NM_001165963.4(SCN1A):c.5726C>T (p.Thr1909Ile) AND Early infantile epileptic encephalopathy with suppression bursts

Clinical significance:Pathogenic (Last evaluated: Apr 9, 2018)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000705871.1

Allele description [Variation Report for NM_001165963.4(SCN1A):c.5726C>T (p.Thr1909Ile)]

NM_001165963.4(SCN1A):c.5726C>T (p.Thr1909Ile)

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.5726C>T (p.Thr1909Ile)
HGVS:
  • NC_000002.12:g.165991549G>A
  • NG_011906.1:g.87091C>T
  • NM_001165963.4:c.5726C>TMANE SELECT
  • NM_001165963.4:c.5726C>T
  • NM_001165964.3:c.5642C>T
  • NM_001202435.3:c.5726C>T
  • NM_001353948.2:c.5726C>T
  • NM_001353949.2:c.5693C>T
  • NM_001353950.2:c.5693C>T
  • NM_001353951.2:c.5693C>T
  • NM_001353952.2:c.5693C>T
  • NM_001353954.2:c.5690C>T
  • NM_001353955.2:c.5690C>T
  • NM_001353957.2:c.5642C>T
  • NM_001353958.2:c.5642C>T
  • NM_001353960.2:c.5639C>T
  • NM_001353961.2:c.3284C>T
  • NM_006920.6:c.5693C>T
  • NP_001159435.1:p.Thr1909Ile
  • NP_001159436.1:p.Thr1881Ile
  • NP_001189364.1:p.Thr1909Ile
  • NP_001340877.1:p.Thr1909Ile
  • NP_001340878.1:p.Thr1898Ile
  • NP_001340879.1:p.Thr1898Ile
  • NP_001340880.1:p.Thr1898Ile
  • NP_001340881.1:p.Thr1898Ile
  • NP_001340883.1:p.Thr1897Ile
  • NP_001340884.1:p.Thr1897Ile
  • NP_001340886.1:p.Thr1881Ile
  • NP_001340887.1:p.Thr1881Ile
  • NP_001340889.1:p.Thr1880Ile
  • NP_001340890.1:p.Thr1095Ile
  • NP_008851.3:p.Thr1898Ile
  • LRG_8t1:c.5693C>T
  • LRG_8:g.87091C>T
  • NC_000002.11:g.166848059G>A
  • NM_001165963.1:c.5726C>T
  • NM_006920.4:c.5693C>T
  • NR_148667.2:n.6143C>T
Protein change:
T1095I
Links:
UniProtKB/Swiss-Prot: VAR_029729; dbSNP: rs121918793
NCBI 1000 Genomes Browser:
rs121918793
Molecular consequence:
  • NM_001165963.4:c.5726C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001165964.3:c.5642C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001202435.3:c.5726C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001353948.2:c.5726C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001353949.2:c.5693C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001353950.2:c.5693C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001353951.2:c.5693C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001353952.2:c.5693C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001353954.2:c.5690C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001353955.2:c.5690C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001353957.2:c.5642C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001353958.2:c.5642C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001353960.2:c.5639C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001353961.2:c.3284C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_006920.6:c.5693C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NR_148667.2:n.6143C>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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000834888Invitaecriteria provided, single submitter
Pathogenic
(Apr 9, 2018)
germlineclinical testing

PubMed (8)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Ultra-rare genetic variation in common epilepsies: a case-control sequencing study.

Epi4K consortium.; Epilepsy Phenome/Genome Project..

Lancet Neurol. 2017 Feb;16(2):135-143. doi: 10.1016/S1474-4422(16)30359-3.

PubMed [citation]
PMID:
28102150

Genotype-phenotype associations in SCN1A-related epilepsies.

Zuberi SM, Brunklaus A, Birch R, Reavey E, Duncan J, Forbes GH.

Neurology. 2011 Feb 15;76(7):594-600. doi: 10.1212/WNL.0b013e31820c309b. Epub 2011 Jan 19.

PubMed [citation]
PMID:
21248271
See all PubMed Citations (8)

Details of each submission

From Invitae, SCV000834888.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (8)

Description

This sequence change replaces threonine with isoleucine at codon 1909 of the SCN1A protein (p.Thr1909Ile). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals with early infantile epileptic encephalopathy (PMID: 18076640, 12083760, 15277629), and also has been reported to be de novo in an individual affected with Dravet syndrome (PMID: 28708303). This variant is also known as c. 5696C>T (p.Thr1899Ile). ClinVar contains an entry for this variant (Variation ID: 68669). This variant identified in the SCN1A gene is located in the cytoplasmic C-terminal region of the resulting protein (PMID: 25348405, 18804930). Experimental studies have shown that this missense change affecting the normal protein function by decreasing current density and increasing persistent sodium current compared with wild-type SCN1A protein in cells carrying this variant (PMID: 17054685, 21463283). A different variant at this codon (p.Thr1909del) has been determined to be pathogenic (PMID: 21248271,28102150 ). This suggests that the threonine residue is critical for SCN1A protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 8, 2021

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