This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1783 of the SCN1A protein (p.Ala1783Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Dravet syndrome (PMID: 17561957, 18930999, 29460957). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 68571). 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 expected to disrupt SCN1A protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_001165963.4(SCN1A):c.5348C>T (p.Ala1783Val)
Germline
Classification
Help
criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.
Pathogenic
5 out of 6 submissions contributed to this 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.
6
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001165963.4(SCN1A):c.5348C>T (p.Ala1783Val)
Variation ID: 68571 Accession: VCV000068571.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2q24.3 2: 165991927 (GRCh38) [ NCBI UCSC ] 2: 166848437 (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 Oct 31, 2013 Apr 13, 2025 Aug 12, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001165963.4:c.5348C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001159435.1:p.Ala1783Val missense NM_001165964.3:c.5264C>T NP_001159436.1:p.Ala1755Val missense NM_001202435.3:c.5348C>T NP_001189364.1:p.Ala1783Val missense NM_001353948.2:c.5348C>T NP_001340877.1:p.Ala1783Val missense NM_001353949.2:c.5315C>T NP_001340878.1:p.Ala1772Val missense NM_001353950.2:c.5315C>T NP_001340879.1:p.Ala1772Val missense NM_001353951.2:c.5315C>T NP_001340880.1:p.Ala1772Val missense NM_001353952.2:c.5315C>T NP_001340881.1:p.Ala1772Val missense NM_001353954.2:c.5312C>T NP_001340883.1:p.Ala1771Val missense NM_001353955.2:c.5312C>T NP_001340884.1:p.Ala1771Val missense NM_001353957.2:c.5264C>T NP_001340886.1:p.Ala1755Val missense NM_001353958.2:c.5264C>T NP_001340887.1:p.Ala1755Val missense NM_001353960.2:c.5261C>T NP_001340889.1:p.Ala1754Val missense NM_001353961.2:c.2906C>T NP_001340890.1:p.Ala969Val missense NM_006920.6:c.5315C>T NP_008851.3:p.Ala1772Val missense NR_148667.2:n.5765C>T non-coding transcript variant NC_000002.12:g.165991927G>A NC_000002.11:g.166848437G>A NG_011906.1:g.86713C>T LRG_8:g.86713C>T LRG_8t1:c.5315C>T - Protein change
- A1772V, A1783V, A969V, A1754V, A1771V, A1755V
- Other names
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p.A1783V:GCG>GTG
- Canonical SPDI
- NC_000002.12:165991926: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
Help
The frequency of the allele represented by this VCV record.
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- 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. |
|||
| SCN1A | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
2403 | 4979 | |
| LOC102724058 | - | - | - | GRCh38 | - | 2516 |
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. |
|---|---|---|---|---|
| Pathogenic (2) |
criteria provided, single submitter
|
Dec 20, 2014 | RCV000059446.9 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Feb 20, 2024 | RCV000189000.10 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Aug 12, 2024 | RCV001207693.10 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Aug 12, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Early-infantile DEE
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001379057.6
First in ClinVar: Jul 16, 2020 Last updated: Feb 25, 2025 |
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1783 of the SCN1A protein (p.Ala1783Val). … (more)
This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1783 of the SCN1A protein (p.Ala1783Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Dravet syndrome (PMID: 17561957, 18930999, 29460957). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 68571). 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 expected to disrupt SCN1A protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Dec 20, 2014)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: research
|
Dravet syndrome
Affected status: yes
Allele origin:
de novo
|
Center for Bioinformatics, Peking University
Additional submitter:
Pediatric Department, Peking University First Hospital
Study: University Clinical Cooperation “985 Project” PKU-2014-1-1
Accession: SCV000221927.1 First in ClinVar: Jul 02, 2015 Last updated: Jul 02, 2015
Comment:
Dravet syndrome (DS) probands were recruited from the outpatient and inpatient child neurology units of Peking University First Hospital from 2005 till present. The study … (more)
Dravet syndrome (DS) probands were recruited from the outpatient and inpatient child neurology units of Peking University First Hospital from 2005 till present. The study was approved by the Ethics Committee of Peking University First Hospital and the Institutional Review Board at Peking University. Participants or their parents provided written informed consent before enrollment. We collected a total of 267 mutations from 255 families with probands diagnosed with DS in China. All probands fulfilled the clinical diagnostic criteria. (less)
|
Number of individuals with the variant: 1
Ethnicity/Population group: Chinese
|
|
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Pathogenic
(Jun 26, 2023)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: not provided
Allele origin:
germline
|
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Accession: SCV004026438.1
First in ClinVar: Aug 19, 2023 Last updated: Aug 19, 2023 |
Comment:
PM1, PP3, PM5, PP2, PS4, PM2_SUP
|
|
|
Pathogenic
(Feb 20, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000242631.12
First in ClinVar: Aug 07, 2015 Last updated: Jul 23, 2024 |
Comment:
A different missense change at this residue (p.A1755T) has been reported in the published literature and at GeneDx in association with SCN1A-related epilepsy (PMID: 20431604, … (more)
A different missense change at this residue (p.A1755T) has been reported in the published literature and at GeneDx in association with SCN1A-related epilepsy (PMID: 20431604, 17347258); Published functional studies demonstrate that this variant significantly affects activation and slow inactivation properties of SCN1A NaV1.1 channels (PMID: 34776868); This substitution is predicted to be within the transmembrane segment S6 of the fourth homologous domain; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21703448, 29056246, 30368457, 32090326, 29573403, 33902251, 35074891, 30552426, 17561957, 34776868, 29460957, 20431604, 17347258) (less)
|
|
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Pathogenic
(Jun 02, 2016)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000341355.5
First in ClinVar: Dec 06, 2016 Last updated: Apr 13, 2025 |
Number of individuals with the variant: 1
Zygosity: Single Heterozygote
Sex: mixed
|
|
|
not provided
(-)
N
Not contributing to aggregate classification
|
no classification provided
Method: not provided
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Severe myoclonic epilepsy in infancy
Affected status: not provided
Allele origin:
unknown
|
UniProtKB/Swiss-Prot
Accession: SCV000090971.1
First in ClinVar: Oct 31, 2013 Last updated: Oct 31, 2013 |
|
|
Comment:
Comment:
PM1, PP3, PM5, PP2, PS4, PM2_SUP
Comment:
A different missense change at this residue (p.A1755T) has been reported in the published literature and at GeneDx in association with SCN1A-related epilepsy (PMID: 20431604, 17347258); Published functional studies demonstrate that this variant significantly affects activation and slow inactivation properties of SCN1A NaV1.1 channels (PMID: 34776868); This substitution is predicted to be within the transmembrane segment S6 of the fourth homologous domain; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21703448, 29056246, 30368457, 32090326, 29573403, 33902251, 35074891, 30552426, 17561957, 34776868, 29460957, 20431604, 17347258)
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:
This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1783 of the SCN1A protein (p.Ala1783Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Dravet syndrome (PMID: 17561957, 18930999, 29460957). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 68571). 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 expected to disrupt SCN1A protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Comment:
PM1, PP3, PM5, PP2, PS4, PM2_SUP
Comment:
A different missense change at this residue (p.A1755T) has been reported in the published literature and at GeneDx in association with SCN1A-related epilepsy (PMID: 20431604, 17347258); Published functional studies demonstrate that this variant significantly affects activation and slow inactivation properties of SCN1A NaV1.1 channels (PMID: 34776868); This substitution is predicted to be within the transmembrane segment S6 of the fourth homologous domain; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21703448, 29056246, 30368457, 32090326, 29573403, 33902251, 35074891, 30552426, 17561957, 34776868, 29460957, 20431604, 17347258)
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Mosaicism of de novo pathogenic SCN1A variants in epilepsy is a frequent phenomenon that correlates with variable phenotypes. | de Lange IM | Epilepsia | 2018 | PMID: 29460957 |
| 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 |
| Spectrum of SCN1A gene mutations associated with Dravet syndrome: analysis of 333 patients. | Depienne C | Journal of medical genetics | 2009 | PMID: 18930999 |
| Idiopathic epilepsies with seizures precipitated by fever and SCN1A abnormalities. | Marini C | Epilepsia | 2007 | PMID: 17561957 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=SCN1A | - | - | - | - |
| http://www.openbioinformatics.org/annovar/annovar_startup.html | - | - | - | - |
Text-mined citations for rs121917921 ...
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 Jun 14, 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.