ClinVar Genomic variation as it relates to human health
NM_001165963.4(SCN1A):c.4973C>T (p.Thr1658Met)
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.4973C>T (p.Thr1658Met)
Variation ID: 68643 Accession: VCV000068643.6
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2q24.3 2: 165992302 (GRCh38) [ NCBI UCSC ] 2: 166848812 (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 Feb 14, 2024 Jan 6, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001165963.4:c.4973C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001159435.1:p.Thr1658Met missense NM_001165964.3:c.4889C>T NP_001159436.1:p.Thr1630Met missense NM_001202435.3:c.4973C>T NP_001189364.1:p.Thr1658Met missense NM_001353948.2:c.4973C>T NP_001340877.1:p.Thr1658Met missense NM_001353949.2:c.4940C>T NP_001340878.1:p.Thr1647Met missense NM_001353950.2:c.4940C>T NP_001340879.1:p.Thr1647Met missense NM_001353951.2:c.4940C>T NP_001340880.1:p.Thr1647Met missense NM_001353952.2:c.4940C>T NP_001340881.1:p.Thr1647Met missense NM_001353954.2:c.4937C>T NP_001340883.1:p.Thr1646Met missense NM_001353955.2:c.4937C>T NP_001340884.1:p.Thr1646Met missense NM_001353957.2:c.4889C>T NP_001340886.1:p.Thr1630Met missense NM_001353958.2:c.4889C>T NP_001340887.1:p.Thr1630Met missense NM_001353960.2:c.4886C>T NP_001340889.1:p.Thr1629Met missense NM_001353961.2:c.2531C>T NP_001340890.1:p.Thr844Met missense NM_006920.6:c.4940C>T NP_008851.3:p.Thr1647Met missense NR_148667.2:n.5390C>T non-coding transcript variant NC_000002.12:g.165992302G>A NC_000002.11:g.166848812G>A NG_011906.1:g.86338C>T LRG_8:g.86338C>T LRG_8t1:c.4940C>T - Protein change
- T1647M, T1658M, T844M, T1630M, T1629M, T1646M
- Other names
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- Canonical SPDI
- NC_000002.12:165992301: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
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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
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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 |
2176 | 4518 | |
LOC102724058 | - | - | - | GRCh38 | - | 2288 |
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/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jan 1, 2018 | RCV000059523.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 6, 2022 | RCV000529623.5 |
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
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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
(Dec 20, 2014)
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criteria provided, single submitter
Method: research
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Dravet syndrome
Affected status: yes
Allele origin:
inherited
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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: SCV000221965.1 First in ClinVar: Jul 02, 2015 Last updated: Jul 02, 2015 |
Number of individuals with the variant: 2
Ethnicity/Population group: Chinese
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Likely pathogenic
(Jan 01, 2018)
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criteria provided, single submitter
Method: clinical testing
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Severe myoclonic epilepsy in infancy
Affected status: yes
Allele origin:
maternal
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NeuroMeGen, Hospital Clinico Santiago de Compostela
Accession: SCV000693792.1
First in ClinVar: Jul 02, 2015 Last updated: Jul 02, 2015 |
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Pathogenic
(Jan 06, 2022)
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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: SCV000633868.4
First in ClinVar: Dec 26, 2017 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Thr1658 amino acid residue in SCN1A. Other variant(s) that disrupt this … (more)
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Thr1658 amino acid residue in SCN1A. Other variant(s) that disrupt this residue have been observed in individuals with SCN1A-related conditions (PMID: 17561957; Invitae), which suggests that this may be a clinically significant amino acid residue. 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: 68643). This missense change has been observed in individual(s) with Dravet syndrome (PMID: 18930999, 20522430). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 1658 of the SCN1A protein (p.Thr1658Met). (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:
germline
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UniProtKB/Swiss-Prot
Accession: SCV000091054.1
First in ClinVar: Oct 31, 2013 Last updated: Oct 31, 2013 |
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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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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 |
Mechanisms for variable expressivity of inherited SCN1A mutations causing Dravet syndrome. | Depienne C | Journal of medical genetics | 2010 | PMID: 20522430 |
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.openbioinformatics.org/annovar/annovar_startup.html | - | - | - | - |
Text-mined citations for rs121917922 ...
HelpRecord last updated Feb 14, 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.