VCV001916227.4 - ClinVar

NM_001165963.4(SCN1A):c.1184C>A (p.Ala395Asp)

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.

(2)

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.

Likely 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_001165963.4(SCN1A):c.1184C>A (p.Ala395Asp)

Variation ID: 1916227 Accession: VCV001916227.4

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2q24.3 2: 166046963 (GRCh38) [ NCBI UCSC ] 2: 166903473 (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 7, 2023	Jul 23, 2024	Apr 25, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001165963.4:c.1184C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001159435.1:p.Ala395Asp	missense
NM_001165963.1:c.1184C>A
NM_001165964.3:c.1184C>A	NP_001159436.1:p.Ala395Asp	missense
NM_001202435.3:c.1184C>A	NP_001189364.1:p.Ala395Asp	missense
NM_001353948.2:c.1184C>A	NP_001340877.1:p.Ala395Asp	missense
NM_001353949.2:c.1184C>A	NP_001340878.1:p.Ala395Asp	missense
NM_001353950.2:c.1184C>A	NP_001340879.1:p.Ala395Asp	missense
NM_001353951.2:c.1184C>A	NP_001340880.1:p.Ala395Asp	missense
NM_001353952.2:c.1184C>A	NP_001340881.1:p.Ala395Asp	missense
NM_001353954.2:c.1184C>A	NP_001340883.1:p.Ala395Asp	missense
NM_001353955.2:c.1184C>A	NP_001340884.1:p.Ala395Asp	missense
NM_001353957.2:c.1184C>A	NP_001340886.1:p.Ala395Asp	missense
NM_001353958.2:c.1184C>A	NP_001340887.1:p.Ala395Asp	missense
NM_001353960.2:c.1184C>A	NP_001340889.1:p.Ala395Asp	missense
NM_001353961.2:c.-1242C>A		5 prime UTR
NM_006920.6:c.1184C>A	NP_008851.3:p.Ala395Asp	missense
NR_148667.2:n.1570C>A		non-coding transcript variant
NC_000002.12:g.166046963G>T
NC_000002.11:g.166903473G>T
NG_011906.1:g.31677C>A
LRG_8:g.31677C>A
LRG_8t1:c.1184C>A	LRG_8p1:p.Ala395Asp

... more HGVS ... less HGVS

Protein change

A395D

Other names

Canonical SPDI

NC_000002.12:166046962:G:T

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	Likely pathogenic (1)	criteria provided, single submitter	Oct 1, 2022	RCV002613187.3
not provided	Likely pathogenic (1)	criteria provided, single submitter	Apr 25, 2024	RCV004593039.1

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.
Likely pathogenic (Oct 01, 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: SCV002950936.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 28, 2024	Publications: PubMed (2) PubMed: 17347258‚ 31765958 Comment: This variant disrupts the p.Ala395 amino acid residue in SCN1A. Other variant(s) that disrupt this residue have been observed in individuals with SCN1A-related conditions (PMID: … (more) This variant disrupts the p.Ala395 amino acid residue in SCN1A. Other variant(s) that disrupt this residue have been observed in individuals with SCN1A-related conditions (PMID: 17347258), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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. This missense change has been observed in individual(s) with SCN1A-related conditions (PMID: 31765958). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 395 of the SCN1A protein (p.Ala395Asp). (less)
Likely pathogenic (Apr 25, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV005079201.1 First in ClinVar: Jul 23, 2024 Last updated: Jul 23, 2024	Comment: Identified in a patient with Dravet syndrome; comprehensive genetic testing and segregation studies were not performed (PMID: 31765958); This substitution is predicted to be within … (more) Identified in a patient with Dravet syndrome; comprehensive genetic testing and segregation studies were not performed (PMID: 31765958); This substitution is predicted to be within the extracellular loop between the S5 and S6 transmembrane segments of the first homologous domain; Not observed in large population cohorts (gnomAD); 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: 31765958) (less)

Comment:

This variant disrupts the p.Ala395 amino acid residue in SCN1A. Other variant(s) that disrupt this residue have been observed in individuals with SCN1A-related conditions (PMID: 17347258), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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. This missense change has been observed in individual(s) with SCN1A-related conditions (PMID: 31765958). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 395 of the SCN1A protein (p.Ala395Asp).

Comment:

Identified in a patient with Dravet syndrome; comprehensive genetic testing and segregation studies were not performed (PMID: 31765958); This substitution is predicted to be within the extracellular loop between the S5 and S6 transmembrane segments of the first homologous domain; Not observed in large population cohorts (gnomAD); 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: 31765958)

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
Mutation spectrum of the SCN1A gene in a Hungarian population with epilepsy.	Till Á	Seizure	2020	PMID: 31765958
The spectrum of SCN1A-related infantile epileptic encephalopathies.	Harkin LA	Brain : a journal of neurology	2007	PMID: 17347258

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.1184C>A (p.Ala395Asp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...