Leukoencephalopathy with vanishing white matter 3

Summary

Leukoencephalopathy with vanishing white matter 3 (MONDO:0957871) is a disease with 1 cohort gene.

At a glance

• Cohort genes: 1
• ClinVar variants: 16

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	leukoencephalopathy with vanishing white matter 3
Mondo ID	MONDO:0957871
OMIM	620313
DOID	DOID:0070372
UMLS	C5830405
MedGen	1841041
GARD	0026885
Is cancer (heuristic)	no

Data availability: 16 ClinVar variants.

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 3

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 4, leukoencephalopathy with vanishing white matter 5

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

16 retrieved; paginated sample, class counts are floors:

6 likely pathogenic, 4 uncertain significance, 3 pathogenic/likely pathogenic, 2 pathogenic, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
40179	NM_020365.5(EIF2B3):c.80T>A (p.Leu27Gln)	EIF2B3	Pathogenic	no assertion criteria provided
4437	NM_020365.5(EIF2B3):c.674G>A (p.Arg225Gln)	EIF2B3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4438	NM_020365.5(EIF2B3):c.1193_1194del (p.Val398fs)	EIF2B3	Pathogenic	no assertion criteria provided
4439	NM_020365.5(EIF2B3):c.260C>T (p.Ala87Val)	EIF2B3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4440	NM_020365.5(EIF2B3):c.1037T>C (p.Ile346Thr)	EIF2B3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1517841	NM_020365.5(EIF2B3):c.673C>T (p.Arg225Trp)	EIF2B3	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3584635	NM_020365.5(EIF2B3):c.938_939del (p.Val313fs)	EIF2B3	Likely pathogenic	criteria provided, single submitter
3584646	NM_020365.5(EIF2B3):c.455-2A>G	EIF2B3	Likely pathogenic	criteria provided, single submitter
3767195	NM_020365.5(EIF2B3):c.614A>G (p.Tyr205Cys)	EIF2B3	Likely pathogenic	criteria provided, single submitter
3767196	NM_020365.5(EIF2B3):c.935G>T (p.Arg312Leu)	EIF2B3	Likely pathogenic	criteria provided, single submitter
431961	NM_020365.5(EIF2B3):c.272G>A (p.Arg91His)	EIF2B3	Likely pathogenic	criteria provided, multiple submitters, no conflicts
285204	NM_020365.5(EIF2B3):c.32G>T (p.Gly11Val)	EIF2B3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1471263	NM_020365.5(EIF2B3):c.497G>A (p.Arg166Lys)	EIF2B3	Uncertain significance	criteria provided, multiple submitters, no conflicts
3064802	NM_020365.5(EIF2B3):c.300T>G (p.Asp100Glu)	EIF2B3	Uncertain significance	criteria provided, single submitter
4072428	NM_020365.5(EIF2B3):c.344A>T (p.His115Leu)	EIF2B3	Uncertain significance	criteria provided, single submitter
876174	NM_020365.5(EIF2B3):c.134G>A (p.Arg45His)	EIF2B3	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

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

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
EIF2B3	Orphanet:157713	Congenital or early infantile CACH syndrome
EIF2B3	Orphanet:157716	Late infantile CACH syndrome
EIF2B3	Orphanet:157719	Juvenile or adult CACH syndrome
EIF2B3	Orphanet:99853	Ovarioleukodystrophy
EIF2B3	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
EIF2B3	HGNC:3259	ENSG00000070785	Q9NR50	Translation initiation factor eIF2B subunit gamma	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
EIF2B3	Translation initiation factor eIF2B subunit gamma	Acts as a component of the translation initiation factor 2B (eIF2B) complex, which catalyzes the exchange of GDP for GTP on the eukaryotic initiation factor 2 (eIF2) complex 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)
EIF2B3	Other/Unknown	no		NTP_transferase_dom, Nucleotide-diphossugar_trans, eIF2B_gamma

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
gluteal muscle	1
triceps brachii	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
EIF2B3	271	ubiquitous	marker	triceps brachii, gluteal muscle, gastrocnemius

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
EIF2B3	3,212

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
EIF2B3	Q9NR50	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	EIF2B3

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×	0.004	EIF2B3
oligodendrocyte development	1	601.9×	0.004	EIF2B3
response to heat	1	421.3×	0.004	EIF2B3
response to peptide hormone	1	391.9×	0.004	EIF2B3
translational initiation	1	358.6×	0.004	EIF2B3
response to glucose	1	255.3×	0.005	EIF2B3
T cell receptor signaling pathway	1	151.8×	0.007	EIF2B3

Therapeutics

Drug target analysis

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

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
EIF2B3	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
EIF2B3	9	Binding:9

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

0 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.

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	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	EIF2B3

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
EIF2B3	9	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.