NM_001165963.4(SCN1A):c.4762T>C (p.Cys1588Arg) AND Early infantile epileptic encephalopathy with suppression bursts

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Feb 24, 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:: RCV000636318.7

Allele description [Variation Report for NM_001165963.4(SCN1A):c.4762T>C (p.Cys1588Arg)]

NM_001165963.4(SCN1A):c.4762T>C (p.Cys1588Arg)

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.4762T>C (p.Cys1588Arg)

Other names:

p.C1588R:TGT>CGT

HGVS:

NC_000002.12:g.165994236A>G
NG_011906.1:g.84404T>C
NM_001165963.4:c.4762T>CMANE SELECT
NM_001165964.3:c.4678T>C
NM_001202435.3:c.4762T>C
NM_001353948.2:c.4762T>C
NM_001353949.2:c.4729T>C
NM_001353950.2:c.4729T>C
NM_001353951.2:c.4729T>C
NM_001353952.2:c.4729T>C
NM_001353954.2:c.4726T>C
NM_001353955.2:c.4726T>C
NM_001353957.2:c.4678T>C
NM_001353958.2:c.4678T>C
NM_001353960.2:c.4675T>C
NM_001353961.2:c.2320T>C
NM_006920.6:c.4729T>C
NP_001159435.1:p.Cys1588Arg
NP_001159436.1:p.Cys1560Arg
NP_001189364.1:p.Cys1588Arg
NP_001340877.1:p.Cys1588Arg
NP_001340878.1:p.Cys1577Arg
NP_001340879.1:p.Cys1577Arg
NP_001340880.1:p.Cys1577Arg
NP_001340881.1:p.Cys1577Arg
NP_001340883.1:p.Cys1576Arg
NP_001340884.1:p.Cys1576Arg
NP_001340886.1:p.Cys1560Arg
NP_001340887.1:p.Cys1560Arg
NP_001340889.1:p.Cys1559Arg
NP_001340890.1:p.Cys774Arg
NP_008851.3:p.Cys1577Arg
LRG_8t1:c.4729T>C
LRG_8:g.84404T>C
NC_000002.11:g.166850746A>G
NM_001165963.1:c.4762T>C
NM_006920.4:c.4729T>C
NR_148667.2:n.5179T>C

Protein change:

C1559R

Links:

UniProtKB/Swiss-Prot: VAR_064319; dbSNP: rs121917919

NCBI 1000 Genomes Browser:

rs121917919

Molecular consequence:

NM_001165963.4:c.4762T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001165964.3:c.4678T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001202435.3:c.4762T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001353948.2:c.4762T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001353949.2:c.4729T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001353950.2:c.4729T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001353951.2:c.4729T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001353952.2:c.4729T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001353954.2:c.4726T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001353955.2:c.4726T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001353957.2:c.4678T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001353958.2:c.4678T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001353960.2:c.4675T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001353961.2:c.2320T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_006920.6:c.4729T>C - missense variant - [Sequence Ontology: SO:0001583]
NR_148667.2:n.5179T>C - 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
SCV000757757	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Feb 24, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 17561957, 25818041, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000757757

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Feb 24, 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

Idiopathic epilepsies with seizures precipitated by fever and SCN1A abnormalities.

Marini C, Mei D, Temudo T, Ferrari AR, Buti D, Dravet C, Dias AI, Moreira A, Calado E, Seri S, Neville B, Narbona J, Reid E, Michelucci R, Sicca F, Cross HJ, Guerrini R.

Epilepsia. 2007 Sep;48(9):1678-1685. doi: 10.1111/j.1528-1167.2007.01122.x. Epub 2007 Jun 11.

PubMed [citation]

PMID:: 17561957

Diagnostic yield of genetic testing in epileptic encephalopathy in childhood.

Mercimek-Mahmutoglu S, Patel J, Cordeiro D, Hewson S, Callen D, Donner EJ, Hahn CD, Kannu P, Kobayashi J, Minassian BA, Moharir M, Siriwardena K, Weiss SK, Weksberg R, Snead OC 3rd.

Epilepsia. 2015 May;56(5):707-16. doi: 10.1111/epi.12954. Epub 2015 Mar 25.

PubMed [citation]

PMID:: 25818041

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000757757.5

#	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. 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. ClinVar contains an entry for this variant (Variation ID: 68552). This missense change has been observed in individual(s) with SCN1A-related conditions (PMID: 17561957, 25818041). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 1588 of the SCN1A protein (p.Cys1588Arg).

#	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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