ClinVar Genomic variation as it relates to human health
NM_001165963.4(SCN1A):c.4942C>T (p.Arg1648Cys)
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.4942C>T (p.Arg1648Cys)
Variation ID: 68641 Accession: VCV000068641.5
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2q24.3 2: 165992333 (GRCh38) [ NCBI UCSC ] 2: 166848843 (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 15, 2024 Sep 15, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001165963.4:c.4942C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001159435.1:p.Arg1648Cys missense NM_001165964.3:c.4858C>T NP_001159436.1:p.Arg1620Cys missense NM_001202435.3:c.4942C>T NP_001189364.1:p.Arg1648Cys missense NM_001353948.2:c.4942C>T NP_001340877.1:p.Arg1648Cys missense NM_001353949.2:c.4909C>T NP_001340878.1:p.Arg1637Cys missense NM_001353950.2:c.4909C>T NP_001340879.1:p.Arg1637Cys missense NM_001353951.2:c.4909C>T NP_001340880.1:p.Arg1637Cys missense NM_001353952.2:c.4909C>T NP_001340881.1:p.Arg1637Cys missense NM_001353954.2:c.4906C>T NP_001340883.1:p.Arg1636Cys missense NM_001353955.2:c.4906C>T NP_001340884.1:p.Arg1636Cys missense NM_001353957.2:c.4858C>T NP_001340886.1:p.Arg1620Cys missense NM_001353958.2:c.4858C>T NP_001340887.1:p.Arg1620Cys missense NM_001353960.2:c.4855C>T NP_001340889.1:p.Arg1619Cys missense NM_001353961.2:c.2500C>T NP_001340890.1:p.Arg834Cys missense NM_006920.6:c.4909C>T NP_008851.3:p.Arg1637Cys missense NR_148667.2:n.5359C>T non-coding transcript variant NC_000002.12:g.165992333G>A NC_000002.11:g.166848843G>A NG_011906.1:g.86307C>T LRG_8:g.86307C>T LRG_8t1:c.4909C>T - Protein change
- R1637C, R1648C, R834C, R1619C, R1620C, R1636C
- Other names
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- Canonical SPDI
- NC_000002.12:165992332:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- Acceleration of recovery from fast inactivation Functional Epilepsy Nomenclature for Ion Channels [FENICS-0053]
- Increase in slope of activation Functional Epilepsy Nomenclature for Ion Channels [FENICS-0035]
- Increase in slope of fast inactivation Functional Epilepsy Nomenclature for Ion Channels [FENICS-0073]
- Increase in slope of slow inactivation Functional Epilepsy Nomenclature for Ion Channels [FENICS-0121]
- Mild depolarizing shift of voltage dependence of activation Functional Epilepsy Nomenclature for Ion Channels [FENICS-0024]
- Mild hyperpolarizing shift of voltage dependence of fast inactivation Functional Epilepsy Nomenclature for Ion Channels [FENICS-0067]
- Normal entry into slow inactivation Functional Epilepsy Nomenclature for Ion Channels [FENICS-0104]
- Normal peak current Functional Epilepsy Nomenclature for Ion Channels [FENICS-0096]
- Normal recovery from slow inactivation Functional Epilepsy Nomenclature for Ion Channels [FENICS-0108]
- Normal voltage dependence of slow inactivation Functional Epilepsy Nomenclature for Ion Channels [FENICS-0118]
- Overall mixed or unclear functional effect with respect to biophysical channel activity Functional Epilepsy Nomenclature for Ion Channels [FENICS-0148]
- Severe increase in persistent current Functional Epilepsy Nomenclature for Ion Channels [FENICS-0043]
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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
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. |
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SCN1A | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
2180 | 4526 | |
LOC102724058 | - | - | - | GRCh38 | - | 2292 |
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
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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 (3) |
criteria provided, single submitter
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Nov 25, 2014 | RCV000059520.5 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 6, 2022 | RCV003233101.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 15, 2023 | RCV003588572.1 |
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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Pathogenic
(Nov 25, 2014)
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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: unknown
Allele origin:
germline
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Athena Diagnostics
Accession: SCV000255832.2
First in ClinVar: Oct 19, 2015 Last updated: Oct 19, 2015 |
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Pathogenic
(Dec 06, 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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GeneDx
Accession: SCV003931061.1
First in ClinVar: Jun 17, 2023 Last updated: Jun 17, 2023 |
Comment:
Observed in multiple unrelated patients with infantile-onset epilepsy referred for genetic testing at GeneDx and in published literature (Ohmori et al., 2002); Published functional studies … (more)
Observed in multiple unrelated patients with infantile-onset epilepsy referred for genetic testing at GeneDx and in published literature (Ohmori et al., 2002); Published functional studies demonstrate a damaging effect as this variant alters the closing and extended opening of sodium channels, impairing normal channel function and subsequent neuron firing (Rhodes et al., 2004; Thompson et al., 2012); Additional functional studies in a drosophila model demonstrate that R1648C exhibits spontaneous and temperature-sensitive seizure activity, recapitulating the disease state (Roemmich et al., 2021); Missense variants in this gene are often considered pathogenic (HGMD); 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: 31069529, 11567038, 25378155, 10742094, 31625145, Nisevic_2015_Review, 33236643, 30735520, 20735403, Giunti_2019_Abstract, 31782251, 31879226, 17054685, 32581296, 30038559, 22701429, 26544041, 15263074, 23086956, 18275929, 29573403, 32090326, 12083760, 34475263) (less)
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Pathogenic
(Sep 15, 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: SCV004292115.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
Experimental studies have shown that this missense change affects SCN1A function (PMID: 15263074, 23086956). Advanced modeling of protein sequence and biophysical properties (such as structural, … (more)
Experimental studies have shown that this missense change affects SCN1A function (PMID: 15263074, 23086956). 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. ClinVar contains an entry for this variant (Variation ID: 68641). This variant is also known as C4912T (p.R1638C). This missense change has been observed in individual(s) with severe myoclonic epilepsy in infancy (PMID: 12083760). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1648 of the SCN1A protein (p.Arg1648Cys). This variant disrupts the p.Arg1648 amino acid residue in SCN1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10742094, 20522430). 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)
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not provided
(-)
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no classification provided
Method: not provided
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Severe myoclonic epilepsy in infancy
Affected status: not provided
Allele origin:
not provided
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UniProtKB/Swiss-Prot
Accession: SCV000091051.1
First in ClinVar: Oct 31, 2013 Last updated: Oct 31, 2013 |
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not provided
(-)
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no classification provided
Method: literature only
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Severe myoclonic epilepsy in infancy
Affected status: not applicable
Allele origin:
not applicable
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Channelopathy-Associated Epilepsy Research Center
Accession: SCV004809278.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
Method: whole-cell patch-clamp recording
Result:
Severe increase in persistent current;Normal peak current;Increase in slope of slow inactivation;Mild depolarizing shift of voltage dependence of activation;Increase in slope of activation;Mild hyperpolarizing shift of voltage dependence of fast inactivation;Increase in slope of fast inactivation;Acceleration of recovery from fast inactivation;Normal entry into slow inactivation;Normal voltage dependence of slow inactivation;Normal recovery from slow inactivation;Overall mixed or unclear functional effect with respect to biophysical channel activity
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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. |
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Severe increase in persistent current
Normal peak current
Increase in slope of slow inactivation
Mild depolarizing shift of voltage dependence of activation
Increase in slope of activation
Mild hyperpolarizing shift of voltage dependence of fast inactivation
Increase in slope of fast inactivation
Acceleration of recovery from fast inactivation
Normal entry into slow inactivation
Normal voltage dependence of slow inactivation
Normal recovery from slow inactivation
Overall mixed or unclear functional effect with respect to biophysical channel activity
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Channelopathy-Associated Epilepsy Research Center
Accession: SCV004809278.1
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Nontruncating SCN1A mutations associated with severe myoclonic epilepsy of infancy impair cell surface expression. | Thompson CH | The Journal of biological chemistry | 2012 | PMID: 23086956 |
Mechanisms for variable expressivity of inherited SCN1A mutations causing Dravet syndrome. | Depienne C | Journal of medical genetics | 2010 | PMID: 20522430 |
Noninactivating voltage-gated sodium channels in severe myoclonic epilepsy of infancy. | Rhodes TH | Proceedings of the National Academy of Sciences of the United States of America | 2004 | PMID: 15263074 |
Significant correlation of the SCN1A mutations and severe myoclonic epilepsy in infancy. | Ohmori I | Biochemical and biophysical research communications | 2002 | PMID: 12083760 |
Mutations of SCN1A, encoding a neuronal sodium channel, in two families with GEFS+2. | Escayg A | Nature genetics | 2000 | PMID: 10742094 |
Text-mined citations for rs121918791 ...
HelpRecord last updated May 08, 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.