NM_001165963.4(SCN1A):c.3641T>A (p.Ile1214Lys) AND Early infantile epileptic encephalopathy with suppression bursts

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Feb 7, 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:: RCV003021295.3

Allele description [Variation Report for NM_001165963.4(SCN1A):c.3641T>A (p.Ile1214Lys)]

NM_001165963.4(SCN1A):c.3641T>A (p.Ile1214Lys)

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.3641T>A (p.Ile1214Lys)

HGVS:

NC_000002.12:g.166013808A>T
NG_011906.1:g.64832T>A
NM_001165963.4:c.3641T>AMANE SELECT
NM_001165964.3:c.3557T>A
NM_001202435.3:c.3641T>A
NM_001353948.2:c.3641T>A
NM_001353949.2:c.3608T>A
NM_001353950.2:c.3608T>A
NM_001353951.2:c.3608T>A
NM_001353952.2:c.3608T>A
NM_001353954.2:c.3605T>A
NM_001353955.2:c.3605T>A
NM_001353957.2:c.3557T>A
NM_001353958.2:c.3557T>A
NM_001353960.2:c.3554T>A
NM_001353961.2:c.1199T>A
NM_006920.6:c.3608T>A
NP_001159435.1:p.Ile1214Lys
NP_001159436.1:p.Ile1186Lys
NP_001189364.1:p.Ile1214Lys
NP_001340877.1:p.Ile1214Lys
NP_001340878.1:p.Ile1203Lys
NP_001340879.1:p.Ile1203Lys
NP_001340880.1:p.Ile1203Lys
NP_001340881.1:p.Ile1203Lys
NP_001340883.1:p.Ile1202Lys
NP_001340884.1:p.Ile1202Lys
NP_001340886.1:p.Ile1186Lys
NP_001340887.1:p.Ile1186Lys
NP_001340889.1:p.Ile1185Lys
NP_001340890.1:p.Ile400Lys
NP_008851.3:p.Ile1203Lys
NP_008851.3:p.Ile1203Lys
LRG_8t1:c.3608T>A
LRG_8:g.64832T>A
LRG_8p1:p.Ile1203Lys
NC_000002.11:g.166870318A>T
NM_006920.4:c.3608T>A
NR_148667.2:n.3994T>A

Protein change:

I1185K

Molecular consequence:

NM_001165963.4:c.3641T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001165964.3:c.3557T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001202435.3:c.3641T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001353948.2:c.3641T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001353949.2:c.3608T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001353950.2:c.3608T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001353951.2:c.3608T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001353952.2:c.3608T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001353954.2:c.3605T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001353955.2:c.3605T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001353957.2:c.3557T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001353958.2:c.3557T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001353960.2:c.3554T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001353961.2:c.1199T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_006920.6:c.3608T>A - missense variant - [Sequence Ontology: SO:0001583]
NR_148667.2:n.3994T>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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003312323	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Feb 7, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 22848613, 31864146, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003312323

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Feb 7, 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

Identification of SCN1A and PCDH19 mutations in Chinese children with Dravet syndrome.

Kwong AK, Fung CW, Chan SY, Wong VC.

PLoS One. 2012;7(7):e41802. doi: 10.1371/journal.pone.0041802. Epub 2012 Jul 25.

PubMed [citation]

PMID:: 22848613
PMCID:: PMC3405017

A single-center, retrospective analysis of genotype-phenotype correlations in children with Dravet syndrome.

Gertler TS, Calhoun J, Laux L.

Seizure. 2020 Feb;75:1-6. doi: 10.1016/j.seizure.2019.12.009. Epub 2019 Dec 13. Erratum in: Seizure. 2020 Aug;80:281. doi: 10.1016/j.seizure.2020.04.004.

PubMed [citation]

PMID:: 31864146
PMCID:: PMC7112984

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003312323.2

#	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 isoleucine, which is neutral and non-polar, with lysine, which is basic and polar, at codon 1214 of the SCN1A protein (p.Ile1214Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Dravet syndrome (Invitae). 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 variant disrupts the p.Ile1214 amino acid residue in SCN1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22848613, 31864146). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as 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

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