Autosomal dominant nonsyndromic hearing loss 36

Summary

Autosomal dominant nonsyndromic hearing loss 36 (MONDO:0011708) is a disease caused by TMC1 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: TMC1 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 105

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal dominant nonsyndromic hearing loss 36
Mondo ID	MONDO:0011708
MeSH	C564675
OMIM	606705
DOID	DOID:0110563
UMLS	C1847626
MedGen	376173
GARD	0018115
Is cancer (heuristic)	no

Also known as: autosomal dominant deafness 36 · autosomal dominant nonsyndromic deafness 36 · autosomal dominant nonsyndromic deafness caused by mutation in TMC1 · autosomal dominant nonsyndromic deafness type 36 · deafness, autosomal dominant 36 · deafness, autosomal dominant type 36 · DFNA36 · TMC1 autosomal dominant nonsyndromic deafness

Data availability: 105 ClinVar variants · 3 GenCC gene-disease records · 2 cell lines.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal dominant disease › autosomal dominant nonsyndromic hearing loss › autosomal dominant nonsyndromic hearing loss 36

Related subtypes (75): autosomal dominant nonsyndromic hearing loss 1, autosomal dominant nonsyndromic hearing loss 2A, autosomal dominant nonsyndromic hearing loss 4A, autosomal dominant nonsyndromic hearing loss 6, autosomal dominant nonsyndromic hearing loss 5, autosomal dominant nonsyndromic hearing loss 10, autosomal dominant nonsyndromic hearing loss 11, autosomal dominant nonsyndromic hearing loss 9, autosomal dominant nonsyndromic hearing loss 7, autosomal dominant nonsyndromic hearing loss 12, autosomal dominant nonsyndromic hearing loss 3A, autosomal dominant nonsyndromic hearing loss 13, autosomal dominant nonsyndromic hearing loss 15, autosomal dominant nonsyndromic hearing loss 17, autosomal dominant nonsyndromic hearing loss 16, autosomal dominant nonsyndromic hearing loss 20, autosomal dominant nonsyndromic hearing loss 23, autosomal dominant nonsyndromic hearing loss 25, autosomal dominant nonsyndromic hearing loss 18, autosomal dominant nonsyndromic hearing loss 24, autosomal dominant nonsyndromic hearing loss 22, autosomal dominant nonsyndromic hearing loss 30, autosomal dominant nonsyndromic hearing loss 21, autosomal dominant nonsyndromic hearing loss 44, autosomal dominant nonsyndromic hearing loss 48, autosomal dominant nonsyndromic hearing loss 41, autosomal dominant nonsyndromic hearing loss 49, autosomal dominant nonsyndromic hearing loss 43, autosomal dominant nonsyndromic hearing loss 28, autosomal dominant nonsyndromic hearing loss 31, autosomal dominant nonsyndromic hearing loss 47, autosomal dominant auditory neuropathy 1, autosomal dominant nonsyndromic hearing loss 53, autosomal dominant nonsyndromic hearing loss 27, autosomal dominant nonsyndromic hearing loss 59, autosomal dominant nonsyndromic hearing loss 3B, autosomal dominant nonsyndromic hearing loss 2B, autosomal dominant nonsyndromic hearing loss 50, autosomal dominant nonsyndromic hearing loss 51, autosomal dominant nonsyndromic hearing loss 64, autosomal dominant nonsyndromic hearing loss 33, autosomal dominant nonsyndromic hearing loss 4B, autosomal dominant nonsyndromic hearing loss 56, autosomal dominant nonsyndromic hearing loss 54, autosomal dominant nonsyndromic hearing loss 58, autosomal dominant nonsyndromic hearing loss 65, autosomal dominant nonsyndromic hearing loss 67, autosomal dominant nonsyndromic hearing loss 40, autosomal dominant nonsyndromic hearing loss 69, autosomal dominant nonsyndromic hearing loss 68, autosomal dominant nonsyndromic hearing loss 70, autosomal dominant nonsyndromic hearing loss 66, hearing loss, autosomal dominant 74, hearing loss, autosomal dominant 77, hearing loss, autosomal dominant 81, hearing loss, autosomal dominant 82, hearing loss, autosomal dominant 83, hearing loss, autosomal dominant 84, hearing loss, autosomal dominant 80, hearing loss, autosomal dominant 37, hearing loss, autosomal dominant 75, hearing loss, autosomal dominant 76, hearing loss, autosomal dominant 71, hearing loss, autosomal dominant 72, hearing loss, autosomal dominant 73, hearing loss, autosomal dominant 34, with or without inflammation, hearing loss, autosomal dominant 78, hearing loss, autosomal dominant 79, hearing loss, autosomal dominant 85, hearing loss, autosomal dominant 86, hearing loss, autosomal dominant 87, hearing loss, autosomal dominant 88, hearing loss, autosomal dominant 89, hearing loss, autosomal dominant 90, autosomal dominant nonsyndromic hearing loss 91

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

105 retrieved; paginated sample, class counts are floors:

40 uncertain significance, 29 conflicting classifications of pathogenicity, 12 pathogenic, 8 likely pathogenic, 8 pathogenic/likely pathogenic, 5 benign, 3 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1297078	NM_138691.3(TMC1):c.150del (p.Asn50fs)	TMC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
183668	NM_138691.3(TMC1):c.1253T>A (p.Met418Lys)	TMC1	Pathogenic	no assertion criteria provided
2136778	NM_138691.3(TMC1):c.2030T>C (p.Ile677Thr)	TMC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
228405	NM_138691.3(TMC1):c.1236del (p.Met413fs)	TMC1	Pathogenic	criteria provided, multiple submitters, no conflicts
228408	NM_138691.3(TMC1):c.1939T>C (p.Ser647Pro)	TMC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
236041	NM_138691.3(TMC1):c.15dup (p.Val6fs)	TMC1	Pathogenic	criteria provided, single submitter
242394	NM_138691.3(TMC1):c.1810C>T (p.Arg604Ter)	TMC1	Pathogenic	criteria provided, multiple submitters, no conflicts
2443844	NM_138691.3(TMC1):c.1627G>A (p.Asp543Asn)	TMC1	Pathogenic	no assertion criteria provided
2635879	NM_138691.3(TMC1):c.2050G>C (p.Asp684His)	TMC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2683613	NM_138691.3(TMC1):c.1764G>A (p.Trp588Ter)	TMC1	Pathogenic	criteria provided, multiple submitters, no conflicts
2735280	NM_138691.3(TMC1):c.1166G>A (p.Arg389Gln)	TMC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3597493	NM_138691.3(TMC1):c.535+1G>C	TMC1	Pathogenic	criteria provided, single submitter
4102	NM_138691.3(TMC1):c.1714G>A (p.Asp572Asn)	TMC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4103	NM_138691.3(TMC1):c.100C>T (p.Arg34Ter)	TMC1	Pathogenic	criteria provided, multiple submitters, no conflicts
4105	NM_138691.3(TMC1):c.1714G>C (p.Asp572His)	TMC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
47856	NM_138691.3(TMC1):c.1165C>T (p.Arg389Ter)	TMC1	Pathogenic	criteria provided, multiple submitters, no conflicts
47864	NM_138691.3(TMC1):c.1763+3A>G	TMC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
504715	NM_138691.3(TMC1):c.236+1G>A	TMC1	Pathogenic	criteria provided, multiple submitters, no conflicts
545971	NM_138691.3(TMC1):c.1534C>T (p.Arg512Ter)	TMC1	Pathogenic	criteria provided, multiple submitters, no conflicts
2445617	NM_206933.4(USH2A):c.10593del (p.Ile3532fs)	USH2A	Pathogenic	no assertion criteria provided
1185098	NM_138691.3(TMC1):c.797T>C (p.Ile266Thr)	TMC1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2905762	NM_138691.3(TMC1):c.1405-2A>T	TMC1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3597492	NM_138691.3(TMC1):c.115A>T (p.Arg39Ter)	TMC1	Likely pathogenic	criteria provided, single submitter
3597494	NM_138691.3(TMC1):c.643-2A>G	TMC1	Likely pathogenic	criteria provided, single submitter
3597495	NM_138691.3(TMC1):c.1299C>G (p.Tyr433Ter)	TMC1	Likely pathogenic	criteria provided, single submitter
47876	NM_138691.3(TMC1):c.674C>T (p.Pro225Leu)	TMC1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2445618	NM_206933.4(USH2A):c.10724G>T (p.Cys3575Phe)	USH2A	Likely pathogenic	criteria provided, single submitter
2445620	NM_206933.4(USH2A):c.7120+1475A>G	USH2A	Likely pathogenic	no assertion criteria provided
1172666	NM_138691.3(TMC1):c.821C>T (p.Pro274Leu)	TMC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1303343	NM_138691.3(TMC1):c.2027T>A (p.Val676Asp)	TMC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 4 · 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
TMC1	Definitive	Autosomal recessive	autosomal recessive nonsyndromic hearing loss 7	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TMC1	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
TMC1	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
USH2A	Orphanet:231178	Usher syndrome type 2
USH2A	Orphanet:791	Retinitis pigmentosa

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TMC1	HGNC:16513	ENSG00000165091	Q8TDI8	Transmembrane channel-like protein 1	gencc,clinvar
USH2A	HGNC:12601	ENSG00000042781	O75445	Usherin	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TMC1	Transmembrane channel-like protein 1	Pore-forming subunit of the mechanotransducer (MET) non-selective cation channel complex located at the tips of stereocilia of cochlear hair cells and that mediates sensory transduction in the auditory system.
USH2A	Usherin	Involved in hearing and vision as member of the USH2 complex.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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
Antibody/Immunoglobulin	1	14.6×	0.135
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TMC1	Other/Unknown	no		TMC_dom, TMC
USH2A	Antibody/Immunoglobulin	yes		Laminin_G, LE_dom, FN3_dom

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
buccal mucosa cell	2
male germ line stem cell (sensu Vertebrata) in testis	2
primordial germ cell in gonad	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TMC1	150		marker	male germ line stem cell (sensu Vertebrata) in testis, buccal mucosa cell, primordial germ cell in gonad
USH2A	30	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, right lobe of liver, buccal mucosa cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
USH2A	2,332
TMC1	1,291

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TMC1	Q8TDI8	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
USH2A	O75445

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 2 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Sensory processing of sound by outer hair cells of the cochlea	1	203.9×	0.006	TMC1
Sensory processing of sound by inner hair cells of the cochlea	1	163.1×	0.006	TMC1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
vestibular reflex	1	2106.5×	0.002	TMC1
maintenance of animal organ identity	1	1685.2×	0.002	USH2A
inner ear receptor cell differentiation	1	1685.2×	0.002	USH2A
hair cell differentiation	1	1053.2×	0.002	USH2A
regulation of calcium ion transmembrane transport	1	1053.2×	0.002	TMC1
sensory perception of light stimulus	1	936.2×	0.002	USH2A
auditory receptor cell development	1	936.2×	0.002	TMC1
inner ear auditory receptor cell differentiation	1	601.9×	0.003	USH2A
detection of mechanical stimulus involved in sensory perception of sound	1	468.1×	0.003	TMC1
establishment of protein localization	1	216.1×	0.006	USH2A
photoreceptor cell maintenance	1	179.3×	0.007	USH2A
establishment of localization in cell	1	80.2×	0.014	USH2A
sensory perception of sound	1	50.5×	0.021	USH2A
visual perception	1	39.8×	0.025	USH2A

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TMC1	0	0
USH2A	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	0
D	Druggable family + AlphaFold only, no drug	1	USH2A
E	Difficult family or no structure, no drug	1	TMC1

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
TMC1	0	—
USH2A	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.