The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.90; 3Cnet: 0.99). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000068505). The variant has been previously reported as assumed (i.e. paternity and maternity not confirmed) de novo in at least one similarly affected unrelated individual (PMID: 17054684). Different missense changes at the same codon (p.Arg393His, p.Arg393Pro, p.Arg393Ser) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000068504 , VCV000068506 , VCV000530476). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
ClinVar Genomic variation as it relates to human health
NM_001165963.4(SCN1A):c.1177C>T (p.Arg393Cys)
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.
(10)
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
10
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001165963.4(SCN1A):c.1177C>T (p.Arg393Cys)
Variation ID: 68505 Accession: VCV000068505.44
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 2q24.3 2: 166046970 (GRCh38) [ NCBI UCSC ] 2: 166903480 (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 31, 2013 Oct 20, 2024 Jan 3, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001165963.4:c.1177C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001159435.1:p.Arg393Cys missense NM_001165964.3:c.1177C>T NP_001159436.1:p.Arg393Cys missense NM_001202435.3:c.1177C>T NP_001189364.1:p.Arg393Cys missense NM_001353948.2:c.1177C>T NP_001340877.1:p.Arg393Cys missense NM_001353949.2:c.1177C>T NP_001340878.1:p.Arg393Cys missense NM_001353950.2:c.1177C>T NP_001340879.1:p.Arg393Cys missense NM_001353951.2:c.1177C>T NP_001340880.1:p.Arg393Cys missense NM_001353952.2:c.1177C>T NP_001340881.1:p.Arg393Cys missense NM_001353954.2:c.1177C>T NP_001340883.1:p.Arg393Cys missense NM_001353955.2:c.1177C>T NP_001340884.1:p.Arg393Cys missense NM_001353957.2:c.1177C>T NP_001340886.1:p.Arg393Cys missense NM_001353958.2:c.1177C>T NP_001340887.1:p.Arg393Cys missense NM_001353960.2:c.1177C>T NP_001340889.1:p.Arg393Cys missense NM_001353961.2:c.-1249C>T 5 prime UTR NM_006920.6:c.1177C>T NP_008851.3:p.Arg393Cys missense NR_148667.2:n.1563C>T non-coding transcript variant NC_000002.12:g.166046970G>A NC_000002.11:g.166903480G>A NG_011906.1:g.31670C>T LRG_8:g.31670C>T LRG_8t1:c.1177C>T P35498:p.Arg393Cys - Protein change
- R393C
- Other names
-
p.R393C:CGT>TGT
- Canonical SPDI
- NC_000002.12:166046969: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. |
|||
| SCN1A | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
2245 | 4634 | |
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 (3) |
criteria provided, multiple submitters, no conflicts
|
Sep 1, 2022 | RCV000059377.8 | |
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Jan 3, 2024 | RCV000188854.33 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Oct 13, 2023 | RCV000554304.11 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Aug 6, 2018 | RCV000857236.3 | |
| Pathogenic (1) |
criteria provided, single submitter
|
- | RCV002262611.4 |
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 06, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Seizure
Intellectual disability, mild
Affected status: yes
Allele origin:
germline
|
Center of Genomic medicine, Geneva, University Hospital of Geneva
Accession: SCV000999823.1
First in ClinVar: Dec 06, 2019 Last updated: Dec 06, 2019 |
Number of individuals with the variant: 1
Age: 40-49 years
Sex: male
|
|
|
Pathogenic
(May 28, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Severe myoclonic epilepsy in infancy
Affected status: unknown
Allele origin:
unknown
|
Mendelics
Accession: SCV001136059.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Developmental and epileptic encephalopathy 6B
Severe myoclonic epilepsy in infancy Generalized epilepsy with febrile seizures plus, type 2 Migraine, familial hemiplegic, 3 (Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
|
Suma Genomics
Accession: SCV002543784.1
First in ClinVar: Jul 09, 2022 Last updated: Jul 09, 2022 |
|
|
|
Pathogenic
(Sep 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Severe myoclonic epilepsy in infancy
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002573275.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of … (more)
The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.90; 3Cnet: 0.99). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000068505). The variant has been previously reported as assumed (i.e. paternity and maternity not confirmed) de novo in at least one similarly affected unrelated individual (PMID: 17054684). Different missense changes at the same codon (p.Arg393His, p.Arg393Pro, p.Arg393Ser) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000068504 , VCV000068506 , VCV000530476). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Intellectual disability (present) , Seizure (present) , Attention deficit hyperactivity disorder (present)
|
|
|
Pathogenic
(Oct 13, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Early infantile epileptic encephalopathy with suppression bursts
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000633810.8
First in ClinVar: Dec 26, 2017 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 393 of the SCN1A protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 393 of the SCN1A protein (p.Arg393Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Dravet syndrome (PMID: 17054684, 18930999, 21868258, 22848613, 23934111). In at least one individual the variant was observed to be de novo. This variant is also known as 2:166903480G>A. ClinVar contains an entry for this variant (Variation ID: 68505). 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. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Sep 24, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000233030.5
First in ClinVar: Jun 28, 2015 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
|
|
|
Pathogenic
(Mar 11, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV004225969.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
PP3, PM1, PM2, PM5, PM6, PS2, PS4_moderate
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Jan 03, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000242484.12
First in ClinVar: Aug 07, 2015 Last updated: Sep 16, 2024 |
Comment:
This substitution is predicted to be within the extracellular loop between the S5 and S6 transmembrane segments of the first homologous domain.; In silico analysis … (more)
This substitution is predicted to be within the extracellular loop between the S5 and S6 transmembrane segments of the first homologous domain.; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17347258, 29186148, 17054684, 18930999, 24502503, 17561957, 23934111, 21868258, 32090326, 31873310, 35074891, 31440721) (less)
|
|
|
Pathogenic
(May 01, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001249703.26
First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 2
|
|
|
not provided
(-)
|
no classification provided
Method: not provided
|
Severe myoclonic epilepsy in infancy
Affected status: not provided
Allele origin:
unknown
|
UniProtKB/Swiss-Prot
Accession: SCV000090901.1
First in ClinVar: Oct 31, 2013 Last updated: Oct 31, 2013
Comment:
Some patients have myoclonic astatic epilepsy
|
|
Comment:
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 393 of the SCN1A protein (p.Arg393Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Dravet syndrome (PMID: 17054684, 18930999, 21868258, 22848613, 23934111). In at least one individual the variant was observed to be de novo. This variant is also known as 2:166903480G>A. ClinVar contains an entry for this variant (Variation ID: 68505). 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. For these reasons, this variant has been classified as Pathogenic.
Comment:
PP3, PM1, PM2, PM5, PM6, PS2, PS4_moderate
Comment:
This substitution is predicted to be within the extracellular loop between the S5 and S6 transmembrane segments of the first homologous domain.; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17347258, 29186148, 17054684, 18930999, 24502503, 17561957, 23934111, 21868258, 32090326, 31873310, 35074891, 31440721)
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:
The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.90; 3Cnet: 0.99). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000068505). The variant has been previously reported as assumed (i.e. paternity and maternity not confirmed) de novo in at least one similarly affected unrelated individual (PMID: 17054684). Different missense changes at the same codon (p.Arg393His, p.Arg393Pro, p.Arg393Ser) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000068504 , VCV000068506 , VCV000530476). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 393 of the SCN1A protein (p.Arg393Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Dravet syndrome (PMID: 17054684, 18930999, 21868258, 22848613, 23934111). In at least one individual the variant was observed to be de novo. This variant is also known as 2:166903480G>A. ClinVar contains an entry for this variant (Variation ID: 68505). 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. For these reasons, this variant has been classified as Pathogenic.
Comment:
PP3, PM1, PM2, PM5, PM6, PS2, PS4_moderate
Comment:
This substitution is predicted to be within the extracellular loop between the S5 and S6 transmembrane segments of the first homologous domain.; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17347258, 29186148, 17054684, 18930999, 24502503, 17561957, 23934111, 21868258, 32090326, 31873310, 35074891, 31440721)
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Biological concepts in human sodium channel epilepsies and their relevance in clinical practice. | Brunklaus A | Epilepsia | 2020 | PMID: 32090326 |
| A case-control collapsing analysis identifies epilepsy genes implicated in trio sequencing studies focused on de novo mutations. | Zhu X | PLoS genetics | 2017 | PMID: 29186148 |
| Long-term course of Dravet syndrome: a study from an epilepsy center in Japan. | Takayama R | Epilepsia | 2014 | PMID: 24502503 |
| De novo mutations in epileptic encephalopathies. | Epi4K Consortium | Nature | 2013 | PMID: 23934111 |
| Identification of SCN1A and PCDH19 mutations in Chinese children with Dravet syndrome. | Kwong AK | PloS one | 2012 | PMID: 22848613 |
| SCN1A mutational analysis in Korean patients with Dravet syndrome. | Lim BC | Seizure | 2011 | PMID: 21868258 |
| The SCN1A variant database: a novel research and diagnostic tool. | Claes LR | Human mutation | 2009 | PMID: 19585586 |
| Spectrum of SCN1A gene mutations associated with Dravet syndrome: analysis of 333 patients. | Depienne C | Journal of medical genetics | 2009 | PMID: 18930999 |
| Familial occurrence of febrile seizures and epilepsy in severe myoclonic epilepsy of infancy (SMEI) patients with SCN1A mutations. | Mancardi MM | Epilepsia | 2006 | PMID: 17054684 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=SCN1A | - | - | - | - |
Text-mined citations for rs121917929 ...
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 Nov 10, 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.