NM_001040142.2(SCN2A):c.4643T>C (p.Met1548Thr) AND multiple conditions

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jan 16, 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:: RCV002521495.3

Allele description [Variation Report for NM_001040142.2(SCN2A):c.4643T>C (p.Met1548Thr)]

NM_001040142.2(SCN2A):c.4643T>C (p.Met1548Thr)

Gene:

SCN2A:sodium voltage-gated channel alpha subunit 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2q24.3

Genomic location:

Preferred name:

NM_001040142.2(SCN2A):c.4643T>C (p.Met1548Thr)

HGVS:

NC_000002.12:g.165386837T>C
NG_008143.1:g.152436T>C
NM_001040142.2:c.4643T>CMANE SELECT
NM_001040143.2:c.4643T>C
NM_001371246.1:c.4643T>C
NM_001371247.1:c.4643T>C
NM_021007.3:c.4643T>C
NP_001035232.1:p.Met1548Thr
NP_001035233.1:p.Met1548Thr
NP_001358175.1:p.Met1548Thr
NP_001358176.1:p.Met1548Thr
NP_066287.2:p.Met1548Thr
NP_066287.2:p.Met1548Thr
NC_000002.11:g.166243347T>C
NM_021007.2:c.4643T>C

Protein change:

M1548T

Links:

dbSNP: rs1057519524

NCBI 1000 Genomes Browser:

rs1057519524

Molecular consequence:

NM_001040142.2:c.4643T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001040143.2:c.4643T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001371246.1:c.4643T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001371247.1:c.4643T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_021007.3:c.4643T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Seizures, benign familial infantile, 3 (BFIS3)
Synonyms:: CONVULSIONS, BENIGN FAMILIAL INFANTILE, 3; Familial neonatal seizures
Identifiers:: MONDO: MONDO:0011904; MedGen: C1843140; Orphanet: 140927; Orphanet: 306; OMIM: 607745

Name:: Developmental and epileptic encephalopathy, 11 (DEE11)
Synonyms:: Early infantile epileptic encephalopathy 11
Identifiers:: MONDO: MONDO:0013388; MedGen: C3150987; Orphanet: 1934; OMIM: 613721

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003524741	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jan 16, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 28379373, 27864847, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003524741

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Jan 16, 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

Genetic and phenotypic heterogeneity suggest therapeutic implications in SCN2A-related disorders.

Wolff M, Johannesen KM, Hedrich UBS, Masnada S, Rubboli G, Gardella E, Lesca G, Ville D, Milh M, Villard L, Afenjar A, Chantot-Bastaraud S, Mignot C, Lardennois C, Nava C, Schwarz N, Gérard M, Perrin L, Doummar D, Auvin S, Miranda MJ, Hempel M, et al.

Brain. 2017 May 1;140(5):1316-1336. doi: 10.1093/brain/awx054.

PubMed [citation]

PMID:: 28379373

Diagnostic Targeted Resequencing in 349 Patients with Drug-Resistant Pediatric Epilepsies Identifies Causative Mutations in 30 Different Genes.

Parrini E, Marini C, Mei D, Galuppi A, Cellini E, Pucatti D, Chiti L, Rutigliano D, Bianchini C, Virdò S, De Vita D, Bigoni S, Barba C, Mari F, Montomoli M, Pisano T, Rosati A; Clinical Study Group, Guerrini R.

Hum Mutat. 2017 Feb;38(2):216-225. doi: 10.1002/humu.23149. Epub 2016 Dec 9.

PubMed [citation]

PMID:: 27864847

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003524741.2

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

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. This variant disrupts the p.Met1548 amino acid residue in SCN2A. Other variant(s) that disrupt this residue have been observed in individuals with SCN2A-related conditions (PMID: 28379373), which suggests that this may be a clinically significant amino acid residue. 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: "Benign"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 375506). This missense change has been observed in individual(s) with epileptic encephalopathy (PMID: 27864847). 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 threonine, which is neutral and polar, at codon 1548 of the SCN2A protein (p.Met1548Thr).

#	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

ClinVar

Relating variation to medicine