VCV000100782.47 - ClinVar

NM_001958.5(EEF1A2):c.208G>A (p.Gly70Ser)

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.

(11)

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

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001958.5(EEF1A2):c.208G>A (p.Gly70Ser)

Variation ID: 100782 Accession: VCV000100782.47

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 20q13.33 20: 63495972 (GRCh38) [ NCBI UCSC ] 20: 62127325 (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	Jun 8, 2015	Jan 4, 2025	Apr 16, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001958.5:c.208G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001949.1:p.Gly70Ser	missense
NC_000020.11:g.63495972C>T
NC_000020.10:g.62127325C>T
NG_034083.1:g.8344G>A
	Q05639:p.Gly70Ser

... more HGVS ... less HGVS

Protein change

G70S

Other names

Canonical SPDI

NC_000020.11:63495971:C:T

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

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: CA150649 UniProtKB: Q05639#VAR_069395 OMIM: 602959.0001 dbSNP: rs587777162 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.
EEF1A2		No evidence available	No evidence available	GRCh38 GRCh37	511	672

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.
Developmental and epileptic encephalopathy, 33	Pathogenic (2)	criteria provided, single submitter	Oct 8, 2023	RCV000087144.15
not provided	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Apr 15, 2024	RCV000327695.28
Inborn genetic diseases	Pathogenic (1)	criteria provided, single submitter	Jan 20, 2015	RCV000623753.4
EEF1A2-related developmental and degenerative epileptic-dyskinetic encephalopathy	Pathogenic (1)	criteria provided, single submitter	Feb 13, 2020	RCV001030061.3
EEF1A2-related disorder	Pathogenic (1)	no assertion criteria provided	Dec 22, 2023	RCV003894943.2
Intellectual disability	Pathogenic (1)	criteria provided, single submitter	Sep 1, 2017	RCV000679972.5
Intellectual disability, autosomal dominant 38	Pathogenic (1)	criteria provided, single submitter	Oct 2, 2021	RCV001775080.3
Developmental and epileptic encephalopathy, 33 Intellectual disability, autosomal dominant 38	Pathogenic (1)	criteria provided, single submitter	Apr 16, 2024	RCV004819218.1

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 (Feb 13, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	EEF1A2-related developmental and degenerative epileptic-dyskinetic encephalopathy (Autosomal dominant inheritance) Affected status: yes Allele origin: de novo	Epilepsy Neurogenetics Initiative, Children's Hospital of Philadelphia Accession: SCV001192841.1 First in ClinVar: Apr 06, 2020 Last updated: Apr 06, 2020	Comment: The EEF1A2 c.208G>A; p.Gly70Ser variant has been identified in two individuals with a developmental and epileptic encephalopathy characterized by global developmental delays, severe intellectual disability, … (more) The EEF1A2 c.208G>A; p.Gly70Ser variant has been identified in two individuals with a developmental and epileptic encephalopathy characterized by global developmental delays, severe intellectual disability, and intractable infantile or early childhood onset epilepsy. One individual had a hyperkinetic movement disorder and followed a neurodegenerative course, with developmental regression and death in early childhood. The variant is de novo in both individuals. The variant is absent from population databases (ExAC, gnomAD) and is predicted to have a damaging effect on the protein by in silico models. Therefore, this variant has been classified as pathogenic. (less) Clinical Features: Absent speech (present) , Inability to walk (present) , Global developmental delay (present) , Intellectual disability, severe (present) , Generalized myoclonic seizures (present) , Generalized … (more) Absent speech (present) , Inability to walk (present) , Global developmental delay (present) , Intellectual disability, severe (present) , Generalized myoclonic seizures (present) , Generalized tonic-clonic seizures without focal onset (present) , Generalized tonic seizures (present) , Atypical absence seizures (present) , EEG with burst suppression (present) , Multifocal epileptiform discharges (present) , Cerebral cortical atrophy (present) , Developmental regression (present) , Muscular hypotonia (present) , Ankle clonus (present) , Hyperreflexia (present) , Choreoathetosis (present) , Generalized dystonia (present) , Stereotypy (present) , Intermittent hyperpnea at rest (present) (less)
Pathogenic (Sep 01, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Intellectual disability (Autosomal dominant inheritance) Affected status: yes Allele origin: de novo	Baylor Genetics Accession: SCV000807406.2 First in ClinVar: Sep 17, 2018 Last updated: Dec 11, 2022	Publications: PubMed (3) PubMed: 25326635‚ 23033978‚ 23647072 Comment: This mutation has been previously reported as disease-causing and was found once in our laboratory de novo in a 1-year-old female with epileptic encephalopathy, global … (more) This mutation has been previously reported as disease-causing and was found once in our laboratory de novo in a 1-year-old female with epileptic encephalopathy, global developmental delay, hypotonia, dysphagia, and hemagioma (less)
Pathogenic (Oct 08, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Developmental and epileptic encephalopathy, 33 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000962952.4 First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024	Publications: PubMed (8) PubMed: 23033978‚ 23647072‚ 26795593‚ 27441201‚ 27652284‚ 28628100‚ 28378778‚ 28911200 Comment: This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 70 of the EEF1A2 protein (p.Gly70Ser). … (more) This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 70 of the EEF1A2 protein (p.Gly70Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with epileptic encephalopathy (PMID: 23033978, 23647072, 26795593, 27441201, 27652284, 28628100). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 100782). 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 EEF1A2 protein function. Experimental studies have shown that this missense change affects EEF1A2 function (PMID: 28378778, 28911200). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (May 01, 2019)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001249245.27 First in ClinVar: May 12, 2020 Last updated: Dec 22, 2024	Number of individuals with the variant: 1
Pathogenic (Apr 16, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Developmental and epileptic encephalopathy, 33 Intellectual disability, autosomal dominant 38 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: de novo	Institute of Human Genetics, Heidelberg University Accession: SCV005440663.1 First in ClinVar: Jan 04, 2025 Last updated: Jan 04, 2025	Sex: female
Pathogenic (Oct 02, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Intellectual disability, autosomal dominant 38 Affected status: yes Allele origin: germline	3billion Accession: SCV002012021.1 First in ClinVar: Nov 11, 2021 Last updated: Nov 11, 2021	Publications: PubMed (2) PubMed: 23033978‚ 23647072 Comment: Same nucleotide change resulting in same amino acid change has been previously reported at least twice as de novoo in similarly affected indivisual (PMID: 23033978,23647072, … (more) Same nucleotide change resulting in same amino acid change has been previously reported at least twice as de novoo in similarly affected indivisual (PMID: 23033978,23647072, PS2, PS4_M). 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). 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: 0.919, 3Cnet: 0.730, PP3). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Autistic behavior (present) , Abnormal facial shape (present) , Delayed fine motor development (present) , Delayed gross motor development (present) , Intellectual disability (present) , … (more) Autistic behavior (present) , Abnormal facial shape (present) , Delayed fine motor development (present) , Delayed gross motor development (present) , Intellectual disability (present) , Specific learning disability (present) , Microcephaly (present) , Delayed speech and language development (present) , Global developmental delay (present) , Depressed nasal bridge (present) , Thick upper lip vermilion (present) , Short philtrum (present) , Thick eyebrow (present) , Hypertelorism (present) (less) Zygosity: Single Heterozygote
Pathogenic (Jan 20, 2015)	criteria provided, single submitter (Ambry exome assertion method (8-5-2015)) Method: clinical testing	Inborn genetic diseases Affected status: yes Allele origin: germline	Ambry Genetics Accession: SCV000740726.3 First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023	Publications: PubMed (1) PubMed: 25326326 Observation 1: Number of individuals with the variant: 1 Clinical Features: Neurodegeneration (present) , Epileptic encephalopathy (present) , Dystonia (present) , Chorea (present) , Seizures (present) , Muscular hypotonia (present) , Myoclonus (present) , Developmental regression … (more) Neurodegeneration (present) , Epileptic encephalopathy (present) , Dystonia (present) , Chorea (present) , Seizures (present) , Muscular hypotonia (present) , Myoclonus (present) , Developmental regression (present) , Esotropia (present) , Hypermetropia (present) , Breathing dysregulation (present) , Insomnia (present) , Movement disorder (present) , Weight loss (present) , Failure to thrive (present) (less) Sex: male Ethnicity/Population group: Caucasian Observation 2: Number of individuals with the variant: 1 Clinical Features: Seizures (present) , Muscular hypotonia (present) , Autistic behavior (present) , Growth delay (present) , Esotropia (present) , Failure to thrive (present) , Behavioral abnormality … (more) Seizures (present) , Muscular hypotonia (present) , Autistic behavior (present) , Growth delay (present) , Esotropia (present) , Failure to thrive (present) , Behavioral abnormality (present) , Aggressive behavior (present) , Epileptic encephalopathy (present) (less) Sex: male Ethnicity/Population group: Caucasian
Pathogenic (Apr 15, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000329965.7 First in ClinVar: Dec 06, 2016 Last updated: Sep 29, 2024	Comment: Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more) Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23647072, 29455050, 28628100, 26795593, 27441201, 28191890, 28378778, 32062104, 33004838, 31440721, 32196822, 23033978) (less)
Pathogenic (Jul 01, 2013)	no assertion criteria provided Method: literature only	DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 33 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000120006.4 First in ClinVar: Mar 02, 2014 Last updated: Dec 07, 2020	Publications: PubMed (2) PubMed: 23033978‚ 23647072 Comment on evidence: In a 22-year-old woman (trio 91) with developmental and epileptic encephalopathy-33 (DEE33; 616409), de Ligt et al. (2012) identified a de novo heterozygous c.208G-A transition … (more) In a 22-year-old woman (trio 91) with developmental and epileptic encephalopathy-33 (DEE33; 616409), de Ligt et al. (2012) identified a de novo heterozygous c.208G-A transition in the EEF1A2 gene, resulting in a gly70-to-ser (G70S) substitution at a highly conserved residue. The patient had neonatal hypotonia and developed seizures at age 4 months. She had severely delayed psychomotor development, with limited speech, autistic features, and aggressive behavior. The patient was ascertained from a larger cohort of 100 patients with severe intellectual disability who underwent exome sequencing. Functional studies of the variant were not performed. Veeramah et al. (2013) identified a de novo heterozygous G70S substitution in a 14-year-old boy with DEE33. He developed refractory seizures with hypsarrhythmia at age 10 weeks, and later showed severe developmental delay, with episodic regression, acquired microcephaly, hypotonia, incoordination, and gait instability. He was nonverbal. The phenotype was consistent with a clinical diagnosis of West syndrome. The mutation, which was found by whole-exome sequencing, was not present in the 1000 Genomes Project or Exome Sequencing Project databases. The patient was 1 of 10 probands with epileptic encephalopathy who underwent whole-exome sequencing. Functional studies of the variant were not performed. (less)
Pathogenic (Apr 08, 2019)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: de novo	Department of Genetics, Robert DEBRE University Hospital Accession: SCV004171541.1 First in ClinVar: Dec 02, 2023 Last updated: Dec 02, 2023	Clinical Features: Intellectual disability (present)
Pathogenic (Dec 22, 2023)	no assertion criteria provided Method: clinical testing	EEF1A2-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004708610.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: The EEF1A2 c.208G>A variant is predicted to result in the amino acid substitution p.Gly70Ser. This is a recurrent de novo variant reported in individuals with … (more) The EEF1A2 c.208G>A variant is predicted to result in the amino acid substitution p.Gly70Ser. This is a recurrent de novo variant reported in individuals with intellectual disability (Table S3, de Ligt et al. 2012. PubMed ID: 23033978; Table S1, Lam et al 2016. PubMed ID: 27441201; Table S1, Carvill et al. 2020. PubMed ID: 32196822). This variant has not been reported in a large population database, indicating this variant is rare. This variant is classified as pathogenic in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/100782/). This variant is interpreted as pathogenic. (less)
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Comment:

The EEF1A2 c.208G>A; p.Gly70Ser variant has been identified in two individuals with a developmental and epileptic encephalopathy characterized by global developmental delays, severe intellectual disability, and intractable infantile or early childhood onset epilepsy. One individual had a hyperkinetic movement disorder and followed a neurodegenerative course, with developmental regression and death in early childhood. The variant is de novo in both individuals. The variant is absent from population databases (ExAC, gnomAD) and is predicted to have a damaging effect on the protein by in silico models. Therefore, this variant has been classified as pathogenic.

Comment:

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 70 of the EEF1A2 protein (p.Gly70Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with epileptic encephalopathy (PMID: 23033978, 23647072, 26795593, 27441201, 27652284, 28628100). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 100782). 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 EEF1A2 protein function. Experimental studies have shown that this missense change affects EEF1A2 function (PMID: 28378778, 28911200). For these reasons, this variant has been classified as Pathogenic.

Comment:

Same nucleotide change resulting in same amino acid change has been previously reported at least twice as de novoo in similarly affected indivisual (PMID: 23033978,23647072, PS2, PS4_M). 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). 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: 0.919, 3Cnet: 0.730, PP3). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23647072, 29455050, 28628100, 26795593, 27441201, 28191890, 28378778, 32062104, 33004838, 31440721, 32196822, 23033978)

Comment:

The EEF1A2 c.208G>A variant is predicted to result in the amino acid substitution p.Gly70Ser. This is a recurrent de novo variant reported in individuals with intellectual disability (Table S3, de Ligt et al. 2012. PubMed ID: 23033978; Table S1, Lam et al 2016. PubMed ID: 27441201; Table S1, Carvill et al. 2020. PubMed ID: 32196822). This variant has not been reported in a large population database, indicating this variant is rare. This variant is classified as pathogenic in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/100782/). This variant is interpreted as pathogenic.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Homozygous EEF1A2 mutation causes dilated cardiomyopathy, failure to thrive, global developmental delay, epilepsy and early death.	Cao S	Human molecular genetics	2017	PMID: 28911200
Hotspots of missense mutation identify neurodevelopmental disorder genes and functional domains.	Geisheker MR	Nature neuroscience	2017	PMID: 28628100
Biallelic mutations in the gene encoding eEF1A2 cause seizures and sudden death in F0 mice.	Davies FC	Scientific reports	2017	PMID: 28378778
Targeted sequencing of 351 candidate genes for epileptic encephalopathy in a large cohort of patients.	de Kovel CG	Molecular genetics & genomic medicine	2016	PMID: 27652284
Novel de novo EEF1A2 missense mutations causing epilepsy and intellectual disability.	Lam WW	Molecular genetics & genomic medicine	2016	PMID: 27441201
Diagnostic exome sequencing provides a molecular diagnosis for a significant proportion of patients with epilepsy.	Helbig KL	Genetics in medicine : official journal of the American College of Medical Genetics	2016	PMID: 26795593
Mammalian translation elongation factor eEF1A2: X-ray structure and new features of GDP/GTP exchange mechanism in higher eukaryotes.	Crepin T	Nucleic acids research	2014	PMID: 25326326
Exome sequencing reveals new causal mutations in children with epileptic encephalopathies.	Veeramah KR	Epilepsia	2013	PMID: 23647072
Diagnostic exome sequencing in persons with severe intellectual disability.	de Ligt J	The New England journal of medicine	2012	PMID: 23033978

Text-mined citations for rs587777162 ...

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 Jan 04, 2025

ClinVar Genomic variation as it relates to human health

NM_001958.5(EEF1A2):c.208G>A (p.Gly70Ser)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs587777162 ...