VCV002135501.2 - ClinVar

NM_001165963.4(SCN1A):c.603-2A>C

Germline

Classification

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.

(1)

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

criteria provided, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001165963.4(SCN1A):c.603-2A>C

Variation ID: 2135501 Accession: VCV002135501.2

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2q24.3 2: 166052945 (GRCh38) [ NCBI UCSC ] 2: 166909455 (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	Feb 8, 2023	Feb 20, 2024	May 8, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_001165963.4:c.603-2A>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice acceptor
NM_001165964.3:c.603-2A>C		splice acceptor
NM_001202435.3:c.603-2A>C		splice acceptor
NM_001353948.2:c.603-2A>C		splice acceptor
NM_001353949.2:c.603-2A>C		splice acceptor
NM_001353950.2:c.603-2A>C		splice acceptor
NM_001353951.2:c.603-2A>C		splice acceptor
NM_001353952.2:c.603-2A>C		splice acceptor
NM_001353954.2:c.603-2A>C		splice acceptor
NM_001353955.2:c.603-2A>C		splice acceptor
NM_001353957.2:c.603-2A>C		splice acceptor
NM_001353958.2:c.603-2A>C		splice acceptor
NM_001353960.2:c.603-2A>C		splice acceptor
NM_001353961.2:c.-1823-2A>C		splice acceptor
NM_006920.6:c.603-2A>C		splice acceptor
NC_000002.12:g.166052945T>G
NC_000002.11:g.166909455T>G
NG_011906.1:g.25695A>C
LRG_8:g.25695A>C

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000002.12:166052944:T:G

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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

VarSome

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
Gene	OMIM	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	2241	4627

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.
Early infantile epileptic encephalopathy with suppression bursts	Pathogenic (1)	criteria provided, single submitter	May 8, 2022	RCV003066335.3

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 08, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Early infantile epileptic encephalopathy with suppression bursts Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003352724.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 20, 2024	Publications: PubMed (4) PubMed: 16199547‚ 17347258‚ 18930999‚ 21719429 Comment: This sequence change affects an acceptor splice site in intron 4 of the SCN1A gene. It is expected to disrupt RNA splicing. Variants that disrupt … (more) This sequence change affects an acceptor splice site in intron 4 of the SCN1A gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and 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). Disruption of this splice site has been observed in individual(s) with Dravet syndrome (PMID: 21719429). In at least one individual the variant was observed to be de novo. 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)

Comment:

This sequence change affects an acceptor splice site in intron 4 of the SCN1A gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and 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). Disruption of this splice site has been observed in individual(s) with Dravet syndrome (PMID: 21719429). In at least one individual the variant was observed to be de novo. 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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Dravet syndrome as epileptic encephalopathy: evidence from long-term course and neuropathology.	Catarino CB	Brain : a journal of neurology	2011	PMID: 21719429
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
Splicing in action: assessing disease causing sequence changes.	Baralle D	Journal of medical genetics	2005	PMID: 16199547

Text-mined citations for this variant ...

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_001165963.4(SCN1A):c.603-2A>C

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...