contractures, pterygia, and variable skeletal fusions syndrome 1B

Summary

contractures, pterygia, and variable skeletal fusions syndrome 1B (MONDO:0020746) is a disease caused by MYH3 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: MYH3 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 50

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	contractures, pterygia, and variable skeletal fusions syndrome 1B
Mondo ID	MONDO:0020746
OMIM	618469
DOID	DOID:0081322
UMLS	C5193114
MedGen	1676457
GARD	0025234
Is cancer (heuristic)	no

Also known as: contractures, pterygia, and spondylocarpotarsal fusion syndrome 1B

Data availability: 50 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › autosomal recessive multiple pterygium syndrome › contractures, pterygia, and variable skeletal fusions syndrome 1B

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

50 retrieved; paginated sample, class counts are floors:

21 benign, 9 pathogenic, 9 uncertain significance, 3 conflicting classifications of pathogenicity, 3 benign/likely benign, 3 likely pathogenic, 2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1177399	NM_002470.4(MYH3):c.2501T>C (p.Phe834Ser)	MYH3	Pathogenic	criteria provided, single submitter
1299399	NM_002470.4(MYH3):c.2103G>C (p.Glu701Asp)	MYH3	Pathogenic	no assertion criteria provided
1299400	NM_002470.4(MYH3):c.2045C>A (p.Pro682Gln)	MYH3	Pathogenic	no assertion criteria provided
14138	NM_002470.4(MYH3):c.2015G>A (p.Arg672His)	MYH3	Pathogenic	criteria provided, multiple submitters, no conflicts
1708265	NM_002470.4(MYH3):c.4111C>T (p.Gln1371Ter)	MYH3	Pathogenic/Likely pathogenic	criteria provided, single submitter
4819625	NM_002470.4(MYH3):c.2489G>A (p.Trp830Ter)	MYH3	Pathogenic	criteria provided, single submitter
587701	NM_002470.4(MYH3):c.4647+1G>A	MYH3	Pathogenic	criteria provided, single submitter
587703	NM_002470.4(MYH3):c.141T>G (p.Tyr47Ter)	MYH3	Pathogenic	criteria provided, single submitter
587706	NM_002470.4(MYH3):c.-9+1G>A	MYH3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
634845	NM_002470.4(MYH3):c.1141+131_3256del	MYH3	Pathogenic	no assertion criteria provided
694360	NM_002470.4(MYH3):c.1748A>C (p.Tyr583Ser)	MYH3	Pathogenic	criteria provided, multiple submitters, no conflicts
3341291	NM_002470.4(MYH3):c.3007dup (p.Ala1003fs)	MYH3	Likely pathogenic	criteria provided, single submitter
4291831	NM_002470.4(MYH3):c.4179del (p.Lys1393fs)	MYH3	Likely pathogenic	criteria provided, single submitter
4531632	NM_002470.4(MYH3):c.3976-2A>C	MYH3	Likely pathogenic	criteria provided, single submitter
211557	NM_002470.4(MYH3):c.875C>G (p.Ser292Cys)	MYH3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
503890	NM_002470.4(MYH3):c.1986_1990del (p.Asn662fs)	MYH3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
885219	NM_002470.4(MYH3):c.3532G>A (p.Asp1178Asn)	MYH3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1471249	NM_002470.4(MYH3):c.4840C>T (p.Arg1614Trp)	MYH3	Uncertain significance	criteria provided, multiple submitters, no conflicts
161596	NM_002470.4(MYH3):c.118G>A (p.Val40Met)	MYH3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1675303	NM_002470.4(MYH3):c.5457G>C (p.Arg1819Ser)	MYH3	Uncertain significance	criteria provided, single submitter
2169063	NM_002470.4(MYH3):c.3469G>A (p.Val1157Ile)	MYH3	Uncertain significance	criteria provided, multiple submitters, no conflicts
2725211	NM_002470.4(MYH3):c.5332G>A (p.Ala1778Thr)	MYH3	Uncertain significance	criteria provided, multiple submitters, no conflicts
3367105	NM_002470.4(MYH3):c.3472A>C (p.Thr1158Pro)	MYH3	Uncertain significance	criteria provided, single submitter
3382401	NM_002470.4(MYH3):c.3872A>C (p.Gln1291Pro)	MYH3	Uncertain significance	criteria provided, single submitter
3382472	NM_002470.4(MYH3):c.204+1G>A	MYH3	Uncertain significance	criteria provided, single submitter
3581605	NM_002470.4(MYH3):c.5316G>C (p.Lys1772Asn)	MYH3	Uncertain significance	criteria provided, single submitter
1222180	NM_002470.4(MYH3):c.2682+30_2682+31del	MYH3	Benign	criteria provided, multiple submitters, no conflicts
1262563	NM_002470.4(MYH3):c.643-43dup	MYH3	Benign	criteria provided, multiple submitters, no conflicts
129649	NM_002470.4(MYH3):c.2151C>A (p.Gly717=)	MYH3	Benign	criteria provided, multiple submitters, no conflicts
129650	NM_002470.4(MYH3):c.2532A>G (p.Ala844=)	MYH3	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 14 · Orphanet: 6 · 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
MYH3	Strong	Autosomal recessive	contractures, pterygia, and variable skeletal fusions syndrome 1B	14

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MYH3	Orphanet:1146	Distal arthrogryposis type 1
MYH3	Orphanet:1147	Sheldon-Hall syndrome
MYH3	Orphanet:2053	Freeman-Sheldon syndrome
MYH3	Orphanet:2990	Autosomal recessive multiple pterygium syndrome
MYH3	Orphanet:3275	Spondylocarpotarsal synostosis
MYH3	Orphanet:65743	Autosomal dominant multiple pterygium syndrome

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
MYH3	HGNC:7573	ENSG00000109063	P11055	Myosin-3	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MYH3	Myosin-3	Muscle contraction.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · 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
Scaffold/PPI	1	17.3×	0.058

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MYH3	Scaffold/PPI	no		Myosin_head_motor_dom-like, Myosin_tail, SH3_Myosin

Expression context

Cohort genes with no expression data: 0.

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 testis	1
right testis	1
testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MYH3	203	tissue_specific	yes	left testis, right testis, testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MYH3	1,795

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MYH3	P11055	74.35

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. 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
Striated Muscle Contraction	1	308.6×	0.006	MYH3
Muscle contraction	1	77.2×	0.013	MYH3

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
muscle filament sliding	1	1053.2×	0.003	MYH3
actin filament-based movement	1	802.5×	0.003	MYH3
skeletal muscle contraction	1	510.7×	0.003	MYH3
face morphogenesis	1	495.6×	0.003	MYH3
ATP metabolic process	1	468.1×	0.003	MYH3
embryonic limb morphogenesis	1	401.2×	0.003	MYH3
sarcomere organization	1	383.0×	0.003	MYH3
muscle contraction	1	208.1×	0.005	MYH3
muscle organ development	1	166.8×	0.006	MYH3

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MYH3	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	MYH3

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)
MYH3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.