EIF2B3
protein-codingeukaryotic translation initiation factor 2B subunit gamma
Gene summary
The protein encoded by this gene is one of the subunits of initiation factor eIF2B, which catalyzes the exchange of eukaryotic initiation factor 2-bound GDP for GTP. It has also been found to function as a cofactor of hepatitis C virus internal ribosome entry site-mediated translation. Mutations in this gene have been associated with leukodystrophy with vanishing white matter. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2009]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~136.2 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0020507
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0020506
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0011380
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0011380
Submitter: Genomics England PanelApp
Inheritance Pattern: AR
Disease ID:MONDO:0957871
Submitter: ClinGen
EIF2B3 was first associated with autosomal recessive leukoencephalopathy with vanishing white matter in 2002 (van der Knapp., PMID: 11835386). Individuals with EIF2B3-related leukoencephalopathy present with gait dysfunction, spasticity, cognitive decline, and white matter abnormalities on MRI. Some individuals develop ovarian failure. Onset is variable from infancy to adulthood, and progression of disease is often in the setting of fever, trauma, or stress. Vanishing white matter disease has also been referred to as Childhood Ataxia with Central Nervous System Hypomyelination (CACH). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found that a phenotypic spectrum exists and there is no difference in molecular mechanism or inheritance pattern. Therefore, we chose to curate this gene-disease relationship under the disease term leukoencephalopathy with vanishing white matter 3 (OMIM:606273, MONDO:0957871). Sixteen variants (missense, frameshift) that have been reported in 14 probands in 11 publications (PMIDs: 11835386, 37171481, 15136673, 28904586, 31072091, 21484434, 22312164, 35389136, 38872124, 28597716, 19158808) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is reported to be loss of function. This gene-disease relationship is also supported by experimental evidence, (PMIDs: 33517449, 24532666). The zebrafish model is associated with defects in myelin development and glial cell differentiation as well as increased expression of genes in the induced stress response pathway. Protein interaction studies have shown that the subunit encoded by EIF2B3 interacts with the subunit of a previously curated gene EIF2B5. In summary, definitive evidence supports the relationship between EIF2B3 and autosomal recessive leukoencephalopathy. 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 Leukodystrophy and Leukoencephalopathy GCEP on the meeting date October 16, 2024 (SOP Version 11).
Clinical Genomic Database (CGD)
Manifestation: Endocrine; Neurologic; Obstetric
Intervention: Obstetric
Rationale: Individuals with Ovarioleukodystrophy may suffer from premature ovarian failure, and measures to allow reproduction (eg,through egg preservation) may be desired
Comments: The evidence is unclear, but it is possible that certain circumstances may aggravate the condition and accelerate neurological decline, including head trauma (children may benefit from wearing helmets), contact sports, and stressful situations (including high body temperature, and prophylactic measures and rapid treatment related to infections may be beneficial)
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to EIF2B3 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_020365.5. 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 | 100 | 103 | |||
| missense | 2 | 13 | 112 | 6 | 1 | 134 |
| nonsense | 1 | 1 | ||||
| start loss | 1 | 1 | ||||
| frameshift | 1 | 2 | 3 | |||
| splice donor/acceptor (+/-2bp) | 1 | 1 | 2 | |||
| Total | 3 | 17 | 117 | 106 | 1 | 244 |
Highest pathogenic variant AF is 0.0001586204
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_065098.1 | 11 | MANE Select | |
| Ensembl | ENSP00000353575.2 | 11 | MANE Select | |
| RefSeq | NP_001160060.1 | 9 | Standard | |
| RefSeq | NP_001248347.1 | 10 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- RNA transport - Homo sapiens (human)
- Translation Factors
- Recycling of eIF2:GDP
- Eukaryotic Translation Initiation
- Translation
Biological Process
- translational initiation
- response to heat
- response to glucose
- oligodendrocyte development
- hippocampus development
Molecular Function
- translation initiation factor activity
- guanyl-nucleotide exchange factor activity
- protein binding
- translation factor activity, RNA binding
- nucleotidyltransferase activity
Cellular Component
- cytoplasm
- cytosol
- eukaryotic translation initiation factor 2B complex
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000360403
- Coding exons
- 11
- Length
- 135833
- Individuals with no LoFs
- 125740
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 8
- Defined
- 125748
- p
- 0.0000318
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.04 | 198 | 244 | 0.812 | 0.0000129 | 2952 |
| Missense (PolyPhen) | 20 | 31.108 | 0.64293 | 383 | ||
| Synonymous | 1.41 | 68 | 84.5 | 0.805 | 0.00000412 | 867 |
| Loss of Function | 3.63 | 5 | 24.3 | 0.206 | 0.00000127 | 302 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.000029 | 0.000029 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.000054 | 0.000054 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000035 | 0.000035 | rare |
| South Asian | 0.000065 | 0.000065 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Catalyzes the exchange of eukaryotic initiation factor 2-bound GDP for GTP.;
- Disease
- DISEASE: Leukodystrophy with vanishing white matter (VWM) [MIM:603896]: A leukodystrophy that occurs mainly in children. Neurological signs include progressive cerebellar ataxia, spasticity, inconstant optic atrophy and relatively preserved mental abilities. The disease is chronic-progressive with, in most individuals, additional episodes of rapid deterioration following febrile infections or minor head trauma. While childhood onset is the most common form of the disorder, some severe forms are apparent at birth. A severe, early-onset form seen among the Cree and Chippewayan populations of Quebec and Manitoba is called Cree leukoencephalopathy. Milder forms may not become evident until adolescence or adulthood. Some females with milder forms of the disease who survive to adolescence exhibit ovarian dysfunction. This variant of the disorder is called ovarioleukodystrophy. {ECO:0000269|PubMed:11835386, ECO:0000269|PubMed:19158808, ECO:0000269|PubMed:21484434}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.168
Intolerance Scores
- LoFtool
- 0.122
- RVIS EVS
- -0.12
- RVIS percentile EVS
- 45.13
Essentials
- Essential (CRISPR)
- E
- Essential (CRISPR2)
- E
- Essential (gene trap)
- E
- Indispensability pred.
- E
- Indispensability score
- 0.923
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |