EIF2B4

protein-coding

eukaryotic translation initiation factor 2B subunit delta

Gene summary

Eukaryotic initiation factor 2B (EIF2B), which is necessary for protein synthesis, is a GTP exchange factor composed of five different subunits. The protein encoded by this gene is the fourth, or delta, subunit. Defects in this gene are a cause of leukoencephalopathy with vanishing white matter (VWM) and ovarioleukodystrophy. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

MANE transcript

NM_001034116.2

Inheritance

ClinVar variants

P:44U:144B:163

Top phenotype

Leukoencephalopathy with vanishing white matter 4

gnomAD constraint

pLI —, LoF o/e 0.14

Max pathogenic AF

—

Genomic locus

chr2:27,364,352-27,370,338

External References & Databases

Ensembl (ENSG00000115211)

Transcript & Mutation Effects

hg38 • Region Span ~6.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

leukoencephalopathy with vanishing white matter 4DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0957872

Submitter: G2P

leukoencephalopathy with vanishing white matterSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011380

Submitter: Genomics England PanelApp

ovarioleukodystrophySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0020506

Submitter: Orphanet

leukoencephalopathy with vanishing white matter 4DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0957872

Submitter: ClinGen

EIF2B4 was first reported in relation to autosomal recessive leukoencephalopathy with vanishing white matter 4 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 females 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 4 (OMIM:620314, MONDO:0957872). Eight variants (missense, nonsense, canonical) that have been reported in 8 probands in 4 publications (PMIDs: 11835386, 15136673, 14566705, 22128017) 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: 33300869, 26974157, 24532666). The zebrafish model is associated with impaired motor behavior and abnormal CNS development. The mouse model is associated with growth restriction, progressive ataxia, epileptic seizures. Protein interaction studies have shown that the subunit encoded by EIF2B4 interacts with the subunit of a previously curated gene EIF2B5. In summary, definitive evidence supports the relationship between EIF2B4 and leukoencephalopathy with vanishing white matter 4. This has been repeatedly demonstrated in 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 December 4, 2024 (SOP Version 11).

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: PanelApp Australia

Clinical Genomic Database (CGD)

Leukoencephalopathy with vanishing white matter 4AR

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; 11835386; 14566705; 15054402; 15776425; 18263758; 20301435

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to EIF2B4 variants in ClinVar

7 Conditions Cataloged

not providedTotal: 402

Inborn genetic diseasesTotal: 65

Vanishing white matter diseaseTotal: 53

not specifiedTotal: 39

Leukoencephalopathy with vanishing white matter 4Total: 24

EIF2B4-related disorderTotal: 12

Leukoencephalopathy with vanishing white matter 1Total: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001034116.2. 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	154 clinvar	1 clinvar	158
missense	5 clinvar	15 clinvar	137 clinvar	7 clinvar	1 clinvar	165
nonsense	5 clinvar		1 clinvar			6
start loss						0
frameshift	7 clinvar	2 clinvar	1 clinvar			10
splice donor/acceptor (+/-2bp)	2 clinvar	8 clinvar	2 clinvar			12
Total	19	25	144	161	2	351

Highest pathogenic variant AF is 0.00007621186

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 109 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001034116.2	RefSeq	NP_001029288.1	13	MANE Select
ENST00000347454.9	Ensembl	ENSP00000233552.6	13	MANE Select
NM_001318965.2	RefSeq	NP_001305894.1	12	Standard
NM_001318966.2	RefSeq	NP_001305895.1	12	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

ovarian follicle development
translational initiation
regulation of translation
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

cytoplasm
cytosol
eukaryotic translation initiation factor 2B complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000451130
Coding exons: 12
Length: 6135
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	0.798	257	296	0.869	0.0000188	3428
Missense (PolyPhen)		75	109.24	0.68658		1333
Synonymous	-1.35	133	115	1.16	0.00000596	1173
Loss of Function	4.18	4	27.8	0.144	0.00000165	321

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.00014	0.00014	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000044	0.000044	rare
South Asian	0.00016	0.00016	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:11835386, ECO:0000269|PubMed:12707859, ECO:0000269|PubMed:15776425}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.132

Intolerance Scores

LoFtool: 0.0313
RVIS EVS: -0.76
RVIS percentile EVS: 13.45

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.902

Gene Damage Prediction

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