TPM3

Chr 1ADAR

tropomyosin 3

Also known as: CAPM1, CFTD, CMYO4A, CMYO4B, CMYP4A, CMYP4B, HEL-189, HEL-S-82p

NCBI Gene: 7170 ENSG00000143549 UniProt: P06753 OMIM: 191030

The protein stabilizes actin filaments and regulates access of other actin-binding proteins as part of the cytoskeletal structure. Mutations cause autosomal dominant nemaline myopathy and other congenital myopathies, with both autosomal dominant and autosomal recessive inheritance patterns observed. The pathogenic mechanism involves dominant-negative effects that disrupt normal cytoskeletal function.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

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]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismAD/ARLOEUF 0.692 OMIM phenotypes

Clinical Summary— TPM3

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Gene-Disease Validity (ClinGen)

TPM3-related myopathy · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Low constraint (pLI 0.01) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

38 unique Pathogenic / Likely Pathogenic· 217 VUS of 438 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — TPM3

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.69LOEUF

pLI 0.007

Z-score 2.56

OE 0.37 (0.21–0.69)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

2.35Z-score

OE missense 0.45 (0.37–0.55)

65 obs / 144.7 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.37 (0.21–0.69)

0≤0.351.4

Missense OE?0.45 (0.37–0.55)

0≤0.61.4

Synonymous OE?0.96

0≤1.21.6

LoF obs/exp: 7 / 19.0Missense obs/exp: 65 / 144.7Syn Z: 0.24

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveTPM3-related congenital myopathyOTHERAD

This gene — mechanism propensity

0.92top 5%

GOF

0.73top 25%

LOF

0.1994th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median · 1 literature citation

GOFprediction above median · 1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNEvidence for a dominant negative disease mechanism in cap myopathy due to TPM3.1

GOFMutations in repeating motifs of tropomyosin cause gain of function in skeletal muscle myopathy patients.2

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

References

ClinVar Variant Classifications

438 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic14

Likely Pathogenic24

VUS217

Likely Benign121

Benign13

Conflicting16

Pathogenic

Likely Pathogenic

217

VUS

121

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	4	9	1	0	14
Likely Pathogenic	8	14	2	0	24
VUS	7	101	107	2	217
Likely Benign	0	2	78	41	121
Benign	0	0	13	0	13
Conflicting	—				16
Total	19	126	201	43	405

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

15 pathogenic / likely-pathogenic (of 22) ClinVar copy-number / structural variants overlap TPM3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →