Usher syndrome type 1C

Summary

Usher syndrome type 1C (MONDO:0010171) is a disease caused by USH1C (GenCC Definitive), with 2 cohort genes and 1 clinical trial.

At a glance

• Causal gene: USH1C (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 415
• Clinical trials: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Usher syndrome type 1C
Mondo ID	MONDO:0010171
OMIM	276904
DOID	DOID:0110830
UMLS	C1848604
MedGen	338506
GARD	0005437
Is cancer (heuristic)	no

Also known as: USH1C · Usher syndrome type 1C · Usher syndrome, Acadian variety · Usher syndrome, type 1C · USHER syndrome, type IC

Data availability: 415 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › Usher syndrome › Usher syndrome type 1 › Usher syndrome type 1C

Related subtypes (8): Usher syndrome type 1D, Usher syndrome type 1F, Usher syndrome type 1E, Usher syndrome type 1G, Usher syndrome type 1H, Usher syndrome type 1K, Usher syndrome, type 1D/F, Usher syndrome type 1B

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

415 retrieved; paginated sample, class counts are floors:

181 uncertain significance, 52 likely pathogenic, 45 benign, 42 conflicting classifications of pathogenicity, 36 likely benign, 28 pathogenic/likely pathogenic, 25 pathogenic, 6 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
941545	NM_001365088.1(SLC12A6):c.316+1G>A	SLC12A6	Pathogenic/Likely 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
1073507	NM_153676.4(USH1C):c.948_955del (p.Glu316fs)	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
1333674	NM_153676.4(USH1C):c.917_939dup (p.Gln315fs)	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
1726834	NM_153676.4(USH1C):c.546G>A (p.Trp182Ter)	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
218193	NM_153676.4(USH1C):c.7C>T (p.Arg3Ter)	USH1C	Pathogenic	no assertion criteria provided
2197225	NM_153676.4(USH1C):c.579+1G>A	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
2735559	NM_153676.4(USH1C):c.521+1G>A	USH1C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2833905	NM_153676.4(USH1C):c.579+1G>T	USH1C	Pathogenic	criteria provided, multiple submitters, no conflicts
2864223	NM_153676.4(USH1C):c.75T>G (p.Tyr25Ter)	USH1C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2914399	NM_153676.4(USH1C):c.24del (p.Glu8fs)	USH1C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3601011	NM_153676.4(USH1C):c.141dup (p.Leu48fs)	USH1C	Pathogenic	criteria provided, single submitter
3601020	NM_153676.4(USH1C):c.777_778del (p.Glu260fs)	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
39428	NM_153676.4(USH1C):c.2227-1G>A	USH1C	Pathogenic	no assertion criteria provided
4062527	NM_153676.4(USH1C):c.36+1G>C	USH1C	Pathogenic	criteria provided, single submitter
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
4815459	NM_153676.4(USH1C):c.579+1del	USH1C	Pathogenic	criteria provided, single submitter
500413	NM_153676.4(USH1C):c.1039C>T (p.Gln347Ter)	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	Definitive	Autosomal recessive	Usher syndrome type 1C	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
SLC12A6	Orphanet:1496	Corpus callosum agenesis-neuronopathy syndrome

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
SLC12A6	HGNC:10914	ENSG00000140199	Q9UHW9	Solute carrier family 12 member 6	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.
SLC12A6	Solute carrier family 12 member 6	Mediates electroneutral potassium-chloride cotransport when activated by cell swelling.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 1 · 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	1	8.6×	0.225
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
USH1C	Scaffold/PPI	no		PDZ, Harmonin_N, PDZ_sf
SLC12A6	Other/Unknown	no		KCL_cotranspt, AA-permease/SLC12A_dom, SLC12A_fam

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
C1 segment of cervical spinal cord	1
mucosa of transverse colon	1
rectum	1
blood	1
esophagus squamous epithelium	1
secondary oocyte	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
SLC12A6	274	ubiquitous	marker	esophagus squamous epithelium, blood, secondary oocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SLC12A6	1,463
USH1C	291

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
USH1C	Q9Y6N9	11
SLC12A6	Q9UHW9	8

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. 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
Defective SLC12A6 causes agenesis of the corpus callosum, with peripheral neuropathy (ACCPN)	1	5710.0×	0.002	SLC12A6
Cation-coupled Chloride cotransporters	1	815.7×	0.006	SLC12A6
SLC transporter disorders	1	102.0×	0.022	SLC12A6
Sensory processing of sound by outer hair cells of the cochlea	1	102.0×	0.022	USH1C
Sensory processing of sound by inner hair cells of the cochlea	1	81.6×	0.022	USH1C
Disorders of transmembrane transporters	1	69.6×	0.022	SLC12A6
R-HSA-425393	1	64.9×	0.022	SLC12A6
SLC-mediated transmembrane transport	1	29.6×	0.042	SLC12A6
Transport of small molecules	1	12.6×	0.087	SLC12A6
Disease	1	6.5×	0.147	SLC12A6

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
protein localization to microvillus	1	4213.0×	0.003	USH1C
parallel actin filament bundle assembly	1	2808.7×	0.003	USH1C
cellular hypotonic salinity response	1	2808.7×	0.003	SLC12A6
auditory receptor cell morphogenesis	1	2106.5×	0.003	USH1C
regulation of microvillus length	1	1203.7×	0.003	USH1C
equilibrioception	1	1203.7×	0.003	USH1C
brush border assembly	1	1203.7×	0.003	USH1C
sensory perception of light stimulus	1	936.2×	0.004	USH1C
chloride ion homeostasis	1	766.0×	0.004	SLC12A6
retinal cone cell development	1	702.2×	0.004	USH1C
cellular hypotonic response	1	702.2×	0.004	SLC12A6
inner ear auditory receptor cell differentiation	1	601.9×	0.004	USH1C
inner ear receptor cell stereocilium organization	1	421.3×	0.005	USH1C
potassium ion homeostasis	1	383.0×	0.005	SLC12A6
cell volume homeostasis	1	300.9×	0.006	SLC12A6
actin filament bundle assembly	1	227.7×	0.008	USH1C
potassium ion import across plasma membrane	1	183.2×	0.009	SLC12A6
photoreceptor cell maintenance	1	179.3×	0.009	USH1C
G2/M transition of mitotic cell cycle	1	156.0×	0.009	USH1C
inner ear morphogenesis	1	150.5×	0.009	USH1C
cellular response to glucose stimulus	1	133.8×	0.010	SLC12A6
chloride transmembrane transport	1	118.7×	0.011	SLC12A6
monoatomic ion transport	1	78.0×	0.016	SLC12A6
potassium ion transmembrane transport	1	68.0×	0.017	SLC12A6
protein-containing complex assembly	1	56.9×	0.020	USH1C
sensory perception of sound	1	50.5×	0.021	USH1C
chemical synaptic transmission	1	38.6×	0.027	SLC12A6
angiogenesis	1	31.2×	0.032	SLC12A6

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
SLC12A6	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, SLC12A6

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	—
SLC12A6	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns