Submissions for variant NM_020822.3(KCNT1):c.1421G>A (p.Arg474His)

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
UCLA Clinical Genomics Center, UCLA	RCV000032795	SCV000255509	pathogenic	Developmental and epileptic encephalopathy, 14	2014-02-04	criteria provided, single submitter	clinical testing
GeneDx	RCV000414268	SCV000490584	pathogenic	not provided	2023-07-13	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect, with increased channel activity but minor change in protein expression compared to the wild type variant (Kim et al., 2014); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29455050, 32167590, 25482562, 25326637, 23086397, 26140313, 24315024, 25568878, 27779742, 27081515, 27652284, 28488083, 28987752, 29291456, 31872048, 31532509, 32081855, 31054119, 31532594, 31349857, 32139178, 32505479, 34489640, 33822359, 34055682, 35571021, 35365919, 36007526, 34580403, 31440721, 35715422, 34114611, 35346832, 37062836, 37177976)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000546032	SCV000652908	pathogenic	Developmental and epileptic encephalopathy, 14; Autosomal dominant nocturnal frontal lobe epilepsy 5	2023-12-22	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 474 of the KCNT1 protein (p.Arg474His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with early onset epileptic encephalopathies, malignant migrating partial seizures of infancy, migrating focal seizure of infancy, and/or nocturnal frontal lobe epilepsy (PMID: 23086397, 25326637, 25482562, 26140313, 26740507). In at least one individual the variant was observed to be de novo. This variant is also known as c.1286G>A:p.R429H. ClinVar contains an entry for this variant (Variation ID: 39595). 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. This variant disrupts the p.Arg474 amino acid residue in KCNT1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26140313, 27652284). 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.
Ambry Genetics	RCV000624507	SCV000741205	pathogenic	Inborn genetic diseases	2015-11-20	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000032795	SCV000807326	pathogenic	Developmental and epileptic encephalopathy, 14	2023-03-19	criteria provided, single submitter	clinical testing
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000032795	SCV000928394	likely pathogenic	Developmental and epileptic encephalopathy, 14	2018-12-03	criteria provided, single submitter	clinical testing	PS3, PM2, PM5, PP3
Génétique des Maladies du Développement, Hospices Civils de Lyon	RCV000032795	SCV001164145	pathogenic	Developmental and epileptic encephalopathy, 14	2017-02-14	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000414268	SCV001247123	pathogenic	not provided	2019-05-01	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000032795	SCV001429527	pathogenic	Developmental and epileptic encephalopathy, 14	2017-06-21	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000032795	SCV002820286	likely pathogenic	Developmental and epileptic encephalopathy, 14		criteria provided, single submitter	clinical testing	The missense variant p.R474H in KCNT1 (NM_020822.3) has been previously reported as a de novo variant in individuals with malignant migrating partial seizures of infancy (MMPSI) and West syndrome (Lee et al 2014; Barcia et al 2012; Ohba et al 2015). A different missense variant at the same position (R474C) has been reported as a pathogenic variant in individuals with epilepsy of infancy with migrating focal seizures (EIFMS) (Ohba et al, 2015). The variant has been submitted to ClinVar as Pathogenic. The p.R474H variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.R474H missense variant is predicted to be damaging by both SIFT and PolyPhen2. The arginine residue at codon 474 of KCNT1 is conserved in all mammalian species. The nucleotide c.1421 in KCNT1 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000032795	SCV003807651	pathogenic	Developmental and epileptic encephalopathy, 14	2022-07-25	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderated, PM5 moderated, PM6 moderated, PP3 supporting
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000414268	SCV004026310	pathogenic	not provided	2023-03-21	criteria provided, single submitter	clinical testing	PS4, PP3, PM2_SUP, PM5
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV001253027	SCV004046120	pathogenic	Autosomal dominant nocturnal frontal lobe epilepsy 5		criteria provided, single submitter	clinical testing	This variant has been previously reported as a de novo change in patients with malignant migrating partial seizures in infancy with and without systemic pulmonary collateral arteries (MMPSI) (PMID: 23086397, 28987752), malignant migrating focal seizures in infancy (PMID: 27779742), epilepsy of infancy with migrating focal seizures (EIMFS) (PMID: 31872048, 31532509, 32167590, 32505479) and sleep-related hypermotor epilepsy (PMID: 32167590). Overexpression studies demonstrated that this variant leads to increased Kcnt1 current amplitude (PMID: 25482562). It is absent from the gnomAD population database and thus is presumed to be rare. The c.1421G>A (p.Arg474His) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.1421G>A (p.Arg474His) variant is classified as Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003390714	SCV004119738	pathogenic	KCNT1-related disorder	2023-04-12	criteria provided, single submitter	clinical testing	The KCNT1 c.1421G>A variant is predicted to result in the amino acid substitution p.Arg474His. This variant has been reported many times to have arisen de novo in individuals with infantile-onset epilepsy (see for examples Barcia et al. 2012. PubMed ID: 23086397; Ohba et al. 2015. PubMed ID: 26140313). A functional study found that the p.Arg474His variant causes an increase in activity of the encoded potassium channel (Kim et al. 2014. PubMed ID: 25482562), indicating a gain of function mechanism. This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating it is rare or absent in the general population. This variant has been interpreted as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/39595). Given all the evidence, we too interpret c.1421G>A (p.Arg474His) as pathogenic.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV004018702	SCV005016563	pathogenic	Developmental and epileptic encephalopathy, 15	2024-03-14	criteria provided, single submitter	clinical testing
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV000546032	SCV005418630	pathogenic	Developmental and epileptic encephalopathy, 14; Autosomal dominant nocturnal frontal lobe epilepsy 5		criteria provided, single submitter	clinical testing	PM2_Supporting+PP3+PM5+PS2_VeryStrong+PS4+PP4
OMIM	RCV000032795	SCV000056563	pathogenic	Developmental and epileptic encephalopathy, 14	2012-11-01	no assertion criteria provided	literature only
Pediatric Genetics Clinic, Sheba Medical Center	RCV000032795	SCV001712189	pathogenic	Developmental and epileptic encephalopathy, 14	2021-05-13	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Strasbourg University Hospital	RCV002274887	SCV002562819	pathogenic	Seizure		no assertion criteria provided	clinical testing
Center of Excellence for Medical Genomics, Chulalongkorn University	RCV001253027	SCV002570033	pathogenic	Autosomal dominant nocturnal frontal lobe epilepsy 5	2002-09-08	no assertion criteria provided	research
Genetics and Genomic Medicine Centre, NeuroGen Healthcare, NeuroGen Healthcare	RCV000414268	SCV004174993	pathogenic	not provided	2022-10-02	no assertion criteria provided	clinical testing