NM_001165963.4(SCN1A):c.4322C>T (p.Ala1441Val) AND Early infantile epileptic encephalopathy with suppression bursts

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Feb 25, 2022
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:: RCV001939397.7

Allele description [Variation Report for NM_001165963.4(SCN1A):c.4322C>T (p.Ala1441Val)]

NM_001165963.4(SCN1A):c.4322C>T (p.Ala1441Val)

Genes:

SCN1A:sodium voltage-gated channel alpha subunit 1 [Gene - OMIM - HGNC]
LOC102724058:uncharacterized LOC102724058 [Gene]

Variant type:

single nucleotide variant

Cytogenetic location:

2q24.3

Genomic location:

Preferred name:

NM_001165963.4(SCN1A):c.4322C>T (p.Ala1441Val)

HGVS:

NC_000002.12:g.165999739G>A
NG_011906.1:g.78901C>T
NM_001165963.4:c.4322C>TMANE SELECT
NM_001165964.3:c.4238C>T
NM_001202435.3:c.4322C>T
NM_001353948.2:c.4322C>T
NM_001353949.2:c.4289C>T
NM_001353950.2:c.4289C>T
NM_001353951.2:c.4289C>T
NM_001353952.2:c.4289C>T
NM_001353954.2:c.4286C>T
NM_001353955.2:c.4286C>T
NM_001353957.2:c.4238C>T
NM_001353958.2:c.4238C>T
NM_001353960.2:c.4235C>T
NM_001353961.2:c.1880C>T
NM_006920.6:c.4289C>T
NP_001159435.1:p.Ala1441Val
NP_001159436.1:p.Ala1413Val
NP_001189364.1:p.Ala1441Val
NP_001340877.1:p.Ala1441Val
NP_001340878.1:p.Ala1430Val
NP_001340879.1:p.Ala1430Val
NP_001340880.1:p.Ala1430Val
NP_001340881.1:p.Ala1430Val
NP_001340883.1:p.Ala1429Val
NP_001340884.1:p.Ala1429Val
NP_001340886.1:p.Ala1413Val
NP_001340887.1:p.Ala1413Val
NP_001340889.1:p.Ala1412Val
NP_001340890.1:p.Ala627Val
NP_008851.3:p.Ala1430Val
LRG_8:g.78901C>T
NC_000002.11:g.166856249G>A
NR_148667.2:n.4739C>T

Protein change:

A1412V

Links:

dbSNP: rs2105486615

NCBI 1000 Genomes Browser:

rs2105486615

Molecular consequence:

NM_001165963.4:c.4322C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001165964.3:c.4238C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001202435.3:c.4322C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001353948.2:c.4322C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001353949.2:c.4289C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001353950.2:c.4289C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001353951.2:c.4289C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001353952.2:c.4289C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001353954.2:c.4286C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001353955.2:c.4286C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001353957.2:c.4238C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001353958.2:c.4238C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001353960.2:c.4235C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001353961.2:c.1880C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_006920.6:c.4289C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_148667.2:n.4739C>T - 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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002235941	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Feb 25, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 25459968, 31765958, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002235941

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Feb 25, 2022)

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

Electroencephalographic features of patients with SCN1A-positive Dravet syndrome.

Lee HF, Chi CS, Tsai CR, Chen CH, Wang CC.

Brain Dev. 2015 Jun;37(6):599-611. doi: 10.1016/j.braindev.2014.10.003. Epub 2014 Oct 27.

PubMed [citation]

PMID:: 25459968

Mutation spectrum of the SCN1A gene in a Hungarian population with epilepsy.

Till Á, Zima J, Fekete A, Bene J, Czakó M, Szabó A, Melegh B, Hadzsiev K.

Seizure. 2020 Jan;74:8-13. doi: 10.1016/j.seizure.2019.10.019. Epub 2019 Nov 8.

PubMed [citation]

PMID:: 31765958

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002235941.3

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

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ala1441 amino acid residue in SCN1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25459968; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 Dravet syndrome (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 valine, which is neutral and non-polar, at codon 1441 of the SCN1A protein (p.Ala1441Val).

#	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

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