Leukoencephalopathy with vanishing white matter 2

Summary

Leukoencephalopathy with vanishing white matter 2 (MONDO:0957870) is a disease caused by EIF2B2 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: EIF2B2 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 19

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	leukoencephalopathy with vanishing white matter 2
Mondo ID	MONDO:0957870
OMIM	620312
DOID	DOID:0070373
UMLS	C5830404
MedGen	1841040
GARD	0026884
Is cancer (heuristic)	no

Data availability: 19 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 2

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 3, 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

19 retrieved; paginated sample, class counts are floors:

9 pathogenic/likely pathogenic, 3 likely pathogenic, 3 uncertain significance, 3 pathogenic, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
208575	NM_014239.4(EIF2B2):c.599G>T (p.Gly200Val)	EIF2B2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
280422	NM_014239.4(EIF2B2):c.3G>T (p.Met1Ile)	EIF2B2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
40180	NM_014239.4(EIF2B2):c.254T>A (p.Val85Glu)	EIF2B2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4075750	NM_014239.4(EIF2B2):c.794_798del (p.Leu265fs)	EIF2B2	Pathogenic	no assertion criteria provided
4336	NM_014239.4(EIF2B2):c.638A>G (p.Glu213Gly)	EIF2B2	Pathogenic	criteria provided, multiple submitters, no conflicts
4337	NM_014239.4(EIF2B2):c.947T>A (p.Val316Asp)	EIF2B2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4338	NM_014239.4(EIF2B2):c.547C>T (p.Arg183Ter)	EIF2B2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4339	NM_014239.4(EIF2B2):c.512C>T (p.Ser171Phe)	EIF2B2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4340	NM_014239.4(EIF2B2):c.607_612delinsTG (p.Met203fs)	EIF2B2	Pathogenic	criteria provided, multiple submitters, no conflicts
495050	NM_014239.4(EIF2B2):c.818A>G (p.Lys273Arg)	EIF2B2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
522641	NM_014239.4(EIF2B2):c.922G>A (p.Val308Met)	EIF2B2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
632219	NM_014239.4(EIF2B2):c.570del (p.Ile190fs)	EIF2B2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1205361	NM_014239.4(EIF2B2):c.285-1G>A	EIF2B2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2800462	NM_014239.4(EIF2B2):c.832-2A>G	EIF2B2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3576753	NM_014239.4(EIF2B2):c.544_545insA (p.Ala182fs)	EIF2B2	Likely pathogenic	criteria provided, single submitter
632220	NM_014239.4(EIF2B2):c.890del (p.Phe297fs)	EIF2B2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3776282	NM_014239.4(EIF2B2):c.973A>G (p.Ile325Val)	EIF2B2	Uncertain significance	criteria provided, single submitter
3891903	NM_014239.4(EIF2B2):c.677T>G (p.Met226Arg)	EIF2B2	Uncertain significance	criteria provided, single submitter
493146	NM_014239.4(EIF2B2):c.826C>T (p.Pro276Ser)	EIF2B2	Uncertain significance	criteria provided, multiple submitters, no conflicts

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
EIF2B2	Definitive	Autosomal recessive	leukoencephalopathy with vanishing white matter	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
EIF2B2	Orphanet:157713	Congenital or early infantile CACH syndrome
EIF2B2	Orphanet:157716	Late infantile CACH syndrome
EIF2B2	Orphanet:157719	Juvenile or adult CACH syndrome
EIF2B2	Orphanet:99853	Ovarioleukodystrophy
EIF2B2	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
EIF2B2	HGNC:3258	ENSG00000119718	P49770	Translation initiation factor eIF2B subunit beta	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
EIF2B2	Translation initiation factor eIF2B subunit beta	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)
EIF2B2	Other/Unknown	no		IF-2B-related, NagB/RpiA_transferase-like, IF_2B-like_C

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
left lobe of thyroid gland	1
right lobe of thyroid gland	1
thyroid gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
EIF2B2	298	ubiquitous	marker	left lobe of thyroid gland, right lobe of thyroid gland, thyroid gland

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
EIF2B2	2,800

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
EIF2B2	P49770	27

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	EIF2B2

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	EIF2B2
oligodendrocyte development	1	601.9×	0.004	EIF2B2
regulation of translational initiation	1	468.1×	0.004	EIF2B2
response to heat	1	421.3×	0.004	EIF2B2
ovarian follicle development	1	391.9×	0.004	EIF2B2
response to peptide hormone	1	391.9×	0.004	EIF2B2
translational initiation	1	358.6×	0.004	EIF2B2
response to glucose	1	255.3×	0.005	EIF2B2
myelination	1	251.5×	0.005	EIF2B2
T cell receptor signaling pathway	1	151.8×	0.007	EIF2B2
central nervous system development	1	115.4×	0.009	EIF2B2

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
EIF2B2	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
EIF2B2	1	Binding:1

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	EIF2B2

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)
EIF2B2	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.