PM2, PM5, PP5
ClinVar Genomic variation as it relates to human health
NM_020822.3(KCNT1):c.1193G>A (p.Arg398Gln)
Germline
Classification
Help
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.
(15)
Help
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.
Pathogenic/Likely pathogenic
15
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_020822.3(KCNT1):c.1193G>A (p.Arg398Gln)
Variation ID: 39599 Accession: VCV000039599.26
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: 9q34.3 9: 135765188 (GRCh38) [ NCBI UCSC ] 9: 138657034 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Oct 5, 2015 Aug 25, 2024 Jun 10, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_020822.3:c.1193G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_065873.2:p.Arg398Gln missense NM_001272003.2:c.1058G>A NP_001258932.1:p.Arg353Gln missense NC_000009.12:g.135765188G>A NC_000009.11:g.138657034G>A NG_033070.1:g.68004G>A - Protein change
- R398Q, R353Q
- Other names
- -
- Canonical SPDI
- NC_000009.12:135765187:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
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. |
|||
| KCNT1 | - | - |
GRCh38 GRCh37 |
2243 | 2322 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
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
Help
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Jan 4, 2022 | RCV000032799.18 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Sep 19, 2023 | RCV000412976.14 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Jan 8, 2024 | RCV000553512.19 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Aug 24, 2022 | RCV000787272.11 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jun 10, 2024 | RCV004576914.2 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Apr 25, 2021 | RCV001375627.10 | |
|
KCNT1-related disorder
|
Pathogenic (1) |
criteria provided, single submitter
|
Apr 13, 2023 | RCV003398586.5 |
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
Help
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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|---|---|---|---|---|---|
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Likely pathogenic
(Sep 07, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal dominant nocturnal frontal lobe epilepsy 5
Affected status: yes
Allele origin:
unknown
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001440375.2
First in ClinVar: Oct 31, 2020 Last updated: Sep 26, 2021 |
|
|
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Pathogenic
(May 04, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Developmental and epileptic encephalopathy, 14
Affected status: unknown
Allele origin:
germline
|
Mendelics
Accession: SCV002516611.1
First in ClinVar: May 28, 2022 Last updated: May 28, 2022 |
|
|
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Pathogenic
(Aug 24, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Developmental and epileptic encephalopathy, 14
Affected status: yes
Allele origin:
germline
|
Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Accession: SCV002577445.1
First in ClinVar: Oct 08, 2022 Last updated: Oct 08, 2022 |
Comment:
PM2, PM5, PP5
|
|
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Pathogenic
(Apr 13, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
KCNT1-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004104638.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The KCNT1 c.1193G>A variant is predicted to result in the amino acid substitution p.Arg398Gln. This variant has been reported in at least 14 individuals with … (more)
The KCNT1 c.1193G>A variant is predicted to result in the amino acid substitution p.Arg398Gln. This variant has been reported in at least 14 individuals with KCNT1-related epilepsy (see for example, Heron et al. 2012. PubMed ID: 23086396; Kim et al. 2014. PubMed ID: 25482562; Møller et al. 2015. PubMed ID: 26122718; Allen et al. 2016. PubMed ID: 26648591; Barcia et al. 2019. PubMed ID: 31872048) and is documented to have occurred de novo in at least 3 cases (Abdelnour et al. 2018. PubMed ID: 29291456; Monies et al. 2019. PubMed ID: 31130284; Borlot et al. 2020. PubMed ID: 32167590). In vitro experimental studies suggest that this variant impacts protein function (Milligan et al. 2014. PubMed ID: 24591078). 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. Taken together, this variant is interpreted as pathogenic. (less)
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Pathogenic
(Jun 10, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Seizures
Affected status: yes
Allele origin:
unknown
|
Génétique des Maladies du Développement, Hospices Civils de Lyon
Accession: SCV005060861.1
First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024 |
Zygosity: Single Heterozygote
Sex: male
|
|
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Pathogenic
(Oct 12, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal dominant nocturnal frontal lobe epilepsy 5
Developmental and epileptic encephalopathy, 14
Affected status: yes
Allele origin:
germline
|
Baylor Genetics
Accession: SCV000992727.1
First in ClinVar: Sep 21, 2019 Last updated: Sep 21, 2019 |
|
|
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Pathogenic
(Apr 25, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Epilepsy syndrome
Earlier presentation (at 2 months
(more...)
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
|
Centre for Inherited Metabolic Diseases, Karolinska University Hospital
Accession: SCV001572550.1
First in ClinVar: May 01, 2021 Last updated: May 01, 2021 |
Clinical Features:
Autism (present) , Intellectual disability (present) , Nocturnal seizures (present)
Zygosity: Single Heterozygote
Family history: no
Sex: female
Secondary finding: no
|
|
|
Likely pathogenic
(Jan 04, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal dominant nocturnal frontal lobe epilepsy 5
Affected status: yes
Allele origin:
germline
|
MGZ Medical Genetics Center
Accession: SCV002580571.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PS3_MOD, PS4_MOD, PM6, PM2_SUP
|
Number of individuals with the variant: 1
Sex: female
|
|
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Pathogenic
(Feb 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000490582.4
First in ClinVar: Jan 09, 2017 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate that R398Q results in a gain of function that causes an increase in current amplitude and altered channel activation and deactivation … (more)
Published functional studies demonstrate that R398Q results in a gain of function that causes an increase in current amplitude and altered channel activation and deactivation kinetics (Milligan et al., 2014); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28488083, 24591078, 25482562, 23086396, 26122718, 26648591, 26140313, 31872048, 31130284, 32167590, 31216405, 29291456, 28252636, 33726816) (less)
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Pathogenic
(Jan 08, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
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
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000652903.8
First in ClinVar: Dec 26, 2017 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 398 of the KCNT1 protein (p.Arg398Gln). … (more)
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 398 of the KCNT1 protein (p.Arg398Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant nocturnal frontal lobe epilepsy (ADFLE), malignant migrating partial seizures of infancy (MMPSI), malignant migrating focal seizures of infancy (MMFSI), and focal epilepsy (PMID: 23086396, 25482562, 26122718, 26140313, 26648591). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 39599). 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) performed at Invitae indicates that this missense variant is not expected to disrupt KCNT1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects KCNT1 function (PMID: 24591078). For these reasons, this variant has been classified as Pathogenic. (less)
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|
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Pathogenic
(Sep 19, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics Laboratory, Skane University Hospital Lund
Accession: SCV005198566.1
First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024 |
|
|
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Pathogenic
(Mar 29, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Developmental and epileptic encephalopathy, 14
Autosomal dominant nocturnal frontal lobe epilepsy 5
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002797633.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
|
Pathogenic
(May 03, 2019)
|
no assertion criteria provided
Method: clinical testing
|
Developmental and epileptic encephalopathy, 14
Affected status: yes
Allele origin:
de novo
|
Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust
Accession: SCV000926200.1
First in ClinVar: Jul 14, 2019 Last updated: Jul 14, 2019 |
|
|
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Pathogenic
(Nov 01, 2012)
|
no assertion criteria provided
Method: literature only
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EPILEPSY, NOCTURNAL FRONTAL LOBE, 5
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000056567.3
First in ClinVar: Apr 04, 2013 Last updated: Jan 20, 2018 |
Comment on evidence:
In 4 affected individuals of an Israeli family with nocturnal frontal lobe epilepsy (ENFL5; 615005), Heron et al. (2012) identified a heterozygous 1193G-A transition in … (more)
In 4 affected individuals of an Israeli family with nocturnal frontal lobe epilepsy (ENFL5; 615005), Heron et al. (2012) identified a heterozygous 1193G-A transition in the KCNT1 gene, resulting in an arg398-to-gln (R398Q) substitution. No functional studies were performed. Two of the 4 patients had behavioral or psychiatric abnormalities, but all were cognitively normal. (less)
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not provided
(-)
|
no classification provided
Method: literature only
|
Autosomal dominant nocturnal frontal lobe epilepsy 5
Affected status: unknown
Allele origin:
germline
|
GeneReviews
Accession: SCV000211889.3
First in ClinVar: Oct 05, 2015 Last updated: Oct 01, 2022 |
|
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Comment:
Comment:
The KCNT1 c.1193G>A variant is predicted to result in the amino acid substitution p.Arg398Gln. This variant has been reported in at least 14 individuals with KCNT1-related epilepsy (see for example, Heron et al. 2012. PubMed ID: 23086396; Kim et al. 2014. PubMed ID: 25482562; Møller et al. 2015. PubMed ID: 26122718; Allen et al. 2016. PubMed ID: 26648591; Barcia et al. 2019. PubMed ID: 31872048) and is documented to have occurred de novo in at least 3 cases (Abdelnour et al. 2018. PubMed ID: 29291456; Monies et al. 2019. PubMed ID: 31130284; Borlot et al. 2020. PubMed ID: 32167590). In vitro experimental studies suggest that this variant impacts protein function (Milligan et al. 2014. PubMed ID: 24591078). 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. Taken together, this variant is interpreted as pathogenic.
Comment on condition
Earlier presentation (at 2 months of age) and more severe neurodevelopmental abnormalities than in typical nocturnal frontal lobe epilepsy.
Comment:
Published functional studies demonstrate that R398Q results in a gain of function that causes an increase in current amplitude and altered channel activation and deactivation kinetics (Milligan et al., 2014); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28488083, 24591078, 25482562, 23086396, 26122718, 26648591, 26140313, 31872048, 31130284, 32167590, 31216405, 29291456, 28252636, 33726816)
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 398 of the KCNT1 protein (p.Arg398Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant nocturnal frontal lobe epilepsy (ADFLE), malignant migrating partial seizures of infancy (MMPSI), malignant migrating focal seizures of infancy (MMFSI), and focal epilepsy (PMID: 23086396, 25482562, 26122718, 26140313, 26648591). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 39599). 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) performed at Invitae indicates that this missense variant is not expected to disrupt KCNT1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects KCNT1 function (PMID: 24591078). For these reasons, this variant has been classified as Pathogenic.
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. |
Comment:
PM2, PM5, PP5
Comment:
The KCNT1 c.1193G>A variant is predicted to result in the amino acid substitution p.Arg398Gln. This variant has been reported in at least 14 individuals with KCNT1-related epilepsy (see for example, Heron et al. 2012. PubMed ID: 23086396; Kim et al. 2014. PubMed ID: 25482562; Møller et al. 2015. PubMed ID: 26122718; Allen et al. 2016. PubMed ID: 26648591; Barcia et al. 2019. PubMed ID: 31872048) and is documented to have occurred de novo in at least 3 cases (Abdelnour et al. 2018. PubMed ID: 29291456; Monies et al. 2019. PubMed ID: 31130284; Borlot et al. 2020. PubMed ID: 32167590). In vitro experimental studies suggest that this variant impacts protein function (Milligan et al. 2014. PubMed ID: 24591078). 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. Taken together, this variant is interpreted as pathogenic.
Comment on condition
Earlier presentation (at 2 months of age) and more severe neurodevelopmental abnormalities than in typical nocturnal frontal lobe epilepsy.
Comment:
Published functional studies demonstrate that R398Q results in a gain of function that causes an increase in current amplitude and altered channel activation and deactivation kinetics (Milligan et al., 2014); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28488083, 24591078, 25482562, 23086396, 26122718, 26648591, 26140313, 31872048, 31130284, 32167590, 31216405, 29291456, 28252636, 33726816)
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 398 of the KCNT1 protein (p.Arg398Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant nocturnal frontal lobe epilepsy (ADFLE), malignant migrating partial seizures of infancy (MMPSI), malignant migrating focal seizures of infancy (MMFSI), and focal epilepsy (PMID: 23086396, 25482562, 26122718, 26140313, 26648591). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 39599). 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) performed at Invitae indicates that this missense variant is not expected to disrupt KCNT1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects KCNT1 function (PMID: 24591078). For these reasons, this variant has been classified as Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Autosomal Dominant Sleep-Related Hypermotor (Hyperkinetic) Epilepsy. | Adam MP | - | 2023 | PMID: 20301348 |
| Unexplained early onset epileptic encephalopathy: Exome screening and phenotype expansion. | Allen NM | Epilepsia | 2016 | PMID: 26648591 |
| De novo KCNT1 mutations in early-onset epileptic encephalopathy. | Ohba C | Epilepsia | 2015 | PMID: 26140313 |
| Mutations in KCNT1 cause a spectrum of focal epilepsies. | Møller RS | Epilepsia | 2015 | PMID: 26122718 |
| Human slack potassium channel mutations increase positive cooperativity between individual channels. | Kim GE | Cell reports | 2014 | PMID: 25482562 |
| KCNT1 gain of function in 2 epilepsy phenotypes is reversed by quinidine. | Milligan CJ | Annals of neurology | 2014 | PMID: 24591078 |
| Missense mutations in the sodium-gated potassium channel gene KCNT1 cause severe autosomal dominant nocturnal frontal lobe epilepsy. | Heron SE | Nature genetics | 2012 | PMID: 23086396 |
Text-mined citations for rs397515407 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Jan 04, 2025
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.