Submissions for variant NM_172107.4(KCNQ2):c.793G>A (p.Ala265Thr)

dbSNP: rs794727740

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000187875	SCV000231221	likely pathogenic	not provided	2014-10-22	criteria provided, single submitter	clinical testing
GeneDx	RCV000187875	SCV000241475	pathogenic	not provided	2023-03-23	criteria provided, single submitter	clinical testing	Missense variants in this gene are often considered pathogenic (HGMD); 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: 23692823, 28133863, 28867141, 29056246, 28191890, 24318194, 27779742, 25533962, 28135719, 27535030, 33084218, 31957018, 31785789, 33811133, 31440721, 34992632, 27602407)
Genetic Services Laboratory, University of Chicago	RCV000192955	SCV000247667	likely pathogenic	Seizure	2014-06-03	criteria provided, single submitter	clinical testing
Invitae	RCV000555510	SCV000634076	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2023-08-17	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 265 of the KCNQ2 protein (p.Ala265Thr). This variant is present in population databases (rs794727740, gnomAD 0.0009%). This missense change has been observed in individual(s) with early onset epileptic encephalopathy (PMID: 23692823, 27535030, 27602407, 27779742). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 197891). 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. 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, 22926866). 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.
CeGaT Center for Human Genetics Tuebingen	RCV000187875	SCV001247386	pathogenic	not provided	2018-07-01	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000187875	SCV001448017	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000179032	SCV003921969	pathogenic	Developmental and epileptic encephalopathy, 7	2020-11-05	criteria provided, single submitter	clinical testing	0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with early infantile epileptic encephalopathy 7 (MIM#613720) (PMID: 24318194). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to threonine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0701 - Other missense variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Two different variants in the same codon resulting in changes to a valine and proline have been previously reported as pathogenic in patients with early infantile epileptic encephalopathy (ClinVar, PMID: 31552204). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been previously reported as pathogenic in patients with early infantile epileptic encephalopathy (ClinVar, PMID: 29056246, PMID: 27535030). (SP) 1102 - Strong phenotype match for this individual. (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
NeuroMeGen, Hospital Clinico Santiago de Compostela	RCV000179032	SCV000258972	pathogenic	Developmental and epileptic encephalopathy, 7		no assertion criteria provided	clinical testing
GeneReviews	RCV000179032	SCV000484577	not provided	Developmental and epileptic encephalopathy, 7		no assertion provided	literature only	EE (epileptic encephalopathy)