9-135765706-G-A

Position:

• chr9-135765706-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_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: Genomes: not found (cov: 32)
• Consequence: KCNT1 ENST00000371757.7 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:14
• Conservation: PhyloP100: 9.77

Genes affected

KCNT1 (HGNC:18865): (potassium sodium-activated channel subfamily T member 1) Potassium channels represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. This gene encodes a sodium-activated potassium channel subunit which is thought to function in ion conductance and developmental signaling pathways. Mutations in this gene cause the early-onset epileptic disorders, malignant migrating partial seizures of infancy and autosomal dominant nocturnal frontal lobe epilepsy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2012]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.854
• PP5: Variant 9-135765706-G-A is Pathogenic according to our data. Variant chr9-135765706-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 39593.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-135765706-G-A is described in Lovd as [Pathogenic].

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

Significance: Pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	35
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.39	.;.;.;.;.;.;.;.;T;.
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.85	D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Uncertain	2.3	.;.;.;.;.;.;.;.;M;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.8	.;.;D;D;.;.;.;.;D;D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0030	.;.;D;D;.;.;.;.;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	.;.;.;.;.;.;.;.;D;.
Vest4		0.97
MutPred		0.60		.;.;.;.;.;.;Loss of MoRF binding (P = 0.0218);Loss of MoRF binding (P = 0.0218);Loss of MoRF binding (P = 0.0218);Loss of MoRF binding (P = 0.0218);
MVP		0.77
MPC		1.7
ClinPred		0.99	D
GERP RS		3.5
Varity_R		0.77
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs397515402; hg19: chr9-138657552;