Megalencephalic leukoencephalopathy with subcortical cysts 1

Summary

Megalencephalic leukoencephalopathy with subcortical cysts 1 (MONDO:0024555) is a disease caused by variants in MLC1 and GPRC5B, with 4 cohort genes and 2 clinical trials.

At a glance

• Causal genes: MLC1 (GenCC Definitive), GPRC5B (GenCC Strong)
• Cohort genes: 4
• ClinVar variants: 294
• Clinical trials: 2

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	megalencephalic leukoencephalopathy with subcortical cysts 1
Mondo ID	MONDO:0024555
OMIM	604004
DOID	DOID:0080316
UMLS	C5779875
MedGen	1826136
GARD	0025430
Is cancer (heuristic)	no

Also known as: megalencephalic leukoencephalopathy with subcortical cysts · megalencephalic leukoencephalopathy with subcortical cysts 1 · MLC1 · VL

Data availability: 294 ClinVar variants · 6 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › brain disorder › leukoencephalopathy, megalencephalic › megalencephalic leukoencephalopathy with subcortical cysts › megalencephalic leukoencephalopathy with subcortical cysts 1

Related subtypes (2): megalencephalic leukoencephalopathy with subcortical cysts 2A, megalencephalic leukoencephalopathy with subcortical cysts 2B, remitting, with or without intellectual disability

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

294 retrieved; paginated sample, class counts are floors:

94 uncertain significance, 64 likely pathogenic, 52 benign, 21 pathogenic/likely pathogenic, 19 pathogenic, 19 conflicting classifications of pathogenicity, 14 likely benign, 9 benign/likely benign, 2 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1331500	NM_015166.4(MLC1):c.251G>A (p.Arg84His)	LOC125446261	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
21522	NM_015166.4(MLC1):c.178-10T>A	LOC125446261	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
646457	NM_015166.4(MLC1):c.218G>A (p.Gly73Glu)	LOC125446261	Pathogenic	criteria provided, multiple submitters, no conflicts
1067995	NM_015166.4(MLC1):c.423+1G>T	MLC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1332811	NM_015166.4(MLC1):c.368C>T (p.Thr123Ile)	MLC1	Pathogenic	criteria provided, single submitter
1335979	NM_015166.4(MLC1):c.639dup (p.Ile214fs)	MLC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1455282	NM_015166.4(MLC1):c.881C>T (p.Pro294Leu)	MLC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1691319	NM_015166.4(MLC1):c.736del (p.Ser246fs)	MLC1	Pathogenic	criteria provided, multiple submitters, no conflicts
1702863	NM_015166.4(MLC1):c.908_918delinsGCA (p.Val303fs)	MLC1	Pathogenic	criteria provided, multiple submitters, no conflicts
188980	NM_015166.4(MLC1):c.714+1G>A	MLC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
189169	NM_015166.4(MLC1):c.324del (p.Asn110fs)	MLC1	Pathogenic	criteria provided, multiple submitters, no conflicts
202208	NM_015166.4(MLC1):c.223del (p.Val75fs)	MLC1	Pathogenic	no assertion criteria provided
2138459	NM_015166.4(MLC1):c.597+1G>A	MLC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
242875	NM_015166.4(MLC1):c.617G>T (p.Gly206Val)	MLC1	Pathogenic	no assertion criteria provided
2441418	NM_015166.4(MLC1):c.849del (p.Ile283_Met284insTer)	MLC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2676562	NM_015166.4(MLC1):c.177+1del	MLC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2676575	NM_015166.4(MLC1):c.772-1G>C	MLC1	Pathogenic	criteria provided, multiple submitters, no conflicts
31622	NM_015166.4(MLC1):c.206C>T (p.Ser69Leu)	MLC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
370408	NM_015166.4(MLC1):c.973C>T (p.Gln325Ter)	MLC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
370785	NM_015166.4(MLC1):c.136del (p.Cys46fs)	MLC1	Pathogenic	criteria provided, multiple submitters, no conflicts
371207	NM_015166.4(MLC1):c.449_455del (p.Leu150fs)	MLC1	Pathogenic	criteria provided, multiple submitters, no conflicts
371381	NM_015166.4(MLC1):c.67C>T (p.Gln23Ter)	MLC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
371509	NM_015166.4(MLC1):c.525+1G>A	MLC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4714	NM_015166.4(MLC1):c.278C>T (p.Ser93Leu)	MLC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4716	NM_015166.4(MLC1):c.895-2A>G	MLC1	Pathogenic	no assertion criteria provided
4717	NM_015166.4(MLC1):c.423C>A (p.Asn141Lys)	MLC1	Pathogenic	no assertion criteria provided
4718	NM_015166.4(MLC1):c.422A>G (p.Asn141Ser)	MLC1	Pathogenic	no assertion criteria provided
4719	NM_015166.4(MLC1):c.274C>T (p.Pro92Ser)	MLC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4720	NM_015166.4(MLC1):c.594_597del (p.Ser197_Tyr198insTer)	MLC1	Pathogenic	criteria provided, multiple submitters, no conflicts
4721	NM_015166.4(MLC1):c.176G>A (p.Gly59Glu)	MLC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 3 · 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
MLC1	Definitive	Autosomal recessive	megalencephalic leukoencephalopathy with subcortical cysts 1	6
GPRC5B	Strong	Autosomal dominant	megalencephalic leukoencephalopathy with subcortical cysts 1	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MLC1	Orphanet:2478	Megalencephalic leukoencephalopathy with subcortical cysts
HEPACAM	Orphanet:210548	Macrocephaly-intellectual disability-autism syndrome
HEPACAM	Orphanet:2478	Megalencephalic leukoencephalopathy with subcortical cysts

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MLC1	HGNC:17082	ENSG00000100427	Q15049	Membrane protein MLC1	gencc,clinvar
GPRC5B	HGNC:13308	ENSG00000167191	Q9NZH0	G-protein coupled receptor family C group 5 member B	gencc
HEPACAM	HGNC:26361	ENSG00000165478	Q14CZ8	Hepatic and glial cell adhesion molecule	clinvar
GSTT2	HGNC:4642	ENSG00000099984	P0CG29	Glutathione S-transferase theta-2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MLC1	Membrane protein MLC1	Transmembrane protein mainly expressed in brain astrocytes that may play a role in transport across the blood-brain and brain-cerebrospinal fluid barriers.
GPRC5B	G-protein coupled receptor family C group 5 member B	G-protein coupled receptor involved in the regulation of cell volume.
HEPACAM	Hepatic and glial cell adhesion molecule	Involved in regulating cell motility and cell-matrix interactions.
GSTT2	Glutathione S-transferase theta-2	Conjugation of reduced glutathione to a wide number of exogenous and endogenous hydrophobic electrophiles.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.5

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
Antibody/Immunoglobulin	1	7.3×	0.235
GPCR	1	6.0×	0.235
Other/Unknown	2	0.9×	0.769

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MLC1	Other/Unknown	no		Membrane_MLC1
GPRC5B	GPCR	yes		GPCR_3_C, RA-inducible_GPCR3
HEPACAM	Antibody/Immunoglobulin	yes		Ig_sub2, Ig_sub, Ig-like_dom
GSTT2	Other/Unknown	no		Glutathione_S-Trfase_N, GST_C, Glutathione-S-Trfase_C-like

Expression context

Cohort genes with no expression data: 0.

3 cohort genes 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
medial globus pallidus	2
caudate nucleus	1
nucleus accumbens	1
ventricular zone	1
globus pallidus	1
inferior olivary complex	1
lateral globus pallidus	1
substantia nigra pars reticulata	1
lower esophagus mucosa	1
male germ line stem cell (sensu Vertebrata) in testis	1
stromal cell of endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MLC1	192	broad	marker	nucleus accumbens, ventricular zone, caudate nucleus
GPRC5B	278	ubiquitous	marker	medial globus pallidus, globus pallidus, inferior olivary complex
HEPACAM	167	broad	marker	lateral globus pallidus, substantia nigra pars reticulata, medial globus pallidus
GSTT2	124	broad	yes	male germ line stem cell (sensu Vertebrata) in testis, stromal cell of endometrium, lower esophagus mucosa

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GPRC5B	1,112
HEPACAM	661
MLC1	630
GSTT2	5

Intra-cohort edges

A	B	Sources
HEPACAM	MLC1	string_interaction

Structural data

PDB: 2 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
HEPACAM	Q14CZ8	1
GSTT2	P0CG29	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
GPRC5B	Q9NZH0	74.39
MLC1	Q15049	71.29

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 4 evidence-associated genes (0 with Reactome annotation).

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of response to osmotic stress	1	2106.5×	0.006	MLC1
caveolin-mediated endocytosis	1	842.6×	0.008	MLC1
protein localization to cell-cell junction	1	468.1×	0.008	HEPACAM
positive regulation of intracellular transport	1	421.3×	0.008	MLC1
cellular response to cholesterol	1	210.7×	0.012	MLC1
cell volume homeostasis	1	150.5×	0.014	GPRC5B
glutathione metabolic process	1	87.8×	0.021	GSTT2
vesicle-mediated transport	1	24.1×	0.066	MLC1
regulation of cell cycle	1	18.6×	0.076	HEPACAM
immune response	1	11.8×	0.103	HEPACAM
protein transport	1	11.0×	0.103	MLC1
intracellular signal transduction	1	9.5×	0.103	GPRC5B
cell adhesion	1	9.4×	0.103	HEPACAM

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 4 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MLC1	0	0
GPRC5B	0	0
HEPACAM	0	0
GSTT2	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
GPRC5B	2	Binding:2
MLC1	1	Binding:1
GSTT2	1	ADMET:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; 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	1	HEPACAM
D	Druggable family + AlphaFold only, no drug	1	GPRC5B
E	Difficult family or no structure, no drug	2	MLC1, GSTT2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
MLC1	1	—
GPRC5B	2	—
HEPACAM	0	—
GSTT2	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03047369	Not specified	RECRUITING	The Myelin Disorders Biorepository Project
NCT02699190	Not specified	COMPLETED	LeukoSEQ: Whole Genome Sequencing as a First-Line Diagnostic Tool for Leukodystrophies