NTRK3
Chr 15neurotrophic receptor tyrosine kinase 3
Also known as: GP145-TrkC, TRKC, gp145(trkC)
This gene encodes a member of the neurotrophic tyrosine receptor kinase (NTRK) family. This kinase is a membrane-bound receptor that, upon neurotrophin binding, phosphorylates itself and members of the MAPK pathway. Signalling through this kinase leads to cell differentiation and may play a role in the development of proprioceptive neurons that sense body position. Mutations in this gene have been associated with medulloblastomas, secretory breast carcinomas and other cancers. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2011]
Disputed — evidence questions this relationship
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Highly LoF-intolerant (top ~10% of genes)
Mild missense constraint
This gene — mechanism propensity
This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.
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.
Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.
ClinVar Variant Classifications
138 submitted variants in ClinVar
Classification Summary
Curated Variants Distribution
Classified variants from ClinVar · 5 ACMG categories
| Classification | LoF | Missense + Inframe | Non-coding | Synonymous | Total |
|---|---|---|---|---|---|
Pathogenic | 0 | 0 | 1 | 0 | 1 |
Likely Pathogenic | 0 | 0 | 0 | 0 | 0 |
VUS | 2 | 56 | 0 | 0 | 58 |
Likely Benign | 0 | 1 | 4 | 17 | 22 |
Benign | 0 | 1 | 37 | 8 | 46 |
Conflicting | — | 1 | |||
| Total | 2 | 58 | 42 | 25 | 128 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →33 pathogenic / likely-pathogenic (of 39) ClinVar copy-number / structural variants overlap NTRK3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →
Protein Context — Lollipop Plot
NTRK3 · protein map & ClinVar variants
Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.
External Resources
Links to major genomics databases and tools
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
A Study to Test the Safety and Efficacy of the Drug Larotrectinib for the Treatment of Tumors With NTRK-fusion in Children
ACTIVE NOT RECRUITINGIntegrated Genomics in Oncogene-driven NSCLC With Acquired Resistance
ENROLLING BY INVITATIONRNASARC - Molecular Screening Program of Soft Tissue Sarcomas With Complex Genomic Profile to Detect NTRK1/2/3, ROS1 or ALK Gene Fusions.
ACTIVE NOT RECRUITINGA Study of Repotrectinib (TPX-0005) in Patients With Advanced Solid Tumors Harboring ALK, ROS1, or NTRK1-3 Rearrangements
RECRUITINGCanadian Profiling and Targeted Agent Utilization Trial (CAPTUR)
RECRUITINGBasket Study of Entrectinib (RXDX-101) for the Treatment of Patients With Solid Tumors Harboring NTRK 1/2/3 (Trk A/B/C), ROS1, or ALK Gene Rearrangements (Fusions)
ACTIVE NOT RECRUITINGTargeted Therapy Directed by Genetic Testing in Treating Patients With Advanced Refractory Solid Tumors, Lymphomas, or Multiple Myeloma (The MATCH Screening Trial)
ACTIVE NOT RECRUITINGStudy Of Entrectinib (Rxdx-101) in Children and Adolescents With Locally Advanced Or Metastatic Solid Or Primary CNS Tumors And/Or Who Have No Satisfactory Treatment Options
ACTIVE NOT RECRUITINGTargeted Therapy Directed by Genetic Testing in Treating Pediatric Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders (The Pediatric MATCH Screening Trial)
ACTIVE NOT RECRUITINGEfficacy and Prognosis of Microwave Ablation Treatment for Papillary Thyroid Microcarcinoma Assessed by Contrast-Enhanced Ultrasound Combined With Genetic and Molecular Diagnostics: A Prospective Observational Study
RECRUITINGSpanish Study for Molecular Characterization of Thyroid Carcinoma
ACTIVE NOT RECRUITINGExternal Resources
Links to major genomics databases and tools