Autosomal recessive nonsyndromic hearing loss 7

Summary

Autosomal recessive nonsyndromic hearing loss 7 (MONDO:0010967) is a disease caused by TMC1 (GenCC Definitive), with 3 cohort genes.

At a glance

• Causal gene: TMC1 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 189

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal recessive nonsyndromic hearing loss 7
Mondo ID	MONDO:0010967
MeSH	C563417
OMIM	600974
DOID	DOID:0110520
UMLS	C1832978
MedGen	322084
GARD	0022587
Is cancer (heuristic)	no

Also known as: autosomal recessive deafness 7 · autosomal recessive nonsyndromic deafness 7 · autosomal recessive nonsyndromic deafness caused by mutation in TMC1 · autosomal recessive nonsyndromic deafness type 7 · autosomal recessive nonsyndromic hearing loss 7 · deafness, autosomal recessive 11 · deafness, autosomal recessive 7 · deafness, autosomal recessive type 7 · DFNB11 · DFNB7 · TMC1 autosomal recessive nonsyndromic deafness

Data availability: 189 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal recessive disease › hearing loss, autosomal recessive › autosomal recessive nonsyndromic hearing loss 7

Related subtypes (101): autosomal recessive nonsyndromic hearing loss 5, autosomal recessive nonsyndromic hearing loss 1A, autosomal recessive nonsyndromic hearing loss 2, autosomal recessive nonsyndromic hearing loss 3, autosomal recessive nonsyndromic hearing loss 4, autosomal recessive nonsyndromic hearing loss 6, autosomal recessive nonsyndromic hearing loss 9, autosomal recessive nonsyndromic hearing loss 8, autosomal recessive nonsyndromic hearing loss 12, autosomal recessive nonsyndromic hearing loss 15, autosomal recessive nonsyndromic hearing loss 18A, autosomal recessive nonsyndromic hearing loss 17, autosomal recessive nonsyndromic hearing loss 13, autosomal recessive nonsyndromic hearing loss 21, autosomal recessive nonsyndromic hearing loss 14, autosomal recessive nonsyndromic hearing loss 16, autosomal recessive nonsyndromic hearing loss 20, autosomal recessive nonsyndromic hearing loss 26, autosomal recessive nonsyndromic hearing loss 27, autosomal recessive nonsyndromic hearing loss 22, autosomal recessive nonsyndromic hearing loss 31, autosomal recessive nonsyndromic hearing loss 30, autosomal recessive nonsyndromic hearing loss 33, autosomal recessive nonsyndromic hearing loss 37, autosomal recessive nonsyndromic hearing loss 38, autosomal recessive nonsyndromic hearing loss 40, autosomal recessive nonsyndromic hearing loss 39, autosomal recessive nonsyndromic hearing loss 35, autosomal recessive nonsyndromic hearing loss 32, autosomal recessive nonsyndromic hearing loss 36, autosomal recessive nonsyndromic hearing loss 48, autosomal recessive nonsyndromic hearing loss 23, autosomal recessive nonsyndromic hearing loss 42, autosomal recessive nonsyndromic hearing loss 46, autosomal recessive nonsyndromic hearing loss 53, autosomal recessive nonsyndromic hearing loss 28, autosomal recessive nonsyndromic hearing loss 51, autosomal recessive nonsyndromic hearing loss 47, autosomal recessive nonsyndromic hearing loss 55, autosomal recessive nonsyndromic hearing loss 62, autosomal recessive nonsyndromic hearing loss 49, autosomal recessive nonsyndromic hearing loss 44, autosomal recessive nonsyndromic hearing loss 66, autosomal recessive nonsyndromic hearing loss 59, autosomal recessive nonsyndromic hearing loss 65, autosomal recessive nonsyndromic hearing loss 67, autosomal recessive nonsyndromic hearing loss 68, autosomal recessive nonsyndromic hearing loss 24, autosomal recessive nonsyndromic hearing loss 63, autosomal recessive nonsyndromic hearing loss 45, autosomal recessive nonsyndromic hearing loss 1B, autosomal recessive nonsyndromic hearing loss 71, autosomal recessive nonsyndromic hearing loss 77, autosomal recessive nonsyndromic hearing loss 25, autosomal recessive nonsyndromic hearing loss 79, autosomal recessive nonsyndromic hearing loss 84A, autosomal recessive nonsyndromic hearing loss 85, autosomal recessive nonsyndromic hearing loss 91, autosomal recessive nonsyndromic hearing loss 83, autosomal recessive nonsyndromic hearing loss 74, autosomal recessive nonsyndromic hearing loss 61, autosomal recessive nonsyndromic hearing loss 89, autosomal recessive nonsyndromic hearing loss 29, autosomal recessive nonsyndromic hearing loss 96, autosomal recessive nonsyndromic hearing loss 86, autosomal recessive nonsyndromic hearing loss 98, autosomal recessive nonsyndromic hearing loss 93, autosomal recessive nonsyndromic hearing loss 70, autosomal recessive nonsyndromic hearing loss 84B, autosomal recessive nonsyndromic hearing loss 18B, autosomal recessive nonsyndromic hearing loss 88, autosomal recessive nonsyndromic hearing loss 76, autosomal recessive nonsyndromic hearing loss 101, autosomal recessive nonsyndromic hearing loss 102, autosomal recessive nonsyndromic hearing loss 103, autosomal recessive nonsyndromic hearing loss 104, autosomal recessive nonsyndromic hearing loss 97, hearing loss, autosomal recessive 111, hearing loss, autosomal recessive 118, with cochlear aplasia, hearing loss, autosomal recessive 119, hearing loss, autosomal recessive 117, hearing loss, autosomal recessive 112, hearing loss, autosomal recessive 113, hearing loss, autosomal recessive 100, hearing loss, autosomal recessive 94, hearing loss, autosomal recessive 114, hearing loss, autosomal recessive 115, hearing loss, autosomal recessive 99, hearing loss, autosomal recessive 106, hearing loss, autosomal recessive 107, hearing loss, autosomal recessive 108, hearing loss, autosomal recessive 57, hearing loss, autosomal recessive 109, hearing loss, autosomal recessive 116, hearing loss, autosomal recessive 110, hearing loss, autosomal recessive 120, hearing loss, autosomal recessive 121, hearing loss, autosomal recessive 122, hearing loss, autosomal recessive 123, autosomal recessive nonsyndromic hearing loss 124, hearing loss, autosomal recessive 125

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

189 retrieved; paginated sample, class counts are floors:

55 pathogenic, 48 uncertain significance, 36 likely pathogenic, 31 conflicting classifications of pathogenicity, 11 pathogenic/likely pathogenic, 5 benign, 3 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
424807	NM_138691.2(TMC1):c.[1810C>T];[674C>T]		Pathogenic	no assertion criteria provided
424812	NM_138691.2(TMC1):c.[1810C>T];[1939T>C]		Pathogenic	no assertion criteria provided
424813	NM_138691.2(TMC1):c.[1165C>T];[1939T>C]		Pathogenic	no assertion criteria provided
424814	NM_138691.2(TMC1):c.[1210T>C];[1939T>C]		Pathogenic	no assertion criteria provided
1185107	NM_144672.4(OTOA):c.1560_1563del (p.Phe521fs)	OTOA	Pathogenic	criteria provided, single submitter
1213521	NM_138691.3(TMC1):c.884+1G>A	TMC1	Pathogenic	criteria provided, multiple submitters, no conflicts
1297078	NM_138691.3(TMC1):c.150del (p.Asn50fs)	TMC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1334111	NM_138691.3(TMC1):c.1184del (p.Gln395fs)	TMC1	Pathogenic	criteria provided, single submitter
1799539	NM_138691.3(TMC1):c.1750C>T (p.Gln584Ter)	TMC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1799540	NM_138691.3(TMC1):c.1250G>A (p.Gly417Glu)	TMC1	Pathogenic	criteria provided, single submitter
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
236042	NM_138691.3(TMC1):c.229del (p.Arg77fs)	TMC1	Pathogenic	no assertion criteria provided
242394	NM_138691.3(TMC1):c.1810C>T (p.Arg604Ter)	TMC1	Pathogenic	criteria provided, multiple submitters, no conflicts
2499514	NM_138691.3(TMC1):c.64+2T>A	TMC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
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
2735278	NM_138691.3(TMC1):c.790C>T (p.Arg264Ter)	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
3024460	NM_138691.3(TMC1):c.871del (p.Val291fs)	TMC1	Pathogenic	no assertion criteria provided
3066070	NM_138691.3(TMC1):c.1566+4A>G	TMC1	Pathogenic	no assertion criteria provided
3597493	NM_138691.3(TMC1):c.535+1G>C	TMC1	Pathogenic	criteria provided, single submitter
3601883	NM_138691.3(TMC1):c.1154G>A (p.Trp385Ter)	TMC1	Pathogenic	criteria provided, single submitter
3601885	NM_138691.3(TMC1):c.1262C>T (p.Pro421Leu)	TMC1	Pathogenic	criteria provided, single submitter
3601886	NM_138691.3(TMC1):c.128_138del (p.Lys43fs)	TMC1	Pathogenic	criteria provided, single submitter
3601891	NM_138691.3(TMC1):c.1512del (p.Phe504fs)	TMC1	Pathogenic	criteria provided, single submitter
3601892	NM_138691.3(TMC1):c.1598del (p.Leu533fs)	TMC1	Pathogenic	criteria provided, single submitter
3601893	NM_138691.3(TMC1):c.1662_1663del (p.Asn554fs)	TMC1	Pathogenic	criteria provided, single submitter

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
OTOA	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
TRPM6	Orphanet:30924	Primary hypomagnesemia with secondary hypocalcemia

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TMC1	HGNC:16513	ENSG00000165091	Q8TDI8	Transmembrane channel-like protein 1	gencc,clinvar
OTOA	HGNC:16378	ENSG00000155719	Q7RTW8	Otoancorin	clinvar
TRPM6	HGNC:17995	ENSG00000119121	Q9BX84	Transient receptor potential cation channel subfamily M member 6	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.
OTOA	Otoancorin	May act as an adhesion molecule.
TRPM6	Transient receptor potential cation channel subfamily M member 6	Bifunctional protein that combines an ion channel with an intrinsic kinase domain, enabling it to modulate cellular functions either by conducting ions through the pore or by phosphorylating downstream proteins via its kinase domain.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

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
Kinase	1	9.2×	0.209
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TMC1	Other/Unknown	no		TMC_dom, TMC
OTOA	Other/Unknown	no		Stereocilin-rel
TRPM6	Kinase	yes		a-kinase_dom, Ion_trans_dom, Kinase-like_dom_sf

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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
primordial germ cell in gonad	2
buccal mucosa cell	1
male germ line stem cell (sensu Vertebrata) in testis	1
left testis	1
testis	1
colonic mucosa	1
jejunal mucosa	1
mucosa of sigmoid colon	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
OTOA	86		yes	primordial germ cell in gonad, left testis, testis
TRPM6	178	tissue_specific	marker	colonic mucosa, mucosa of sigmoid colon, jejunal mucosa

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TMC1	1,291
TRPM6	950
OTOA	435

Intra-cohort edges

A	B	Sources
OTOA	TMC1	string_interaction

Structural data

PDB: 1 · AlphaFold-only: 2 · 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
OTOA	Q7RTW8	84.12
TRPM6	Q9BX84	65.03

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
TRP channels	1	135.9×	0.018	TRPM6
Sensory processing of sound by outer hair cells of the cochlea	1	68.0×	0.018	TMC1
Post-translational modification: synthesis of GPI-anchored proteins	1	56.0×	0.018	OTOA
Sensory processing of sound by inner hair cells of the cochlea	1	54.4×	0.018	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 3 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	1404.3×	0.005	TMC1
magnesium ion transmembrane transport	1	1404.3×	0.005	TRPM6
regulation of calcium ion transmembrane transport	1	702.2×	0.006	TMC1
auditory receptor cell development	1	624.1×	0.006	TMC1
detection of mechanical stimulus involved in sensory perception of sound	1	312.1×	0.008	TMC1
transmission of nerve impulse	1	216.1×	0.008	OTOA
protein tetramerization	1	208.1×	0.008	TRPM6
monoatomic cation transmembrane transport	1	208.1×	0.008	TRPM6
response to toxic substance	1	70.2×	0.020	TRPM6
calcium ion transmembrane transport	1	70.2×	0.020	TRPM6
calcium ion transport	1	60.4×	0.021	TRPM6
cell-matrix adhesion	1	54.5×	0.021	OTOA
multicellular organism growth	1	45.7×	0.023	OTOA
sensory perception of sound	1	33.6×	0.029	OTOA

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
TRPM6	TOFACITINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TRPM6	2	4
TMC1	0	0
OTOA	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
TOFACITINIB	4	TRPM6
TG100-115	2	TRPM6

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
TRPM6	56	Binding:55, Functional:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

2 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.

Compound	Max phase	Cohort target (bioactivity)
TOFACITINIB	4	TRPM6
TG100-115	2	TRPM6

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	TRPM6
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	TMC1, OTOA

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	—
OTOA	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.