NM_001165963.4(SCN1A):c.5054C>T (p.Ala1685Val) AND Early infantile epileptic encephalopathy with suppression bursts

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Mar 27, 2021
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:: RCV001854246.4

Allele description [Variation Report for NM_001165963.4(SCN1A):c.5054C>T (p.Ala1685Val)]

NM_001165963.4(SCN1A):c.5054C>T (p.Ala1685Val)

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.5054C>T (p.Ala1685Val)

HGVS:

NC_000002.12:g.165992221G>A
NG_011906.1:g.86419C>T
NM_001165963.4:c.5054C>TMANE SELECT
NM_001165964.3:c.4970C>T
NM_001202435.3:c.5054C>T
NM_001353948.2:c.5054C>T
NM_001353949.2:c.5021C>T
NM_001353950.2:c.5021C>T
NM_001353951.2:c.5021C>T
NM_001353952.2:c.5021C>T
NM_001353954.2:c.5018C>T
NM_001353955.2:c.5018C>T
NM_001353957.2:c.4970C>T
NM_001353958.2:c.4970C>T
NM_001353960.2:c.4967C>T
NM_001353961.2:c.2612C>T
NM_006920.6:c.5021C>T
NP_001159435.1:p.Ala1685Val
NP_001159436.1:p.Ala1657Val
NP_001189364.1:p.Ala1685Val
NP_001340877.1:p.Ala1685Val
NP_001340878.1:p.Ala1674Val
NP_001340879.1:p.Ala1674Val
NP_001340880.1:p.Ala1674Val
NP_001340881.1:p.Ala1674Val
NP_001340883.1:p.Ala1673Val
NP_001340884.1:p.Ala1673Val
NP_001340886.1:p.Ala1657Val
NP_001340887.1:p.Ala1657Val
NP_001340889.1:p.Ala1656Val
NP_001340890.1:p.Ala871Val
NP_008851.3:p.Ala1674Val
LRG_8t1:c.5021C>T
LRG_8:g.86419C>T
NC_000002.11:g.166848731G>A
NM_001165963.1:c.5054C>T
NM_006920.4:c.5021C>T
NR_148667.2:n.5471C>T

Protein change:

A1656V

Links:

UniProtKB/Swiss-Prot: VAR_029715; dbSNP: rs121918744

NCBI 1000 Genomes Browser:

rs121918744

Molecular consequence:

NM_001165963.4:c.5054C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001165964.3:c.4970C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001202435.3:c.5054C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001353948.2:c.5054C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001353949.2:c.5021C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001353950.2:c.5021C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001353951.2:c.5021C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001353952.2:c.5021C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001353954.2:c.5018C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001353955.2:c.5018C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001353957.2:c.4970C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001353958.2:c.4970C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001353960.2:c.4967C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001353961.2:c.2612C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_006920.6:c.5021C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_148667.2:n.5471C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Functional consequence:

Absence of peak current [Functional Epilepsy Nomenclature for Ion Channels: FENICS-0083]
Overall loss-of-function [Functional Epilepsy Nomenclature for Ion Channels: FENICS-0141]

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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neuronal cell adhesion molecule isoform X15 [Homo sapiens]
neuronal cell adhesion molecule isoform X15 [Homo sapiens]
gi|767947941|ref|XP_011514570.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002223001	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Mar 27, 2021)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 11823106, 12566275, 14672992, 22525008, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002223001

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Mar 27, 2021)

germline

clinical testing

PubMed (5)
[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

Autosomal dominant epilepsy with febrile seizures plus with missense mutations of the (Na+)-channel alpha 1 subunit gene, SCN1A.

Ito M, Nagafuji H, Okazawa H, Yamakawa K, Sugawara T, Mazaki-Miyazaki E, Hirose S, Fukuma G, Mitsudome A, Wada K, Kaneko S.

Epilepsy Res. 2002 Jan;48(1-2):15-23.

PubMed [citation]

PMID:: 11823106

Mutations of sodium channel alpha subunit type 1 (SCN1A) in intractable childhood epilepsies with frequent generalized tonic-clonic seizures.

Fujiwara T, Sugawara T, Mazaki-Miyazaki E, Takahashi Y, Fukushima K, Watanabe M, Hara K, Morikawa T, Yagi K, Yamakawa K, Inoue Y.

Brain. 2003 Mar;126(Pt 3):531-46.

PubMed [citation]

PMID:: 12566275

See all PubMed Citations (5)

Details of each submission

From Invitae, SCV002223001.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This variant has been observed in individual(s) with SCN1A-related conditions (PMID: 11823106). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 68648). This variant is also known as c.5021C>T (Ala1674Val). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ala1685 amino acid residue in SCN1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22525008, 12566275). 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. Experimental studies have shown that this variant affects SCN1A protein function (PMID: 14672992, 22525008). This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with valine at codon 1685 of the SCN1A protein (p.Ala1685Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine.

#	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: Apr 15, 2024

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