Bethlem myopathy 2

Summary

Bethlem myopathy 2 (MONDO:0034022) is a disease caused by COL12A1 (GenCC Strong), with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: COL12A1 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 3,451
• Phenotypes (HPO): 49

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		8	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

49 HPO clinical features (Orphanet curated; top 49 by frequency):

HPO ID	Term	Frequency
HP:0001371	Flexion contracture	Very frequent (80-99%)
HP:0001382	Joint hypermobility	Very frequent (80-99%)
HP:0001270	Motor delay	Frequent (30-79%)
HP:0003324	Generalized muscle weakness	Frequent (30-79%)
HP:0003557	Increased variability in muscle fiber diameter	Frequent (30-79%)
HP:0025335	Delayed ability to stand	Frequent (30-79%)
HP:0031936	Delayed ability to walk	Frequent (30-79%)
HP:0000347	Micrognathia	Occasional (5-29%)
HP:0000545	Myopia	Occasional (5-29%)
HP:0000592	Blue sclerae	Occasional (5-29%)
HP:0000767	Pectus excavatum	Occasional (5-29%)
HP:0000974	Hyperextensible skin	Occasional (5-29%)
HP:0000977	Soft skin	Occasional (5-29%)
HP:0000980	Pallor	Occasional (5-29%)
HP:0001058	Poor wound healing	Occasional (5-29%)
HP:0001181	Adducted thumb	Occasional (5-29%)
HP:0001182	Tapered finger	Occasional (5-29%)
HP:0001252	Hypotonia	Occasional (5-29%)
HP:0001284	Areflexia	Occasional (5-29%)
HP:0001319	Neonatal hypotonia	Occasional (5-29%)
HP:0001508	Failure to thrive	Occasional (5-29%)
HP:0001601	Laryngomalacia	Occasional (5-29%)
HP:0001762	Talipes equinovarus	Occasional (5-29%)
HP:0001763	Pes planus	Occasional (5-29%)
HP:0002650	Scoliosis	Occasional (5-29%)
HP:0002705	High, narrow palate	Occasional (5-29%)
HP:0002751	Kyphoscoliosis	Occasional (5-29%)
HP:0002803	Congenital contracture	Occasional (5-29%)
HP:0002808	Kyphosis	Occasional (5-29%)
HP:0002828	Multiple joint contractures	Occasional (5-29%)
HP:0002987	Elbow flexion contracture	Occasional (5-29%)
HP:0003044	Shoulder flexion contracture	Occasional (5-29%)
HP:0003199	Decreased muscle mass	Occasional (5-29%)
HP:0003307	Hyperlordosis	Occasional (5-29%)
HP:0003546	Exercise intolerance	Occasional (5-29%)
HP:0003701	Proximal muscle weakness	Occasional (5-29%)
HP:0005879	Congenital finger flexion contractures	Occasional (5-29%)
HP:0005988	Congenital muscular torticollis	Occasional (5-29%)
HP:0006380	Knee flexion contracture	Occasional (5-29%)
HP:0006466	Ankle flexion contracture	Occasional (5-29%)
HP:0008180	Mildly elevated creatine kinase	Occasional (5-29%)
HP:0008366	Foot joint contracture	Occasional (5-29%)
HP:0008780	Congenital bilateral hip dislocation	Occasional (5-29%)
HP:0009473	Joint contracture of the hand	Occasional (5-29%)
HP:0010499	Patellar subluxation	Occasional (5-29%)
HP:0010862	Delayed fine motor development	Occasional (5-29%)
HP:0030051	Tip-toe gait	Occasional (5-29%)
HP:0030319	Weakness of facial musculature	Occasional (5-29%)
HP:0032152	Keratosis pilaris	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Bethlem myopathy 2
Mondo ID	MONDO:0034022
OMIM	616471
Orphanet	536516
DOID	DOID:0061201
UMLS	C4225313
MedGen	907426
GARD	0016121
Is cancer (heuristic)	no

Also known as: Bethlem myopathy 2 · Bethlem myopathy caused by mutation in COL12A1 · Bethlem myopathy type 2 · BTHLM2 · COL12A1 Bethlem myopathy · EDS, myopathic type · Ehlers-Danlos syndrome, myopathic type · myopathic EDS · myopathic Ehlers-Danlos syndrome

Data availability: 3,451 ClinVar variants · 2 GenCC gene-disease records.

Disease family

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 › Bethlem myopathy 2

Related subtypes (3): Bethlem myopathy 1A, 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

600 retrieved; paginated sample, class counts are floors:

326 uncertain significance, 170 likely benign, 76 conflicting classifications of pathogenicity, 8 benign, 8 pathogenic, 7 benign/likely benign, 3 likely pathogenic, 2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1062642	NM_004370.6(COL12A1):c.8100+3_8100+6del	COL12A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1069771	NM_004370.6(COL12A1):c.8571del (p.Pro2858fs)	COL12A1	Pathogenic	criteria provided, single submitter
1070407	NM_004370.6(COL12A1):c.7085del (p.Gln2362fs)	COL12A1	Pathogenic	criteria provided, single submitter
1073075	NC_000006.11:g.(?75796253)(75912518_?)del	COL12A1	Pathogenic	criteria provided, single submitter
1215037	NM_004370.6(COL12A1):c.5794+2T>A	COL12A1	Pathogenic	criteria provided, multiple submitters, no conflicts
1395130	NM_004370.6(COL12A1):c.27_42del (p.Ala10fs)	COL12A1	Pathogenic	criteria provided, single submitter
1444852	NM_004370.6(COL12A1):c.6737_6812del (p.Gln2246fs)	COL12A1	Pathogenic	criteria provided, single submitter
1453491	NM_004370.6(COL12A1):c.6819del (p.Phe2273fs)	COL12A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1455959	NC_000006.11:g.(?75855798)(75861023_?)del	COL12A1	Pathogenic	criteria provided, single submitter
1459613	NC_000006.11:g.(?75833026)(75912508_?)del	COL12A1	Pathogenic	criteria provided, single submitter
1066887	NM_004370.6(COL12A1):c.6872-2A>G	COL12A1	Likely pathogenic	criteria provided, single submitter
1467502	NM_004370.6(COL12A1):c.8265+1G>A	COL12A1	Likely pathogenic	criteria provided, single submitter
1473846	NM_004370.6(COL12A1):c.8393_8415+5del	COL12A1	Likely pathogenic	criteria provided, single submitter
1001973	NM_004370.6(COL12A1):c.8857G>T (p.Ala2953Ser)	COL12A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1002779	NM_004370.6(COL12A1):c.5614C>T (p.Arg1872Cys)	COL12A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1009475	NM_004370.6(COL12A1):c.74-15CT[3]	COL12A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1020289	NM_004370.6(COL12A1):c.569C>A (p.Thr190Asn)	COL12A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1022101	NM_004370.6(COL12A1):c.1772C>G (p.Pro591Arg)	COL12A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1026861	NM_004370.6(COL12A1):c.4650C>G (p.His1550Gln)	COL12A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1036247	NM_004370.6(COL12A1):c.3952G>A (p.Ala1318Thr)	COL12A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1040854	NM_004370.6(COL12A1):c.6427G>C (p.Val2143Leu)	COL12A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1043877	NM_004370.6(COL12A1):c.7432C>T (p.Arg2478Trp)	COL12A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1044820	NM_004370.6(COL12A1):c.6549T>A (p.Asn2183Lys)	COL12A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1045236	NM_004370.6(COL12A1):c.5996T>G (p.Leu1999Arg)	COL12A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1047680	NM_004370.6(COL12A1):c.4781G>A (p.Arg1594His)	COL12A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1049088	NM_004370.6(COL12A1):c.1574A>T (p.Tyr525Phe)	COL12A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1051021	NM_004370.6(COL12A1):c.7331C>T (p.Ala2444Val)	COL12A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1053272	NM_004370.6(COL12A1):c.3714T>C (p.Ile1238=)	COL12A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1053823	NM_004370.6(COL12A1):c.5510G>A (p.Gly1837Glu)	COL12A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1054455	NM_004370.6(COL12A1):c.5673C>G (p.Ile1891Met)	COL12A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 10 · 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
COL12A1	Strong	Autosomal dominant	Bethlem myopathy 2	8

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
COL4A2	Orphanet:36383	COL4A1/2-related familial vascular leukoencephalopathy
COL4A2	Orphanet:99810	Familial porencephaly
NOG	Orphanet:140908	Brachydactyly type B2
NOG	Orphanet:140917	Stapes ankylosis with broad thumbs and toes
NOG	Orphanet:1412	Tarsal-carpal coalition syndrome
NOG	Orphanet:3237	Multiple synostoses syndrome
NOG	Orphanet:3250	Proximal symphalangism

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
COL12A1	HGNC:2188	ENSG00000111799	Q99715	Collagen alpha-1(XII) chain	gencc,clinvar
COL4A2	HGNC:2203	ENSG00000134871	P08572	Collagen alpha-2(IV) chain	clinvar
NOG	HGNC:7866	ENSG00000183691	Q13253	Noggin	clinvar

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.
COL4A2	Collagen alpha-2(IV) chain	Type IV collagen is the major structural component of glomerular basement membranes (GBM), forming a ‘chicken-wire’ meshwork together with laminins, proteoglycans and entactin/nidogen.
NOG	Noggin	Inhibitor of bone morphogenetic proteins (BMP) signaling which is required for growth and patterning of the neural tube and somite.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

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	9.7×	0.199
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
COL12A1	Antibody/Immunoglobulin	yes		VWF_A, FN3_dom, Collagen
COL4A2	Other/Unknown	no		Collagen_IV_NC, Collagen, CTDL_fold
NOG	Other/Unknown	no		Noggin, Cystine-knot_cytokine

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
calcaneal tendon	1
cartilage tissue	1
tibia	1
decidua	1
placenta	1
saphenous vein	1
buccal mucosa cell	1
male germ line stem cell (sensu Vertebrata) in testis	1
pigmented layer of retina	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
COL12A1	240	ubiquitous	marker	tibia, calcaneal tendon, cartilage tissue
COL4A2	284	ubiquitous	marker	saphenous vein, decidua, placenta
NOG	155	broad	marker	pigmented layer of retina, buccal mucosa cell, male germ line stem cell (sensu Vertebrata) in testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
COL4A2	2,746
NOG	2,338
COL12A1	2,219

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
COL4A2	P08572	4
NOG	Q13253	2
COL12A1	Q99715	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 17. Enrichment computed across 3 evidence-associated genes (3 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 3 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	2	173.0×	4e-04	COL12A1, COL4A2
Assembly of collagen fibrils and other multimeric structures	2	133.6×	4e-04	COL12A1, COL4A2
Collagen degradation	2	117.1×	4e-04	COL12A1, COL4A2
Collagen biosynthesis and modifying enzymes	2	113.6×	4e-04	COL12A1, COL4A2
Anchoring fibril formation	1	253.8×	0.011	COL4A2
Scavenging by Class A Receptors	1	200.3×	0.011	COL4A2
Fibronectin matrix formation	1	190.3×	0.011	COL4A2
Crosslinking of collagen fibrils	1	190.3×	0.011	COL4A2
Attachment of bacteria to epithelial cells	1	165.5×	0.011	COL4A2
Formation of paraxial mesoderm	1	135.9×	0.012	NOG
Laminin interactions	1	126.9×	0.012	COL4A2
Signaling by BMP	1	119.0×	0.012	NOG
Signaling by PDGF	1	84.6×	0.015	COL4A2
NCAM1 interactions	1	82.8×	0.015	COL4A2
Non-integrin membrane-ECM interactions	1	51.4×	0.021	COL4A2
ECM proteoglycans	1	50.1×	0.021	COL4A2
Integrin cell surface interactions	1	44.8×	0.022	COL4A2

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
endodermal cell differentiation	2	330.4×	9e-04	COL12A1, COL4A2
collagen fibril organization	2	149.8×	0.002	COL12A1, COL4A2
negative regulation of cardiac epithelial to mesenchymal transition	1	5617.3×	0.005	NOG
positive regulation of glomerulus development	1	2808.7×	0.005	NOG
neural plate morphogenesis	1	1872.4×	0.005	NOG
cell differentiation in hindbrain	1	1872.4×	0.005	NOG
neural plate anterior/posterior regionalization	1	1872.4×	0.005	NOG
short-term synaptic potentiation	1	1872.4×	0.005	NOG
prostatic bud formation	1	1404.3×	0.006	NOG
axial mesoderm development	1	1123.5×	0.006	NOG
notochord morphogenesis	1	1123.5×	0.006	NOG
ventricular compact myocardium morphogenesis	1	802.5×	0.007	NOG
regulation of fibroblast growth factor receptor signaling pathway	1	802.5×	0.007	NOG
atrial cardiac muscle tissue morphogenesis	1	802.5×	0.007	NOG
ureteric bud formation	1	802.5×	0.007	NOG
negative regulation of cartilage development	1	702.2×	0.007	NOG
negative regulation of cardiac muscle cell proliferation	1	624.1×	0.007	NOG
heart trabecula morphogenesis	1	624.1×	0.007	NOG
membranous septum morphogenesis	1	561.7×	0.007	NOG
pharyngeal arch artery morphogenesis	1	561.7×	0.007	NOG
negative regulation of astrocyte differentiation	1	510.7×	0.007	NOG
embryonic skeletal joint morphogenesis	1	510.7×	0.007	NOG
endoderm formation	1	468.1×	0.007	NOG
endocardial cushion formation	1	468.1×	0.007	NOG
collagen-activated tyrosine kinase receptor signaling pathway	1	432.1×	0.007	COL4A2
nodal signaling pathway	1	374.5×	0.008	NOG
somite development	1	374.5×	0.008	NOG
lung morphogenesis	1	351.1×	0.008	NOG
cranial skeletal system development	1	312.1×	0.009	NOG
positive regulation of branching involved in ureteric bud morphogenesis	1	267.5×	0.010	NOG

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) 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
COL4A2	0	0
NOG	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	1	COL12A1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	COL4A2, NOG

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)
COL12A1	0	—
COL4A2	0	—
NOG	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.