NM_001165963.4(SCN1A):c.5555T>C (p.Met1852Thr) AND Early infantile epileptic encephalopathy with suppression bursts

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Feb 21, 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:: RCV001854247.3

Allele description [Variation Report for NM_001165963.4(SCN1A):c.5555T>C (p.Met1852Thr)]

NM_001165963.4(SCN1A):c.5555T>C (p.Met1852Thr)

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.5555T>C (p.Met1852Thr)

HGVS:

NC_000002.12:g.165991720A>G
NG_011906.1:g.86920T>C
NM_001165963.4:c.5555T>CMANE SELECT
NM_001165964.3:c.5471T>C
NM_001202435.3:c.5555T>C
NM_001353948.2:c.5555T>C
NM_001353949.2:c.5522T>C
NM_001353950.2:c.5522T>C
NM_001353951.2:c.5522T>C
NM_001353952.2:c.5522T>C
NM_001353954.2:c.5519T>C
NM_001353955.2:c.5519T>C
NM_001353957.2:c.5471T>C
NM_001353958.2:c.5471T>C
NM_001353960.2:c.5468T>C
NM_001353961.2:c.3113T>C
NM_006920.6:c.5522T>C
NP_001159435.1:p.Met1852Thr
NP_001159436.1:p.Met1824Thr
NP_001189364.1:p.Met1852Thr
NP_001340877.1:p.Met1852Thr
NP_001340878.1:p.Met1841Thr
NP_001340879.1:p.Met1841Thr
NP_001340880.1:p.Met1841Thr
NP_001340881.1:p.Met1841Thr
NP_001340883.1:p.Met1840Thr
NP_001340884.1:p.Met1840Thr
NP_001340886.1:p.Met1824Thr
NP_001340887.1:p.Met1824Thr
NP_001340889.1:p.Met1823Thr
NP_001340890.1:p.Met1038Thr
NP_008851.3:p.Met1841Thr
LRG_8t1:c.5522T>C
LRG_8:g.86920T>C
NC_000002.11:g.166848230A>G
NM_001165963.1:c.5555T>C
NM_006920.4:c.5522T>C
NR_148667.2:n.5972T>C

Protein change:

M1038T

Links:

UniProtKB/Swiss-Prot: VAR_029727; dbSNP: rs121918783

NCBI 1000 Genomes Browser:

rs121918783

Molecular consequence:

NM_001165963.4:c.5555T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001165964.3:c.5471T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001202435.3:c.5555T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001353948.2:c.5555T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001353949.2:c.5522T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001353950.2:c.5522T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001353951.2:c.5522T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001353952.2:c.5522T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001353954.2:c.5519T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001353955.2:c.5519T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001353957.2:c.5471T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001353958.2:c.5471T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001353960.2:c.5468T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001353961.2:c.3113T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_006920.6:c.5522T>C - missense variant - [Sequence Ontology: SO:0001583]
NR_148667.2:n.5972T>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Functional consequence:

Mild decrease in peak current [Functional Epilepsy Nomenclature for Ion Channels: FENICS-0085]
Normal persistent current [Functional Epilepsy Nomenclature for Ion Channels: FENICS-0044]
Normal rate of recovery from fast inactivation [Functional Epilepsy Nomenclature for Ion Channels: FENICS-0054]
Normal voltage dependence of activation [Functional Epilepsy Nomenclature for Ion Channels: FENICS-0032]
Normal voltage dependence of fast inactivation [Functional Epilepsy Nomenclature for Ion Channels: FENICS-0070]
Overall loss-of-function [Functional Epilepsy Nomenclature for Ion Channels: FENICS-0141]

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
SCV002223528	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Feb 21, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 12919402, 26096185, 31019026, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002223528

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Feb 21, 2023)

germline

clinical testing

PubMed (4)
[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

Two novel SCN1A missense mutations in generalized epilepsy with febrile seizures plus.

Annesi G, Gambardella A, Carrideo S, Incorpora G, Labate A, Pasqua AA, Civitelli D, Polizzi A, Annesi F, Spadafora P, Tarantino P, Cirò Candiano IC, Romeo N, De Marco EV, Ventura P, LePiane E, Zappia M, Aguglia U, Pavone L, Quattrone A.

Epilepsia. 2003 Sep;44(9):1257-8. No abstract available.

PubMed [citation]

PMID:: 12919402

Amplicon Resequencing Identified Parental Mosaicism for Approximately 10% of "de novo" SCN1A Mutations in Children with Dravet Syndrome.

Xu X, Yang X, Wu Q, Liu A, Yang X, Ye AY, Huang AY, Li J, Wang M, Yu Z, Wang S, Zhang Z, Wu X, Wei L, Zhang Y.

Hum Mutat. 2015 Sep;36(9):861-72. doi: 10.1002/humu.22819. Epub 2015 Jul 24.

PubMed [citation]

PMID:: 26096185
PMCID:: PMC5034833

See all PubMed Citations (4)

Details of each submission

From Invitae, SCV002223528.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1852 of the SCN1A protein (p.Met1852Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of SCN1A-related conditions (PMID: 12919402, 26096185, 31019026). In at least one individual the variant was observed to be de novo. This variant is also known as p.Met1841Thr. ClinVar contains an entry for this variant (Variation ID: 68664). 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.

#	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: Apr 15, 2024

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