VCV000946767.9 - ClinVar

NM_001040142.2(SCN2A):c.843G>A (p.Trp281Ter)

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.

(3)

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, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001040142.2(SCN2A):c.843G>A (p.Trp281Ter)

Variation ID: 946767 Accession: VCV000946767.9

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2q24.3 2: 165310468 (GRCh38) [ NCBI UCSC ] 2: 166166978 (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	Jul 16, 2020	Feb 28, 2024	Nov 3, 2021

HGVS

Nucleotide	Protein	Molecular consequence
NM_001040142.2:c.843G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001035232.1:p.Trp281Ter	nonsense
NM_001371246.1:c.843G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001358175.1:p.Trp281Ter	nonsense
NM_001040143.2:c.843G>A	NP_001035233.1:p.Trp281Ter	nonsense
NM_001371247.1:c.843G>A	NP_001358176.1:p.Trp281Ter	nonsense
NM_021007.3:c.843G>A	NP_066287.2:p.Trp281Ter	nonsense
NC_000002.12:g.165310468G>A
NC_000002.11:g.166166978G>A
NG_008143.1:g.76067G>A

... more HGVS ... less HGVS

Protein change

W281*

Other names

Canonical SPDI

NC_000002.12:165310467:G:A

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.
SCN2A		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	2587	2662

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.
Developmental and epileptic encephalopathy, 11 Seizures, benign familial infantile, 3	Pathogenic (1)	criteria provided, single submitter	Jun 22, 2019	RCV001217698.13
Developmental and epileptic encephalopathy, 11 Episodic ataxia, type 9 Seizures, benign familial infantile, 3	Likely pathogenic (1)	no assertion criteria provided	Apr 21, 2020	RCV001270381.9
not provided	Pathogenic (1)	criteria provided, single submitter	Nov 3, 2021	RCV003238322.9

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.
Pathogenic (Jun 22, 2019)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Seizures, benign familial infantile, 3 Developmental and epileptic encephalopathy, 11 Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001389547.5 First in ClinVar: Jul 16, 2020 Last updated: Feb 28, 2024	Publications: PubMed (3) PubMed: 22495306‚ 23020937‚ 24650168 Comment: For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in SCN2A are known to be pathogenic (PMID: 22495306, 23020937, 24650168). This variant … (more) For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in SCN2A are known to be pathogenic (PMID: 22495306, 23020937, 24650168). This variant has not been reported in the literature in individuals with SCN2A-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Trp281*) in the SCN2A gene. It is expected to result in an absent or disrupted protein product. (less)
Pathogenic (Nov 03, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden Accession: SCV002011437.3 First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023
Likely pathogenic (Apr 21, 2020)	no assertion criteria provided Method: clinical testing	Developmental and epileptic encephalopathy, 11 Episodic ataxia, type 9 Seizures, benign familial infantile, 3 Affected status: yes Allele origin: de novo	Service de Génétique Moléculaire, Hôpital Robert Debré Accession: SCV001450661.1 First in ClinVar: Dec 17, 2020 Last updated: Dec 17, 2020

Comment:

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in SCN2A are known to be pathogenic (PMID: 22495306, 23020937, 24650168). This variant has not been reported in the literature in individuals with SCN2A-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Trp281*) in the SCN2A gene. It is expected to result in an absent or disrupted protein product.

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
De novo SCN2A splice site mutation in a boy with Autism spectrum disorder.	Tavassoli T	BMC medical genetics	2014	PMID: 24650168
Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study.	Rauch A	Lancet (London, England)	2012	PMID: 23020937
De novo mutations revealed by whole-exome sequencing are strongly associated with autism.	Sanders SJ	Nature	2012	PMID: 22495306

Text-mined citations for this variant ...

Record last updated Oct 27, 2024

ClinVar Genomic variation as it relates to human health

NM_001040142.2(SCN2A):c.843G>A (p.Trp281Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...