rs587777162
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2PP2PP3_ModeratePP5_Very_Strong
The NM_001958.5(EEF1A2):c.208G>A(p.Gly70Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 33)
Consequence
EEF1A2
NM_001958.5 missense
NM_001958.5 missense
Scores
12
6
1
Clinical Significance
Conservation
PhyloP100: 7.80
Genes affected
EEF1A2 (HGNC:3192): (eukaryotic translation elongation factor 1 alpha 2) This gene encodes an isoform of the alpha subunit of the elongation factor-1 complex, which is responsible for the enzymatic delivery of aminoacyl tRNAs to the ribosome. This isoform (alpha 2) is expressed in brain, heart and skeletal muscle, and the other isoform (alpha 1) is expressed in brain, placenta, lung, liver, kidney, and pancreas. This gene may be critical in the development of ovarian cancer. [provided by RefSeq, Mar 2014]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 13 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, EEF1A2
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.937
PP5
?
Variant 20-63495972-C-T is Pathogenic according to our data. Variant chr20-63495972-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 100782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-63495972-C-T is described in Lovd as [Likely_pathogenic]. Variant chr20-63495972-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
EEF1A2 | NM_001958.5 | c.208G>A | p.Gly70Ser | missense_variant | 3/8 | ENST00000217182.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EEF1A2 | ENST00000217182.6 | c.208G>A | p.Gly70Ser | missense_variant | 3/8 | 1 | NM_001958.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 15, 2018 | The G70S pathogenic variant in the EEF1A2 gene has been reported previously as de novo in twounrelated children with epileptic encephalopathy and severe intellectual disability (deLigt et al., 2012;Veeramah et al., 2013). The G70S variant was not observed in approximately 6500 individuals ofEuropean and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is nota common benign variant in these populations. The G70S variant is a non-conservative amino acidsubstitution, which occurs at a position that is conserved across species. In silico analysis predicts thisvariant is probably damaging to the protein structure/function. We interpret G70S as a pathogenicvariant - |
Pathogenic, no assertion criteria provided | clinical testing | Department of Genetics, Robert DEBRE University Hospital | Apr 08, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | May 01, 2019 | - - |
Developmental and epileptic encephalopathy, 33 Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 01, 2013 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 08, 2023 | 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. - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 20, 2015 | - - |
Intellectual disability, autosomal dominant 38 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Oct 02, 2021 | 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. - |
EEF1A2-related developmental and degenerative epileptic-dyskinetic encephalopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | research | Epilepsy Neurogenetics Initiative, Children's Hospital of Philadelphia | Feb 13, 2020 | 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. - |
EEF1A2-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 22, 2023 | 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. - |
Intellectual disability Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 01, 2017 | 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 - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Pathogenic
D;.;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
H;.;.;.
MutationTaster
Benign
D;D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;.;.;.
REVEL
Pathogenic
Sift
Uncertain
D;.;.;.
Sift4G
Pathogenic
D;.;.;.
Polyphen
D;.;.;.
Vest4
MutPred
Gain of phosphorylation at G70 (P = 0.0143);Gain of phosphorylation at G70 (P = 0.0143);Gain of phosphorylation at G70 (P = 0.0143);Gain of phosphorylation at G70 (P = 0.0143);
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at