Leukoencephalopathy with vanishing white matter 5

Summary

Leukoencephalopathy with vanishing white matter 5 (MONDO:0957873) is a disease caused by EIF2B5 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: EIF2B5 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 45

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	leukoencephalopathy with vanishing white matter 5
Mondo ID	MONDO:0957873
OMIM	620315
DOID	DOID:0070367
UMLS	C5779973
MedGen	1830483
GARD	0026887
Is cancer (heuristic)	no

Data availability: 45 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › neurodegenerative disease › inherited neurodegenerative disorder › leukodystrophy › leukoencephalopathy with vanishing white matter › leukoencephalopathy with vanishing white matter 5

Related subtypes (8): leukoencephalopathy, progressive, with ovarian failure, congenital or early infantile CACH syndrome, late infantile CACH syndrome, juvenile or adult CACH syndrome, leukoencephalopathy with vanishing white matter 1, leukoencephalopathy with vanishing white matter 2, leukoencephalopathy with vanishing white matter 3, leukoencephalopathy with vanishing white matter 4

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

45 retrieved; paginated sample, class counts are floors:

14 pathogenic/likely pathogenic, 12 likely pathogenic, 10 pathogenic, 6 conflicting classifications of pathogenicity, 3 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
3897880	NM_003907.3:c.[1280C>T];[1340C>T]		Pathogenic	criteria provided, single submitter
1071095	NM_003907.3(EIF2B5):c.416_417dup (p.Ala140fs)	EIF2B5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1184948	NM_003907.3(EIF2B5):c.913A>T (p.Met305Leu)	EIF2B5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1208981	NM_003907.3(EIF2B5):c.1280C>T (p.Pro427Leu)	EIF2B5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1453777	NM_003907.3(EIF2B5):c.203T>C (p.Leu68Ser)	EIF2B5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
195203	NM_003907.3(EIF2B5):c.318A>T (p.Leu106Phe)	EIF2B5	Pathogenic	criteria provided, multiple submitters, no conflicts
1996707	NM_003907.3(EIF2B5):c.1960del (p.Phe653_Leu654insTer)	EIF2B5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2734601	NM_003907.3(EIF2B5):c.1813del (p.Leu605fs)	EIF2B5	Pathogenic	criteria provided, multiple submitters, no conflicts
285116	NM_003907.3(EIF2B5):c.241G>A (p.Glu81Lys)	EIF2B5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3024560	NM_003907.3(EIF2B5):c.1841C>G (p.Ser614Ter)	EIF2B5	Pathogenic	criteria provided, single submitter
40178	NM_003907.3(EIF2B5):c.808G>C (p.Asp270His)	EIF2B5	Pathogenic	no assertion criteria provided
420049	NM_003907.3(EIF2B5):c.1946T>C (p.Ile649Thr)	EIF2B5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4531885	NM_003907.3(EIF2B5):c.791_792insAC (p.Phe264fs)	EIF2B5	Pathogenic	criteria provided, single submitter
590938	NM_003907.3(EIF2B5):c.1030C>T (p.Arg344Ter)	EIF2B5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
5942	NM_003907.3(EIF2B5):c.271A>G (p.Thr91Ala)	EIF2B5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
5943	NM_003907.3(EIF2B5):c.1882T>C (p.Trp628Arg)	EIF2B5	Pathogenic	no assertion criteria provided
5945	NM_003907.3(EIF2B5):c.338G>A (p.Arg113His)	EIF2B5	Pathogenic	criteria provided, multiple submitters, no conflicts
5946	NM_003907.3(EIF2B5):c.584G>A (p.Arg195His)	EIF2B5	Pathogenic	criteria provided, multiple submitters, no conflicts
5949	NM_003907.3(EIF2B5):c.545C>T (p.Thr182Met)	EIF2B5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
5950	NM_003907.3(EIF2B5):c.944G>A (p.Arg315His)	EIF2B5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
5952	NM_003907.3(EIF2B5):c.167T>G (p.Phe56Cys)	EIF2B5	Pathogenic	no assertion criteria provided
666195	NM_003907.3(EIF2B5):c.1015C>T (p.Arg339Trp)	EIF2B5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
872660	NM_003907.3(EIF2B5):c.1208C>T (p.Ala403Val)	EIF2B5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
942204	NM_003907.3(EIF2B5):c.806G>A (p.Arg269Gln)	EIF2B5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3588974	NM_003907.3(EIF2B5):c.-8AGA[2] (p.Met1del)	EIF2B5	Likely pathogenic	criteria provided, single submitter
3588975	NM_003907.3(EIF2B5):c.320+2T>C	EIF2B5	Likely pathogenic	criteria provided, single submitter
3588977	NM_003907.3(EIF2B5):c.913A>G (p.Met305Val)	EIF2B5	Likely pathogenic	criteria provided, single submitter
3588978	NM_003907.3(EIF2B5):c.1491G>A (p.Trp497Ter)	EIF2B5	Likely pathogenic	criteria provided, single submitter
3588979	NM_003907.3(EIF2B5):c.1546G>T (p.Gly516Ter)	EIF2B5	Likely pathogenic	criteria provided, single submitter
3588980	NM_003907.3(EIF2B5):c.1746-1G>T	EIF2B5	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 5 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
EIF2B5	Definitive	Autosomal recessive	leukoencephalopathy with vanishing white matter	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
EIF2B5	Orphanet:157713	Congenital or early infantile CACH syndrome
EIF2B5	Orphanet:157716	Late infantile CACH syndrome
EIF2B5	Orphanet:157719	Juvenile or adult CACH syndrome
EIF2B5	Orphanet:99853	Ovarioleukodystrophy
EIF2B5	Orphanet:99854	Cree leukoencephalopathy

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
EIF2B5	HGNC:3261	ENSG00000145191	Q13144	Translation initiation factor eIF2B subunit epsilon	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
EIF2B5	Translation initiation factor eIF2B subunit epsilon	Acts as a component of the translation initiation factor 2B (eIF2B) complex, which catalyzes the exchange of GDP for GTP on eukaryotic initiation factor 2 (eIF2) gamma subunit.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
EIF2B5	Other/Unknown	no		W2_domain, Trimer_LpxA-like_sf, ARM-type_fold

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
gastrocnemius	1
sural nerve	1
tendon of biceps brachii	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
EIF2B5	286	ubiquitous	marker	sural nerve, tendon of biceps brachii, gastrocnemius

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
EIF2B5	2,989

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
EIF2B5	Q13144	26

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Recycling of eIF2:GDP	1	1268.9×	8e-04	EIF2B5

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
cytoplasmic translational initiation	1	1404.3×	0.005	EIF2B5
astrocyte development	1	1123.5×	0.005	EIF2B5
positive regulation of translational initiation	1	842.6×	0.005	EIF2B5
astrocyte differentiation	1	766.0×	0.005	EIF2B5
oligodendrocyte development	1	601.9×	0.005	EIF2B5
response to heat	1	421.3×	0.005	EIF2B5
ovarian follicle development	1	391.9×	0.005	EIF2B5
response to peptide hormone	1	391.9×	0.005	EIF2B5
translational initiation	1	358.6×	0.005	EIF2B5
response to glucose	1	255.3×	0.005	EIF2B5
myelination	1	251.5×	0.005	EIF2B5
hippocampus development	1	230.8×	0.005	EIF2B5
response to endoplasmic reticulum stress	1	166.8×	0.007	EIF2B5
T cell receptor signaling pathway	1	151.8×	0.007	EIF2B5
positive regulation of apoptotic process	1	56.7×	0.018	EIF2B5

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 1 · Undrugged: 0

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
EIF2B5	1	2

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	EIF2B5

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
EIF2B5	7	Binding:7

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

1 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
MOLIBRESIB	2	EIF2B5

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	1	EIF2B5
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

0 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Clinical trials & evidence

Clinical trials

Clinical trials: 0.