rs587777264

Positions:

• chr9-135759686-G-A
• chr9-135759686-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_020822.3(KCNT1):​c.862G>A​(p.Gly288Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,452,748 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: KCNT1 NM_020822.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:15
• Conservation: PhyloP100: 9.63

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, 0.895
• PP5: Variant 9-135759686-G-A is Pathogenic according to our data. Variant chr9-135759686-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 126421.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-135759686-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.862G>A	p.Gly288Ser	missense_variant	11/31	ENST00000371757.7	NP_065873.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNT1	ENST00000371757.7	c.862G>A	p.Gly288Ser	missense_variant	11/31	1	NM_020822.3	ENSP00000360822	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1452748 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 721694

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.04e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 04, 2022	PS2, PS3, PS4, PM1, PM2 -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 10, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 31, 2023	Published functional studies demonstrate a damaging effect; KCNT1 channels with the G288S variant displayed increased maximal current density, a larger instantaneous component of current activation, and more hyperpolarized voltages, suggesting a gain-of-function effect (Rizzo et al., 2016); 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; In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 26784557, 24029078, 25482562, 26993267, 26597493, 30185235, 31532594, 31054490, 30782581, 31872048, 32167590, 31216405, 31170314, 36007526, 31440721, 35715422, 34114611, 34489640, 33851778, 33726816, 34020146) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	KCNT1: PS2:Very Strong, PM2, PS3:Supporting, PS4:Supporting -

Developmental and epileptic encephalopathy, 14 Pathogenic:5

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 25, 2020	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain-of-function is a known mechanism of disease for this gene (PMID 26784557). (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from a glycine to a serine (exon 11). (N) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools and is very highly conserved with a minor amino acid change. (P) 0600 - Variant is located in an annotated domain or motif (helical region of the ion transport domain). (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0801 - Strong previous evidence of pathogenicity in unrelated individuals (ClinVar, PMID 26140313, PMID 26784557). (P) 0905 - No segregation evidence has been identified for this variant. (N) 1002 - Moderate functional evidence supporting abnormal protein function. Functional studies with this variant demonstrated gain of function effects on channel function (PMID 26784557). (P) 1205 - Variant is maternally inherited. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -
Pathogenic, criteria provided, single submitter	clinical testing	Génétique des Maladies du Développement, Hospices Civils de Lyon	-	20A3406 -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 01, 2017	This mutation has been previously reported as disease-causing and was found twice in our laboratory de novo in individuals with infantile onset epileptic encephalopathy -
Pathogenic, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 14, 2024	- -

Developmental and epileptic encephalopathy, 14;C3554306:Autosomal dominant nocturnal frontal lobe epilepsy 5 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Mar 30, 2021	KCNT1 NM_020822.2 exon 11 p.Gly288Ser (c.862G>A): This variant has been reported in the literature in multiple individuals affected with epilepsy including MMPSI, ADNFLE and hypomyelinating leukodystrophy, several of whom were reported to be de novo (Selected publications: Ishii 2013 PMID:24029708, Kim 2014 PMID:25482562, Arai-Ichinoi 2016 PMID:26597493, Rizzo 2016 PMID:26784557, Liu 2018 PMID:30185235, Routier 2019 PMID:31170314).This variant is not present in large control database but is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:126421). Evolutionary conservation supports that this variant may impact the protein; computational predictive tools are unclear. Additionally, in vitro functional studies also suggest that this variant will impact the protein's activity (Kim 2014 PMID:25482562, Rizzo 2016 PMID:26784557). In summary, this variant is classified as pathogenic based on the data above. -
Pathogenic, criteria provided, single submitter	clinical testing	Suma Genomics, Suma Genomics	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 288 of the KCNT1 protein (p.Gly288Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with epilepsy, most of whom displayed malignant migrating partial seizures in infancy (PMID: 24029078, 26122718, 26140313, 26597493). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 126421). 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. For these reasons, this variant has been classified as Pathogenic. -

Autosomal dominant nocturnal frontal lobe epilepsy 5 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Dec 04, 2019

This variant is a recurrent gain of function alteration at a CG dinucleotide sequence in the pore region of the KCNT1 channel. The c.862G>A variant has been reported either as a de novo change or with unknown inheritance in several children with typical migrating malignant partial seizures in infancy (MMPSI) (PMID: 24029078, 26122718, 26140313, 30185235, 26993267, 25482562). Severe delayed myelination was reported in three of these patients (PMID: 26597493, 25482562). Two of these children had seizures that were initially resistant to different drugs, and responded to vagus nerve stimulation or clorazepate (PMID: 24029078). The c.862G>A, p.Gly288Ser variant was also identified in a child with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) (PMID: 25482562). Other KCNT1 missense variants, including a recurrent c.1283G>A alteration identified in three sporadic cases, are located at CG dinucleotides, suggesting that the CpG dinucleotide at these various KCNT1 positions, may be hot spots for point mutations. Functional characterization of the c.862G>A, p.Gly288Ser alteration using heterologous systems showed an increased KCNT1 current (PMID: 26784557, 25482562). The c.862G>A, p.Gly288Ser is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. In addition, it affects a highly conserved amino acid and is predicted to have a deleterious effect on protein function by the majority of in silico tools used for the analysis. The c.862G>A, p.Gly288Ser variant is reported in ClinVar (Variation ID: 126421). Based on the available evidence, the c.862G>A, p.Gly288Ser variant is classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.60	.;.;.;.;.;.;.;.;.;D;.
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.5	.;.;.;.;.;.;.;.;.;M;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-5.3	.;.;D;D;D;.;.;.;.;D;D
REVEL	Uncertain	0.48
Sift	Benign	0.086	.;.;T;T;T;.;.;.;.;T;T
Sift4G	Uncertain	0.054	T;T;T;D;T;T;T;T;T;T;T
Polyphen		0.95	.;.;.;.;.;.;.;.;.;P;.
Vest4		0.98
MutPred		0.53		.;.;.;.;.;.;.;Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);
MVP		0.95
MPC		1.6
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.62
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs587777264; hg19: chr9-138651532;