NM_001040142.2(SCN2A):c.5317G>A (p.Ala1773Thr) AND Developmental and epileptic encephalopathy, 11

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Oct 2, 2021
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:: RCV001250742.7

Allele description [Variation Report for NM_001040142.2(SCN2A):c.5317G>A (p.Ala1773Thr)]

NM_001040142.2(SCN2A):c.5317G>A (p.Ala1773Thr)

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.5317G>A (p.Ala1773Thr)

Other names:

p.A1773T:GCG>ACG; NM_001040142.2(SCN2A):c.5317G>A; p.Ala1773Thr

HGVS:

NC_000002.12:g.165389123G>A
NG_008143.1:g.154722G>A
NM_001040142.2:c.5317G>AMANE SELECT
NM_001040143.2:c.5317G>A
NM_001371246.1:c.5317G>A
NM_001371247.1:c.5317G>A
NM_021007.3:c.5317G>A
NP_001035232.1:p.Ala1773Thr
NP_001035233.1:p.Ala1773Thr
NP_001358175.1:p.Ala1773Thr
NP_001358176.1:p.Ala1773Thr
NP_066287.2:p.Ala1773Thr
NP_066287.2:p.Ala1773Thr
NC_000002.11:g.166245633G>A
NM_001040142.1:c.5317G>A
NM_001040142.2:c.5317G>A
NM_021007.2:c.5317G>A

Protein change:

A1773T

Links:

dbSNP: rs796053162

NCBI 1000 Genomes Browser:

rs796053162

Molecular consequence:

NM_001040142.2:c.5317G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001040143.2:c.5317G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001371246.1:c.5317G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001371247.1:c.5317G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_021007.3:c.5317G>A - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

Decrease in slope of activation [Functional Epilepsy Nomenclature for Ion Channels: FENICS-0034]
Mild-moderate slowing of recovery from fast inactivation [Functional Epilepsy Nomenclature for Ion Channels: FENICS-0056]
Moderate decrease in peak current [Functional Epilepsy Nomenclature for Ion Channels: FENICS-0086]
Moderate depolarizing shift of voltage dependence of fast inactivation [Functional Epilepsy Nomenclature for Ion Channels: FENICS-0063]
Moderate hyperpolarizing shift of voltage dependence of activation [Functional Epilepsy Nomenclature for Ion Channels: FENICS-0030]
Normal slope of fast inactivation [Functional Epilepsy Nomenclature for Ion Channels: FENICS-0074]
Overall loss-of-function [Functional Epilepsy Nomenclature for Ion Channels: FENICS-0141]

Observations:

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
SCV001426159	Blueprint Genetics	criteria provided, single submitter (Blueprint Genetics Variant Classification Scheme)	Likely pathogenic (May 14, 2018)	germline	clinical testing	Citation Link,
SCV001438071	Génétique des Maladies du Développement, Hospices Civils de Lyon	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	de novo	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001760061	Genomics England Pilot Project, Genomics England	no assertion criteria provided (ACGS Guidelines, 2016)	Likely pathogenic	germline	clinical testing	Citation Link,
SCV002012289	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 2, 2021)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 28379373, 34469436, 28947817, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	1	not provided	clinical testing
not provided	de novo	yes	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

Next-generation sequencing in childhood-onset epilepsies: Diagnostic yield and impact on neuronal ceroid lipofuscinosis type 2 (CLN2) disease diagnosis.

Gall K, Izzo E, Seppälä EH, Alakurtti K, Koskinen L, Saarinen I, Singh A, Myllykangas S, Koskenvuo J, Alastalo TP.

PLoS One. 2021;16(9):e0255933. doi: 10.1371/journal.pone.0255933.

PubMed [citation]

PMID:: 34469436
PMCID:: PMC8409681

See all PubMed Citations (4)

Details of each submission

From Blueprint Genetics, SCV001426159.1

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

#	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 Génétique des Maladies du Développement, Hospices Civils de Lyon, SCV001438071.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1		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 Genomics England Pilot Project, Genomics England, SCV001760061.1

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

#	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 3billion, SCV002012289.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (4)

Description

Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (PMID: 34469436, 28947817, PS1). The missense variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PM1). It is not observed in the gnomAD v2.1.1 dataset (PM2). A different missense change at the same codon (p.Ala1773Val) has been reported as pathogenic (PMID:28379373, PM5). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.94, 3Cnet: 0.996, PP3). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

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

Last Updated: Aug 4, 2024

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