Submissions for variant NM_020822.3(KCNT1):c.785G>A (p.Arg262Gln)

dbSNP: rs1554771469

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000497817	SCV000589778	pathogenic	not provided	2023-01-13	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); 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: 26122718, 31780880, 34440436, 29100083)
Invitae	RCV001058624	SCV001223209	pathogenic	Developmental and epileptic encephalopathy, 14; Autosomal dominant nocturnal frontal lobe epilepsy 5	2023-12-11	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 262 of the KCNT1 protein (p.Arg262Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with malignant partial seizures of infancy as well as intractable focal epilepsy with pervasive developmental disorder (PMID: 26122718; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 432096). 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 not expected to disrupt KCNT1 protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000497817	SCV001446666	likely pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000497817	SCV001500583	pathogenic	not provided	2021-01-01	criteria provided, single submitter	clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV001526614	SCV001737044	pathogenic	Autosomal dominant nocturnal frontal lobe epilepsy 5		criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002413365	SCV002670074	uncertain significance	Inborn genetic diseases	2017-09-11	criteria provided, single submitter	clinical testing	The p.R262Q variant (also known as c.785G>A), located in coding exon 10 of the KCNT1 gene, results from a G to A substitution at nucleotide position 785. The arginine at codon 262 is replaced by glutamine, an amino acid with highly similar properties. In one study, this variant was reported as a de novo occurrence in an individual of European origin with MMPSI (malignant migrating partial seizures of infancy), developmental delay, hypotonia, hyperreflexia, progressive microcephaly, and visual impairment (Møller RS et al. Epilepsia, 2015 Sep;56:e114-20). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.