EIF2S3

protein-coding

eukaryotic translation initiation factor 2 subunit gamma

Gene summary

The protein encoded by this gene is the largest subunit of a heterotrimeric GTP-binding protein involved in the recruitment of methionyl-tRNA(i) to the 40 S ribosomal subunit. [provided by RefSeq, Jan 2010]

Previous symbols:

EIF2G

MANE transcript

NM_001415.4

Inheritance

ClinVar variants

P:10U:127B:17

Top phenotype

MEHMO syndrome

gnomAD constraint

pLI —, LoF o/e 0.07

Max pathogenic AF

—

Genomic locus

chrX:24,054,946-24,078,810

External References & Databases

Ensembl (ENSG00000130741)

Transcript & Mutation Effects

hg38 • Region Span ~23.9 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

MEHMO syndromeSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010258

Submitter: PanelApp Australia

MEHMO syndromeSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010258

Submitter: Genomics England PanelApp

diabetes mellitusSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0005015

Submitter: Genomics England PanelApp

MEHMO syndromeSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010258

Submitter: G2P

MEHMO syndromeSUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010258

Submitter: Orphanet

MEHMO syndromeSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010258

Submitter: Labcorp Genetics (formerly Invitae)

MEHMO syndromeDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010258

Submitter: ClinGen

The *EIF2S3* gene encodes the γ subunit of eukaryotic translation initiation factor-2 (eIF2), a heterotrimeric GTP-binding protein involved in the recruitment of methionyl-tRNA(i) to the 40S ribosomal subunit. The acronym MEHMO (mental retardation, epileptic seizures, hypogonadism and -genitalism, microcephaly, obesity) was coined by Steinmuller et al. (PMID: 9781023) who described a large three-generation family with five affected boys and mapped the disease locus to the short arm of chromosome X. Using chromosome X-exome sequencing, Skopkova et al. (2017) identified a frameshift mutation, I465Sfs, in *EIF2S3* in an affected male in the family reported by Steinmüller et al. (1998). Functional assays using a yeast/human (Sc/Hs) chimeric form of eIF2γ in yeast demonstrated the variant impairs eIF2γ function. The same variant was also detected in other 3 unrelated families with typical MEHMO syndrome features in affected males. Sequencing data suggested a founder effect for this variant (PMIDs: 27333055, 28055140, 29303605). Five missense mutations, which exhibited reduced growth rate and/or impaired translation function in yeast, were also reported in male patients exhibiting either typical features of MEHMO or milder phenotypes with a subset of MEHMO features, supporting variable clinical expressivity of MEHMO in patients with deleterious *EIF2S3* variants (PMIDs: 23063529, 27333055, 30878599, 32799315). The association is seen in 14 probands in 6 publications (PMID: 27333055, 28055140, 23063529, 29303605, 30878599, 32799315). The mechanism for disease is expected to be hemizygous loss of function. All reported female carriers are asymptomatic. Morpholino-based knockdown of the zebrafish *EIF2S3* ortholog recapitulates the human microcephaly and short stature phenotype (PMID: 27333055). An *EIF2S3* knockdown human pancreatic β cell line showed impaired cell survival and increased caspase activities (PMID: 30878599). In summary, the *EIF2S3*/MEHMO syndrome gene-disease relationship is definitive. 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 Intellectual Disability and Autism Gene Curation Expert Panel on November 11, 2021 (SOP version 8).

Clinical Genomic Database (CGD)

MEHMO syndromeXL

Manifestation: Craniofacial; Endocrine; Musculoskeletal; Neurologic

Intervention: Endocrine

Rationale: Awareness of endocrine manifestations, including growth hormone deficiency and hypogonadism, may allow early recognition and treatment

Refs: 23063529; 27333055; 28055140

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to EIF2S3 variants in ClinVar

6 Conditions Cataloged

not providedTotal: 51

MEHMO syndromeTotal: 20

not specifiedTotal: 13

Inborn genetic diseasesTotal: 13

EIF2S3-related disorderTotal: 5

Intellectual disabilityTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001415.4. 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			17 clinvar	14 clinvar	2 clinvar	33
missense	3 clinvar	6 clinvar	74 clinvar	1 clinvar		84
nonsense			4 clinvar			4
start loss						0
frameshift		1 clinvar	1 clinvar			2
splice donor/acceptor (+/-2bp)			31 clinvar			31
Total	3	7	127	15	2	154

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 33 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001415.4	RefSeq	NP_001406.1	12	MANE Select
ENST00000253039.9	Ensembl	ENSP00000253039.4	12	MANE Select
ENST00000423068.1	Ensembl	ENSP00000391383.1	5	Standard
ENST00000864815.1	Ensembl	ENSP00000534874.1	12	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
eif2s3	Danio rerio	Structure: trunk Quality: necrotic abnormal

Gene / Model

Organism

Observed Phenotype

eif2s3

Danio rerio

Structure: trunk

Quality: necrotic

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

RNA transport - Homo sapiens (human)
Translation Factors
double stranded rna induced gene expression
skeletal muscle hypertrophy is regulated via akt-mtor pathway
Formation of the ternary complex, and subsequently, the 43S complex

Biological Process

formation of translation preinitiation complex
translational initiation
transmembrane transport

Molecular Function

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

Cellular Component

nucleus
cytoplasm
cytosol
eukaryotic translation initiation factor 2 complex
extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000253039
Coding exons: 12
Length: 23256
Individuals with no LoFs: 125716
Homozygous LoFs: 0
Heterozygous LoFs: 21
Defined: 125737
p: 0.0000835

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.61	42	177	0.237	0.0000130	3052
Missense (PolyPhen)		0	44.217	0		855
Synonymous	-0.130	63	61.7	1.02	0.00000462	944
Loss of Function	3.32	1	14.7	0.0678	0.00000100	295

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00032	0.00025	rare
Latino/Admixed American	0.000081	0.000058	rare
Ashkenazi Jewish	0.00014	0.000099	rare
East Asian	0	0.0	absent
Finnish	0.00019	0.00014	rare
European (Non-Finnish)	0.00013	0.000088	rare
South Asian	0	0.0	absent
Other	0.00024	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: As a subunit of eukaryotic initiation factor 2 (eIF2), involved in the early steps of protein synthesis. In the presence of GTP, eIF2 forms a ternary complex with initiator tRNA Met-tRNAi and then recruits the 40S ribosomal complex, a step that determines the rate of protein translation. This step is followed by mRNA binding to form the 43S pre-initiation complex. Junction of the 60S ribosomal subunit to form the 80S initiation complex is preceded by hydrolysis of the GTP bound to eIF2 and release of an eIF2-GDP binary complex. In order for eIF2 to recycle and catalyze another round of initiation, the GDP bound to eIF2 must exchange with GTP by way of a reaction catalyzed by eIF2B (By similarity). Along with its paralog on chromosome Y, may contribute to spermatogenesis up to the round spermatid stage (By similarity). {ECO:0000250, ECO:0000250|UniProtKB:Q9Z0N1}.;

Recessive Scores

pRec: 0.218

Intolerance Scores

LoFtool: 0.117
RVIS EVS: 0.13
RVIS percentile EVS: 62.74

Essentials

Essential (CRISPR): N
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.973

Gene Damage Prediction

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