rs786205866

Positions:

• chr20-63495062-C-T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PS1_Moderate PM1 PM2 PP2 PP3_Strong PP5_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: Genomes: not found (cov: 34)
• Consequence: EEF1A2 NM_001958.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13
• 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]

ACMG classification

Verdict is Pathogenic. Variant got 19 ACMG points.

• PS1: Transcript NM_001958.5 (EEF1A2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_001958.5
• 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, 0.957
• PP5: Variant 20-63495062-C-T is Pathogenic according to our data. Variant chr20-63495062-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 192252.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.78	D;.;.
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Benign	-0.34	T
MutationAssessor	Uncertain	2.6	M;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.94	D
PROVEAN	Uncertain	-2.8	D;.;.
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D;.;.
Sift4G	Uncertain	0.0030	D;.;.
Polyphen		1.0	D;.;.
Vest4		0.97
MutPred		0.86		Gain of methylation at E122 (P = 0.0026);Gain of methylation at E122 (P = 0.0026);Gain of methylation at E122 (P = 0.0026);
MVP		0.67
MPC		3.1
ClinPred		0.99	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.81
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs786205866; hg19: chr20-62126415;