The Arg1525Stop variant in the SCN1A gene has been reported in several individuals with SCN1A-related disorders (Kearney et al., 2006; Harkin et al., 2007). This variant is predicted to cause loss of normal protein function through protein truncation or nonsense-mediated mRNA decay. This variant has been seen apparently mosaic.
ClinVar Genomic variation as it relates to human health
NM_001165963.4(SCN1A):c.4573C>T (p.Arg1525Ter)
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.
(7)
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
7
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001165963.4(SCN1A):c.4573C>T (p.Arg1525Ter)
Variation ID: 189911 Accession: VCV000189911.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2q24.3 2: 165996021 (GRCh38) [ NCBI UCSC ] 2: 166852531 (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 Jul 2, 2015 Feb 14, 2024 Nov 13, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001165963.4:c.4573C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001159435.1:p.Arg1525Ter nonsense NM_001165964.3:c.4489C>T NP_001159436.1:p.Arg1497Ter nonsense NM_001202435.1:c.4573C>T NM_001202435.3:c.4573C>T NP_001189364.1:p.Arg1525Ter nonsense NM_001353948.2:c.4573C>T NP_001340877.1:p.Arg1525Ter nonsense NM_001353949.2:c.4540C>T NP_001340878.1:p.Arg1514Ter nonsense NM_001353950.2:c.4540C>T NP_001340879.1:p.Arg1514Ter nonsense NM_001353951.2:c.4540C>T NP_001340880.1:p.Arg1514Ter nonsense NM_001353952.2:c.4540C>T NP_001340881.1:p.Arg1514Ter nonsense NM_001353954.2:c.4537C>T NP_001340883.1:p.Arg1513Ter nonsense NM_001353955.2:c.4537C>T NP_001340884.1:p.Arg1513Ter nonsense NM_001353957.2:c.4489C>T NP_001340886.1:p.Arg1497Ter nonsense NM_001353958.2:c.4489C>T NP_001340887.1:p.Arg1497Ter nonsense NM_001353960.2:c.4486C>T NP_001340889.1:p.Arg1496Ter nonsense NM_001353961.2:c.2131C>T NP_001340890.1:p.Arg711Ter nonsense NM_006920.6:c.4540C>T NP_008851.3:p.Arg1514Ter nonsense NR_148667.2:n.4990C>T non-coding transcript variant NC_000002.12:g.165996021G>A NC_000002.11:g.166852531G>A NG_011906.1:g.82619C>T LRG_8:g.82619C>T - Protein change
- R1514*, R1525*, R1513*, R1496*, R1497*, R711*
- Other names
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p.R1525*:CGA>TGA
- Canonical SPDI
- NC_000002.12:165996020: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
Help
The frequency of the allele represented by this VCV record.
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- 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. |
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| SCN1A | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
2231 | 4609 | |
| LOC102724058 | - | - | - | GRCh38 | - | 2319 |
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 (4) |
criteria provided, multiple submitters, no conflicts
|
Mar 31, 2023 | RCV000188962.8 | |
| Pathogenic (1) |
criteria provided, single submitter
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Dec 20, 2014 | RCV000180863.4 | |
| Pathogenic (1) |
criteria provided, single submitter
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Apr 10, 2022 | RCV002221506.3 | |
| Pathogenic (1) |
criteria provided, single submitter
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Nov 13, 2023 | RCV001382664.6 |
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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|---|---|---|---|---|---|
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Pathogenic
(Dec 20, 2014)
|
criteria provided, single submitter
Method: research
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Dravet syndrome
Affected status: yes
Allele origin:
de novo
|
Center for Bioinformatics, Peking University
Additional submitter:
Pediatric Department, Peking University First Hospital
Study: University Clinical Cooperation “985 Project” PKU-2014-1-1
Accession: SCV000221828.1 First in ClinVar: Jul 02, 2015 Last updated: Jul 02, 2015
Comment:
Dravet syndrome (DS) probands were recruited from the outpatient and inpatient child neurology units of Peking University First Hospital from 2005 till present. The study … (more)
Dravet syndrome (DS) probands were recruited from the outpatient and inpatient child neurology units of Peking University First Hospital from 2005 till present. The study was approved by the Ethics Committee of Peking University First Hospital and the Institutional Review Board at Peking University. Participants or their parents provided written informed consent before enrollment. We collected a total of 267 mutations from 255 families with probands diagnosed with DS in China. All probands fulfilled the clinical diagnostic criteria. (less)
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Number of individuals with the variant: 2
Ethnicity/Population group: Chinese
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Pathogenic
(Jun 29, 2016)
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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: SCV000242593.12
First in ClinVar: Aug 07, 2015 Last updated: Oct 09, 2016 |
Comment:
The Arg1525Stop variant in the SCN1A gene has been reported in several individuals with SCN1A-related disorders (Kearney et al., 2006; Harkin et al., 2007). This … (more)
The Arg1525Stop variant in the SCN1A gene has been reported in several individuals with SCN1A-related disorders (Kearney et al., 2006; Harkin et al., 2007). This variant is predicted to cause loss of normal protein function through protein truncation or nonsense-mediated mRNA decay. This variant has been seen apparently mosaic. (less)
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Pathogenic
(Apr 10, 2022)
|
criteria provided, single submitter
Method: clinical testing
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Migraine, familial hemiplegic, 3
Affected status: yes
Allele origin:
germline
|
DASA
Accession: SCV002499419.1
First in ClinVar: Apr 16, 2022 Last updated: Apr 16, 2022 |
Comment:
The c.4573C>T;p.(Arg1525*) variant creates a premature translational stop signal in the SCN1A gene. It is expected to result in an absent or disrupted protein product … (more)
The c.4573C>T;p.(Arg1525*) variant creates a premature translational stop signal in the SCN1A gene. It is expected to result in an absent or disrupted protein product -PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 189911; PMID: 28079314; 27465585; 17347258; 16458823) - PS4. This variant is not present in population databases (rs794726752- gnomAD; ABraOM no frequency - http://abraom.ib.usp.br) - PM2. The variant was assumed de novo, but without confirmation of paternity and maternity (PMID: 27465585) - PM6. In summary, the currently available evidence indicates that the variant is pathogenic. (less)
Number of individuals with the variant: 1
Sex: female
Geographic origin: Brazil
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Pathogenic
(Mar 31, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Athena Diagnostics
Accession: SCV004230006.1
First in ClinVar: Jan 26, 2024 Last updated: Jan 26, 2024 |
Comment:
This variant is expected to result in the loss of a functional protein. This variant has been identified in multiple unrelated individuals with Dravet syndrome … (more)
This variant is expected to result in the loss of a functional protein. This variant has been identified in multiple unrelated individuals with Dravet syndrome and severe myoclonic epilepsy of infancy (SMEI) and has been confirmed to occur de novo in multiple individuals. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). (less)
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Pathogenic
(Nov 13, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001581559.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg1525*) in the SCN1A gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Arg1525*) in the SCN1A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SCN1A are known to be pathogenic (PMID: 17347258, 18930999). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with SCN1A-related conditions (PMID: 16458823, 27465585, 28079314). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 189911). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001809042.1 First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001929100.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
|
Comment:
Comment:
The c.4573C>T;p.(Arg1525*) variant creates a premature translational stop signal in the SCN1A gene. It is expected to result in an absent or disrupted protein product -PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 189911; PMID: 28079314; 27465585; 17347258; 16458823) - PS4. This variant is not present in population databases (rs794726752- gnomAD; ABraOM no frequency - http://abraom.ib.usp.br) - PM2. The variant was assumed de novo, but without confirmation of paternity and maternity (PMID: 27465585) - PM6. In summary, the currently available evidence indicates that the variant is pathogenic.
Comment:
This variant is expected to result in the loss of a functional protein. This variant has been identified in multiple unrelated individuals with Dravet syndrome and severe myoclonic epilepsy of infancy (SMEI) and has been confirmed to occur de novo in multiple individuals. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org).
Comment:
This sequence change creates a premature translational stop signal (p.Arg1525*) in the SCN1A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SCN1A are known to be pathogenic (PMID: 17347258, 18930999). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with SCN1A-related conditions (PMID: 16458823, 27465585, 28079314). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 189911). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
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 Arg1525Stop variant in the SCN1A gene has been reported in several individuals with SCN1A-related disorders (Kearney et al., 2006; Harkin et al., 2007). This variant is predicted to cause loss of normal protein function through protein truncation or nonsense-mediated mRNA decay. This variant has been seen apparently mosaic.
Comment:
The c.4573C>T;p.(Arg1525*) variant creates a premature translational stop signal in the SCN1A gene. It is expected to result in an absent or disrupted protein product -PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 189911; PMID: 28079314; 27465585; 17347258; 16458823) - PS4. This variant is not present in population databases (rs794726752- gnomAD; ABraOM no frequency - http://abraom.ib.usp.br) - PM2. The variant was assumed de novo, but without confirmation of paternity and maternity (PMID: 27465585) - PM6. In summary, the currently available evidence indicates that the variant is pathogenic.
Comment:
This variant is expected to result in the loss of a functional protein. This variant has been identified in multiple unrelated individuals with Dravet syndrome and severe myoclonic epilepsy of infancy (SMEI) and has been confirmed to occur de novo in multiple individuals. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org).
Comment:
This sequence change creates a premature translational stop signal (p.Arg1525*) in the SCN1A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SCN1A are known to be pathogenic (PMID: 17347258, 18930999). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with SCN1A-related conditions (PMID: 16458823, 27465585, 28079314). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 189911). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Development and Validation of a Prediction Model for Early Diagnosis of SCN1A-Related Epilepsies. | Brunklaus A | Neurology | 2022 | PMID: 35074891 |
| Biological concepts in human sodium channel epilepsies and their relevance in clinical practice. | Brunklaus A | Epilepsia | 2020 | PMID: 32090326 |
| Neurological Diseases With Autism Spectrum Disorder: Role of ASD Risk Genes. | Xiong J | Frontiers in neuroscience | 2019 | PMID: 31031587 |
| Establishment of a human induced stem cell line (FUi002-A) from Dravet syndrome patient carrying heterozygous R1525X mutation in SCN1A gene. | Tanaka Y | Stem cell research | 2018 | PMID: 29981888 |
| High frequency of mosaic pathogenic variants in genes causing epilepsy-related neurodevelopmental disorders. | Stosser MB | Genetics in medicine : official journal of the American College of Medical Genetics | 2018 | PMID: 28837158 |
| SCN1A Gene Mutation and Adaptive Functioning in 18 Vietnamese Children with Dravet Syndrome. | Do TT | Journal of clinical neurology (Seoul, Korea) | 2017 | PMID: 28079314 |
| Pitfalls in genetic testing: the story of missed SCN1A mutations. | Djémié T | Molecular genetics & genomic medicine | 2016 | PMID: 27465585 |
| 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 |
| Prevalence of SCN1A mutations in children with suspected Dravet syndrome and intractable childhood epilepsy. | Wang JW | Epilepsy research | 2012 | PMID: 23195492 |
| Genotype-phenotype associations in SCN1A-related epilepsies. | Zuberi SM | Neurology | 2011 | PMID: 21248271 |
| Timing of de novo mutagenesis--a twin study of sodium-channel mutations. | Vadlamudi L | The New England journal of medicine | 2010 | PMID: 20879882 |
| Mutational analysis of the SCN1A, SCN1B and GABRG2 genes in 150 Italian patients with idiopathic childhood epilepsies. | Orrico A | Clinical genetics | 2009 | PMID: 19522081 |
| Spectrum of SCN1A gene mutations associated with Dravet syndrome: analysis of 333 patients. | Depienne C | Journal of medical genetics | 2009 | PMID: 18930999 |
| The spectrum of SCN1A-related infantile epileptic encephalopathies. | Harkin LA | Brain : a journal of neurology | 2007 | PMID: 17347258 |
| Recurrent de novo mutations of SCN1A in severe myoclonic epilepsy of infancy. | Kearney JA | Pediatric neurology | 2006 | PMID: 16458823 |
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Text-mined citations for rs794726752 ...
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 Sep 29, 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.