NM_001040142.2(SCN2A):c.3631G>A (p.Glu1211Lys) AND Developmental and epileptic encephalopathy, 11

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Sep 28, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000022767.31

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:: 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
SCV000044056	OMIM	no assertion criteria provided	Pathogenic (Sep 29, 2009)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000255458	UCLA Clinical Genomics Center, UCLA - CES	criteria provided, single submitter (Lee et al. (JAMA. 2014))	Likely pathogenic (Jul 16, 2013)	de novo	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004013955	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 28, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004048337	Neuberg Centre For Genomic Medicine, NCGM	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	de novo	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

De novo mutations of voltage-gated sodium channel alphaII gene SCN2A in intractable epilepsies.

Ogiwara I, Ito K, Sawaishi Y, Osaka H, Mazaki E, Inoue I, Montal M, Hashikawa T, Shike T, Fujiwara T, Inoue Y, Kaneda M, Yamakawa K.

Neurology. 2009 Sep 29;73(13):1046-53. doi: 10.1212/WNL.0b013e3181b9cebc.

PubMed [citation]

PMID:: 19786696
PMCID:: PMC2754324

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

See all PubMed Citations (3)

Details of each submission

From OMIM, SCV000044056.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In a 22-year-old man with developmental and epileptic encephalopathy-11 (DEE11; 613721), Ogiwara et al. (2009) identified a de novo heterozygous c.3631G-A transition in the SCN2A gene, resulting in a glu1211-to-lys (E1211K) substitution. The patient had onset of infantile spasms at age 11 months, which evolved to frequent occurrence of refractory tonic-clonic seizures at age 2 to 3 years. He also showed marked developmental delay and severe intellectual disability in infancy and childhood. Febrile seizures occurred after age 10 years. After an episode of status epilepticus at age 17 years, he became quadriplegic and speechless. In vitro electrophysiologic studies indicated that the E1211K mutant channel had properties compatible with both augmented and reduced channel activities. There was an 18-mV hyperpolarizing shift in the voltage dependence of activation, as well as a 22-mV hyperpolarizing shift in the voltage dependence of steady-state inactivation and slowed recovery from inactivation.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From UCLA Clinical Genomics Center, UCLA - CES, SCV000255458.2

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	de novo	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratory of Medical Genetics, National & Kapodistrian University of Athens, SCV004013955.1

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

Description

PM2, PP3, PP5

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Neuberg Centre For Genomic Medicine, NCGM, SCV004048337.1

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

Description

The amino acid Glu at position 1211 is changed to a Lys changing protein sequence and it might alter its composition and physico-chemical properties. This variant has been reported in individuals with clinical features of early infantile epileptic encephalopathy (Ogiwara et al, 2009, Lee et al, 2014). Experimental studies have shown that this missense change significantly changed the functional property of the sodium channels leading to both augmented and reduced channel activities by electrophysiological analyses in the cells (Ogiwara et al, 2009). The p.Glu1211Lys variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Glu1211Lys in SCN2A is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. 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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 30, 2024

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