NM_001330260.2(SCN8A):c.5614C>T (p.Arg1872Trp) AND Early infantile epileptic encephalopathy with suppression bursts

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Dec 11, 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:: RCV000229600.15

Allele description [Variation Report for NM_001330260.2(SCN8A):c.5614C>T (p.Arg1872Trp)]

NM_001330260.2(SCN8A):c.5614C>T (p.Arg1872Trp)

Gene:

SCN8A:sodium voltage-gated channel alpha subunit 8 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

12q13.13

Genomic location:

Preferred name:

NM_001330260.2(SCN8A):c.5614C>T (p.Arg1872Trp)

HGVS:

NC_000012.12:g.51807100C>T
NG_021180.3:g.222143C>T
NM_001177984.3:c.5491C>T
NM_001330260.2:c.5614C>TMANE SELECT
NM_001369788.1:c.5491C>T
NM_014191.4:c.5614C>T
NP_001171455.1:p.Arg1831Trp
NP_001317189.1:p.Arg1872Trp
NP_001356717.1:p.Arg1831Trp
NP_055006.1:p.Arg1872Trp
NP_055006.1:p.Arg1872Trp
LRG_1389t1:c.5614C>T
LRG_1389t2:c.5614C>T
LRG_1389:g.222143C>T
LRG_1389p1:p.Arg1872Trp
LRG_1389p2:p.Arg1872Trp
NC_000012.11:g.52200884C>T
NM_014191.2:c.5614C>T
NM_014191.3:c.5614C>T
Q9UQD0:p.Arg1872Trp
p.R1872W

Protein change:

R1831W

Links:

UniProtKB: Q9UQD0#VAR_071681; dbSNP: rs796053228

NCBI 1000 Genomes Browser:

rs796053228

Molecular consequence:

NM_001177984.3:c.5491C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001330260.2:c.5614C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369788.1:c.5491C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_014191.4:c.5614C>T - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

Increase in persistent current [Functional Epilepsy Nomenclature for Ion Channels: FENICS-0040]
Normal peak current [Functional Epilepsy Nomenclature for Ion Channels: FENICS-0096]
Normal slope of activation [Functional Epilepsy Nomenclature for Ion Channels: FENICS-0036]
Normal voltage dependence of activation [Functional Epilepsy Nomenclature for Ion Channels: FENICS-0032]
Overall gain-of-function effect with respect to biophysical channel activity [Functional Epilepsy Nomenclature for Ion Channels: FENICS-0140]
Slowing of fast inactivation [Functional Epilepsy Nomenclature for Ion Channels: FENICS-0048]

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
SCV000289942	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 11, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 24888894, 25951352, 26900580, 25568300, 26029160, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000289942

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 11, 2023)

germline

clinical testing

PubMed (6)
[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

Early onset epileptic encephalopathy caused by de novo SCN8A mutations.

Ohba C, Kato M, Takahashi S, Lerman-Sagie T, Lev D, Terashima H, Kubota M, Kawawaki H, Matsufuji M, Kojima Y, Tateno A, Goldberg-Stern H, Straussberg R, Marom D, Leshinsky-Silver E, Nakashima M, Nishiyama K, Tsurusaki Y, Miyake N, Tanaka F, Matsumoto N, Saitsu H.

Epilepsia. 2014 Jul;55(7):994-1000. doi: 10.1111/epi.12668. Epub 2014 Jun 2.

PubMed [citation]

PMID:: 24888894

Electroclinical features of epileptic encephalopathy caused by SCN8A mutation.

Takahashi S, Yamamoto S, Okayama A, Araki A, Saitsu H, Matsumoto N, Azuma H.

Pediatr Int. 2015 Aug;57(4):758-62. doi: 10.1111/ped.12622. Epub 2015 May 6.

PubMed [citation]

PMID:: 25951352

See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000289942.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1872 of the SCN8A protein (p.Arg1872Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with early infantile epileptic encephalopathy (PMID: 24888894, 25568300, 25951352). ClinVar contains an entry for this variant (Variation ID: 207131). 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 SCN8A protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SCN8A function (PMID: 26900580). This variant disrupts the p.Arg1872 amino acid residue in SCN8A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25568300, 26029160). 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: Nov 10, 2024

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