rs397515402
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong
The ENST00000371757.7(KCNT1):c.1283G>A(p.Arg428Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R428W) has been classified as Uncertain significance.
Frequency
Consequence
ENST00000371757.7 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
KCNT1 | NM_020822.3 | c.1283G>A | p.Arg428Gln | missense_variant | 13/31 | ENST00000371757.7 | NP_065873.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
KCNT1 | ENST00000371757.7 | c.1283G>A | p.Arg428Gln | missense_variant | 13/31 | 1 | NM_020822.3 | ENSP00000360822 | A2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 33
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Developmental and epileptic encephalopathy, 14 Pathogenic:6
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | May 20, 2023 | The observed missense c.1283G>A(p.Arg428Gln) variant in KCNT1 gene has been reported in heterozygous state in individuals affected with KCNT1 related diseases (Alsaleem M, et. al., 2019; Barcia G, et. al., 2019; Datta AN, et. al., 2019). Experimental studies have shown that this missense change affects KCNT1 function (Milligan CJ, et. al., 2014; Barcia G, et.al., 2012). The p.Arg428Gln variant is absent in gnomAD Exomes database. This variant has been reported to the ClinVar database as Pathogenic (multiple submissions). Multiple lines of computational evidence (Polyphen - probably damaging, SIFT - damaging and MutationTaster - disease causing) predict a damaging effect on protein structure and function for this variant. The amino acid change p.Arg428Gln in KCNT1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 428 is changed to a Gln changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 2012 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Sep 02, 2022 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with developmental and epileptic encephalopathy 14 (MIM#614959). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 26740507). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2: 3 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by clinical laboratories in ClinVar and observed in four unrelated individuals with malignant migrating partial seizures of infancy (MMPSI) (ClinVar, PMID: 23086397, 25042079). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Pathogenic, criteria provided, single submitter | clinical testing | New York Genome Center | Sep 19, 2020 | The heterozygous c.1283G>A (p.Arg428Gln) variant identified in the KCNT1 gene substitutes a well conserved Arginine for Glutamine at amino acid 428/1236 (coding exon 13/31). This variant is absent from gnomAD(v3.0) suggesting it is not a common benign variant in the populations represented in that database. In silico algorithms predict this variant to be Deleterious (Provean; score:-3.81) and Damaging (SIFT; score:0.003) tothe function of the canonical transcript. This variant is reported as Pathogenic in ClinVar (VarID:39593), and has been reported in many affected individuals in the literature [PMID:31872048, 23086397,31653631, 31208268, 30234941, others]. Functional studies suggest this variant leads to constitutive activation of the of the potassium channel [PMID:23086397, 24591078]. Given its absence in population databases, in silico predictions of a damaging effect, functional studies supporting pathogenicity, and its observation in many affected individuals in the literature, the c.1283G>A (p.Arg428Gln) variant identified in the KCNT1 gene is reported as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | Apr 03, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Génétique des Maladies du Développement, Hospices Civils de Lyon | May 29, 2018 | - - |
not provided Pathogenic:5
Pathogenic, no assertion criteria provided | clinical testing | Genetics and Genomic Medicine Centre, NeuroGen Healthcare, NeuroGen Healthcare | Jan 20, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Oct 30, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 16, 2022 | Published functional study demonstrates a strong gain-of-function in KCNT1 channel properties, which correlate with the more severe MMPSI phenotype (Milligan et al., 2014).; Not observed 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: 25482562, 27779742, 30182418, 23086397, 25042079, 30182498, 30782581, 31653631, 31872048, 31560846, 31532509, 32167590, 33258288, 33619735, 26748457, 24591078) - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2023 | KCNT1: PS2:Very Strong, PM2, PS4:Moderate, PS3:Supporting - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Apr 02, 2022 | - - |
Developmental and epileptic encephalopathy, 14;C3554306:Autosomal dominant nocturnal frontal lobe epilepsy 5 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 18, 2023 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 428 of the KCNT1 protein (p.Arg428Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with early infantile epileptic encephalopathy (PMID: 23086397, 25042079, 26140313, 27779742). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 39593). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on KCNT1 protein function. Experimental studies have shown that this missense change affects KCNT1 function (PMID: 23086397, 24591078). For these reasons, this variant has been classified as Pathogenic. - |
See cases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Jan 18, 2022 | ACMG classification criteria: PS3, PS4, PM2, PM6, PP3 - |
Autosomal dominant nocturnal frontal lobe epilepsy 5 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Dec 12, 2013 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at