autosomal recessive nonsyndromic hearing loss 18A

Summary

autosomal recessive nonsyndromic hearing loss 18A (MONDO:0011192) is a disease caused by USH1C (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: USH1C (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 244

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal recessive nonsyndromic hearing loss 18A
Mondo ID	MONDO:0011192
MeSH	C566580
OMIM	602092
DOID	DOID:0110473
UMLS	C1865870
MedGen	356389
GARD	0022592
Is cancer (heuristic)	no

Also known as: autosomal recessive deafness 18A · autosomal recessive nonsyndromic deafness 18A · autosomal recessive nonsyndromic deafness caused by mutation in USH1C · autosomal recessive nonsyndromic deafness type 18A · deafness, autosomal recessive 18 · deafness, autosomal recessive 18A · deafness, autosomal recessive 18a · deafness, autosomal recessive type 18A · DFNB18A · USH1C autosomal recessive nonsyndromic deafness

Data availability: 244 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 18A

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 7, 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 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

244 retrieved; paginated sample, class counts are floors:

77 uncertain significance, 56 likely pathogenic, 36 benign, 24 pathogenic/likely pathogenic, 23 pathogenic, 15 likely benign, 12 conflicting classifications of pathogenicity, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1031570	NM_153676.4(USH1C):c.586C>T (p.Arg196Ter)	USH1C	Pathogenic	criteria provided, multiple submitters, no conflicts
1069539	NM_153676.4(USH1C):c.36+1G>A	USH1C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1069904	NM_153676.4(USH1C):c.238del (p.Arg80fs)	USH1C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1074506	NM_153676.4(USH1C):c.375del (p.Ser125fs)	USH1C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1076666	NM_153676.4(USH1C):c.1030G>T (p.Glu344Ter)	USH1C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1422631	NM_153676.4(USH1C):c.348_373del (p.His116fs)	USH1C	Pathogenic	criteria provided, multiple submitters, no conflicts
1426729	NM_153676.4(USH1C):c.658C>T (p.Arg220Ter)	USH1C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1698964	NM_153676.4(USH1C):c.388-1G>A	USH1C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1939547	NM_153676.4(USH1C):c.496_496+4del	USH1C	Pathogenic	criteria provided, multiple submitters, no conflicts
2039338	NM_153676.4(USH1C):c.917_938delinsCTTGCC (p.Glu306fs)	USH1C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2197225	NM_153676.4(USH1C):c.579+1G>A	USH1C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2579696	NM_153676.4(USH1C):c.105-2A>G	USH1C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2679425	NM_153676.4(USH1C):c.1096del (p.Glu366fs)	USH1C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2679426	NM_153676.4(USH1C):c.70del (p.Asp24fs)	USH1C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3601013	NM_153676.4(USH1C):c.2226+2T>G	USH1C	Pathogenic	criteria provided, single submitter
3601014	NM_153676.4(USH1C):c.37-1G>T	USH1C	Pathogenic	criteria provided, single submitter
3601015	NM_153676.4(USH1C):c.378_379insT (p.Gly127fs)	USH1C	Pathogenic	criteria provided, single submitter
3601959	NM_153676.4(USH1C):c.133G>T (p.Asp45Tyr)	USH1C	Pathogenic	criteria provided, single submitter
371731	NM_153676.4(USH1C):c.463C>T (p.Arg155Ter)	USH1C	Pathogenic	criteria provided, multiple submitters, no conflicts
371732	NM_153676.4(USH1C):c.496+1G>A	USH1C	Pathogenic	criteria provided, multiple submitters, no conflicts
39427	NM_153676.4(USH1C):c.308G>A (p.Arg103His)	USH1C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
424972	NM_153676.4(USH1C):c.841_848del (p.Ser281fs)	USH1C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
437936	NM_153676.4(USH1C):c.748_759+5del	USH1C	Pathogenic	criteria provided, multiple submitters, no conflicts
500413	NM_153676.4(USH1C):c.1039C>T (p.Gln347Ter)	USH1C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
5140	NM_153676.4(USH1C):c.497-2del	USH1C	Pathogenic	criteria provided, multiple submitters, no conflicts
5141	NM_153676.4(USH1C):c.238dup (p.Arg80fs)	USH1C	Pathogenic	criteria provided, multiple submitters, no conflicts
5143	NM_153676.4(USH1C):c.216G>A (p.Val72=)	USH1C	Pathogenic	criteria provided, multiple submitters, no conflicts
5146	NM_153676.4(USH1C):c.91C>T (p.Arg31Ter)	USH1C	Pathogenic	criteria provided, multiple submitters, no conflicts
5147	NM_153676.4(USH1C):c.1019+5G>C	USH1C	Pathogenic	no assertion criteria provided
551392	NM_153676.4(USH1C):c.2227-1G>T	USH1C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 13 · Orphanet: 3 · 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
USH1C	Strong	Autosomal recessive	autosomal recessive nonsyndromic hearing loss 18A	13

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
USH1C	Orphanet:231169	Usher syndrome type 1
USH1C	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
USH1G	Orphanet:231169	Usher syndrome type 1

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
USH1C	HGNC:12597	ENSG00000006611	Q9Y6N9	Harmonin	gencc,clinvar
USH1G	HGNC:16356	ENSG00000182040	Q495M9	pre-mRNA splicing regulator USH1G	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
USH1C	Harmonin	Anchoring/scaffolding protein that is a part of the functional network formed by USH1C, USH1G, CDH23 and MYO7A that mediates mechanotransduction in cochlear hair cells.
USH1G	pre-mRNA splicing regulator USH1G	Plays a role in pre-mRNA splicing by regulating the release and transfer of U4/U6.U5 tri-small nuclear ribonucleoprotein (tri-snRNP) complexes from their assembly site in Cajal bodies to nuclear speckles, thereby contributing to the assemb…

Protein-family classification

Druggable: 0 · Difficult: 2 · Unknown: 0 · Druggable fraction: 0.0

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
Scaffold/PPI	2	17.3×	0.003

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
USH1C	Scaffold/PPI	no		PDZ, Harmonin_N, PDZ_sf
USH1G	Scaffold/PPI	no		SAM, Ankyrin_rpt, SAM/pointed_sf

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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
C1 segment of cervical spinal cord	1
mucosa of transverse colon	1
rectum	1
esophagus squamous epithelium	1
lower esophagus mucosa	1
male germ line stem cell (sensu Vertebrata) in testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
USH1C	203	broad	marker	mucosa of transverse colon, C1 segment of cervical spinal cord, rectum
USH1G	69	broad	yes	lower esophagus mucosa, male germ line stem cell (sensu Vertebrata) in testis, esophagus squamous epithelium

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
USH1G	1,354
USH1C	291

Intra-cohort edges

A	B	Sources
USH1C	USH1G	biogrid_interaction, intact

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
USH1C	Q9Y6N9	11
USH1G	Q495M9	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 2 evidence-associated genes (2 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 2 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	2	203.9×	4e-05	USH1C, USH1G
Sensory processing of sound by inner hair cells of the cochlea	2	163.1×	4e-05	USH1C, USH1G

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
equilibrioception	2	2407.4×	2e-06	USH1C, USH1G
sensory perception of light stimulus	2	1872.4×	2e-06	USH1C, USH1G
inner ear receptor cell stereocilium organization	2	842.6×	8e-06	USH1C, USH1G
photoreceptor cell maintenance	2	358.6×	3e-05	USH1C, USH1G
inner ear morphogenesis	2	300.9×	4e-05	USH1C, USH1G
sensory perception of sound	2	100.9×	3e-04	USH1C, USH1G
protein localization to microvillus	1	4213.0×	6e-04	USH1C
parallel actin filament bundle assembly	1	2808.7×	8e-04	USH1C
auditory receptor cell morphogenesis	1	2106.5×	9e-04	USH1C
regulation of microvillus length	1	1203.7×	0.001	USH1C
brush border assembly	1	1203.7×	0.001	USH1C
regulation of clathrin-dependent endocytosis	1	842.6×	0.002	USH1G
retinal cone cell development	1	702.2×	0.002	USH1C
inner ear auditory receptor cell differentiation	1	601.9×	0.002	USH1C
actin filament bundle assembly	1	227.7×	0.005	USH1C
G2/M transition of mitotic cell cycle	1	156.0×	0.007	USH1C
protein-containing complex assembly	1	56.9×	0.017	USH1C

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
USH1C	0	0
USH1G	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	0
E	Difficult family or no structure, no drug	2	USH1C, USH1G

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)
USH1C	0	—
USH1G	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.