TPM3

protein-coding

tropomyosin 3, the group of Tropomyosins

Gene summary

This gene encodes a member of the tropomyosin family of actin-binding proteins. Tropomyosins are dimers of coiled-coil proteins that provide stability to actin filaments and regulate access of other actin-binding proteins. Mutations in this gene result in autosomal dominant nemaline myopathy and other muscle disorders. This locus is involved in translocations with other loci, including anaplastic lymphoma receptor tyrosine kinase (ALK) and neurotrophic tyrosine kinase receptor type 1 (NTRK1), which result in the formation of fusion proteins that act as oncogenes. There are numerous pseudogenes for this gene on different chromosomes. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2013]

Previous symbols:

NEM1

MANE transcript

NM_152263.4

Inheritance

SD, AR, AD

ClinVar variants

P:38U:116B:46

Top phenotype

Congenital myopathy 4A, autosomal dominant; Congenital myopathy 4B, autosomal recessive

gnomAD constraint

pLI —, LoF o/e 0.37

Max pathogenic AF

—

Genomic locus

chr1:154,155,308-154,194,648

External References & Databases

Ensembl (ENSG00000143549)

Transcript & Mutation Effects

hg38 • Region Span ~39.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

congenital myopathy 4B, autosomal recessiveMODERATE

Inheritance Pattern: SD

Disease ID:MONDO:0012239

Submitter: Ambry Genetics

congenital myopathy 4B, autosomal recessiveSTRONG

Inheritance Pattern: SD

Disease ID:MONDO:0012239

Submitter: PanelApp Australia

TPM3-related myopathyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0100108

Submitter: ClinGen

*TPM3* was first reported in relation to autosomal recessive *TPM3*-related myopathy in 1999 (PMID: 10619715). Cases of *TPM3*-related myopathy have historically been categorized by histological features in muscle biopsy and include nemaline myopathy, cap myopathy, and myopathy with fiber-type disproportion on a spectrum of severity. Several unique loss-of-function null variants (e.g. nonsense, splice-site, frameshift) have been reported in humans, in an autosomal recessive manner. Case-level genetic evidence supporting this gene-disease relationship (11 points) includes published reports of at least six probands observed to have loss of function variants and parents who are asymptomatic heterozygous carriers (PMIDs: 10619715, 12196661, 18382475, 19953533, 37393515). Additionally, these probands display various phenotypes, with the majority showing hypotonia, poor head control, inability to walk, scoliosis, Type 1 muscle fiber atrophy/hypotrophy, delayed motor milestones, muscle weakness, and nemaline bodies. This gene-disease association is additionally supported by TPM3's biochemical function, unique expression in the skeletal muscle tissue, physical protein interaction with ACTA1 (PMID: 22749829), and altered function of TPM3 mutant proteins dramatically changing myofilament function (PMID: 21357678). Experimental-level genetic evidence supporting this gene-disease relationship scored 3 points. In summary, there is definitive evidence (14 points) to support the relationship between *TPM3* and autosomal recessive *TPM3*-related myopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Congenital Myopathies Gene Curation Expert Panel on the meeting date April 8, 2024 (SOP Version 10).

congenital myopathy 4B, autosomal recessiveSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012239

Submitter: Labcorp Genetics (formerly Invitae)

congenital myopathy 4A, autosomal dominantDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0800341

Submitter: G2P

TPM3-related myopathyDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100108

Submitter: ClinGen

*TPM3* was first reported in relation to autosomal dominant *TPM3*-related myopathy in 1995 (Laing et al., PMID: 7704029). Cases of *TPM3*-related myopathy have historically been categorized by histological features in muscle biopsy and include nemaline myopathy, cap myopathy, and myopathy with fiber-type disproportion on a spectrum of severity. In support of the autosomal dominant form of *TPM3*-related myopathy, case-level genetic evidence includes at least sixteen probands with unique missense variants in *TPM3*, including eleven de novo cases (PMIDs: 7704029, 18300303, 20554445, 24692096, 26418456, 33768912, 38219297). These probands display various phenotypes, with the majority showing hypotonia, delayed motor milestones, muscle weakness, fiber atrophy, ptosis, contractures, and Type 1 muscle fiber hypotrophy and predominance. Variants in this gene segregated with disease in three families (1.5 points, PMIDs: 7704029, 18300303). Majority of the missense variants cause a dominant negative effect where the inclusion of mutant TPM3 leads to reduced calcium sensitivity with subsequent reduction in contractile ability, resulting in muscular hypotonia and weakness. Some variants, however, lead to increased calcium sensitivity with subsequent increase in contractile ability, resulting in muscle stiffness. (Marttila et al 2014, PMID: 24692096). This gene-disease association is additionally supported by TPM3's biochemical function, unique expression in the skeletal muscle tissue, physical protein interaction with ACTA1 (PMID: 22749829) and altered function of TPM3 mutant proteins dramatically changing myofilament function (PMID: 21357678). Additionally, a study involving a knock-in mouse model of the well-characterized *TPM3* variant Met9Arg recapitulates phenotypes of nemaline and other myopathies similar to those of the human disorder (PMID:11157795). Experimental-level genetic evidence supporting this gene-disease relationship scored 6 points. In summary, there is definitive evidence (13.5 points) to support the relationship between *TPM3* and autosomal dominant *TPM3*-related myopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Congenital Myopathies Gene Curation Expert Panel on the meeting date April 8, 2024 (SOP Version 10).

congenital fiber-type disproportion myopathyMODERATE

Inheritance Pattern: SD

Disease ID:MONDO:0009711

Submitter: Ambry Genetics

congenital fiber-type disproportion myopathySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0009711

Submitter: Orphanet

intermediate nemaline myopathySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015736

Submitter: Orphanet

congenital generalized hypercontractile muscle stiffness syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018780

Submitter: Orphanet

cap myopathySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015753

Submitter: Orphanet

childhood-onset nemaline myopathySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015738

Submitter: Orphanet

congenital myopathy 4A, autosomal dominantSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0800341

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Congenital myopathy 4A, autosomal dominant; Congenital myopathy 4B, autosomal recessiveAD/AR

Manifestation: Craniofacial; Musculoskeletal

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 18300303; 10619715; 12196661; 18382475

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TPM3 variants in ClinVar

13 Conditions Cataloged

Congenital myopathy 4B, autosomal recessiveTotal: 219

Congenital myopathy with fiber type disproportionTotal: 213

not providedTotal: 87

Congenital myopathy 4A, autosomal dominantTotal: 20

not specifiedTotal: 19

TPM3-related disorderTotal: 11

Inborn genetic diseasesTotal: 9

Centronuclear myopathyTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_152263.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			3 clinvar	45 clinvar		48
missense	8 clinvar	16 clinvar	105 clinvar	1 clinvar		130
nonsense	1 clinvar	3 clinvar				4
start loss						0
frameshift	3 clinvar	3 clinvar				6
splice donor/acceptor (+/-2bp)		4 clinvar	8 clinvar			12
Total	12	26	116	46	0	200

Highest pathogenic variant AF is 0.000004959401

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 67 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_152263.4	RefSeq	NP_689476.2	10	MANE Select
ENST00000651641.1	Ensembl	ENSP00000498577.1	10	MANE Select
NM_001043351.2	RefSeq	NP_001036816.1	8	Standard
NM_001043352.2	RefSeq	NP_001036817.1	8	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
tpm3	Danio rerio	Structure: slow muscle cell Quality: decreased thickness abnormal

Gene / Model

Organism

Observed Phenotype

tpm3

Danio rerio

Structure: slow muscle cell

Quality: decreased thickness

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Cardiac muscle contraction - Homo sapiens (human)
Dilated cardiomyopathy (DCM) - Homo sapiens (human)
Hypertrophic cardiomyopathy (HCM) - Homo sapiens (human)
Adrenergic signaling in cardiomyocytes - Homo sapiens (human)
Pathways in cancer - Homo sapiens (human)

Biological Process

muscle contraction
actin filament organization
muscle filament sliding

Molecular Function

molecular_function
protein binding
actin filament binding

Cellular Component

stress fiber
cytosol
cytoskeleton
muscle thin filament tropomyosin
actin filament

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000368530
Coding exons: 10
Length: 39341
Individuals with no LoFs: 125729
Homozygous LoFs: 0
Heterozygous LoFs: 19
Defined: 125748
p: 0.0000756

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.35	65	145	0.449	0.00000845	1887
Missense (PolyPhen)		25	60.882	0.41063		801
Synonymous	0.243	50	52.2	0.957	0.00000273	491
Loss of Function	2.56	7	19.0	0.368	0.00000104	249

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.00014	0.00014	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0.000047	0.000046	rare
European (Non-Finnish)	0.00011	0.00011	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Binds to actin filaments in muscle and non-muscle cells. Plays a central role, in association with the troponin complex, in the calcium dependent regulation of vertebrate striated muscle contraction. Smooth muscle contraction is regulated by interaction with caldesmon. In non-muscle cells is implicated in stabilizing cytoskeleton actin filaments. {ECO:0000250|UniProtKB:P09493}.;
Disease: DISEASE: Nemaline myopathy 1 (NEM1) [MIM:609284]: A form of nemaline myopathy with autosomal dominant or recessive inheritance. Nemaline myopathies are disorders characterized by muscle weakness of varying onset and severity, and abnormal thread-like or rod-shaped structures in muscle fibers on histologic examination. Autosomal dominant NEM1 is characterized by a moderate phenotype with onset between birth and early second decade of life. Weakness is diffuse and symmetric with slow progression often with need for a wheelchair in adulthood. The autosomal recessive form has onset at birth with moderate to severe hypotonia and diffuse weakness. In the most severe cases, death can occur before 2 years. Less severe cases have delayed major motor milestones, and these patients may walk, but often need a wheelchair before 10 years. {ECO:0000269|PubMed:10587521, ECO:0000269|PubMed:17376686, ECO:0000269|PubMed:24692096, ECO:0000269|PubMed:7704029}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=A chromosomal aberration involving TPM3 is found in papillary thyroid carcinomas (PTCs). A rearrangement with NTRK1 generates the TRK fusion transcript by fusing the amino end of isoform 2 of TPM3 to the 3'-end of NTRK1. {ECO:0000269|PubMed:2869410}.; DISEASE: Myopathy, congenital, with fiber-type disproportion (CFTD) [MIM:255310]: A genetically heterogeneous disorder in which there is relative hypotrophy of type 1 muscle fibers compared to type 2 fibers on skeletal muscle biopsy. However, these findings are not specific and can be found in many different myopathic and neuropathic conditions. {ECO:0000269|PubMed:18300303, ECO:0000269|PubMed:19953533, ECO:0000269|PubMed:20951040, ECO:0000269|PubMed:24692096}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Cap myopathy 1 (CAPM1) [MIM:609284]: A rare congenital skeletal muscle disorder characterized by the presence of cap-like structures which are well demarcated and peripherally located under the sarcolemma and show abnormal accumulation of sarcomeric proteins. Clinical features are early onset of hypotonia and slowly progressive muscle weakness. Respiratory problems are common. {ECO:0000269|PubMed:18300303, ECO:0000269|PubMed:19487656, ECO:0000269|PubMed:19553118, ECO:0000269|PubMed:24239060, ECO:0000269|PubMed:24692096}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.466

Intolerance Scores

LoFtool: 0.0953
RVIS EVS: 0.3
RVIS percentile EVS: 72.01

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): K
Indispensability pred.: E
Indispensability score: 0.964

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium