ClinVar Genomic variation as it relates to human health
NM_001165963.4(SCN1A):c.5536_5539del (p.Lys1846fs)
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_001165963.4(SCN1A):c.5536_5539del (p.Lys1846fs)
Variation ID: 189881 Accession: VCV000189881.24
- Type and length
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Microsatellite, 4 bp
- Location
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Cytogenetic: 2q24.3 2: 165991736-165991739 (GRCh38) [ NCBI UCSC ] 2: 166848246-166848249 (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 Jul 2, 2015 Apr 15, 2024 Dec 31, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001165963.4:c.5536_5539del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001159435.1:p.Lys1846fs frameshift NM_001165963.4:c.5536_5539delAAAC MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_001165963.1:c.5536_5539delAAAC NM_001165963.2:c.5536_5539delAAAC NM_001165964.3:c.5452_5455del NP_001159436.1:p.Lys1818fs frameshift NM_001202435.3:c.5536_5539del NP_001189364.1:p.Lys1846fs frameshift NM_001353948.2:c.5536_5539del NP_001340877.1:p.Lys1846fs frameshift NM_001353949.2:c.5503_5506del NP_001340878.1:p.Lys1835fs frameshift NM_001353950.2:c.5503_5506del NP_001340879.1:p.Lys1835fs frameshift NM_001353951.2:c.5503_5506del NP_001340880.1:p.Lys1835fs frameshift NM_001353952.2:c.5503_5506del NP_001340881.1:p.Lys1835fs frameshift NM_001353954.2:c.5500_5503del NP_001340883.1:p.Lys1834fs frameshift NM_001353955.2:c.5500_5503del NP_001340884.1:p.Lys1834fs frameshift NM_001353957.2:c.5452_5455del NP_001340886.1:p.Lys1818fs frameshift NM_001353958.2:c.5452_5455del NP_001340887.1:p.Lys1818fs frameshift NM_001353960.2:c.5449_5452del NP_001340889.1:p.Lys1817fs frameshift NM_001353961.2:c.3094_3097del NP_001340890.1:p.Lys1032fs frameshift NM_006920.6:c.5503_5506del NP_008851.3:p.Lys1835fs frameshift NR_148667.2:n.5949AAAC[1] non-coding transcript variant NC_000002.12:g.165991737TTTG[1] NC_000002.11:g.166848247TTTG[1] NG_011906.1:g.86897AAAC[1] LRG_8:g.86897AAAC[1] - Protein change
- K1032fs, K1818fs, K1846fs, K1835fs, K1817fs, K1834fs
- Other names
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- Canonical SPDI
- NC_000002.12:165991735:GTTTGTTTG:GTTTG
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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
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. |
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SCN1A | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
2175 | 4517 | |
LOC102724058 | - | - | - | GRCh38 | - | 2288 |
Conditions - Germline
Condition
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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
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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 (2) |
criteria provided, multiple submitters, no conflicts
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Dec 20, 2014 | RCV000180834.5 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Oct 1, 2022 | RCV000189067.13 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 31, 2023 | RCV000555321.8 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Feb 21, 2022 | RCV001842506.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 19, 2023 | RCV003389241.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 3, 2017 | RCV002345570.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 19, 2023 | RCV003237341.3 |
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
(-)
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criteria provided, single submitter
Method: clinical testing
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Severe myoclonic epilepsy in infancy
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Lifecell International Pvt. Ltd
Accession: SCV001754811.1
First in ClinVar: Jul 24, 2021 Last updated: Jul 24, 2021 |
Comment:
A heterozygous one-base pair deletion in exon 29 of the SCN1A gene (c.5536_5539delAAAC) that results in a frameshift and premature truncation of the protein 11 … (more)
A heterozygous one-base pair deletion in exon 29 of the SCN1A gene (c.5536_5539delAAAC) that results in a frameshift and premature truncation of the protein 11 amino acids downstream to codon 1846(p.K1846SfsTer11) was detected. This frameshift variant is not reported in both the 1000 genomes and gnomAD databases. This variant is predicted to be damaging by Mutation taster and the region is conserved across species. There are 14 downstream pathogenic loss of function variants, with the furthest variant being 80 residues downstream of this variant. This indicates that the region is critical to protein function. This gene has a low rate of benign loss of function variants as indicated by a low upper bound of the observed/expected confidence interval 0.07. The observed variant is a loss of function variant in this gene, which is intolerant of Loss of Function variants, as indicated by the presence of existing pathogenic loss of function variant NP_001159435.1:p.M1I and 448 others. The observed variant has been previously classified as Pathogenic in ClinVar (Variation ID 189881 as of 2021-03-04) with respect to severe myoclonic epilepsy in infancy and 2 other conditions with a status of (2 stars) criteria provided, multiple submitters, no conflicts. Based on the above evidence this variant has been classified as pathogenic according to the ACMG guidelines. (less)
Ethnicity/Population group: Asian
Geographic origin: India
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Pathogenic
(Oct 03, 2019)
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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: SCV000242698.9
First in ClinVar: Aug 07, 2015 Last updated: Apr 17, 2019 |
Comment:
Frameshift variant in the C-terminus predicted to result in protein truncation as the last 164 amino acids are lost and replaced with 10 incorrect amino … (more)
Frameshift variant in the C-terminus predicted to result in protein truncation as the last 164 amino acids are lost and replaced with 10 incorrect amino acids; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 18930999, 31864146, 26096185, 32090326, 16458823, 17347258, 18413471, 11359211, 17054684, 14504318, 21719429, 30945278, 31765958, 31031587) (less)
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Pathogenic
(Aug 03, 2017)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002651675.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The c.5536_5539delAAAC pathogenic mutation, located in coding exon 26 of the SCN1A gene, results from a deletion of 4 nucleotides at nucleotide positions 5536 to … (more)
The c.5536_5539delAAAC pathogenic mutation, located in coding exon 26 of the SCN1A gene, results from a deletion of 4 nucleotides at nucleotide positions 5536 to 5539, causing a translational frameshift with a predicted alternate stop codon (p.K1846Sfs*11). This mutation has been detected in several individuals with Dravet syndrome, severe myoclonic epilepsy of infancy, and/or epileptic encephalopathy (Claes L et al. Am. J. Hum. Genet., 2001 Jun;68:1327-32; Heron SE et al. J. Med. Genet., 2010 Feb;47:137-41; Claes LR et al. Hum. Mutat., 2009 Oct;30:E904-20); Sun H et al. J. Hum. Genet., 2010 Jul;55:421-7; Spatola M et al. Eur. Neurol., 2013 Nov;69:119-21; Catarino CB et al. Brain, 2011 Oct;134:2982-3010; Wallace RH et al. Neurology, 2003 Sep;61:765-9). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
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Pathogenic
(Oct 19, 2020)
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criteria provided, single submitter
Method: clinical testing
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Generalized epilepsy with febrile seizures plus, type 2
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002766667.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function … (more)
Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with SCN1A -related epilepsy (PMID: 28488083). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0205 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with less than 1/3 of the protein sequence affected. (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other truncating variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Multiple premature termination variants downstream have been reported as pathogenic (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has previously been described as pathogenic in multiple patients, including as de novo in patients with Dravet syndrome or infantile onset generalised tonic-clonic seizures (ClinVar, VCGS, PMIDs: 21719429, 29141279, 18413471). (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
(Jun 19, 2023)
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criteria provided, single submitter
Method: clinical testing
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Developmental and epileptic encephalopathy 6B
Affected status: yes
Allele origin:
germline
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Institute of Human Genetics, Heidelberg University
Accession: SCV003936058.1
First in ClinVar: Jul 01, 2023 Last updated: Jul 01, 2023 |
Sex: male
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Pathogenic
(Dec 31, 2023)
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criteria provided, single submitter
Method: clinical testing
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Early infantile epileptic encephalopathy with suppression bursts
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000633873.6
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Lys1846Serfs*11) in the SCN1A gene. While this is not anticipated to result in nonsense mediated decay, … (more)
This sequence change creates a premature translational stop signal (p.Lys1846Serfs*11) in the SCN1A gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 164 amino acid(s) of the SCN1A protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Dravet syndrome (also known as severe myoclonic epilepsy of infancy) (PMID: 11359211, 14504318, 21719429). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 189881). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Oct 01, 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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV002822706.8
First in ClinVar: Jan 21, 2023 Last updated: Apr 15, 2024 |
Comment:
SCN1A: PS2, PS4, PM2, PVS1:Moderate
Number of individuals with the variant: 1
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Pathogenic
(Dec 20, 2014)
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criteria provided, single submitter
Method: research
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Dravet syndrome
Affected status: yes
Allele origin:
de novo
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Center for Bioinformatics, Peking University
Additional submitter:
Pediatric Department, Peking University First Hospital
Study: University Clinical Cooperation “985 Project” PKU-2014-1-1
Accession: SCV000221798.1 First in ClinVar: Jul 02, 2015 Last updated: Jul 02, 2015 |
Number of individuals with the variant: 4
Ethnicity/Population group: Chinese
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Pathogenic
(Jun 19, 2023)
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criteria provided, single submitter
Method: clinical testing
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SCN1A seizure disorders
Affected status: unknown
Allele origin:
unknown
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Illumina Laboratory Services, Illumina
Accession: SCV004101319.1
First in ClinVar: Nov 11, 2023 Last updated: Nov 11, 2023 |
Comment:
The SCN1A c.5536_5539del (p.Lys1846SerfsTer11) variant causes a shift in the protein reading frame that is predicted to result in premature termination of the protein. This … (more)
The SCN1A c.5536_5539del (p.Lys1846SerfsTer11) variant causes a shift in the protein reading frame that is predicted to result in premature termination of the protein. This variant occurs in the last exon of the gene and may escape nonsense-mediated mRNA decay. This variant has been reported in individuals with a phenotype consistent with SCN1A seizure disorders, the majority of which were found in a de novo state (PMID: 11359211; 18413471; 20431604; 21719429; 34055682; 34145886; 35701389; 35886038). The p.Lys1846SerfsTer11 variant is not observed in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. The variant was identified in a de novo state. Based on the available evidence, the c.5536_5539del (p.Lys1846SerfsTer11) variant is classified as pathogenic for SCN1A seizure disorders. (less)
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Pathogenic
(Feb 21, 2022)
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criteria provided, single submitter
Method: clinical testing
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Generalized epilepsy with febrile seizures plus, type 2
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV002102456.3
First in ClinVar: Mar 05, 2022 Last updated: Apr 15, 2024 |
Clinical Features:
Generalized-onset seizure (present) , Mild global developmental delay (present) , Febrile seizure (within the age range of 3 months to 6 years) (present)
Sex: male
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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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Exome sequencing for patients with developmental and epileptic encephalopathies in clinical practice. | Scheffer IE | Developmental medicine and child neurology | 2023 | PMID: 35701389 |
Phenotypic and Genotypic Spectrum of Early-Onset Developmental and Epileptic Encephalopathies-Data from a Romanian Cohort. | Riza AL | Genes | 2022 | PMID: 35886038 |
Genome sequencing of 320 Chinese children with epilepsy: a clinical and molecular study. | Zou D | Brain : a journal of neurology | 2021 | PMID: 34145886 |
Detection of Disease-Causing SNVs/Indels and CNVs in Single Test Based on Whole Exome Sequencing: A Retrospective Case Study in Epileptic Encephalopathies. | Sun D | Frontiers in pediatrics | 2021 | PMID: 34055682 |
Efficacy of Stiripentol in Dravet Syndrome with or without SCN1A Mutations. | Cho MJ | Journal of clinical neurology (Seoul, Korea) | 2018 | PMID: 29141279 |
Ion Channel Genes and Epilepsy: Functional Alteration, Pathogenic Potential, and Mechanism of Epilepsy. | Wei F | Neuroscience bulletin | 2017 | PMID: 28488083 |
Amplicon Resequencing Identified Parental Mosaicism for Approximately 10% of "de novo" SCN1A Mutations in Children with Dravet Syndrome. | Xu X | Human mutation | 2015 | PMID: 26096185 |
Effect of vagus nerve stimulation in an adult patient with Dravet syndrome: contribution to sudden unexpected death in epilepsy risk reduction? | Spatola M | European neurology | 2013 | PMID: 23207687 |
Dravet syndrome as epileptic encephalopathy: evidence from long-term course and neuropathology. | Catarino CB | Brain : a journal of neurology | 2011 | PMID: 21719429 |
Analysis of SCN1A mutation and parental origin in patients with Dravet syndrome. | Sun H | Journal of human genetics | 2010 | PMID: 20431604 |
De novo SCN1A mutations in Dravet syndrome and related epileptic encephalopathies are largely of paternal origin. | Heron SE | Journal of medical genetics | 2010 | PMID: 19589774 |
The SCN1A variant database: a novel research and diagnostic tool. | Claes LR | Human mutation | 2009 | PMID: 19585586 |
Cryptogenic epileptic syndromes related to SCN1A: twelve novel mutations identified. | Zucca C | Archives of neurology | 2008 | PMID: 18413471 |
Sodium channel alpha1-subunit mutations in severe myoclonic epilepsy of infancy and infantile spasms. | Wallace RH | Neurology | 2003 | PMID: 14504318 |
De novo mutations in the sodium-channel gene SCN1A cause severe myoclonic epilepsy of infancy. | Claes L | American journal of human genetics | 2001 | PMID: 11359211 |
http://www.openbioinformatics.org/annovar/annovar_startup.html | - | - | - | - |
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Text-mined citations for rs794726726 ...
HelpRecord last updated Apr 15, 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.