NM_001165963.4(SCN1A):c.335C>T (p.Thr112Ile) AND Early infantile epileptic encephalopathy with suppression bursts

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Dec 18, 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:: RCV001854244.4

Allele description [Variation Report for NM_001165963.4(SCN1A):c.335C>T (p.Thr112Ile)]

NM_001165963.4(SCN1A):c.335C>T (p.Thr112Ile)

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.335C>T (p.Thr112Ile)

HGVS:

NC_000002.12:g.166058618G>A
NG_011906.1:g.20022C>T
NM_001165963.4:c.335C>TMANE SELECT
NM_001165964.3:c.335C>T
NM_001202435.3:c.335C>T
NM_001353948.2:c.335C>T
NM_001353949.2:c.335C>T
NM_001353950.2:c.335C>T
NM_001353951.2:c.335C>T
NM_001353952.2:c.335C>T
NM_001353954.2:c.335C>T
NM_001353955.2:c.335C>T
NM_001353957.2:c.335C>T
NM_001353958.2:c.335C>T
NM_001353960.2:c.335C>T
NM_001353961.2:c.-2091C>T
NM_006920.6:c.335C>T
NP_001159435.1:p.Thr112Ile
NP_001159436.1:p.Thr112Ile
NP_001189364.1:p.Thr112Ile
NP_001340877.1:p.Thr112Ile
NP_001340878.1:p.Thr112Ile
NP_001340879.1:p.Thr112Ile
NP_001340880.1:p.Thr112Ile
NP_001340881.1:p.Thr112Ile
NP_001340883.1:p.Thr112Ile
NP_001340884.1:p.Thr112Ile
NP_001340886.1:p.Thr112Ile
NP_001340887.1:p.Thr112Ile
NP_001340889.1:p.Thr112Ile
NP_008851.3:p.Thr112Ile
LRG_8t1:c.335C>T
LRG_8:g.20022C>T
NC_000002.11:g.166915128G>A
NM_006920.4:c.335C>T
NR_148667.2:n.721C>T
P35498:p.Thr112Ile

Protein change:

T112I

Links:

UniProtKB: P35498#VAR_029663; UniProtKB/Swiss-Prot: VAR_029663; dbSNP: rs121918745

NCBI 1000 Genomes Browser:

rs121918745

Molecular consequence:

NM_001353961.2:c.-2091C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001165963.4:c.335C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001165964.3:c.335C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001202435.3:c.335C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001353948.2:c.335C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001353949.2:c.335C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001353950.2:c.335C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001353951.2:c.335C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001353952.2:c.335C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001353954.2:c.335C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001353955.2:c.335C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001353957.2:c.335C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001353958.2:c.335C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001353960.2:c.335C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_006920.6:c.335C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_148667.2:n.721C>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
SCV002248198	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Dec 18, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 12566275, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002248198

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Dec 18, 2022)

germline

clinical testing

PubMed (2)
[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

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

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Invitae, SCV002248198.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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: 68615). This missense change has been observed in individual(s) with clinical features of SCN1A-related conditions (PMID: 12566275; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 112 of the SCN1A protein (p.Thr112Ile).

#	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: Feb 20, 2024

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