NM_001330260.2(SCN8A):c.4934T>G (p.Met1645Arg) AND Early infantile epileptic encephalopathy with suppression bursts

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jul 17, 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:: RCV002810928.3

Allele description [Variation Report for NM_001330260.2(SCN8A):c.4934T>G (p.Met1645Arg)]

NM_001330260.2(SCN8A):c.4934T>G (p.Met1645Arg)

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.4934T>G (p.Met1645Arg)

HGVS:

NC_000012.12:g.51806420T>G
NG_021180.3:g.221463T>G
NM_001177984.3:c.4811T>G
NM_001330260.2:c.4934T>GMANE SELECT
NM_001369788.1:c.4811T>G
NM_014191.4:c.4934T>G
NP_001171455.1:p.Met1604Arg
NP_001317189.1:p.Met1645Arg
NP_001356717.1:p.Met1604Arg
NP_055006.1:p.Met1645Arg
LRG_1389t1:c.4934T>G
LRG_1389t2:c.4934T>G
LRG_1389:g.221463T>G
LRG_1389p1:p.Met1645Arg
LRG_1389p2:p.Met1645Arg
NC_000012.11:g.52200204T>G

Protein change:

M1604R

Molecular consequence:

NM_001177984.3:c.4811T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001330260.2:c.4934T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001369788.1:c.4811T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_014191.4:c.4934T>G - missense variant - [Sequence Ontology: SO:0001583]

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
SCV003205179	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jul 17, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 26544041, 33827760, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003205179

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jul 17, 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

Gene Mutation Analysis in 253 Chinese Children with Unexplained Epilepsy and Intellectual/Developmental Disabilities.

Zhang Y, Kong W, Gao Y, Liu X, Gao K, Xie H, Wu Y, Zhang Y, Wang J, Gao F, Wu X, Jiang Y.

PLoS One. 2015;10(11):e0141782. doi: 10.1371/journal.pone.0141782.

PubMed [citation]

PMID:: 26544041
PMCID:: PMC4636363

Negishi Y, Aoki Y, Itomi K, Yasuda K, Taniguchi H, Ishida A, Arakawa T, Miyamoto S, Nakashima M, Saitsu H, Saitoh S.

Brain Dev. 2021 Aug;43(7):804-808. doi: 10.1016/j.braindev.2021.03.004. Epub 2021 Apr 4.

PubMed [citation]

PMID:: 33827760

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003205179.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Met1645 amino acid residue in SCN8A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26544041, 33827760; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This missense change has been observed in individual(s) with SCN8A-related conditions (Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1645 of the SCN8A protein (p.Met1645Arg).

#	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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