EIF2B3

Chr 1AR

eukaryotic translation initiation factor 2B subunit gamma

Also known as: EIF-2B, EIF2Bgamma, VWM3

NCBI Gene: 8891 ENSG00000070785 UniProt: Q9NR50 OMIM: 606273

The protein encoded by this gene is a subunit of eukaryotic initiation factor 2B (eIF2B), which catalyzes the exchange of GDP for GTP on eIF2 and is essential for protein synthesis regulation. Mutations cause leukoencephalopathy with vanishing white matter (also known as childhood ataxia with central nervous system hypomyelination), an autosomal recessive leukodystrophy characterized by progressive white matter deterioration that can be triggered by stress, fever, or minor trauma. The disease results from loss of eIF2B function, leading to impaired cellular stress responses and white matter degeneration.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

ARLOEUF 0.431 OMIM phenotype

Clinical Summary— EIF2B3

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Gene-Disease Validity (ClinGen)

leukoencephalopathy with vanishing white matter 3 · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.57) — some intolerance to loss-of-function variants.

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ClinVar Variants

17 unique Pathogenic / Likely Pathogenic· 122 VUS of 362 total submissions

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GeneReview available — EIF2B3

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.43LOEUF

pLI 0.567

Z-score 3.63

OE 0.21 (0.11–0.43)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.04Z-score

OE missense 0.81 (0.72–0.91)

198 obs / 243.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.21 (0.11–0.43)

0≤0.351.4

Missense OE?0.81 (0.72–0.91)

0≤0.61.4

Synonymous OE?0.80

0≤1.21.6

LoF obs/exp: 5 / 24.3Missense obs/exp: 198 / 243.9Syn Z: 1.41

ClinVar Variant Classifications

362 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic3

Likely Pathogenic14

VUS122

Likely Benign176

Benign25

Conflicting11

Pathogenic

Likely Pathogenic

122

VUS

176

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	1	2	0	0	3
Likely Pathogenic	3	11	0	0	14
VUS	0	103	16	3	122
Likely Benign	1	6	73	96	176
Benign	0	1	23	1	25
Conflicting	—				11
Total	5	123	112	100	351

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

6 pathogenic / likely-pathogenic (of 17) ClinVar copy-number / structural variants overlap EIF2B3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →