EIF2B1
protein-codingeukaryotic translation initiation factor 2B subunit alpha
Gene summary
This gene encodes one of five subunits of eukaryotic translation initiation factor 2B (EIF2B), a GTP exchange factor for eukaryotic initiation factor 2 and an essential regulator for protein synthesis. Mutations in this gene and the genes encoding other EIF2B subunits have been associated with leukoencephalopathy with vanishing white matter. [provided by RefSeq, Oct 2009]
- EIF2B
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~13.4 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: AD
Disease ID:MONDO:0016391
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0020507
Submitter: ClinGen
EIF2B1 related leukoencephalopathy, autosomal recessive The *EIF2B1* gene encodes one of five subunits of eukaryotic translation initiation factor 2B (EIF2B), a GTP exchange factor for eukaryotic initiation factor 2 and an essential regulator for protein synthesis (NCBI Gene ID: 1967). *EIF2B1* was first associated with autosomal recessive leukoencephalopathy with vanishing white matter in 2002 (van der Knaap et al., PMID: 11835386). Affected individuals 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 1 (OMIM:606686, MONDO:0020507). Eight variants (missense, nonsense, canonical, small in-frame deletion) that have been reported in 9 probands in 8 publications (PMIDs: 11835386, 34302356, 18263758, 15776425, 32865661, 36801247, 25843247, 25761052) are included in this curation. The mechanism of pathogenicity is reported to be loss of function. This gene-disease relationship is also supported by experimental evidence. Protein interaction studies have shown that the subunit encoded by *EIF2B1* interacts with the four other EIF2B complex subunits that are encoded by genes (*EIF2B2*, *EIF2B3*, *EIF2B4*, and *EIF2B5*) definitively known to cause leukoencephalopathy with vanishing (PMID: 24532666). In summary, definitive evidence supports the relationship between *EIF2B1* 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 February 5, 2025 (SOP Version 11).
Inheritance Pattern: AR
Disease ID:MONDO:0011380
Submitter: Genomics England PanelApp
Inheritance Pattern: AR
Disease ID:MONDO:0020506
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0011380
Submitter: PanelApp Australia
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 EIF2B1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001414.4. 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 | 4 | 86 | 1 | 91 | ||
| missense | 4 | 3 | 75 | 2 | 84 | |
| nonsense | 6 | 1 | 1 | 8 | ||
| start loss | 0 | |||||
| frameshift | 11 | 7 | 1 | 19 | ||
| splice donor/acceptor (+/-2bp) | 2 | 6 | 8 | |||
| Total | 23 | 17 | 81 | 88 | 1 | 210 |
Highest pathogenic variant AF is 0.00016726967
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001405.1 | 9 | MANE Select | |
| Ensembl | ENSP00000416250.2 | 9 | MANE Select | |
| Ensembl | ENSP00000443172.1 | 5 | Standard | |
| Ensembl | ENSP00000444183.1 | 5 | 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
- response to peptide hormone
Molecular Function
- translation initiation factor activity
- guanyl-nucleotide exchange factor activity
- protein binding
- identical protein binding
Cellular Component
- cytoplasm
- cytosol
- eukaryotic translation initiation factor 2B complex
- plasma membrane
- membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000424014
- Coding exons
- 9
- Length
- 13361
- Individuals with no LoFs
- 125673
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 75
- Defined
- 125748
- p
- 0.000298
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.38 | 114 | 164 | 0.696 | 0.00000983 | 1974 |
| Missense (PolyPhen) | 38 | 58.661 | 0.64779 | 694 | ||
| Synonymous | -0.614 | 71 | 64.7 | 1.10 | 0.00000436 | 607 |
| Loss of Function | 1.64 | 9 | 16.1 | 0.560 | 8.84e-7 | 198 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00012 | 0.00012 | rare |
| Latino/Admixed American | 0.000058 | 0.000058 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00022 | 0.00022 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.00032 | 0.00032 | rare |
| South Asian | 0.0010 | 0.0010 | notable |
| 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:15776425}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.125
Intolerance Scores
- LoFtool
- 0.364
- RVIS EVS
- -0.38
- RVIS percentile EVS
- 27.42
Essentials
- Essential (CRISPR)
- E
- Essential (CRISPR2)
- E
- Essential (gene trap)
- E
- Indispensability pred.
- E
- Indispensability score
- 0.993
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |