EEF1A2

protein-coding

eukaryotic translation elongation factor 1 alpha 2

Gene summary

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]

Previous symbols:

STNL
STN

MANE transcript

NM_001958.5

Inheritance

ClinVar variants

P:58U:190B:244

Top phenotype

Developmental and epileptic encephalopathy 33; Intellectual developmental disorder, autosomal dominant 38

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chr20:63,488,013-63,499,239

External References & Databases

Ensembl (ENSG00000101210)

Transcript & Mutation Effects

hg38 • Region Span ~11.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

developmental and epileptic encephalopathy, 33MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0014625

Submitter: Ambry Genetics

complex neurodevelopmental disorderSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: PanelApp Australia

developmental and epileptic encephalopathy, 33STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014625

Submitter: Labcorp Genetics (formerly Invitae)

undetermined early-onset epileptic encephalopathySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018614

Submitter: Orphanet

complex neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: ClinGen

EEF1A2 was first reported in relation to autosomal dominant complex neurodevelopmental disorder in 2012 (de Ligt et al., 2012; PMID: 23033978). At least 17 unique variants (missense) have been reported in at least 28 humans (reviewed in Cao et al., 2017 PMID: 28911200; and Lam et al., 2016 PMID: 27441201).Most of these cases are asserted to have occurred de novo. A website dedicated to EEF1A2 and epilepsy maintained by the Cathy Abbot Lab (IGMM, University of Edinburgh) outlines variants of interest, patients numbers, and references (https://eef1a2epilepsy.wordpress.com/). Evidence supporting this gene-disease relationship includes case-level and experimental data. More evidence is available in the literature, however the maximum score for genetic evidence (12 points) has been reached. The mechanism for the disease is presumed loss of protein function (Cao et al., 2017 PMID: 28911200). EEF1A2 has been associated with the following disease entities in the literature or nosological or ontological sites: (1) Epileptic encephalopathy, early infantile, 33 (EIEE33; MIM: 616409); (2) Mental retardation, autosomal dominant 38 (MR38; MIM: 616393); (3) Cardiac, intellectual disability, epilepsy syndrome autosomal recessive inheritance (Cao et al., 2017 PMID: 28911200). Per the criteria outlined by the ClinGen Lumping and Splitting Working Group we found no difference in the molecular mechanism, phenotypic expressivity, or inheritance pattern between the Epileptic encephalopathy, early infantile, 33 (MIM: 616409) and Mental retardation, autosomal dominant 38 (MIM: 616393) and have lumped these disease entities into the broader entity of complex neurodevelopmental disorder. However, per the lumping and splitting criteria we found differences in the phenotypic expressivity and inheritance pattern in for cardiac, intellectual disability, epilepsy syndrome (Cao et al., 2017 PMID: 28911200) compared to the EIEE33 and MR38, therefore this gene-disease relationship represents a separate, independent curation and is not currently represented in this gene-disease classification. In summary, EEF1A2 is definitively associated with autosomal dominant complex neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Epilepsy Gene Curation Expert Panel on March 19, 2019 (SOP version 6).

developmental and epileptic encephalopathy, 33STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014625

Submitter: G2P

Clinical Genomic Database (CGD)

Developmental and epileptic encephalopathy 33; Intellectual developmental disorder, autosomal dominant 38AD

Manifestation: Craniofacial; Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 23033978; 23647072; 24697219

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to EEF1A2 variants in ClinVar

19 Conditions Cataloged

Developmental and epileptic encephalopathy, 33Total: 459

not providedTotal: 221

not specifiedTotal: 112

Inborn genetic diseasesTotal: 77

EEF1A2-related disorderTotal: 33

Intellectual disability, autosomal dominant 38Total: 31

EEF1A2-related developmental and degenerative epileptic-dyskinetic encephalopathyTotal: 9

Intellectual disabilityTotal: 5

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001958.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			3 clinvar	218 clinvar	6 clinvar	227
missense	9 clinvar	48 clinvar	174 clinvar	19 clinvar	1 clinvar	251
nonsense			6 clinvar			6
start loss						0
frameshift		1 clinvar	1 clinvar			2
splice donor/acceptor (+/-2bp)			6 clinvar			6
Total	9	49	190	237	7	492

Highest pathogenic variant AF is 0.0000027462681

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 43 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001958.5	RefSeq	NP_001949.1	7	MANE Select
ENST00000217182.6	Ensembl	ENSP00000217182.3	7	MANE Select
ENST00000298049.12	Ensembl	ENSP00000298049.8	8	Standard
ENST00000298049.13	Ensembl	ENSP00000298049.9	8	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
eef1a2	Danio rerio	Structure: head Quality: decreased size abnormal

Gene / Model

Organism

Observed Phenotype

eef1a2

Danio rerio

Structure: head

Quality: decreased size

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Legionellosis - Homo sapiens (human)
RNA transport - Homo sapiens (human)
Translation Factors
Translation
Metabolism of proteins

Biological Process

translation
translational elongation
response to inorganic substance
positive regulation of apoptotic process
response to electrical stimulus

Molecular Function

translation elongation factor activity
GTPase activity
protein binding
GTP binding
translation factor activity, RNA binding

Cellular Component

nucleus
cytoplasm
eukaryotic translation elongation factor 1 complex
neuronal cell body
myelin sheath

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000217182
Coding exons: 7
Length: 11140
Individuals with no LoFs: 124323
Homozygous LoFs: 0
Heterozygous LoFs: 1
Defined: 124324
p: 0.00000402

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	4.82	69	306	0.225	0.0000212	3026
Missense (PolyPhen)		18	163.77	0.10991		1594
Synonymous	0.831	128	141	0.911	0.0000116	933
Loss of Function	3.71	0	16.0	0.00	7.83e-7	198

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.0000090	0.0000090	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: This protein promotes the GTP-dependent binding of aminoacyl-tRNA to the A-site of ribosomes during protein biosynthesis.;
Disease: DISEASE: Epileptic encephalopathy, early infantile, 33 (EIEE33) [MIM:616409]: A form of epileptic encephalopathy, a heterogeneous group of severe childhood onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. {ECO:0000269|PubMed:23033978, ECO:0000269|PubMed:23647072}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Mental retardation, autosomal dominant 38 (MRD38) [MIM:616393]: A form of mental retardation, a disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. MRD38 common features are severe intellectual disability, autistic behavior, absent speech, neonatal hypotonia, epilepsy and progressive microcephaly. {ECO:0000269|PubMed:24697219}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.476

Intolerance Scores

RVIS EVS: -0.67
RVIS percentile EVS: 15.62

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Indispensability pred.: E
Indispensability score: 0.881

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Low	Low	Low
Primary Immunodeficiency	Medium	Low	Medium
Cancer	Low	Low	Low