NM_001165963.4(SCN1A):c.1852C>T (p.Arg618Cys) AND Early infantile epileptic encephalopathy with suppression bursts

Germline classification:: Pathogenic (1 submission)
Last evaluated:: May 8, 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:: RCV000204396.9

Allele description [Variation Report for NM_001165963.4(SCN1A):c.1852C>T (p.Arg618Cys)]

NM_001165963.4(SCN1A):c.1852C>T (p.Arg618Cys)

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.1852C>T (p.Arg618Cys)

HGVS:

NC_000002.12:g.166043860G>A
NG_011906.1:g.34780C>T
NM_001165963.4:c.1852C>TMANE SELECT
NM_001165964.3:c.1852C>T
NM_001202435.3:c.1852C>T
NM_001353948.2:c.1852C>T
NM_001353949.2:c.1852C>T
NM_001353950.2:c.1852C>T
NM_001353951.2:c.1852C>T
NM_001353952.2:c.1852C>T
NM_001353954.2:c.1849C>T
NM_001353955.2:c.1849C>T
NM_001353957.2:c.1852C>T
NM_001353958.2:c.1852C>T
NM_001353960.2:c.1849C>T
NM_001353961.2:c.-574C>T
NM_006920.6:c.1852C>T
NP_001159435.1:p.Arg618Cys
NP_001159436.1:p.Arg618Cys
NP_001189364.1:p.Arg618Cys
NP_001340877.1:p.Arg618Cys
NP_001340878.1:p.Arg618Cys
NP_001340879.1:p.Arg618Cys
NP_001340880.1:p.Arg618Cys
NP_001340881.1:p.Arg618Cys
NP_001340883.1:p.Arg617Cys
NP_001340884.1:p.Arg617Cys
NP_001340886.1:p.Arg618Cys
NP_001340887.1:p.Arg618Cys
NP_001340889.1:p.Arg617Cys
NP_008851.3:p.Arg618Cys
LRG_8:g.34780C>T
NC_000002.11:g.166900370G>A
NM_001165963.1:c.1852C>T
NR_148667.2:n.2238C>T

Protein change:

R617C

Links:

dbSNP: rs750516202

NCBI 1000 Genomes Browser:

rs750516202

Molecular consequence:

NM_001353961.2:c.-574C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001165963.4:c.1852C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001165964.3:c.1852C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001202435.3:c.1852C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001353948.2:c.1852C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001353949.2:c.1852C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001353950.2:c.1852C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001353951.2:c.1852C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001353952.2:c.1852C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001353954.2:c.1849C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001353955.2:c.1849C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001353957.2:c.1852C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001353958.2:c.1852C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001353960.2:c.1849C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_006920.6:c.1852C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_148667.2:n.2238C>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
SCV000260566	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (May 8, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 35571373, 25795284, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000260566

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(May 8, 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

Phenotypic and Genotypic Characteristics of SCN1A Associated Seizure Diseases.

Chen C, Fang F, Wang X, Lv J, Wang X, Jin H.

Front Mol Neurosci. 2022;15:821012. doi: 10.3389/fnmol.2022.821012.

PubMed [citation]

PMID:: 35571373
PMCID:: PMC9096348

Homozygous mutations in the SCN1A gene associated with genetic epilepsy with febrile seizures plus and Dravet syndrome in 2 families.

Brunklaus A, Ellis R, Stewart H, Aylett S, Reavey E, Jefferson R, Jain R, Chakraborty S, Jayawant S, Zuberi SM.

Eur J Paediatr Neurol. 2015 Jul;19(4):484-8. doi: 10.1016/j.ejpn.2015.02.001. Epub 2015 Feb 21.

PubMed [citation]

PMID:: 25795284

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000260566.6

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

Description

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. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 220200). This missense change has been observed in individuals with generalized epilepsy with febrile seizures plus (PMID: 35571373; Invitae). This variant was reported in the homozygous state in two siblings affected with febrile seizures plus focal seizures and in the heterozygous state in the unaffected carrier parents (PMID: 25795284). Although SCN1A-related epilepsy is typically dominant, the authors propose that this variant may cause a recessive form of the disorder. This variant is present in population databases (rs750516202, gnomAD 0.0009%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 618 of the SCN1A protein (p.Arg618Cys).

#	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: Oct 8, 2024

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