13	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 196 of the KCNQ2 protein (p.Ala196Val). 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 and early onset epileptic encephalopathy (PMID: 17475800, 23360469, 23708187). 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: 21792). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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: 17475800). For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV001092637	SCV001249242	pathogenic	not provided	2019-03-01	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV001030036	SCV001911527	pathogenic	Developmental and epileptic encephalopathy, 7	2021-09-16	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001092637	SCV002023231	pathogenic	not provided	2019-06-07	criteria provided, single submitter	clinical testing
GeneDx	RCV001092637	SCV004036384	pathogenic	not provided	2023-06-27	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate a damaging effect on channel function (Soldovieri et al., 2007); Missense variants in this gene are often considered pathogenic (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25880994, 24375629, 11690625, 32411386, 34489640, 23360469, 23708187, 16686649, 28717674, 27888506, 17475800)
PreventionGenetics, part of Exact Sciences	RCV004528127	SCV004111964	pathogenic	KCNQ2-related disorder	2023-01-22	criteria provided, single submitter	clinical testing	The KCNQ2 c.587C>T variant is predicted to result in the amino acid substitution p.Ala196Val. This variant has been reported in multiple individuals with KCNQ2 related disorders (Zara et al. 2013. PubMed ID: 23360469; Carvill et al. 2013. PubMed ID: 23708187; Bennett et al. 2017. PubMed ID: 28717674). It has been documented as a de novo finding, and functional studies support its pathogenicity (Soldovieri et al. 2007. PubMed ID: 17475800; Wang et al. 2020. PubMed ID: 32411386; Jiang et al. 2021. PubMed ID: 34489640). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV001092637	SCV004225338	pathogenic	not provided	2022-03-08	criteria provided, single submitter	clinical testing	PP1, PP3, PM2, PM6, PS3, PS4_moderate
GeneReviews	RCV000678083	SCV000041644	not provided	Seizures, benign familial neonatal, 1		no assertion provided	literature only	BFNE (benign familial neonatal epilepsy), Rolandic Seizures, Infantile spams.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001092637	SCV001740336	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001092637	SCV001931984	pathogenic	not provided		no assertion criteria provided	clinical testing
Channelopathy-Associated Epilepsy Research Center	RCV003315300	SCV004015058	not provided	Complex neurodevelopmental disorder		no assertion provided	literature only