NM_001040142.2(SCN2A):c.3631G>A (p.Glu1211Lys) AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 8, 2024
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:: RCV000806278.7

Allele description [Variation Report for NM_001040142.2(SCN2A):c.3631G>A (p.Glu1211Lys)]

NM_001040142.2(SCN2A):c.3631G>A (p.Glu1211Lys)

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.3631G>A (p.Glu1211Lys)

Other names:

p.E1211K:GAA>AAA

HGVS:

NC_000002.12:g.165367327G>A
NG_008143.1:g.132926G>A
NM_001040142.2:c.3631G>AMANE SELECT
NM_001040143.2:c.3631G>A
NM_001371246.1:c.3631G>A
NM_001371247.1:c.3631G>A
NM_021007.3:c.3631G>A
NP_001035232.1:p.Glu1211Lys
NP_001035233.1:p.Glu1211Lys
NP_001358175.1:p.Glu1211Lys
NP_001358176.1:p.Glu1211Lys
NP_066287.2:p.Glu1211Lys
NP_066287.2:p.Glu1211Lys
NC_000002.11:g.166223837G>A
NM_001040142.1:c.3631G>A
NM_001040143.2:c.3631G>A
NM_021007.2:c.3631G>A
Q99250:p.Glu1211Lys

Protein change:

E1211K; GLU1211LYS

Links:

UniProtKB: Q99250#VAR_065180; OMIM: 182390.0009; dbSNP: rs387906684

NCBI 1000 Genomes Browser:

rs387906684

Molecular consequence:

NM_001040142.2:c.3631G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001040143.2:c.3631G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001371246.1:c.3631G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001371247.1:c.3631G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_021007.3:c.3631G>A - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

Mild-moderate slowing of recovery from fast inactivation [Functional Epilepsy Nomenclature for Ion Channels: FENICS-0056]
Overall mixed or unclear functional effect not able to be clearly categorized as Gain- or Loss-of-Function [Functional Epilepsy Nomenclature for Ion Channels: FENICS-0145]
Severe hyperpolarizing shift of voltage dependence of activation [Functional Epilepsy Nomenclature for Ion Channels: FENICS-0031]
Severe hyperpolarizing shift of voltage dependence of fast inactivation [Functional Epilepsy Nomenclature for Ion Channels: FENICS-0069]

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000946267	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 8, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 25326637, 25459969, 28379373, 19786696, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000946267

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 8, 2024)

germline

clinical testing

PubMed (5)
[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

Clinical exome sequencing for genetic identification of rare Mendelian disorders.

Lee H, Deignan JL, Dorrani N, Strom SP, Kantarci S, Quintero-Rivera F, Das K, Toy T, Harry B, Yourshaw M, Fox M, Fogel BL, Martinez-Agosto JA, Wong DA, Chang VY, Shieh PB, Palmer CG, Dipple KM, Grody WW, Vilain E, Nelson SF.

JAMA. 2014 Nov 12;312(18):1880-7. doi: 10.1001/jama.2014.14604.

PubMed [citation]

PMID:: 25326637
PMCID:: PMC4278636

SCN2A mutation in a Chinese boy with infantile spasm - response to Modified Atkins Diet.

Wong VC, Fung CW, Kwong AK.

Brain Dev. 2015 Aug;37(7):729-32. doi: 10.1016/j.braindev.2014.10.008. Epub 2014 Nov 7.

PubMed [citation]

PMID:: 25459969

See all PubMed Citations (5)

Details of each submission

From Invitae, SCV000946267.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1211 of the SCN2A protein (p.Glu1211Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of early infantile epileptic encephalopathy (PMID: 19786696, 25326637, 25459969, 28379373). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 29886). 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 SCN2A protein function with a positive predictive value of 95%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on SCN2A function (PMID: 19786696). 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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