VCV000029886.25 - ClinVar

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

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(10)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 29886 Accession: VCV000029886.25

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2q24.3 2: 165367327 (GRCh38) [ NCBI UCSC ] 2: 166223837 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Apr 4, 2013	Nov 30, 2024	Jul 24, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001040142.2:c.3631G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001035232.1:p.Glu1211Lys	missense
NM_001371246.1:c.3631G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001358175.1:p.Glu1211Lys	missense
NM_001040143.2:c.3631G>A	NP_001035233.1:p.Glu1211Lys	missense
NM_001371247.1:c.3631G>A	NP_001358176.1:p.Glu1211Lys	missense
NM_021007.3:c.3631G>A	NP_066287.2:p.Glu1211Lys	missense
NC_000002.12:g.165367327G>A
NC_000002.11:g.166223837G>A
NG_008143.1:g.132926G>A
	Q99250:p.Glu1211Lys

... more HGVS ... less HGVS

Protein change

E1211K

Other names

p.E1211K:GAA>AAA

Canonical SPDI

NC_000002.12:165367326:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

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]

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA128708 UniProtKB: Q99250#VAR_065180 OMIM: 182390.0009 dbSNP: rs387906684 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
SCN2A		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	2620	2695

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Seizures, benign familial infantile, 3	Pathogenic (1)	criteria provided, single submitter	May 15, 2013	RCV000118248.6
Developmental and epileptic encephalopathy, 11	Pathogenic/Likely pathogenic (4)	criteria provided, multiple submitters, no conflicts	Sep 28, 2022	RCV000022767.31
not provided	Pathogenic (1)	criteria provided, single submitter	Jul 24, 2024	RCV000189138.6
Developmental and epileptic encephalopathy, 11 Seizures, benign familial infantile, 3	Pathogenic (1)	criteria provided, single submitter	Jan 8, 2024	RCV000806278.8
West syndrome	Pathogenic (1)	no assertion criteria provided	Feb 16, 2022	RCV001847619.3
Complex neurodevelopmental disorder	not provided (1)	no classification provided	-	RCV002319425.1
Developmental and epileptic encephalopathy, 11 Episodic ataxia, type 9 Seizures, benign familial infantile, 3	Pathogenic (1)	criteria provided, single submitter	-	RCV004795937.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (May 15, 2013)	criteria provided, single submitter (ACMG Guidelines, 2007) Method: clinical testing	Seizures, benign familial infantile, 3 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV000152615.1 First in ClinVar: May 17, 2014 Last updated: May 17, 2014
Likely pathogenic (Jul 16, 2013)	criteria provided, single submitter (Lee et al. (JAMA. 2014)) Method: clinical testing	Early infantile epileptic encephalopathy 11 (Autosomal dominant inheritance) Affected status: yes Allele origin: de novo	UCLA Clinical Genomics Center, UCLA Study: CES Accession: SCV000255458.2 First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015	Age: 0-9 years Sex: female Testing laboratory: UCLA Clinical Genomics Center
Pathogenic (Sep 28, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Developmental and epileptic encephalopathy, 11 Affected status: yes Allele origin: germline	Laboratory of Medical Genetics, National & Kapodistrian University of Athens Accession: SCV004013955.1 First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023	Comment: PM2, PP3, PP5
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Developmental and epileptic encephalopathy, 11 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Neuberg Centre For Genomic Medicine, NCGM Accession: SCV004048337.1 First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023	Comment: 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 … (more) 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. (less) Clinical Features: Refractory status epilepticus (present) , Infantile spasms (present) , Global developmental delay (present) , Developmental regression (present)
Pathogenic (Jan 08, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Seizures, benign familial infantile, 3 Developmental and epileptic encephalopathy, 11 Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000946267.4 First in ClinVar: Aug 14, 2019 Last updated: Feb 28, 2024	Publications: PubMed (4) PubMed: 19786696‚ 25326637‚ 25459969‚ 28379373 Comment: 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 … (more) 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. (less)
Pathogenic (Jul 24, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000242770.15 First in ClinVar: Aug 07, 2015 Last updated: Sep 16, 2024	Comment: Published functional studies demonstrate a damaging effect and suggest that this variant alters the channel activity of the SCN2A protein (PMID: 19786696, 37578743); In silico … (more) Published functional studies demonstrate a damaging effect and suggest that this variant alters the channel activity of the SCN2A protein (PMID: 19786696, 37578743); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This substitution is predicted to be within the transmembrane segment S1 of the third homologous domain; This variant is associated with the following publications: (PMID: 19786696, 28379373, 29655203, 32090326, 33057194, 25459969, 32651551, 35431799, 36084525, 37329172, 35982159, 31440721, 37578743, 34489640) (less)
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Developmental and epileptic encephalopathy, 11 Episodic ataxia, type 9 Seizures, benign familial infantile, 3 Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: yes Allele origin: germline	Juno Genomics, Hangzhou Juno Genomics, Inc Accession: SCV005417063.1 First in ClinVar: Nov 30, 2024 Last updated: Nov 30, 2024	Comment: PM2_Supporting+PS4_Supporting+PS2+PP4+PP3_Moderate+PP2
Pathogenic (Sep 29, 2009)	no assertion criteria provided Method: literature only	DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 11 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000044056.3 First in ClinVar: Apr 04, 2013 Last updated: Oct 23, 2020	Publications: PubMed (1) PubMed: 19786696 Comment on evidence: 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 … (more) 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. (less)
Pathogenic (Feb 16, 2022)	no assertion criteria provided Method: clinical testing	West syndrome Affected status: yes Allele origin: de novo	Neurology Department, Shenzhen Children's Hospital Accession: SCV002099512.1 First in ClinVar: Mar 19, 2022 Last updated: Mar 19, 2022	Observation 1: Number of individuals with the variant: 1 Observation 2: Number of individuals with the variant: 1 Observation 3: Number of individuals with the variant: 1
not provided (-)	no classification provided Method: literature only	Complex neurodevelopmental disorder Affected status: not applicable Allele origin: not applicable	Channelopathy-Associated Epilepsy Research Center Accession: SCV002605503.1 First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022	Publications: PubMed (1) PubMed: 19786696 Method: whole-cell patch-clamp recording Result: This experiment showed severe hyperpolarizing shift of voltage dependence of activation, severe hyperpolarizing shift of voltage dependence of fast inactivation, and mild-moderate slowing in recovery from fast inactivation. Overall there is mixed/unclear functional effect not able to be clearly categorized as gain- or loss-of-function.

Comment:

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.

Comment:

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.

Comment:

Published functional studies demonstrate a damaging effect and suggest that this variant alters the channel activity of the SCN2A protein (PMID: 19786696, 37578743); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This substitution is predicted to be within the transmembrane segment S1 of the third homologous domain; This variant is associated with the following publications: (PMID: 19786696, 28379373, 29655203, 32090326, 33057194, 25459969, 32651551, 35431799, 36084525, 37329172, 35982159, 31440721, 37578743, 34489640)

Germline Functional Evidence

Functional Help The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence	Method Help A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter.	Result Help A brief description of the result of this method for this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Severe hyperpolarizing shift of voltage dependence of activation (FENICS-0031) Severe hyperpolarizing shift of voltage dependence of fast inactivation (FENICS-0069) Mild-moderate slowing of recovery from fast inactivation (FENICS-0056) Overall mixed or unclear functional effect not able to be clearly categorized as Gain- or Loss-of-Function (FENICS-0145)	whole-cell patch-clamp recording	This experiment showed severe hyperpolarizing shift of voltage dependence of activation, severe hyperpolarizing shift of voltage dependence of fast inactivation, and mild-moderate slowing in recovery from fast inactivation. Overall there is mixed/unclear functional effect not able to be clearly categorized as gain- or loss-of-function.	Channelopathy-Associated Epilepsy Research Center Accession: SCV002605503.1	Publications PubMed (1)

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Genetic and phenotypic heterogeneity suggest therapeutic implications in SCN2A-related disorders.	Wolff M	Brain : a journal of neurology	2017	PMID: 28379373
SCN2A mutation in a Chinese boy with infantile spasm - response to Modified Atkins Diet.	Wong VC	Brain & development	2015	PMID: 25459969
Clinical exome sequencing for genetic identification of rare Mendelian disorders.	Lee H	JAMA	2014	PMID: 25326637
De novo mutations of voltage-gated sodium channel alphaII gene SCN2A in intractable epilepsies.	Ogiwara I	Neurology	2009	PMID: 19786696

Text-mined citations for rs387906684 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 30, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs387906684 ...