20-63490712-G-A

Position:

• chr20-63490712-G-A

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.796C>T​(p.Arg266Trp) variant causes a missense change. 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 (★★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: EEF1A2 NM_001958.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9 U:1
• Conservation: PhyloP100: 5.56

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 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, 0.934
• PP5: Variant 20-63490712-G-A is Pathogenic according to our data. Variant chr20-63490712-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 449242.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-63490712-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EEF1A2	NM_001958.5	c.796C>T	p.Arg266Trp	missense_variant	6/8	ENST00000217182.6	NP_001949.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EEF1A2	ENST00000217182.6	c.796C>T	p.Arg266Trp	missense_variant	6/8	1	NM_001958.5	ENSP00000217182	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1452082 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 721996

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 16, 2022	Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect on protein synthesis and cellular stress response resulting in cell toxicity (Carvill et al., 2020); 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: 30370994, 26795593, 19909265, 32196822, 32429945, 32062104, 31785789) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 20, 2021	- -

Developmental and epileptic encephalopathy, 33 Pathogenic:1 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Undiagnosed Diseases Network, NIH	Apr 19, 2017	- -
Uncertain significance, flagged submission	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 13, 2020	This sequence change replaces arginine with tryptophan at codon 266 of the EEF1A2 protein (p.Arg266Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with EEF1A2-related disease (PMID: 26795593). ClinVar contains an entry for this variant (Variation ID: 449242). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 01, 2015

- -

Intellectual disability, autosomal dominant 38 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 27, 2018

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

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.796C>T; p.Arg266Trp variant has been identified in three individuals with a developmental and epileptic encephalopathy characterized by global developmental delays, moderate to profound intellectual disability, and infantile or early childhood onset epilepsy in two individuals. Two individuals had a hyperkinetic movement disorder characterized by choreoathetosis. The variant is confirmed de novo in all three 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

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jan 26, 2021

Variant summary: EEF1A2 c.796C>T (p.Arg266Trp) results in a non-conservative amino acid change located in the domain 2 (IPR004161) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 241660 control chromosomes (gnomAD). c.796C>T has been reported in the literature in individuals affected with EEF1A2-Related Disorders, with varying phenotypes including developmental delay, intellectual disability, seizures and movement disorders. The first report of the variant was in a patient with infantile onset of focal epilepsy and temporal lobe epilepsy (Helbig_2016). A second report, which may have patient overlap with the patient described in Helbig_2016, reports the variant in three patients with developmental delay and intellectual disability, two of them also had seizures (Carvill_2020). Additional reports of the variant are in a patient with developmental delay, frontal lobe intractable epilepsy, neurogenic bladder, and choreoathetoid cerebral palsy (Fernandez_2017, ASHG poster abstract) and in a patient with dysphagia, muscular hypertonia, mental retardation and brain dysplasia (Wang_2020). All cases have been reported as de novo mutations. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, and classified the variant as pathogenic (4x) / likely pathogenic (1x) or VUS (1x). Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	0.66	D
MutationAssessor	Pathogenic	4.3	H
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-5.6	D
REVEL	Uncertain	0.63
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.69		Loss of methylation at R266 (P = 0.0194);
MVP		0.93
MPC		3.0
ClinPred		1.0	D
GERP RS		1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.56
gMVP		0.94

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: rs1555883505; hg19: chr20-62122065;