The variant is not observed in the gnomAD v2.1.1 dataset. The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.96; 3Cnet: 1.00). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000068592 / PMID: 16525050). Different missense changes at the same codon (p.Arg859His, p.Arg859Pro) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000093639 / PMID: 21864321, 29141311). 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.2575C>T (p.Arg859Cys)
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.
(9)
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
9
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.2575C>T (p.Arg859Cys)
Variation ID: 68592 Accession: VCV000068592.14
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 2q24.3 2: 166039437 (GRCh38) [ NCBI UCSC ] 2: 166895947 (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 Nov 3, 2024 Oct 25, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001165963.4:c.2575C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001159435.1:p.Arg859Cys missense NM_001165964.3:c.2491C>T NP_001159436.1:p.Arg831Cys missense NM_001202435.3:c.2575C>T NP_001189364.1:p.Arg859Cys missense NM_001353948.2:c.2575C>T NP_001340877.1:p.Arg859Cys missense NM_001353949.2:c.2542C>T NP_001340878.1:p.Arg848Cys missense NM_001353950.2:c.2542C>T NP_001340879.1:p.Arg848Cys missense NM_001353951.2:c.2542C>T NP_001340880.1:p.Arg848Cys missense NM_001353952.2:c.2542C>T NP_001340881.1:p.Arg848Cys missense NM_001353954.2:c.2539C>T NP_001340883.1:p.Arg847Cys missense NM_001353955.2:c.2539C>T NP_001340884.1:p.Arg847Cys missense NM_001353957.2:c.2491C>T NP_001340886.1:p.Arg831Cys missense NM_001353958.2:c.2491C>T NP_001340887.1:p.Arg831Cys missense NM_001353960.2:c.2488C>T NP_001340889.1:p.Arg830Cys missense NM_001353961.2:c.133C>T NP_001340890.1:p.Arg45Cys missense NM_006920.6:c.2542C>T NP_008851.3:p.Arg848Cys missense NR_148667.2:n.2928C>T non-coding transcript variant NC_000002.12:g.166039437G>A NC_000002.11:g.166895947G>A NG_011906.1:g.39203C>T LRG_8:g.39203C>T LRG_8t1:c.2542C>T - Protein change
- R848C, R859C, R847C, R45C, R830C, R831C
- Other names
- -
- Canonical SPDI
- NC_000002.12:166039436:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
Increase of decay in current amplitude in use dependence; Functional Epilepsy Nomenclature for Ion Channels [ FENICS-0134]Moderate decrease in peak current; Functional Epilepsy Nomenclature for Ion Channels [ FENICS-0086]Normal persistent current; Functional Epilepsy Nomenclature for Ion Channels [ FENICS-0044]Normal rate of activation; Functional Epilepsy Nomenclature for Ion Channels [ FENICS-0011]Normal voltage dependence of activation; Functional Epilepsy Nomenclature for Ion Channels [ FENICS-0032]Normal voltage dependence of fast inactivation; Functional Epilepsy Nomenclature for Ion Channels [ FENICS-0070]Normal rate of recovery from fast inactivation; Functional Epilepsy Nomenclature for Ion Channels [ FENICS-0054]Normal slope of activation; Functional Epilepsy Nomenclature for Ion Channels [ FENICS-0036]Normal slope of fast inactivation; Functional Epilepsy Nomenclature for Ion Channels [ FENICS-0074]Overall loss-of-function effect with respect to biophysical channel activity; Functional Epilepsy Nomenclature for Ion Channels [ FENICS-0144]
-
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 | |
| SCN1A-AS1 | - | - | - | GRCh38 | - | 2178 |
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. |
|---|---|---|---|---|
| not provided (1) |
no classification provided
|
- | RCV000059468.2 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Oct 25, 2024 | RCV000255099.3 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Mar 25, 2021 | RCV001352915.3 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Dec 2, 2023 | RCV001382870.6 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Feb 23, 2023 | RCV002247462.5 | |
| Pathogenic (2) |
criteria provided, single submitter
|
Aug 5, 2024 | RCV003992174.2 |
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
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
(May 04, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Generalized epilepsy with febrile seizures plus, type 2
Affected status: unknown
Allele origin:
germline
|
Mendelics
Accession: SCV002519031.1
First in ClinVar: May 28, 2022 Last updated: May 28, 2022 |
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Generalized epilepsy with febrile seizures plus, type 2
Affected status: yes
Allele origin:
inherited
|
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille
Accession: SCV002559098.1
First in ClinVar: Aug 15, 2022 Last updated: Aug 15, 2022 |
|
|
|
Pathogenic
(Feb 23, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Generalized epilepsy with febrile seizures plus, type 2
Affected status: yes
Allele origin:
unknown
|
3billion
Accession: SCV003841903.1
First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023 |
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. The variant is located in a mutational hot spot and/or well-established functional domain in which … (more)
The variant is not observed in the gnomAD v2.1.1 dataset. The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.96; 3Cnet: 1.00). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000068592 / PMID: 16525050). Different missense changes at the same codon (p.Arg859His, p.Arg859Pro) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000093639 / PMID: 21864321, 29141311). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Febrile seizure (within the age range of 3 months to 6 years) (present)
|
|
|
Pathogenic
(Mar 25, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Seizure
(Sporadic)
Affected status: yes
Allele origin:
de novo
|
Génétique des Maladies du Développement, Hospices Civils de Lyon
Accession: SCV001547537.1
First in ClinVar: Mar 28, 2021 Last updated: Mar 28, 2021 |
Comment:
de novo, absent from gnomAD, already known pathogenic.
Sex: female
|
|
|
Pathogenic
(Dec 02, 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: SCV001581824.4
First in ClinVar: May 10, 2021 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 859 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 859 of the SCN1A protein (p.Arg859Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Dravet syndrome or generalized epilepsy with febrile seizures (PMID: 16525050, 18930999). 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: 68592). 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%. Experimental studies have shown that this missense change affects SCN1A function (PMID: 16525050, 25576396). This variant disrupts the p.Arg859 amino acid residue in SCN1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21864321, 24277604, 28084635; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Aug 05, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Severe myoclonic epilepsy in infancy
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV005093825.1
First in ClinVar: Aug 11, 2024 Last updated: Aug 11, 2024 |
Clinical Features:
Seizure (present) , Fever (present)
|
|
|
Pathogenic
(Oct 25, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000322029.8
First in ClinVar: Oct 09, 2016 Last updated: Nov 03, 2024 |
Comment:
Published functional studies demonstrate reduced neuronal excitability (PMID: 16525050); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this … (more)
Published functional studies demonstrate reduced neuronal excitability (PMID: 16525050); Not observed at significant frequency 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: 25576396, 20831750, 20100831, 17304347, 25754450, 19292758, 35074891, 32090326, 18930999, 16525050) (less)
|
|
|
not provided
(-)
|
no classification provided
Method: not provided
|
Generalized epilepsy with febrile seizures plus, type 1
Affected status: not provided
Allele origin:
not provided
|
UniProtKB/Swiss-Prot
Accession: SCV000090993.1
First in ClinVar: Oct 31, 2013 Last updated: Oct 31, 2013 |
|
|
|
not provided
(-)
|
no classification provided
Method: literature only
|
Severe myoclonic epilepsy in infancy
Affected status: not applicable
Allele origin:
not applicable
|
Channelopathy-Associated Epilepsy Research Center
Accession: SCV004809284.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
Method: whole-cell patch-clamp recording
Result:
Moderate decrease in peak current;Normal voltage dependence of activation;Normal slope of activation;Normal voltage dependence of fast inactivation;Normal slope of fast inactivation;Normal rate of recovery from fast inactivation;Normal persistent current;Increase of decay in current amplitude in use dependence;Overall loss-of-function effect with respect to biophysical channel activity;Normal rate of activation
|
Comment:
Comment:
de novo, absent from gnomAD, already known pathogenic.
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 859 of the SCN1A protein (p.Arg859Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Dravet syndrome or generalized epilepsy with febrile seizures (PMID: 16525050, 18930999). 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: 68592). 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%. Experimental studies have shown that this missense change affects SCN1A function (PMID: 16525050, 25576396). This variant disrupts the p.Arg859 amino acid residue in SCN1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21864321, 24277604, 28084635; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Comment:
Published functional studies demonstrate reduced neuronal excitability (PMID: 16525050); Not observed at significant frequency 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: 25576396, 20831750, 20100831, 17304347, 25754450, 19292758, 35074891, 32090326, 18930999, 16525050)
Germline Functional Evidence
| Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|---|---|---|---|---|
|
Moderate decrease in peak current
Normal voltage dependence of activation
Normal slope of activation
Normal voltage dependence of fast inactivation
Normal slope of fast inactivation
Normal rate of recovery from fast inactivation
Normal persistent current
Increase of decay in current amplitude in use dependence
Overall loss-of-function effect with respect to biophysical channel activity
Normal rate of activation
|
|
|
Channelopathy-Associated Epilepsy Research Center
Accession: SCV004809284.1
|
|
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.96; 3Cnet: 1.00). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000068592 / PMID: 16525050). Different missense changes at the same codon (p.Arg859His, p.Arg859Pro) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000093639 / PMID: 21864321, 29141311). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
de novo, absent from gnomAD, already known pathogenic.
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 859 of the SCN1A protein (p.Arg859Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Dravet syndrome or generalized epilepsy with febrile seizures (PMID: 16525050, 18930999). 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: 68592). 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%. Experimental studies have shown that this missense change affects SCN1A function (PMID: 16525050, 25576396). This variant disrupts the p.Arg859 amino acid residue in SCN1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21864321, 24277604, 28084635; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Comment:
Published functional studies demonstrate reduced neuronal excitability (PMID: 16525050); Not observed at significant frequency 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: 25576396, 20831750, 20100831, 17304347, 25754450, 19292758, 35074891, 32090326, 18930999, 16525050)
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| [Study on mosaicism of SCN1A gene mutation in parents of children with Dravet syndrome]. | Liu AJ | Zhonghua er ke za zhi = Chinese journal of pediatrics | 2017 | PMID: 29141311 |
| De novo SCN1A pathogenic variants in the GEFS+ spectrum: Not always a familial syndrome. | Myers KA | Epilepsia | 2017 | PMID: 28084635 |
| Rescuable folding defective NaV1.1 (SCN1A) mutants in epilepsy: properties, occurrence, and novel rescuing strategy with peptides targeted to the endoplasmic reticulum. | Bechi G | Neurobiology of disease | 2015 | PMID: 25576396 |
| Febrile temperatures unmask biophysical defects in Nav1.1 epilepsy mutations supportive of seizure initiation. | Volkers L | The Journal of general physiology | 2013 | PMID: 24277604 |
| Nav 1.1 dysfunction in genetic epilepsy with febrile seizures-plus or Dravet syndrome. | Volkers L | The European journal of neuroscience | 2011 | PMID: 21864321 |
| Spectrum of SCN1A gene mutations associated with Dravet syndrome: analysis of 333 patients. | Depienne C | Journal of medical genetics | 2009 | PMID: 18930999 |
| An epilepsy mutation in the sodium channel SCN1A that decreases channel excitability. | Barela AJ | The Journal of neuroscience : the official journal of the Society for Neuroscience | 2006 | PMID: 16525050 |
Text-mined citations for rs121918784 ...
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 03, 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.