X-linked myopathy with excessive autophagy

Summary

X-linked myopathy with excessive autophagy (MONDO:0010684) is a disease caused by VMA21 (GenCC Strong), with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: VMA21 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 92

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		36	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	X-linked myopathy with excessive autophagy
Mondo ID	MONDO:0010684
MeSH	C536522
OMIM	310440
Orphanet	25980
DOID	DOID:0050760
SNOMED CT	719815005
UMLS	C1839615
MedGen	374264
GARD	0003892
NORD	1866
Is cancer (heuristic)	no

Also known as: MEAX · myopathy, X-linked, with excessive autophagy · myopathy, X-linked, with excessive autophagy, X-linked recessive · vacuolar myopathy · XMEA

Data availability: 92 ClinVar variants · 3 GenCC gene-disease records.

Disease family

An umbrella term covering 1 Mondo subtype.

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › muscle tissue disorder › skeletal muscle disorder › myopathy › muscular dystrophy › progressive muscular dystrophy › X-linked myopathy with excessive autophagy

Related subtypes (12): facioscapulohumeral muscular dystrophy, congenital fibrosis of extraocular muscles, Bethlem myopathy, oculopharyngeal muscular dystrophy, myopathy, myofibrillar, 9, with early respiratory failure, progressive scapulohumeroperoneal distal myopathy, symptomatic form of muscular dystrophy of Duchenne and Becker in female carriers, myotonic dystrophy, Emery-Dreifuss muscular dystrophy, limb-girdle muscular dystrophy, childhood-onset progressive contractures-limb-girdle weakness-muscle dystrophy syndrome, oculopharyngodistal myopathy

Subtypes (1): myopathy, autophagic vacuolar, infantile-onset

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

92 retrieved; paginated sample, class counts are floors:

37 uncertain significance, 29 likely benign, 11 benign, 7 pathogenic, 5 conflicting classifications of pathogenicity, 2 benign/likely benign, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
208720	NM_001017980.4(VMA21):c.163+4A>G	VMA21	Pathogenic	criteria provided, multiple submitters, no conflicts
208798	NM_001017980.4(VMA21):c.54-27A>C	VMA21	Pathogenic	criteria provided, single submitter
208799	NM_001017980.4(VMA21):c.54-27A>T	VMA21	Pathogenic	no assertion criteria provided
208801	NM_001017980.4(VMA21):c.164-7T>G	VMA21	Pathogenic	criteria provided, single submitter
208804	NM_001017980.4(VMA21):c.164-6T>G	VMA21	Pathogenic	no assertion criteria provided
208805	NM_001017980.4(VMA21):c.*13_*104del	VMA21	Pathogenic	no assertion criteria provided
208806	NM_001017980.4(VMA21):c.54-16_54-8del	VMA21	Pathogenic	no assertion criteria provided
208802	NM_001017980.4(VMA21):c.272G>C (p.Gly91Ala)	VMA21	Likely pathogenic	criteria provided, single submitter
2422668	NC_000023.10:g.(?149613783)(150573536_?)del	CD99L2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1584991	NM_001017980.4(VMA21):c.76A>G (p.Thr26Ala)	VMA21	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
208803	NM_001017980.4(VMA21):c.*6A>G	VMA21	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2805853	NM_001017980.4(VMA21):c.11C>T (p.Pro4Leu)	VMA21	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
382097	NM_001017980.4(VMA21):c.15T>G (p.Asp5Glu)	VMA21	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2423473	NC_000023.10:g.(?149613783)(150573536_?)dup	HMGB3	Uncertain significance	criteria provided, single submitter
1003479	NM_001017980.4(VMA21):c.245T>G (p.Leu82Arg)	VMA21	Uncertain significance	criteria provided, single submitter
1032544	NM_001017980.4(VMA21):c.202G>T (p.Ala68Ser)	VMA21	Uncertain significance	criteria provided, multiple submitters, no conflicts
1056036	NM_001017980.4(VMA21):c.53+5C>T	VMA21	Uncertain significance	criteria provided, multiple submitters, no conflicts
1057126	NM_001017980.4(VMA21):c.175A>G (p.Met59Val)	VMA21	Uncertain significance	criteria provided, single submitter
1383222	NM_001017980.4(VMA21):c.127G>T (p.Gly43Trp)	VMA21	Uncertain significance	criteria provided, single submitter
1426301	NM_001017980.4(VMA21):c.226G>A (p.Val76Ile)	VMA21	Uncertain significance	criteria provided, multiple submitters, no conflicts
1440949	NM_001017980.4(VMA21):c.86C>T (p.Thr29Met)	VMA21	Uncertain significance	criteria provided, single submitter
1472351	NM_001017980.4(VMA21):c.112A>G (p.Ile38Val)	VMA21	Uncertain significance	criteria provided, single submitter
1695322	NM_001017980.4(VMA21):c.194A>G (p.Tyr65Cys)	VMA21	Uncertain significance	criteria provided, multiple submitters, no conflicts
1709486	NM_001017980.4(VMA21):c.164-3T>A	VMA21	Uncertain significance	criteria provided, single submitter
1714261	NM_001017980.4(VMA21):c.172G>A (p.Gly58Arg)	VMA21	Uncertain significance	criteria provided, single submitter
1928043	NM_001017980.4(VMA21):c.53+4G>T	VMA21	Uncertain significance	criteria provided, single submitter
1931323	NM_001017980.4(VMA21):c.11C>G (p.Pro4Arg)	VMA21	Uncertain significance	criteria provided, single submitter
1932071	NM_001017980.4(VMA21):c.287G>A (p.Arg96His)	VMA21	Uncertain significance	criteria provided, single submitter
1940419	NM_001017980.4(VMA21):c.208A>G (p.Ile70Val)	VMA21	Uncertain significance	criteria provided, single submitter
2061178	NM_001017980.4(VMA21):c.220G>T (p.Val74Phe)	VMA21	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · Orphanet: 1 · 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
VMA21	Strong	X-linked	X-linked myopathy with excessive autophagy	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
VMA21	Orphanet:25980	X-linked myopathy with excessive autophagy

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
VMA21	HGNC:22082	ENSG00000160131	Q3ZAQ7	Vacuolar ATPase assembly integral membrane protein VMA21	gencc,clinvar
CD99L2	HGNC:18237	ENSG00000102181	Q8TCZ2	CD99 antigen-like protein 2	clinvar
HMGB3	HGNC:5004	ENSG00000029993	O15347	High mobility group protein B3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
VMA21	Vacuolar ATPase assembly integral membrane protein VMA21	Required for the assembly of the V0 complex of the vacuolar ATPase (V-ATPase) in the endoplasmic reticulum.
CD99L2	CD99 antigen-like protein 2	Plays a role in a late step of leukocyte extravasation helping cells to overcome the endothelial basement membrane.
HMGB3	High mobility group protein B3	Multifunctional protein with various roles in different cellular compartments.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 3 · 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	3	1.8×	0.174

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
VMA21	Other/Unknown	no		Vma21
CD99L2	Other/Unknown	no		CD99L2
HMGB3	Other/Unknown	no		HMG_box_dom, HMG_boxA_CS, HMG_box_dom_sf

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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
ileal mucosa	1
kidney epithelium	1
primordial germ cell in gonad	1
gastrocnemius	1
prefrontal cortex	1
right frontal lobe	1
ganglionic eminence	1
oocyte	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
VMA21	250	ubiquitous	marker	ileal mucosa, kidney epithelium, primordial germ cell in gonad
CD99L2	243	ubiquitous	marker	prefrontal cortex, gastrocnemius, right frontal lobe
HMGB3	240	ubiquitous	marker	secondary oocyte, oocyte, ganglionic eminence

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HMGB3	2,174
CD99L2	1,241
VMA21	1,091

Structural data

PDB: 1 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
HMGB3	O15347	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
VMA21	Q3ZAQ7	70.41
CD99L2	Q8TCZ2	55.71

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 3 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
Cell surface interactions at the vascular wall	1	95.2×	0.021	CD99L2
Hemostasis	1	36.0×	0.028	CD99L2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of T cell extravasation	1	2808.7×	0.003	CD99L2
negative regulation of B cell differentiation	1	1123.5×	0.003	HMGB3
diapedesis	1	1123.5×	0.003	CD99L2
vacuolar proton-transporting V-type ATPase complex assembly	1	936.2×	0.003	VMA21
positive regulation of neutrophil extravasation	1	802.5×	0.003	CD99L2
DNA geometric change	1	702.2×	0.003	HMGB3
negative regulation of myeloid cell differentiation	1	312.1×	0.005	HMGB3
lysosomal lumen acidification	1	224.7×	0.006	VMA21
DNA recombination	1	112.3×	0.011	HMGB3
cell adhesion	1	12.5×	0.086	CD99L2
innate immune response	1	11.2×	0.087	HMGB3

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 3 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
VMA21	0	0
CD99L2	0	0
HMGB3	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
VMA21	1	Binding:1
HMGB3	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	3	VMA21, CD99L2, HMGB3

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
VMA21	1	—
CD99L2	0	—
HMGB3	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.