ClinVar Genomic variation as it relates to human health
NM_020822.3(KCNT1):c.1283G>A (p.Arg428Gln)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_020822.3(KCNT1):c.1283G>A (p.Arg428Gln)
Variation ID: 39593 Accession: VCV000039593.46
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 9q34.3 9: 135765706 (GRCh38) [ NCBI UCSC ] 9: 138657552 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline May 17, 2014 May 12, 2024 Dec 18, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_020822.3:c.1283G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_065873.2:p.Arg428Gln missense NM_001272003.2:c.1148G>A NP_001258932.1:p.Arg383Gln missense NC_000009.12:g.135765706G>A NC_000009.11:g.138657552G>A NG_033070.1:g.68522G>A - Protein change
- R428Q, R383Q
- Other names
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- Canonical SPDI
- NC_000009.12:135765705:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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KCNT1 | - | - |
GRCh38 GRCh37 |
2206 | 2268 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
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The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Nov 5, 2020 | RCV000032793.15 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 12, 2013 | RCV000117358.6 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Aug 1, 2023 | RCV000413614.29 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 18, 2023 | RCV000805871.7 | |
See cases
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Pathogenic (1) |
criteria provided, single submitter
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Jan 18, 2022 | RCV002251941.2 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Oct 30, 2017)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000854874.1
First in ClinVar: Jan 09, 2017 Last updated: Jan 09, 2017 |
Number of individuals with the variant: 2
Sex: mixed
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Pathogenic
(Apr 03, 2018)
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criteria provided, single submitter
Method: clinical testing
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Developmental and epileptic encephalopathy, 14
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
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Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV001150141.1
First in ClinVar: Feb 03, 2020 Last updated: Feb 03, 2020 |
Sex: male
Tissue: blood
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Pathogenic
(Sep 19, 2020)
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criteria provided, single submitter
Method: clinical testing
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Developmental and epileptic encephalopathy, 14
Affected status: unknown
Allele origin:
germline
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New York Genome Center
Study: CSER-NYCKidSeq
Accession: SCV001815797.1 First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Comment:
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 … (more)
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. (less)
Clinical Features:
Seizure (present) , Intellectual disability (present) , Autism (present)
Secondary finding: no
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Pathogenic
(Apr 02, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002023234.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Dec 12, 2013)
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criteria provided, single submitter
Method: clinical testing
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Epilepsy, nocturnal frontal lobe, 5
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV000151541.1
First in ClinVar: May 17, 2014 Last updated: May 17, 2014 |
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Pathogenic
(Jan 18, 2022)
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criteria provided, single submitter
Method: clinical testing
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See cases
Affected status: yes
Allele origin:
germline
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Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV002523001.1
First in ClinVar: Jun 09, 2022 Last updated: Jun 09, 2022 |
Comment:
ACMG classification criteria: PS3, PS4, PM2, PM6, PP3
Clinical Features:
Autistic behavior (present) , Scoliosis (present) , Neurodevelopmental abnormality (present) , Abnormality of mental function (present) , Seizure (present)
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Pathogenic
(Jun 16, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000490583.4
First in ClinVar: Jan 09, 2017 Last updated: Mar 04, 2023 |
Comment:
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 … (more)
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) (less)
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Pathogenic
(Nov 05, 2020)
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criteria provided, single submitter
Method: clinical testing
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Developmental and epileptic encephalopathy, 14
Affected status: yes
Allele origin:
de novo
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Accession: SCV003921940.1
First in ClinVar: May 06, 2023 Last updated: May 06, 2023 |
Comment:
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) … (more)
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 (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Developmental and epileptic encephalopathy, 14
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004048534.1
First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023 |
Comment:
The missense variant c.1283G>A (p.Arg428Gln) in KCNT1 gene has been reported in many affected individuals in the literature (Datta AN et.al.,2019). Functional studies suggest this … (more)
The missense variant c.1283G>A (p.Arg428Gln) in KCNT1 gene has been reported in many affected individuals in the literature (Datta AN et.al.,2019). Functional studies suggest this variant leads to constitutive activation of the of the potassium channel (Milligan CJ et.al.,2014). This variant has been reported to the ClinVar database as Pathogenic. The p.Arg428Gln variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes.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. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Arg428Gln in KCNT1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. (less)
Clinical Features:
Neonatal seizure (present) , Motor delay (present) , Poor head control (present) , EEG abnormality (present)
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Pathogenic
(Dec 18, 2023)
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criteria provided, single submitter
Method: clinical testing
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Autosomal dominant nocturnal frontal lobe epilepsy 5
Developmental and epileptic encephalopathy, 14
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000945845.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 28, 2024 |
Comment:
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). … (more)
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. (less)
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Pathogenic
(Aug 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001500584.18
First in ClinVar: Mar 14, 2021 Last updated: May 12, 2024 |
Comment:
KCNT1: PS2:Very Strong, PM2, PS4:Moderate, PS3:Supporting
Number of individuals with the variant: 2
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Pathogenic
(May 29, 2018)
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criteria provided, single submitter
Method: clinical testing
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Developmental and epileptic encephalopathy, 14
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
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Génétique des Maladies du Développement, Hospices Civils de Lyon
Accession: SCV001164183.1
First in ClinVar: Mar 01, 2020 Last updated: Mar 01, 2020 |
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Pathogenic
(Nov 01, 2012)
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no assertion criteria provided
Method: literature only
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DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 14
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000056561.4
First in ClinVar: Apr 04, 2013 Last updated: Oct 23, 2020 |
Comment on evidence:
In 3 unrelated patients (patients 2, 3, and 4) of French origin with developmental and epileptic encephalopathy-14 (DEE14; 614959) manifest clinically as malignant migrating partial … (more)
In 3 unrelated patients (patients 2, 3, and 4) of French origin with developmental and epileptic encephalopathy-14 (DEE14; 614959) manifest clinically as malignant migrating partial seizures of infancy (MMPSI), Barcia et al. (2012) identified a de novo heterozygous 1283G-A transition in exon 13 of the KCNT1 gene, resulting in an arg428-to-gln (R428Q) substitution at a highly conserved residue in the cytoplasmic C-terminal domain. The mutation was initially identified by exome sequencing and confirmed by Sanger sequencing in 1 patient; analysis of this gene in subsequent patients identified the same mutation in 2 other individuals with the same disorder. The mutation was not found in 200 controls or in several large control databases. Expression of the corresponding rat mutation, R409Q, in Xenopus oocytes resulted in Kcnt1-generated currents that resembled wildtype in terms of voltage dependence and kinetic behavior but had 2- to 3-fold higher amplitude compared to wildtype, consistent with a gain of function. The mutation was shown to cause constitutive activation of the Kcnt1 channel, mimicking the effects of phosphorylation of the C-terminal domain by protein kinase C (see, e.g., PRKCA, 176960) activation. The patients had onset of seizures at 2 hours, 17 hours, and 2 months of age, respectively. (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Gene mutation analysis of 175 Chinese patients with early-onset epileptic encephalopathy. | Zhang Q | Clinical genetics | 2017 | PMID: 27779742 |
De novo KCNT1 mutations in early-onset epileptic encephalopathy. | Ohba C | Epilepsia | 2015 | PMID: 26140313 |
Targeted treatment of migrating partial seizures of infancy with quinidine. | Bearden D | Annals of neurology | 2014 | PMID: 25042079 |
KCNT1 gain of function in 2 epilepsy phenotypes is reversed by quinidine. | Milligan CJ | Annals of neurology | 2014 | PMID: 24591078 |
De novo gain-of-function KCNT1 channel mutations cause malignant migrating partial seizures of infancy. | Barcia G | Nature genetics | 2012 | PMID: 23086397 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=KCNT1 | - | - | - | - |
Text-mined citations for this variant ...
HelpRecord last updated May 27, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.