Usher syndrome type 3

Summary

Usher syndrome type 3 (MONDO:0016485) is a disease caused by CLRN1 (GenCC Definitive), with 5 cohort genes and 2 clinical trials. Top therapeutic interventions include ciliary neurotrophic factor.

At a glance

• Prevalence: 1-9 / 1 000 000 (Denmark) [Orphanet-validated]
• Causal gene: CLRN1 (GenCC Definitive)
• Cohort genes: 5
• ClinVar variants: 109
• Phenotypes (HPO): 12
• Clinical trials: 2

Clinical features

Epidemiology

Prevalence records

3 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 1 000 000	0.1	Denmark	Validated
Point prevalence	1-9 / 100 000	1.2	Specific population	Validated
Point prevalence	1-9 / 1 000 000		Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

12 HPO clinical features (Orphanet curated; top 12 by frequency):

HPO ID	Term	Frequency
HP:0000375	Abnormal cochlea morphology	Very frequent (80-99%)
HP:0000407	Sensorineural hearing impairment	Very frequent (80-99%)
HP:0000510	Rod-cone dystrophy	Very frequent (80-99%)
HP:0000512	Abnormal electroretinogram	Very frequent (80-99%)
HP:0000572	Visual loss	Very frequent (80-99%)
HP:0000575	Scotoma	Very frequent (80-99%)
HP:0000662	Nyctalopia	Very frequent (80-99%)
HP:0001756	Vestibular hypofunction	Very frequent (80-99%)
HP:0007730	Iris hypopigmentation	Very frequent (80-99%)
HP:0001751	Abnormal vestibular function	Occasional (5-29%)
HP:0000716	Depression	Occasional (5-29%)
HP:0000739	Anxiety	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Usher syndrome type 3
Mondo ID	MONDO:0016485
Orphanet	231183
DOID	DOID:0110828
ICD-11	1734357568
NCIT	C126329
UMLS	C1568248
MedGen	339336
GARD	0005442
Is cancer (heuristic)	no

Also known as: USH3 · Usher syndrome type 3

Data availability: 109 ClinVar variants · 6 GenCC gene-disease records.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › syndromic disease › Usher syndrome › Usher syndrome type 3

Related subtypes (4): Usher syndrome type 1, retinitis pigmentosa-deafness syndrome, Usher syndrome type 2, Usher syndrome, type 4

Subtypes (2): Usher syndrome type 3A, Usher syndrome type 3B

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

109 retrieved; paginated sample, class counts are floors:

52 uncertain significance, 13 pathogenic/likely pathogenic, 11 likely pathogenic, 10 conflicting classifications of pathogenicity, 9 pathogenic, 7 likely benign, 7 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1075882	NM_174878.3(CLRN1):c.31dup (p.Cys11fs)	CLRN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1331448	NM_174878.3(CLRN1):c.190G>A (p.Gly64Arg)	CLRN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1455146	NM_174878.3(CLRN1):c.513T>A (p.Tyr171Ter)	CLRN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
188726	NM_001195794.1(CLRN1):c.149_152delinsTGTCCAAT (p.Ser50fs)	CLRN1	Pathogenic	criteria provided, multiple submitters, no conflicts
188875	NM_174878.3(CLRN1):c.502dup (p.Ile168fs)	CLRN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1966493	NM_174878.3(CLRN1):c.190G>C (p.Gly64Arg)	CLRN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
371628	NM_174878.3(CLRN1):c.619C>T (p.Arg207Ter)	CLRN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4392	NM_052995.2(CLRN1):c.300T>G (p.Tyr100Ter)	CLRN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4395	NM_174878.3(CLRN1):c.144T>G (p.Asn48Lys)	CLRN1	Pathogenic	criteria provided, multiple submitters, no conflicts
4397	NM_174878.3(CLRN1):c.189C>A (p.Tyr63Ter)	CLRN1	Pathogenic	criteria provided, multiple submitters, no conflicts
4398	NM_174878.3(CLRN1):c.188_210del (p.Tyr63fs)	CLRN1	Pathogenic	criteria provided, single submitter
48145	NM_174878.3(CLRN1):c.301_305del (p.Val101fs)	CLRN1	Pathogenic	criteria provided, multiple submitters, no conflicts
48146	NM_174878.3(CLRN1):c.368C>A (p.Ala123Asp)	CLRN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
552163	NM_174878.3(CLRN1):c.541C>T (p.Gln181Ter)	CLRN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
558249	NM_174878.3(CLRN1):c.40G>T (p.Gly14Ter)	CLRN1	Pathogenic	criteria provided, single submitter
633701	NM_174878.3(CLRN1):c.323T>C (p.Leu108Pro)	CLRN1	Pathogenic	criteria provided, single submitter
638640	NM_174878.3(CLRN1):c.433+1G>A	CLRN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
644615	NM_174878.3(CLRN1):c.578del (p.Phe193fs)	CLRN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
651716	NM_174878.3(CLRN1):c.121_136dup (p.Leu46fs)	CLRN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
802016	NM_174878.3(CLRN1):c.128G>T (p.Gly43Val)	CLRN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
812104	NM_174878.3(CLRN1):c.65T>A (p.Leu22His)	CLRN1	Pathogenic	criteria provided, single submitter
812272	NM_174878.3(CLRN1):c.349_358del (p.Ala117fs)	CLRN1	Pathogenic	no assertion criteria provided
2680848	NM_174878.3(CLRN1):c.433+1G>T	CLRN1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
4064866	NM_174878.3(CLRN1):c.463_466del (p.Phe155fs)	CLRN1	Likely pathogenic	criteria provided, single submitter
4393	NM_174878.3(CLRN1):c.359T>A (p.Met120Lys)	CLRN1	Likely pathogenic	criteria provided, single submitter
4394	NM_174878.3(CLRN1):c.459_461del (p.Ile153_Leu154delinsMet)	CLRN1	Likely pathogenic	criteria provided, single submitter
4396	NM_174878.3(CLRN1):c.449T>C (p.Leu150Pro)	CLRN1	Likely pathogenic	criteria provided, single submitter
4816960	NM_174878.3(CLRN1):c.10C>T (p.Gln4Ter)	CLRN1	Likely pathogenic	criteria provided, single submitter
4816961	NM_174878.3(CLRN1):c.127G>T (p.Gly43Ter)	CLRN1	Likely pathogenic	criteria provided, single submitter
4816962	NM_174878.3(CLRN1):c.154_155insTT (p.Gln52fs)	CLRN1	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 26 · Orphanet: 6 · 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
CLRN1	Definitive	Unknown	Usher syndrome type 3	7
ARSG	Strong	Autosomal recessive	Usher syndrome, type 4	6
HARS1	Strong	Autosomal recessive	Usher syndrome type 3B	8
CEP78	Supportive	Autosomal recessive	Usher syndrome type 3	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CLRN1	Orphanet:231183	Usher syndrome type 3
CLRN1	Orphanet:791	Retinitis pigmentosa
HARS1	Orphanet:231183	Usher syndrome type 3
HARS1	Orphanet:488333	Autosomal dominant Charcot-Marie-Tooth disease type 2W
ARSG	Orphanet:231183	Usher syndrome type 3
CEP78	Orphanet:231183	Usher syndrome type 3

Cohort genes → proteins

5 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CLRN1	HGNC:12605	ENSG00000163646	P58418	Clarin-1	gencc,clinvar
HARS1	HGNC:4816	ENSG00000170445	P12081	Histidine–tRNA ligase, cytoplasmic	gencc,clinvar
ARSG	HGNC:24102	ENSG00000141337	Q96EG1	Arylsulfatase G	gencc
CEP78	HGNC:25740	ENSG00000148019	Q5JTW2	Centrosomal protein of 78 kDa	gencc
SIAH2-AS1	HGNC:40526	ENSG00000244265		SIAH2 and CLRN1 antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CLRN1	Clarin-1	May have a role in the excitatory ribbon synapse junctions between hair cells and cochlear ganglion cells and presumably also in analogous synapses within the retina.
HARS1	Histidine–tRNA ligase, cytoplasmic	Catalyzes the ATP-dependent ligation of histidine to the 3’-end of its cognate tRNA, via the formation of an aminoacyl-adenylate intermediate (His-AMP).
ARSG	Arylsulfatase G	Displays arylsulfatase activity at acidic pH towards artificial substrates, such as p-nitrocatechol sulfate and also, but with a lower activity towards p-nitrophenyl sulfate and 4-methylumbelliferyl sulfate.
CEP78	Centrosomal protein of 78 kDa	Centriole wall protein that localizes to mature centrioles and regulates centriole and cilia biogenesis.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 3 · Druggable fraction: 0.4

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
Phosphatase	1	16.8×	0.175
Enzyme (other)	1	2.4×	0.530
Other/Unknown	3	1.1×	0.608

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CLRN1	Other/Unknown	no		Clarin
HARS1	Enzyme (other)	yes	6.1.1.21	WHEP-TRS_dom, Anticodon-bd, HisRS/HisZ
ARSG	Phosphatase	yes		Sulfatase_N, Alkaline_phosphatase_core_sf, Sulfatase_CS
CEP78	Other/Unknown	no		Leu-rich_rpt, Cep78, LRR_dom_sf
SIAH2-AS1	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

4 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)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
buccal mucosa cell	2
oocyte	2
secondary oocyte	2
adrenal tissue	1
right adrenal gland	1
right adrenal gland cortex	1
adenohypophysis	1
lateral nuclear group of thalamus	1
right frontal lobe	1
blood	1
monocyte	1
stromal cell of endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CLRN1	61	tissue_specific	marker	adrenal tissue, right adrenal gland cortex, right adrenal gland
HARS1	291	ubiquitous	marker	lateral nuclear group of thalamus, right frontal lobe, adenohypophysis
ARSG	135	ubiquitous	marker	blood, stromal cell of endometrium, monocyte
CEP78	239	ubiquitous	marker	secondary oocyte, oocyte, buccal mucosa cell
SIAH2-AS1	161	broad	yes	secondary oocyte, oocyte, buccal mucosa cell

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HARS1	2,480
CEP78	1,373
ARSG	1,175
CLRN1	727
SIAH2-AS1	0

Intra-cohort edges

A	B	Sources
ARSG	CEP78	string_interaction

Structural data

PDB: 1 · AlphaFold-only: 3 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
HARS1	P12081	10

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ARSG	Q96EG1	91.90
CLRN1	P58418	90.74
CEP78	Q5JTW2	64.28

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 26. Enrichment computed across 5 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
The activation of arylsulfatases	1	292.8×	0.042	ARSG
Cytosolic tRNA aminoacylation	1	146.4×	0.042	HARS1
Gamma carboxylation, hypusinylation, hydroxylation, and arylsulfatase activation	1	141.0×	0.042	ARSG
Glycosphingolipid metabolism	1	100.2×	0.042	ARSG
Glycosphingolipid catabolism	1	97.6×	0.042	ARSG
Centrosome maturation	1	84.6×	0.042	CEP78
Sphingolipid metabolism	1	56.0×	0.042	ARSG
Loss of Nlp from mitotic centrosomes	1	52.9×	0.042	CEP78
Loss of proteins required for interphase microtubule organization from the centrosome	1	52.9×	0.042	CEP78
AURKA Activation by TPX2	1	50.8×	0.042	CEP78
Recruitment of mitotic centrosome proteins and complexes	1	45.3×	0.042	CEP78
Regulation of PLK1 Activity at G2/M Transition	1	42.3×	0.042	CEP78
Mitotic G2-G2/M phases	1	42.3×	0.042	CEP78
G2/M Transition	1	42.3×	0.042	CEP78
Recruitment of NuMA to mitotic centrosomes	1	38.8×	0.042	CEP78
Anchoring of the basal body to the plasma membrane	1	37.7×	0.042	CEP78
Cilium Assembly	1	36.2×	0.042	CEP78
Mitotic Prometaphase	1	23.1×	0.058	CEP78
Organelle biogenesis and maintenance	1	22.0×	0.058	CEP78
M Phase	1	22.0×	0.058	CEP78
Cell Cycle, Mitotic	1	16.1×	0.076	CEP78
Cell Cycle	1	12.0×	0.096	CEP78
Metabolism of lipids	1	10.5×	0.104	ARSG
Post-translational protein modification	1	6.4×	0.161	ARSG
Metabolism of proteins	1	4.1×	0.232	ARSG
Metabolism	1	3.9×	0.237	ARSG

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
histidyl-tRNA aminoacylation	1	2106.5×	0.011	HARS1
equilibrioception	1	601.9×	0.014	CLRN1
sensory perception of light stimulus	1	468.1×	0.014	CLRN1
sulfur compound metabolic process	1	280.9×	0.014	ARSG
glial cell differentiation	1	221.7×	0.014	ARSG
tRNA aminoacylation for protein translation	1	210.7×	0.014	HARS1
auditory receptor cell stereocilium organization	1	210.7×	0.014	CLRN1
homeostasis of number of cells	1	168.5×	0.014	ARSG
protein localization to centrosome	1	168.5×	0.014	CEP78
positive regulation of lamellipodium assembly	1	150.5×	0.014	CLRN1
cilium organization	1	150.5×	0.014	CEP78
cell motility	1	100.3×	0.018	CLRN1
protein localization to cilium	1	100.3×	0.018	CEP78
photoreceptor cell maintenance	1	89.6×	0.019	CLRN1
lysosome organization	1	76.6×	0.021	ARSG
negative regulation of protein ubiquitination	1	71.4×	0.021	CEP78
retina development in camera-type eye	1	63.8×	0.022	ARSG
neuron apoptotic process	1	46.3×	0.029	ARSG
actin filament organization	1	29.7×	0.040	CLRN1
flagellated sperm motility	1	29.3×	0.040	CEP78
translation	1	25.7×	0.043	HARS1
sensory perception of sound	1	25.2×	0.043	CLRN1
gene expression	1	20.0×	0.049	ARSG
visual perception	1	19.9×	0.049	CLRN1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 5

Druggability breadth: 2 of 5 evidence-associated genes (40%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CLRN1	0	0
HARS1	0	0
ARSG	0	0
CEP78	0	0
SIAH2-AS1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
HARS1	5	Binding:5
ARSG	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
HARS1	6.1.1.21	histidine-tRNA ligase

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; 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	1	HARS1
D	Druggable family + AlphaFold only, no drug	1	ARSG
E	Difficult family or no structure, no drug	3	CLRN1, CEP78, SIAH2-AS1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
CLRN1	0	—
HARS1	5	—
ARSG	2	—
CEP78	0	—
SIAH2-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	1
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01530659	PHASE2	COMPLETED	Retinal Imaging in CNTF -Releasing Encapsulated Cell Implant Treated Patients for Early-stage Retinitis Pigmentosa
NCT06592131	PHASE1	NOT_YET_RECRUITING	BF844 Safety and Pharmacokinetic Study in Healthy Volunteers

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
CILIARY NEUROTROPHIC FACTOR	3	1