TMC1
Chr 9ADARtransmembrane channel like 1
Also known as: DFNA36, DFNB11, DFNB7
TMC1 encodes a pore-forming subunit of the mechanotransducer channel complex located at stereocilia tips in cochlear hair cells, where it mediates auditory sensory transduction by responding to mechanical tension and transporting calcium and monovalent cations. Mutations cause both progressive postlingual hearing loss and profound prelingual deafness with autosomal recessive inheritance. The gene is extremely intolerant to loss-of-function variants (pLI approaching 1), indicating that complete protein loss is likely incompatible with normal development.
Definitive — sufficient evidence for diagnostic panels
2 total gene-disease associations curated
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Typical tolerance to LoF variation
Mild missense constraint
This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. 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.
Literature Evidence
Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.
ClinVar Variant Classifications
100 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 | 3 | 1 | 5 | 0 | 9 |
Likely Pathogenic | 3 | 8 | 2 | 0 | 13 |
VUS | 1 | 20 | 9 | 0 | 30 |
Likely Benign | 0 | 0 | 28 | 12 | 40 |
Benign | 0 | 0 | 3 | 0 | 3 |
Conflicting | — | 5 | |||
| Total | 7 | 29 | 47 | 12 | 100 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →Protein Context — Lollipop Plot
TMC1 · protein map & ClinVar variants
Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.
3D Protein StructureAlphaFold
External Resources
Links to major genomics databases and tools
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
No active trials found for this gene.
Search ClinicalTrials.gov →External Resources
Links to major genomics databases and tools