EIF2B5

protein-coding

eukaryotic translation initiation factor 2B subunit epsilon

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, Nov 2009]

MANE transcript

NM_003907.3

Inheritance

ClinVar variants

P:125U:243B:299

Top phenotype

Leukoencephalopathy with vanishing white matter 5

gnomAD constraint

pLI —, LoF o/e 0.26

Max pathogenic AF

—

Genomic locus

chr3:184,135,038-184,146,127

External References & Databases

Ensembl (ENSG00000145191)

Transcript & Mutation Effects

hg38 • Region Span ~11.1 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

leukoencephalopathy with vanishing white matter 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0020507

Submitter: Labcorp Genetics (formerly Invitae)

leukoencephalopathy with vanishing white matterSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011380

Submitter: Genomics England PanelApp

leukoencephalopathy with vanishing white matterSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011380

Submitter: PanelApp Australia

leukoencephalopathy with vanishing white matterDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011380

Submitter: Myriad Women's Health

leukoencephalopathy with vanishing white matter 5DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0957873

Submitter: Natera

leukoencephalopathy with vanishing white matter 5DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0957873

Submitter: ClinGen

EIF2B5 was first associated with autosomal recessive leukoencephalopathy with vanishing white matter in 2001 (Leegwater et al., PMID: 11704758). 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) and Cree leukoencephalopathy. 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 5 (OMIM:603945, MONDO:0957873). Twelve variants (missense, nonsense) that have been reported in 8 probands in 5 publications (PMIDs: 19158808, 15136673, 21484434 30014503, 17646634) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) 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: 33300869, 20826436). The mouse model of EIF2B5 related leukoencephalopathy exhibits motor deficits, myelin degeneration, abnormal density of oligodendrocytes and astrocytes, and increased sensitivity to brain insult, which recapitulates the human disease. The zebrafish model is associated with impaired motor behavior and myelin defects. In summary, definitive evidence supports the relationship between EIF2B5 and leukoencephalopathy with vanishing white matter 5. 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 July 22, 2024 (SOP Version 10).

ovarioleukodystrophySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0020506

Submitter: Orphanet

leukoencephalopathy with vanishing white matter 5DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0957873

Submitter: G2P

Clinical Genomic Database (CGD)

Leukoencephalopathy with vanishing white matter 5AR

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)

Refs: 11704758; 12325082; 11835386; 14694060; 12707859; 14566705; 15054402; 15136673; 15136690; 15776425; 18263758; 19625339; 20301435; 20975056; 21676421; 22699478

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to EIF2B5 variants in ClinVar

14 Conditions Cataloged

not providedTotal: 684

Vanishing white matter diseaseTotal: 155

Inborn genetic diseasesTotal: 90

not specifiedTotal: 49

Leukoencephalopathy with vanishing white matter 5Total: 48

EIF2B5-related disorderTotal: 14

EIF2B5-related disordersTotal: 11

Leukoencephalopathy with vanishing white matter 1Total: 9

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003907.3. 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			11 clinvar	286 clinvar		297
missense	10 clinvar	52 clinvar	227 clinvar	13 clinvar		302
nonsense	14 clinvar	10 clinvar	1 clinvar			25
start loss		1 clinvar				1
frameshift	19 clinvar	4 clinvar	1 clinvar			24
splice donor/acceptor (+/-2bp)		15 clinvar	3 clinvar			18
Total	43	82	243	299	0	667

Highest pathogenic variant AF is 0.00051172695

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 111 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_003907.3	RefSeq	NP_003898.2	16	MANE Select
ENST00000648915.2	Ensembl	ENSP00000497160.1	16	MANE Select
ENST00000432569.2	Ensembl	ENSP00000414775.1	2	Standard
ENST00000432569.3	Ensembl	ENSP00000414775.1	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

RNA transport - Homo sapiens (human)
Translation Factors
MicroRNAs in cardiomyocyte hypertrophy
skeletal muscle hypertrophy is regulated via akt-mtor pathway
Recycling of eIF2:GDP

Biological Process

ovarian follicle development
translational initiation
aging
response to heat
response to glucose

Molecular Function

translation initiation factor activity
guanyl-nucleotide exchange factor activity
protein binding
translation initiation factor binding

Cellular Component

nucleus
cytoplasm
cytosol
eukaryotic translation initiation factor 2B complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000273783
Coding exons: 16
Length: 549721
Individuals with no LoFs: 125731
Homozygous LoFs: 0
Heterozygous LoFs: 17
Defined: 125748
p: 0.0000676

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.777	346	389	0.889	0.0000231	4710
Missense (PolyPhen)		42	63.524	0.66117		804
Synonymous	0.439	143	150	0.954	0.00000843	1403
Loss of Function	4.25	10	38.5	0.260	0.00000246	415

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.00012	0.00012	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0.000092	0.000092	rare
European (Non-Finnish)	0.000070	0.000070	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

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:11704758, ECO:0000269|PubMed:12325082, ECO:0000269|PubMed:12707859, ECO:0000269|PubMed:15776425, 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: 0.159

Intolerance Scores

LoFtool: 0.0221
RVIS EVS: -0.89
RVIS percentile EVS: 10.43

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.994

Gene Damage Prediction

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