ClinVar Genomic variation as it relates to human health
NM_001165963.4(SCN1A):c.4934G>A (p.Arg1645Gln)
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.4934G>A (p.Arg1645Gln)
Variation ID: 68558 Accession: VCV000068558.22
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2q24.3 2: 165992341 (GRCh38) [ NCBI UCSC ] 2: 166848851 (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 May 1, 2024 Aug 30, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001165963.4:c.4934G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001159435.1:p.Arg1645Gln missense NM_001165964.3:c.4850G>A NP_001159436.1:p.Arg1617Gln missense NM_001202435.3:c.4934G>A NP_001189364.1:p.Arg1645Gln missense NM_001353948.2:c.4934G>A NP_001340877.1:p.Arg1645Gln missense NM_001353949.2:c.4901G>A NP_001340878.1:p.Arg1634Gln missense NM_001353950.2:c.4901G>A NP_001340879.1:p.Arg1634Gln missense NM_001353951.2:c.4901G>A NP_001340880.1:p.Arg1634Gln missense NM_001353952.2:c.4901G>A NP_001340881.1:p.Arg1634Gln missense NM_001353954.2:c.4898G>A NP_001340883.1:p.Arg1633Gln missense NM_001353955.2:c.4898G>A NP_001340884.1:p.Arg1633Gln missense NM_001353957.2:c.4850G>A NP_001340886.1:p.Arg1617Gln missense NM_001353958.2:c.4850G>A NP_001340887.1:p.Arg1617Gln missense NM_001353960.2:c.4847G>A NP_001340889.1:p.Arg1616Gln missense NM_001353961.2:c.2492G>A NP_001340890.1:p.Arg831Gln missense NM_006920.6:c.4901G>A NP_008851.3:p.Arg1634Gln missense NR_148667.2:n.5351G>A non-coding transcript variant NC_000002.12:g.165992341C>T NC_000002.11:g.166848851C>T NG_011906.1:g.86299G>A LRG_8:g.86299G>A LRG_8t1:c.4901G>A - Protein change
- R1634Q, R1645Q, R1616Q, R1617Q, R1633Q, R831Q
- Other names
- p.R1645Q:CGA>CAA
- Canonical SPDI
- NC_000002.12:165992340:C:T
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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
Help
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
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. |
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Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Nov 16, 2016 | RCV000059432.12 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 6, 2020 | RCV000188986.11 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 31, 2018 | RCV000763457.10 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 28, 2018 | RCV001198988.10 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 30, 2023 | RCV001208285.13 | |
Pathogenic (1) |
criteria provided, single submitter
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May 6, 2016 | RCV002316217.9 |
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 16, 2016)
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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:
de novo
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Neurogenetics Laboratory - MEYER, AOU Meyer
Accession: SCV000494514.1
First in ClinVar: Oct 31, 2013 Last updated: Oct 31, 2013 |
Family history: no
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Pathogenic
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Generalized epilepsy with febrile seizures plus, type 2
Severe myoclonic epilepsy in infancy Migraine, familial hemiplegic, 3
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000894234.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Pathogenic
(Nov 28, 2018)
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criteria provided, single submitter
Method: clinical testing
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Migraine, familial hemiplegic, 3
Affected status: yes
Allele origin:
unknown
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001369983.2
First in ClinVar: Jul 04, 2020 Last updated: Jul 04, 2020 |
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PM1,PP2,PP3,PS1.
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Pathogenic
(-)
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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:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV002072919.1
First in ClinVar: Feb 03, 2022 Last updated: Feb 03, 2022 |
Comment:
The missense variant p.R1645Q in SCN1A (NM_001165963.4) has ben previously reported in multiple patients with Dravet syndrome including one where it was confirmed to be … (more)
The missense variant p.R1645Q in SCN1A (NM_001165963.4) has ben previously reported in multiple patients with Dravet syndrome including one where it was confirmed to be de novo (Harkin LA et al; Parrini E et al). The variant has been submitted to ClinVar as Pathogenic.The missense variant c.4934G>A (p.R1645Q) in SCN1A (NM_001165963.4) is not observed in the large population cohorts of the gnomAD and 1000 Genomes datasets (Exome Aggregation Consortium et al., 2016; 1000 Genomes Consortium et al., 2015). The p.R1645Q missense variant is predicted to be damaging by both SIFT and PolyPhen2. The arginine residue at codon 1645 of SCN1A is conserved in all mammalian species. The nucleotide c.4934 in SCN1A is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. (less)
Clinical Features:
Global developmental delay (present) , Seizure (present)
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Pathogenic
(Jul 06, 2020)
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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: SCV000242617.13
First in ClinVar: Aug 07, 2015 Last updated: Mar 04, 2023 |
Comment:
Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Missense variants in this gene are often considered pathogenic (Stenson et … (more)
Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); 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: 19585586, 17347258, 16713920, 19359143, 19589774, 27864847, 31134136, 31031587) (less)
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Pathogenic
(Aug 30, 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: SCV001379664.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, … (more)
For these reasons, this variant has been classified as Pathogenic. 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: 68558). This missense change has been observed in individual(s) with Dravet syndrome (PMID: 17347258, 27864847). In at least one individual the variant was observed to be de novo. This variant is present in population databases (rs121917976, gnomAD 0.0009%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1645 of the SCN1A protein (p.Arg1645Gln). (less)
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Pathogenic
(May 06, 2016)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000851004.6
First in ClinVar: Nov 08, 2018 Last updated: May 01, 2024 |
Comment:
The p.R1645Q pathogenic mutation (also known as c.4934G>A), located in coding exon 26 of the SCN1A gene, results from a G to A substitution at … (more)
The p.R1645Q pathogenic mutation (also known as c.4934G>A), located in coding exon 26 of the SCN1A gene, results from a G to A substitution at nucleotide position 4934. The arginine at codon 1645 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in the literature as de novo in two individuals with the SCN1A-related seizure disorder, Dravet syndrome (Harkin LA, Brain 2007; 130:843-52; Heron SE, J. Med. Genet. 2010; 47(2):137-41; Bolszak M, Epilepsy Res. 2009; 85(2-3):300-4). The position R1645 corresponds to a well-defined arginine (R3) in the voltage sensing motif known to play a significant role in gating function (DeCoursey TE. Physiol Rev. 2013;93(2):599-652). Based on the supporting evidence this alteration is interpreted as a disease-causing mutation. (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:
unknown
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UniProtKB/Swiss-Prot
Accession: SCV000090956.1
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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Diagnostic Targeted Resequencing in 349 Patients with Drug-Resistant Pediatric Epilepsies Identifies Causative Mutations in 30 Different Genes. | Parrini E | Human mutation | 2017 | PMID: 27864847 |
De novo SCN1A mutations in Dravet syndrome and related epileptic encephalopathies are largely of paternal origin. | Heron SE | Journal of medical genetics | 2010 | PMID: 19589774 |
Digenic mutations in severe myoclonic epilepsy of infancy. | Bolszak M | Epilepsy research | 2009 | PMID: 19359143 |
The spectrum of SCN1A-related infantile epileptic encephalopathies. | Harkin LA | Brain : a journal of neurology | 2007 | PMID: 17347258 |
Text-mined citations for rs121917976 ...
HelpRecord last updated May 12, 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.