rs587777162

Positions:

• chr20-63495972-C-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2 PP2 PP3_Moderate PP5_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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11
• 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]

EEF1A2 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), EEF1A2. . Gene score misZ 4.8166 (greater than the threshold 3.09). Trascript score misZ 6.0564 (greater than threshold 3.09). GenCC has associacion of gene with autosomal dominant non-syndromic intellectual disability, undetermined early-onset epileptic encephalopathy, complex neurodevelopmental disorder, developmental and epileptic encephalopathy, 33.
• 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	Protein	UniProt
EEF1A2	NM_001958.5	c.208G>A	p.Gly70Ser	missense_variant	3/8	ENST00000217182.6	NP_001949.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EEF1A2	ENST00000217182.6	c.208G>A	p.Gly70Ser	missense_variant	3/8	1	NM_001958.5	ENSP00000217182.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2019	- -
Pathogenic, no assertion criteria provided	clinical testing	Department of Genetics, Robert DEBRE University Hospital	Apr 08, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 15, 2024	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) -

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	Labcorp Genetics (formerly Invitae), Labcorp	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. -

Developmental and epileptic encephalopathy, 33;C4225343:Intellectual disability, autosomal dominant 38 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, Heidelberg University

Apr 16, 2024

- -

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, no assertion criteria provided

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D;.;.;.
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.94	D;D;D;D
MetaSVM	Uncertain	0.79	D
MutationAssessor	Pathogenic	4.1	H;.;.;.
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-4.1	D;.;.;.
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0010	D;.;.;.
Sift4G	Pathogenic	0.0010	D;.;.;.
Polyphen		1.0	D;.;.;.
Vest4		0.80
MutPred		0.71		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		0.92
MPC		2.8
ClinPred		1.0	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.89
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs587777162; hg19: chr20-62127325; COSMIC: COSV99419032; COSMIC: COSV99419032;