Submissions for variant NM_020822.3(KCNT1):c.2882G>A (p.Arg961His)

dbSNP: rs200694691

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000117366	SCV000151549	uncertain significance	not provided	2013-10-09	criteria provided, single submitter	clinical testing
Neurogenetics Laboratory - MEYER, AOU Meyer	RCV000416953	SCV000494566	uncertain significance	Focal epilepsy	2016-11-16	criteria provided, single submitter	clinical testing
GeneDx	RCV000117366	SCV000582127	likely pathogenic	not provided	2022-10-14	criteria provided, single submitter	clinical testing	Identified in an individual with epileptic encephalopathy who inherited the variant from a parent; however, clinical information about the parent was not provided (Zhu et al., 2017); 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: 30234941, 35940594, 29186148, 34537872, 34114611, 35116000, 32167590, 31054119)
Eurofins Ntd Llc (ga)	RCV000117366	SCV000702631	uncertain significance	not provided	2018-08-14	criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV000117366	SCV000842548	uncertain significance	not provided	2017-11-24	criteria provided, single submitter	clinical testing
Invitae	RCV001061890	SCV001226652	pathogenic	Developmental and epileptic encephalopathy, 14; Autosomal dominant nocturnal frontal lobe epilepsy 5	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 961 of the KCNT1 protein (p.Arg961His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with KCNT1-related conditions (PMID: 29186148, 34114611; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 129360). 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 Human Genetics, University of Leipzig Medical Center	RCV002256047	SCV002526704	uncertain significance	Developmental and epileptic encephalopathy, 14	2022-05-17	criteria provided, single submitter	clinical testing	Despite strong evidence for its pathogenicity, this variant has to be classified as of unknown significance, according to the ACMG-criteria (Richards et al., 2015)_x000D_ Criteria applied: PS4_MOD, PM2_SUP, PP3
Ambry Genetics	RCV002433609	SCV002747121	uncertain significance	Inborn genetic diseases	2017-11-03	criteria provided, single submitter	clinical testing	The p.R961H variant (also known as c.2882G>A), located in coding exon 25 of the KCNT1 gene, results from a G to A substitution at nucleotide position 2882. The arginine at codon 961 is replaced by histidine, an amino acid with highly similar properties. 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.
Baylor Genetics	RCV002256047	SCV003836250	pathogenic	Developmental and epileptic encephalopathy, 14	2022-03-09	criteria provided, single submitter	clinical testing
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV003338416	SCV004047042	likely pathogenic	Autosomal dominant nocturnal frontal lobe epilepsy 5		criteria provided, single submitter	clinical testing	The KCNT1 missense c.2882G>A variant has been reported in individuals affected with Epilepsy nocturnal frontal lobe, 5 (Borlot F et. al., 2020; Zhu X et. al., 2017) and it has been observed de novo in at least one of these individuals. This variant has been reported to the ClinVar database as Conflicting interpretations of pathogenicity (Likely pathogenic and Variant of uncertain significance). The p.Arg961His variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. The amino acid Arg at position 961 is changed to a His changing protein sequence and it might alter its composition and physicochemical properties. The variant is predicted to be damaging by PolyPhen2 and the residue is conserved across species. The amino acid change p.Arg961His in KCNT1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The currently available evidence indicates that the variant is Pathogenic, but additional data are needed to prove that conclusively. For these reasons, this variant has been classified as Likely Pathogenic.