Bethlem myopathy

Summary

Bethlem myopathy (MONDO:0008029) is a disease with 4 cohort genes and 4 clinical trials. The dominant Reactome pathway is Collagen chain trimerization (4 cohort genes).

At a glance

• Prevalence: 1-9 / 1 000 000 (United Kingdom) [Orphanet-validated]
• Cohort genes: 4
• ClinVar variants: 7
• Phenotypes (HPO): 39
• Clinical trials: 4

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 1 000 000	0.77	United Kingdom	Validated
Point prevalence	<1 / 1 000 000		Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

39 HPO clinical features (Orphanet curated; top 39 by frequency):

HPO ID	Term	Frequency
HP:0001324	Muscle weakness	Very frequent (80-99%)
HP:0001371	Flexion contracture	Very frequent (80-99%)
HP:0003458	EMG: myopathic abnormalities	Very frequent (80-99%)
HP:0003560	Muscular dystrophy	Very frequent (80-99%)
HP:0009073	Progressive proximal muscle weakness	Very frequent (80-99%)
HP:0030095	Reduced muscle collagen VI	Very frequent (80-99%)
HP:0000467	Neck muscle weakness	Frequent (30-79%)
HP:0001220	Interphalangeal joint contracture of finger	Frequent (30-79%)
HP:0001239	Wrist flexion contracture	Frequent (30-79%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0002460	Distal muscle weakness	Frequent (30-79%)
HP:0002828	Multiple joint contractures	Frequent (30-79%)
HP:0003236	Elevated circulating creatine kinase concentration	Frequent (30-79%)
HP:0003325	Limb-girdle muscle weakness	Frequent (30-79%)
HP:0003731	Quadriceps muscle weakness	Frequent (30-79%)
HP:0006466	Ankle flexion contracture	Frequent (30-79%)
HP:0009058	Increased muscle lipid content	Frequent (30-79%)
HP:0100490	Camptodactyly of finger	Frequent (30-79%)
HP:0000962	Hyperkeratosis	Occasional (5-29%)
HP:0001073	Cigarette-paper scars	Occasional (5-29%)
HP:0001382	Joint hypermobility	Occasional (5-29%)
HP:0001771	Achilles tendon contracture	Occasional (5-29%)
HP:0002086	Abnormality of the respiratory system	Occasional (5-29%)
HP:0002515	Waddling gait	Occasional (5-29%)
HP:0002650	Scoliosis	Occasional (5-29%)
HP:0002791	Hypoventilation	Occasional (5-29%)
HP:0002938	Lumbar hyperlordosis	Occasional (5-29%)
HP:0002987	Elbow flexion contracture	Occasional (5-29%)
HP:0003306	Spinal rigidity	Occasional (5-29%)
HP:0003327	Axial muscle weakness	Occasional (5-29%)
HP:0003391	Gowers sign	Occasional (5-29%)
HP:0003691	Scapular winging	Occasional (5-29%)
HP:0003700	Generalized amyotrophy	Occasional (5-29%)
HP:0003805	Rimmed vacuoles	Occasional (5-29%)
HP:0009027	Foot dorsiflexor weakness	Occasional (5-29%)
HP:0010176	Curved toe phalanx	Occasional (5-29%)
HP:0012497	Reduced maximal expiratory pressure	Occasional (5-29%)
HP:0032152	Keratosis pilaris	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Bethlem myopathy
Mondo ID	MONDO:0008029
MeSH	C535436
OMIM	158810
Orphanet	610
DOID	DOID:0050663
ICD-11	72734329
NCIT	C126688
SNOMED CT	718572004
UMLS	C1834674
MedGen	331805
GARD	0000873
Is cancer (heuristic)	no

Also known as: benign autosomal dominant myopathy · Bethlem myopathy 1 · Bethlem myopathy type 1 · BTHLM1

Data availability: 7 ClinVar variants · 4 GenCC gene-disease records · 17 cell lines.

Disease family

An umbrella term covering 4 Mondo subtypes.

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 › Bethlem myopathy

Related subtypes (12): facioscapulohumeral muscular dystrophy, congenital fibrosis of extraocular muscles, oculopharyngeal muscular dystrophy, X-linked myopathy with excessive autophagy, 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 (4): Bethlem myopathy 1A, Bethlem myopathy 2, Bethlem myopathy 1B, Bethlem myopathy 1C

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

7 retrieved; paginated sample, class counts are floors:

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

ClinVar	Variant (HGVS)	Gene	Classification	Review
265506	NM_001849.4(COL6A2):c.1970-9G>A	COL6A2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
549682	NM_001849.4(COL6A2):c.1055delG	COL6A2	Pathogenic	criteria provided, single submitter
475853	NM_004370.6(COL12A1):c.2879C>T (p.Thr960Met)	COL12A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
542500	NM_004370.6(COL12A1):c.7690C>T (p.Pro2564Ser)	COL12A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
286822	NM_001849.4(COL6A2):c.2170C>T (p.Arg724Cys)	COL6A2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1467945	NM_004370.6(COL12A1):c.6080G>A (p.Gly2027Glu)	COL12A1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3377442	NM_004369.4(COL6A3):c.8404A>T (p.Thr2802Ser)	COL6A3	Likely benign	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 43 · Orphanet: 14 · 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
COL6A1	Definitive	Autosomal dominant	Bethlem myopathy 1A	9
COL6A3	Definitive	Semidominant	Bethlem myopathy 1A	15
COL12A1	Strong	Autosomal dominant	Bethlem myopathy 2	8
COL6A2	Strong	Autosomal dominant	Bethlem myopathy 1A	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
COL12A1	Orphanet:536516	Myopathic Ehlers-Danlos syndrome
COL12A1	Orphanet:610	Bethlem muscular dystrophy
COL12A1	Orphanet:75840	Ullrich congenital muscular dystrophy
COL6A2	Orphanet:289380	Myosclerosis
COL6A2	Orphanet:610	Bethlem muscular dystrophy
COL6A2	Orphanet:646113	Intermediate collagen VI-related muscular dystrophy
COL6A2	Orphanet:75840	Ullrich congenital muscular dystrophy
COL6A3	Orphanet:464440	Primary dystonia, DYT27 type
COL6A3	Orphanet:610	Bethlem muscular dystrophy
COL6A3	Orphanet:646113	Intermediate collagen VI-related muscular dystrophy
COL6A3	Orphanet:75840	Ullrich congenital muscular dystrophy
COL6A1	Orphanet:610	Bethlem muscular dystrophy
COL6A1	Orphanet:646113	Intermediate collagen VI-related muscular dystrophy
COL6A1	Orphanet:75840	Ullrich congenital muscular dystrophy

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
COL12A1	HGNC:2188	ENSG00000111799	Q99715	Collagen alpha-1(XII) chain	gencc,clinvar
COL6A2	HGNC:2212	ENSG00000142173	P12110	Collagen alpha-2(VI) chain	gencc,clinvar
COL6A3	HGNC:2213	ENSG00000163359	P12111	Collagen alpha-3(VI) chain	gencc,clinvar
COL6A1	HGNC:2211	ENSG00000142156	P12109	Collagen alpha-1(VI) chain	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
COL12A1	Collagen alpha-1(XII) chain	Type XII collagen interacts with type I collagen-containing fibrils, the COL1 domain could be associated with the surface of the fibrils, and the COL2 and NC3 domains may be localized in the perifibrillar matrix.
COL6A2	Collagen alpha-2(VI) chain	Collagen VI acts as a cell-binding protein.
COL6A3	Collagen alpha-3(VI) chain	Collagen VI acts as a cell-binding protein.
COL6A1	Collagen alpha-1(VI) chain	Collagen VI acts as a cell-binding protein.

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	2	14.6×	0.013
Other/Unknown	2	0.9×	0.769

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
COL12A1	Antibody/Immunoglobulin	yes		VWF_A, FN3_dom, Collagen
COL6A2	Other/Unknown	no		VWF_A, Collagen, vWFA_dom_sf
COL6A3	Antibody/Immunoglobulin	yes		VWF_A, Kunitz_BPTI, FN3_dom
COL6A1	Other/Unknown	no		VWF_A, Collagen, vWFA_dom_sf

Expression context

Cohort genes with no expression data: 0.

4 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
stromal cell of endometrium	3
calcaneal tendon	1
cartilage tissue	1
tibia	1
descending thoracic aorta	1
right coronary artery	1
skin of hip	1
visceral pleura	1
lower esophagus muscularis layer	1
tendon of biceps brachii	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
COL12A1	240	ubiquitous	marker	tibia, calcaneal tendon, cartilage tissue
COL6A2	263	ubiquitous	marker	stromal cell of endometrium, right coronary artery, descending thoracic aorta
COL6A3	264	broad	marker	stromal cell of endometrium, visceral pleura, skin of hip
COL6A1	291	ubiquitous	marker	stromal cell of endometrium, tendon of biceps brachii, lower esophagus muscularis layer

Protein interactions among cohort

Intra-cohort edges: 5.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
COL6A1	3,049
COL6A2	2,786
COL6A3	2,267
COL12A1	2,219

Intra-cohort edges

A	B	Sources
COL12A1	COL6A1	string_interaction
COL12A1	COL6A3	string_interaction
COL6A1	COL6A2	string_interaction
COL6A1	COL6A3	string_interaction
COL6A2	COL6A3	string_interaction

Structural data

PDB: 4 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
COL6A3	P12111	6
COL12A1	Q99715	1
COL6A2	P12110	1
COL6A1	P12109	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. Enrichment computed across 4 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Collagen chain trimerization	4	259.6×	2e-09	COL12A1, COL6A2, COL6A3, COL6A1
Assembly of collagen fibrils and other multimeric structures	4	200.3×	2e-09	COL12A1, COL6A2, COL6A3, COL6A1
Collagen degradation	4	175.7×	2e-09	COL12A1, COL6A2, COL6A3, COL6A1
Collagen biosynthesis and modifying enzymes	4	170.4×	2e-09	COL12A1, COL6A2, COL6A3, COL6A1
Signaling by PDGF	3	190.3×	3e-07	COL6A2, COL6A3, COL6A1
NCAM1 interactions	3	186.2×	3e-07	COL6A2, COL6A3, COL6A1
ECM proteoglycans	3	112.7×	1e-06	COL6A2, COL6A3, COL6A1
Integrin cell surface interactions	3	100.8×	2e-06	COL6A2, COL6A3, COL6A1

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
response to UV	3	274.8×	6e-06	COL6A2, COL6A3, COL6A1
phosphatidylinositol 3-kinase/protein kinase B signal transduction	3	158.0×	1e-05	COL6A2, COL6A3, COL6A1
neuron apoptotic process	3	138.9×	1e-05	COL6A2, COL6A3, COL6A1
cell adhesion	4	37.5×	1e-05	COL12A1, COL6A2, COL6A3, COL6A1
endodermal cell differentiation	2	247.8×	3e-04	COL12A1, COL6A1
response to glucose	2	127.7×	0.001	COL6A2, COL6A3
collagen fibril organization	2	112.3×	0.001	COL12A1, COL6A1
response to polyamine macromolecule	1	4213.0×	0.002	COL6A1
muscle cell apoptotic process	1	2106.5×	0.003	COL6A1
response to decreased oxygen levels	1	2106.5×	0.003	COL6A1
limb joint morphogenesis	1	1404.3×	0.004	COL6A1
fat cell proliferation	1	1404.3×	0.004	COL6A1
multicellular organismal locomotion	1	1404.3×	0.004	COL6A1
regulation of collagen fibril organization	1	1404.3×	0.004	COL6A1
muscle system process	1	1053.2×	0.004	COL6A1
sensory perception of mechanical stimulus	1	1053.2×	0.004	COL6A1
response to bleomycin	1	842.6×	0.005	COL6A1
apoptotic nuclear changes	1	702.2×	0.005	COL6A1
skeletal muscle tissue growth	1	702.2×	0.005	COL6A1
mitochondrial depolarization	1	601.9×	0.006	COL6A1
caveola assembly	1	526.6×	0.007	COL6A1
lung epithelial cell differentiation	1	468.1×	0.007	COL6A1
reduction of food intake in response to dietary excess	1	421.3×	0.007	COL6A1
skeletal muscle fiber differentiation	1	421.3×	0.007	COL6A1
mitochondrial transmembrane transport	1	421.3×	0.007	COL6A1
tissue remodeling	1	324.1×	0.009	COL6A1
response to peptide	1	280.9×	0.009	COL6A1
response to reactive oxygen species	1	263.3×	0.009	COL6A1
energy reserve metabolic process	1	263.3×	0.009	COL6A1
collagen metabolic process	1	263.3×	0.009	COL6A1

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 4 evidence-associated genes (75%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
COL12A1	0	0
COL6A2	0	0
COL6A3	0	0
COL6A1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	2	COL12A1, COL6A3
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	COL6A2, COL6A1

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)
COL12A1	0	—
COL6A2	0	—
COL6A3	0	—
COL6A1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 4.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	3
PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01438788	PHASE2	COMPLETED	Low Protein Diet in Patients With Collagen VI Related Myopathies
NCT01895283	Not specified	COMPLETED	The Effect of Aerobic Exercise, on Fitness and Functional Muscle Strength, in Patients With Muscular Dystrophy
NCT03693898	Not specified	UNKNOWN	MR in Patients With Collagen VI Related Myopathies
NCT04020159	Not specified	UNKNOWN	Global Registry for COL6-related Dystrophies