Nemaline myopathy 5

Summary

Nemaline myopathy 5 (MONDO:0011539) is a disease caused by TNNT1 (GenCC Strong), with 3 cohort genes and 1 clinical trial.

At a glance

• Prevalence: >1 / 1000 (Specific population) [Orphanet-validated]
• Causal gene: TNNT1 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 320
• Phenotypes (HPO): 12
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Prevalence at birth	>1 / 1000	200	Specific population	Validated
Point prevalence	<1 / 1 000 000		Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

12 HPO clinical features (Orphanet curated; top 12 by frequency):

HPO ID	Term	Frequency
HP:0000768	Pectus carinatum	Frequent (30-79%)
HP:0001270	Motor delay	Frequent (30-79%)
HP:0001319	Neonatal hypotonia	Frequent (30-79%)
HP:0001337	Tremor	Frequent (30-79%)
HP:0003044	Shoulder flexion contracture	Frequent (30-79%)
HP:0003273	Hip contracture	Frequent (30-79%)
HP:0003323	Progressive muscle weakness	Frequent (30-79%)
HP:0003458	EMG: myopathic abnormalities	Frequent (30-79%)
HP:0003803	Type 1 muscle fiber predominance	Frequent (30-79%)
HP:0007126	Proximal amyotrophy	Frequent (30-79%)
HP:0002747	Respiratory insufficiency due to muscle weakness	Occasional (5-29%)
HP:0001249	Intellectual disability	Excluded (0%)

Identifiers

Disease identifiers

Field	Value
Canonical name	nemaline myopathy 5
Mondo ID	MONDO:0011539
MeSH	C538397
OMIM	605355
Orphanet	98902
DOID	DOID:0110936
UMLS	C1854380
MedGen	344273
GARD	0008334
Is cancer (heuristic)	no

Also known as: Amish nemaline myopathy · ANM · NEM5 · nemaline myopathy 5 · nemaline myopathy caused by mutation in TNNT1 · nemaline myopathy type 5 · nemaline myopathy, caused by mutation in the troponin t1 gene · TNNT1 nemaline myopathy

Data availability: 320 ClinVar variants · 3 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 › congenital myopathy › congenital structural myopathy › nemaline myopathy › nemaline myopathy 5

Related subtypes (7): MYPN-related myopathy, severe congenital nemaline myopathy, typical nemaline myopathy, childhood-onset nemaline myopathy, adult-onset nemaline myopathy, nemaline myopathy 5B, autosomal recessive, childhood-onset, nemaline myopathy 5C, autosomal dominant

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

320 retrieved; paginated sample, class counts are floors:

149 likely benign, 106 uncertain significance, 22 pathogenic, 16 conflicting classifications of pathogenicity, 10 likely pathogenic, 8 benign, 6 benign/likely benign, 3 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
534404	NC_000019.10:g.(?55140863)(55141322_?)del	LOC130065089	Pathogenic	criteria provided, single submitter
583940	NC_000019.10:g.(?55140863)(55147177_?)del	LOC130065089	Pathogenic	criteria provided, single submitter
651255	NC_000019.10:g.(?55140863)(55151937_?)del	LOC130065089	Pathogenic	criteria provided, single submitter
660688	NC_000019.10:g.(?55140873)(55147167_?)del	LOC130065089	Pathogenic	criteria provided, single submitter
625672	GRCh37/hg19 19q13.42(chr19:55652193-55665240)	TNNI3	Pathogenic	criteria provided, single submitter
1175063	NM_003283.6(TNNT1):c.309+1G>A	TNNT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12440	NM_003283.6(TNNT1):c.538G>T (p.Glu180Ter)	TNNT1	Pathogenic	criteria provided, multiple submitters, no conflicts
1285366	NM_003283.6(TNNT1):c.607_610delinsTAGTGCTGT (p.Leu203_Arg204delinsTer)	TNNT1	Pathogenic	criteria provided, single submitter
1413567	NC_000019.9:g.(?55652544)(55656943_?)del	TNNT1	Pathogenic	criteria provided, single submitter
1452357	NM_003283.6(TNNT1):c.78del (p.Glu27fs)	TNNT1	Pathogenic	criteria provided, single submitter
1456474	NM_003283.6(TNNT1):c.415G>T (p.Glu139Ter)	TNNT1	Pathogenic	criteria provided, single submitter
2004473	NM_003283.6(TNNT1):c.626G>A (p.Trp209Ter)	TNNT1	Pathogenic	criteria provided, single submitter
2104989	NM_003283.6(TNNT1):c.61dup (p.Glu21fs)	TNNT1	Pathogenic	criteria provided, single submitter
2503493	NC_000019.10:g.(?55132793)(55132961_55133886)del	TNNT1	Pathogenic	no assertion criteria provided
2503494	NM_003283.6(TNNT1):c.334G>T (p.Glu112Ter)	TNNT1	Pathogenic	no assertion criteria provided
2503496	NM_003283.6(TNNT1):c.16G>T (p.Glu6Ter)	TNNT1	Pathogenic	no assertion criteria provided
3248446	NC_000019.9:g.(?55652231)(55658525_?)del	TNNT1	Pathogenic	criteria provided, single submitter
3248447	NC_000019.9:g.(?55644283)(55653308_?)del	TNNT1	Pathogenic	criteria provided, single submitter
3620500	NM_003283.6(TNNT1):c.431del (p.Ala144fs)	TNNT1	Pathogenic	criteria provided, single submitter
3679087	NM_003283.6(TNNT1):c.7_13dup (p.Glu5fs)	TNNT1	Pathogenic	criteria provided, single submitter
534399	NM_003283.6(TNNT1):c.120dup (p.Lys41fs)	TNNT1	Pathogenic	criteria provided, single submitter
804429	NM_003283.6(TNNT1):c.606_607insTAGTG (p.Leu203Ter)	TNNT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
870626	NM_003283.6(TNNT1):c.353del (p.Thr118fs)	TNNT1	Pathogenic	criteria provided, single submitter
949099	NM_003283.6(TNNT1):c.695dup (p.Leu233fs)	TNNT1	Pathogenic	criteria provided, single submitter
978511	NM_003283.6(TNNT1):c.452del (p.Lys151fs)	TNNT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1066598	NM_003283.6(TNNT1):c.501+1G>A	TNNT1	Likely pathogenic	criteria provided, single submitter
1481323	NM_003283.6(TNNT1):c.387+1G>A	TNNT1	Likely pathogenic	criteria provided, single submitter
1878625	NM_003283.6(TNNT1):c.742A>T (p.Lys248Ter)	TNNT1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2010722	NM_003283.6(TNNT1):c.310-2A>T	TNNT1	Likely pathogenic	criteria provided, single submitter
2500959	NM_003283.6(TNNT1):c.74-67C>A	TNNT1	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · 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
TNNT1	Strong	Autosomal recessive	nemaline myopathy 5	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TNNT1	Orphanet:98902	Amish nemaline myopathy
TNNI3	Orphanet:154	Familial isolated dilated cardiomyopathy
TNNI3	Orphanet:75249	Familial isolated restrictive cardiomyopathy
MVK	Orphanet:29	Mevalonic aciduria
MVK	Orphanet:343	Hyperimmunoglobulinemia D with periodic fever
MVK	Orphanet:735	Porokeratosis of Mibelli
MVK	Orphanet:79152	Disseminated superficial actinic porokeratosis

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
TNNT1	HGNC:11948	ENSG00000105048	P13805	Troponin T, slow skeletal muscle	gencc,clinvar
TNNI3	HGNC:11947	ENSG00000129991	P19429	Troponin I, cardiac muscle	clinvar
MVK	HGNC:7530	ENSG00000110921	Q03426	Mevalonate kinase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TNNT1	Troponin T, slow skeletal muscle	Troponin T is the tropomyosin-binding subunit of troponin, the thin filament regulatory complex which confers calcium-sensitivity to striated muscle actomyosin ATPase activity.
TNNI3	Troponin I, cardiac muscle	Troponin I is the inhibitory subunit of troponin, the thin filament regulatory complex which confers calcium-sensitivity to striated muscle actomyosin ATPase activity.
MVK	Mevalonate kinase	Catalyzes the phosphorylation of mevalonate to mevalonate 5-phosphate, a key step in isoprenoid and cholesterol biosynthesis.

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
Kinase	1	9.2×	0.209
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TNNT1	Other/Unknown	no		Troponin, TNNT, Troponin_sf
TNNI3	Other/Unknown	no		Troponin, Troponin-I_N, Troponin_sf
MVK	Kinase	yes	2.7.1.36	GHMP_knse_ATP-bd_CS, GHMP_kinase_N_dom, Mev_gal_kin

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
diaphragm	1
gluteal muscle	1
skeletal muscle tissue of biceps brachii	1
apex of heart	1
left ventricle myocardium	1
right atrium auricular region	1
lower esophagus mucosa	1
metanephros cortex	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TNNT1	192	ubiquitous	marker	gluteal muscle, skeletal muscle tissue of biceps brachii, diaphragm
TNNI3	169	broad	marker	apex of heart, left ventricle myocardium, right atrium auricular region
MVK	271	ubiquitous	marker	lower esophagus mucosa, right lobe of liver, metanephros cortex

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MVK	3,424
TNNI3	1,836
TNNT1	1,426

Intra-cohort edges

A	B	Sources
TNNI3	TNNT1	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TNNI3	P19429	39
MVK	Q03426	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TNNT1	P13805	74.89

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 9. 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
Striated Muscle Contraction	2	205.8×	3e-04	TNNT1, TNNI3
Cholesterol biosynthesis	1	380.7×	0.012	MVK
Lanosterol biosynthesis	1	253.8×	0.012	MVK
Regulation of cholesterol biosynthesis by SREBP (SREBF)	1	105.7×	0.021	MVK
Activation of gene expression by SREBF (SREBP)	1	86.5×	0.021	MVK
Ion homeostasis	1	68.0×	0.022	TNNI3
Metabolism of steroids	1	45.9×	0.028	MVK
Metabolism of lipids	1	10.5×	0.104	MVK
Metabolism	1	3.9×	0.237	MVK

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
skeletal muscle contraction	2	340.4×	2e-04	TNNT1, TNNI3
slow-twitch skeletal muscle fiber contraction	1	5617.3×	0.001	TNNT1
negative regulation of muscle contraction	1	5617.3×	0.001	TNNT1
regulation of systemic arterial blood pressure by ischemic conditions	1	2808.7×	0.002	TNNI3
isopentenyl diphosphate biosynthetic process, mevalonate pathway	1	1872.4×	0.002	MVK
transition between fast and slow fiber	1	802.5×	0.004	TNNT1
isoprenoid biosynthetic process	1	561.7×	0.004	MVK
negative regulation of ATP-dependent activity	1	561.7×	0.004	TNNI3
regulation of cardiac muscle contraction by calcium ion signaling	1	432.1×	0.005	TNNI3
regulation of smooth muscle contraction	1	401.2×	0.005	TNNI3
muscle filament sliding	1	351.1×	0.005	TNNI3
heart contraction	1	255.3×	0.007	TNNI3
ventricular cardiac muscle tissue morphogenesis	1	234.1×	0.007	TNNI3
cholesterol biosynthetic process	1	140.4×	0.010	MVK
cardiac muscle contraction	1	133.8×	0.010	TNNI3
sarcomere organization	1	127.7×	0.010	TNNT1
vasculogenesis	1	85.1×	0.014	TNNI3
intracellular calcium ion homeostasis	1	48.4×	0.023	TNNI3
negative regulation of inflammatory response	1	45.7×	0.023	MVK
heart development	1	26.2×	0.038	TNNI3

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
TNNT1	0	0
TNNI3	0	0
MVK	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
TNNI3	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
MVK	2.7.1.36	mevalonate kinase

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	MVK
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	TNNT1, TNNI3

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)
TNNT1	0	—
TNNI3	2	—
MVK	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06374719	Not specified	RECRUITING	WiTNNess - TNNT1 Myopathy Natural History Study