rs786205866
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PS1_ModeratePM1PM2PP2PP3_StrongPP5_Very_Strong
The NM_001958.5(EEF1A2):c.364G>A(p.Glu122Lys) 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 Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.
Frequency
Consequence
NM_001958.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 19 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
EEF1A2 | NM_001958.5 | c.364G>A | p.Glu122Lys | missense_variant | 4/8 | ENST00000217182.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EEF1A2 | ENST00000217182.6 | c.364G>A | p.Glu122Lys | missense_variant | 4/8 | 1 | NM_001958.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 34
GnomAD4 exome Cov.: 35
GnomAD4 genome ? Cov.: 34
ClinVar
Submissions by phenotype
not provided Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratoire de Génétique Moléculaire, CHU Bordeaux | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Department of Genetics, Robert DEBRE University Hospital | Apr 26, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 13, 2020 | In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 32196822, 31477274, 27441201, 23033978, 23647072, 26740508, 19636410, 28911200, 28378778, 24697219, 3066688, 26682508) - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | May 01, 2021 | - - |
Developmental and epileptic encephalopathy, 33 Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | Mar 08, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 19, 2024 | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 122 of the EEF1A2 protein (p.Glu122Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with neurological disease, including epilepsy and intellectual disability (PMID: 24697219, 26682508, 27441201). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 192252). 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 not expected to disrupt EEF1A2 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects EEF1A2 function (PMID: 3066688). For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Feb 18, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Génétique des Maladies du Développement, Hospices Civils de Lyon | Oct 25, 2018 | - - |
Intellectual disability, autosomal dominant 38 Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 01, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 04, 2018 | This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease causing [PMID 24697219, 26682508, 27441201] - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 28, 2017 | - - |
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.364G>A; p.Glu122Lys variant has been identified in three individuals with a developmental and epileptic encephalopathy characterized by global developmental delays, moderate to severe intellectual disability, and intractable infantile or early childhood onset epilepsy. One individual had a hyperkinetic movement disorder characterized by choreoathetosis. The variant is confirmed de novo in two individuals; testing of both parents was not performed in the third individual. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at