congenital myopathy 4B, autosomal recessive

Summary

congenital myopathy 4B, autosomal recessive (MONDO:0012239) is a disease caused by TPM3 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: TPM3 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 336

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital myopathy 4B, autosomal recessive
Mondo ID	MONDO:0012239
MeSH	C538348
OMIM	609284
DOID	DOID:0110926
UMLS	C5829889
MedGen	1840525
GARD	0015453
Is cancer (heuristic)	no

Also known as: NEM1 · Nem1 · nemaline myopathy 1 · nemaline myopathy caused by mutation in TPM3 · nemaline myopathy type 1 · TPM3 nemaline myopathy

Data availability: 336 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › intermediate nemaline myopathy › congenital myopathy 4B, autosomal recessive

Related subtypes (3): congenital myopathy 2a, typical, autosomal dominant, nemaline myopathy 2, nemaline myopathy 9

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

336 retrieved; paginated sample, class counts are floors:

182 uncertain significance, 98 likely benign, 16 conflicting classifications of pathogenicity, 12 likely pathogenic, 10 pathogenic, 9 benign/likely benign, 5 benign, 4 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
12446	NM_152263.4(TPM3):c.26T>G (p.Met9Arg)	TPM3	Pathogenic	no assertion criteria provided
12449	NM_152263.4(TPM3):c.94C>T (p.Gln32Ter)	TPM3	Pathogenic	criteria provided, multiple submitters, no conflicts
12450	NM_152263.4(TPM3):c.503G>A (p.Arg168His)	TPM3	Pathogenic	criteria provided, multiple submitters, no conflicts
12451	NM_152263.4(TPM3):c.855del (p.Ter286AsnextTer?)	TPM3	Pathogenic	no assertion criteria provided
12453	NM_152263.4(TPM3):c.502C>G (p.Arg168Gly)	TPM3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12454	NM_152263.4(TPM3):c.502C>T (p.Arg168Cys)	TPM3	Pathogenic	criteria provided, multiple submitters, no conflicts
1394827	NM_152263.4(TPM3):c.87_91del (p.Gln30fs)	TPM3	Pathogenic	criteria provided, single submitter
1412784	NC_000001.10:g.(?154163642)(154164494_?)del	TPM3	Pathogenic	criteria provided, single submitter
1526419	NM_152263.4(TPM3):c.118-12G>A	TPM3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2925294	NM_152263.4(TPM3):c.452A>C (p.Glu151Ala)	TPM3	Pathogenic	criteria provided, single submitter
449764	NM_152263.4(TPM3):c.455C>T (p.Ala152Val)	TPM3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
462142	NM_152263.4(TPM3):c.758C>A (p.Thr253Lys)	TPM3	Pathogenic	criteria provided, single submitter
4785939	NM_152263.4(TPM3):c.688dup (p.Thr230fs)	TPM3	Pathogenic	criteria provided, single submitter
652762	NM_152263.4(TPM3):c.271C>T (p.Arg91Cys)	TPM3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12447	NM_152263.4(TPM3):c.857A>C (p.Ter286Ser)	TPM3	Likely pathogenic	criteria provided, single submitter
1474806	NM_152263.4(TPM3):c.271C>G (p.Arg91Gly)	TPM3	Likely pathogenic	criteria provided, single submitter
1510671	NM_152263.4(TPM3):c.44A>T (p.Asp15Val)	TPM3	Likely pathogenic	criteria provided, single submitter
2141661	NM_152263.4(TPM3):c.272G>A (p.Arg91His)	TPM3	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2939283	NM_152263.4(TPM3):c.243+1G>A	TPM3	Likely pathogenic	criteria provided, single submitter
2951138	NM_152263.4(TPM3):c.137C>T (p.Ala46Val)	TPM3	Likely pathogenic	criteria provided, single submitter
3247695	NC_000001.10:g.(?154148571)(154148744_?)dup	TPM3	Likely pathogenic	criteria provided, single submitter
3338267	NM_152263.4(TPM3):c.41T>G (p.Leu14Ter)	TPM3	Likely pathogenic	criteria provided, single submitter
531180	NM_152263.4(TPM3):c.298C>G (p.Leu100Val)	TPM3	Likely pathogenic	criteria provided, single submitter
801549	NM_152263.4(TPM3):c.43G>A (p.Asp15Asn)	TPM3	Likely pathogenic	criteria provided, single submitter
801550	NM_152263.4(TPM3):c.7G>C (p.Glu3Gln)	TPM3	Likely pathogenic	criteria provided, single submitter
974884	NM_152263.4(TPM3):c.377+863_775+422del	TPM3	Likely pathogenic	criteria provided, single submitter
1518234	NM_152263.4(TPM3):c.401G>A (p.Arg134Gln)	TPM3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
167744	NM_152263.4(TPM3):c.547C>T (p.Arg183Ter)	TPM3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2172695	NM_152263.4(TPM3):c.642+2T>C	TPM3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
292628	NM_152263.4(TPM3):c.*5594G>T	TPM3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 13 · Orphanet: 7 · 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
TPM3	Definitive	Autosomal dominant	TPM3-related myopathy	13

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TPM3	Orphanet:171433	Intermediate nemaline myopathy
TPM3	Orphanet:171439	Childhood-onset nemaline myopathy
TPM3	Orphanet:171881	Cap myopathy
TPM3	Orphanet:178342	Inflammatory myofibroblastic tumor
TPM3	Orphanet:2020	Congenital fiber-type disproportion myopathy
TPM3	Orphanet:476406	Congenital generalized hypercontractile muscle stiffness syndrome
HYAL2	Orphanet:508476	Cleft lip and palate-craniofacial dysmorphism-congenital heart defect-hearing loss syndrome

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TPM3	HGNC:12012	ENSG00000143549	P06753	Tropomyosin alpha-3 chain	gencc,clinvar
HYAL2	HGNC:5321	ENSG00000068001	Q12891	Hyaluronidase-2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TPM3	Tropomyosin alpha-3 chain	Binds to actin filaments in muscle and non-muscle cells.
HYAL2	Hyaluronidase-2	Catalyzes hyaluronan degradation into small fragments that are endocytosed and degraded in lysosomes by HYAL1 and exoglycosidases.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · 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
Enzyme (other)	1	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TPM3	Other/Unknown	no		Tropomyosin
HYAL2	Enzyme (other)	yes	3.2.1.35	Aldolase_TIM, GH_hydrolase_sf, Hyaluronidase

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
diaphragm	1
hindlimb stylopod muscle	1
skeletal muscle tissue of rectus abdominis	1
right lung	1
spleen	1
upper lobe of left lung	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TPM3	243	ubiquitous	marker	diaphragm, hindlimb stylopod muscle, skeletal muscle tissue of rectus abdominis
HYAL2	264	ubiquitous	marker	right lung, spleen, upper lobe of left lung

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TPM3	4,099
HYAL2	2,177

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TPM3	P06753	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
HYAL2	Q12891	91.70

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Hyaluronan metabolism	1	475.8×	0.008	HYAL2
Hyaluronan degradation	1	356.9×	0.008	HYAL2
Striated Muscle Contraction	1	154.3×	0.009	TPM3
RHOV GTPase cycle	1	142.8×	0.009	TPM3
Smooth Muscle Contraction	1	132.8×	0.009	TPM3
Signaling by ALK fusions and activated point mutants	1	75.1×	0.013	TPM3

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
glycosaminoglycan catabolic process	1	1203.7×	0.008	HYAL2
renal water absorption	1	1203.7×	0.008	HYAL2
monocyte activation	1	936.2×	0.008	HYAL2
negative regulation of fibroblast migration	1	766.0×	0.008	HYAL2
cellular response to UV-B	1	702.2×	0.008	HYAL2
positive regulation of urine volume	1	648.1×	0.008	HYAL2
response to reactive oxygen species	1	526.6×	0.008	HYAL2
hyaluronan catabolic process	1	495.6×	0.008	HYAL2
response to antibiotic	1	351.1×	0.010	HYAL2
multicellular organismal-level iron ion homeostasis	1	290.6×	0.011	HYAL2
cellular response to fibroblast growth factor stimulus	1	271.8×	0.011	HYAL2
skeletal system morphogenesis	1	247.8×	0.011	HYAL2
positive regulation of extrinsic apoptotic signaling pathway	1	227.7×	0.011	HYAL2
positive regulation of protein import into nucleus	1	210.7×	0.011	HYAL2
symbiont entry into host cell	1	200.6×	0.011	HYAL2
cellular response to interleukin-1	1	140.4×	0.013	HYAL2
cellular response to transforming growth factor beta stimulus	1	138.1×	0.013	HYAL2
negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	1	131.7×	0.013	HYAL2
cartilage development	1	125.8×	0.013	HYAL2
positive regulation of interleukin-8 production	1	122.1×	0.013	HYAL2
hematopoietic progenitor cell differentiation	1	118.7×	0.013	HYAL2
muscle contraction	1	104.0×	0.014	TPM3
positive regulation of interleukin-6 production	1	83.4×	0.016	HYAL2
cellular response to tumor necrosis factor	1	81.8×	0.016	HYAL2
positive regulation of inflammatory response	1	72.6×	0.016	HYAL2
response to virus	1	72.0×	0.016	HYAL2
negative regulation of cell growth	1	72.0×	0.016	HYAL2
kidney development	1	70.2×	0.016	HYAL2
carbohydrate metabolic process	1	68.0×	0.016	HYAL2
actin filament organization	1	59.3×	0.018	TPM3

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 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
TPM3	0	0
HYAL2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
TPM3	18	Binding:18

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
HYAL2	3.2.1.35, 4.2.2.1	hyaluronoglucosaminidase, hyaluronate lyase

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	1	HYAL2
E	Difficult family or no structure, no drug	1	TPM3

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TPM3	18	—
HYAL2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.