NM_001165963.4(SCN1A):c.2994C>A (p.Asp998Glu) AND Early infantile epileptic encephalopathy with suppression bursts

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Dec 4, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV002514043.3

Allele description [Variation Report for NM_001165963.4(SCN1A):c.2994C>A (p.Asp998Glu)]

NM_001165963.4(SCN1A):c.2994C>A (p.Asp998Glu)

Gene:

SCN1A:sodium voltage-gated channel alpha subunit 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2q24.3

Genomic location:

Preferred name:

NM_001165963.4(SCN1A):c.2994C>A (p.Asp998Glu)

Other names:

p.D998E:GAC>GAA

HGVS:

NC_000002.12:g.166036483G>T
NG_011906.1:g.42157C>A
NM_001165963.4:c.2994C>AMANE SELECT
NM_001165964.3:c.2910C>A
NM_001202435.3:c.2994C>A
NM_001353948.2:c.2994C>A
NM_001353949.2:c.2961C>A
NM_001353950.2:c.2961C>A
NM_001353951.2:c.2961C>A
NM_001353952.2:c.2961C>A
NM_001353954.2:c.2958C>A
NM_001353955.2:c.2958C>A
NM_001353957.2:c.2910C>A
NM_001353958.2:c.2910C>A
NM_001353960.2:c.2907C>A
NM_001353961.2:c.552C>A
NM_006920.6:c.2961C>A
NP_001159435.1:p.Asp998Glu
NP_001159436.1:p.Asp970Glu
NP_001189364.1:p.Asp998Glu
NP_001340877.1:p.Asp998Glu
NP_001340878.1:p.Asp987Glu
NP_001340879.1:p.Asp987Glu
NP_001340880.1:p.Asp987Glu
NP_001340881.1:p.Asp987Glu
NP_001340883.1:p.Asp986Glu
NP_001340884.1:p.Asp986Glu
NP_001340886.1:p.Asp970Glu
NP_001340887.1:p.Asp970Glu
NP_001340889.1:p.Asp969Glu
NP_001340890.1:p.Asp184Glu
NP_008851.3:p.Asp987Glu
LRG_8:g.42157C>A
NC_000002.11:g.166892993G>T
NM_001165963.1:c.2994C>A
NM_001165963.3:c.2994C>A
NR_148667.2:n.3347C>A

Protein change:

D184E

Links:

dbSNP: rs796052991

NCBI 1000 Genomes Browser:

rs796052991

Molecular consequence:

NM_001165963.4:c.2994C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001165964.3:c.2910C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001202435.3:c.2994C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001353948.2:c.2994C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001353949.2:c.2961C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001353950.2:c.2961C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001353951.2:c.2961C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001353952.2:c.2961C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001353954.2:c.2958C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001353955.2:c.2958C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001353957.2:c.2910C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001353958.2:c.2910C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001353960.2:c.2907C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001353961.2:c.552C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_006920.6:c.2961C>A - missense variant - [Sequence Ontology: SO:0001583]
NR_148667.2:n.3347C>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Early infantile epileptic encephalopathy with suppression bursts (EIEE)
Synonyms:: Early infantile epileptic encephalopathy; Ohtahara syndrome; Developmental and epileptic encephalopathy
Identifiers:: MONDO: MONDO:0100062; MedGen: C0393706; Orphanet: 1934; OMIM: PS308350

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003020165	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Dec 4, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 29655203, 18930999, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003020165

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Dec 4, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Diagnostic outcomes for genetic testing of 70 genes in 8565 patients with epilepsy and neurodevelopmental disorders.

Lindy AS, Stosser MB, Butler E, Downtain-Pickersgill C, Shanmugham A, Retterer K, Brandt T, Richard G, McKnight DA.

Epilepsia. 2018 May;59(5):1062-1071. doi: 10.1111/epi.14074. Epub 2018 Apr 14.

PubMed [citation]

PMID:: 29655203

Spectrum of SCN1A gene mutations associated with Dravet syndrome: analysis of 333 patients.

Depienne C, Trouillard O, Saint-Martin C, Gourfinkel-An I, Bouteiller D, Carpentier W, Keren B, Abert B, Gautier A, Baulac S, Arzimanoglou A, Cazeneuve C, Nabbout R, LeGuern E.

J Med Genet. 2009 Mar;46(3):183-91. doi: 10.1136/jmg.2008.062323. Epub 2008 Oct 17.

PubMed [citation]

PMID:: 18930999

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003020165.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 998 of the SCN1A protein (p.Asp998Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of autosomal dominant SCN1A-related conditions and/or SCN1A-related conditions (PMID: 29655203; Invitae). ClinVar contains an entry for this variant (Variation ID: 206795). 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 with a positive predictive value of 95%. This variant disrupts the p.Asp998 amino acid residue in SCN1A. Other variant(s) that disrupt this residue have been observed in individuals with SCN1A-related conditions (PMID: 18930999), 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

ClinVar

Relating variation to medicine