Usher syndrome type 3A

Summary

Usher syndrome type 3A (MONDO:0010170) is a disease caused by CLRN1 (GenCC Definitive), with 3 cohort genes.

At a glance

• Causal gene: CLRN1 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 78

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Usher syndrome type 3A
Mondo ID	MONDO:0010170
OMIM	276902
DOID	DOID:0110841
UMLS	C5779850
MedGen	1830415
GARD	0015242
Is cancer (heuristic)	no

Also known as: CLRN1 Usher syndrome · USH3A · Usher syndrome caused by mutation in CLRN1 · Usher syndrome type 3A · USHER syndrome, type IIIA

Data availability: 78 ClinVar variants · 2 GenCC gene-disease records.

Disease family

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

Related subtypes (1): 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

78 retrieved; paginated sample, class counts are floors:

20 uncertain significance, 15 likely pathogenic, 12 pathogenic, 12 pathogenic/likely pathogenic, 7 conflicting classifications of pathogenicity, 6 benign, 6 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1275768	NM_174878.3(CLRN1):c.148_149insTGTC (p.Ser50fs)	CLRN1	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
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
2040098	NM_174878.3(CLRN1):c.528T>A (p.Tyr176Ter)	CLRN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3601046	NM_174878.3(CLRN1):c.227del (p.Leu76fs)	CLRN1	Pathogenic	criteria provided, single submitter
3601049	NM_174878.3(CLRN1):c.96del (p.Leu32fs)	CLRN1	Pathogenic	criteria provided, single submitter
371376	NM_174878.3(CLRN1):c.13C>T (p.Gln5Ter)	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
4081989	NM_174878.3(CLRN1):c.-10_253+10del	CLRN1	Pathogenic	no assertion criteria provided
4082235	Single allele	CLRN1	Pathogenic	criteria provided, single submitter
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
48142	NM_174878.3(CLRN1):c.127G>A (p.Gly43Arg)	CLRN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
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
644615	NM_174878.3(CLRN1):c.578del (p.Phe193fs)	CLRN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
971183	NM_174878.3(CLRN1):c.606T>G (p.Asn202Lys)	CLRN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
992423	NM_174878.3(CLRN1):c.188A>C (p.Tyr63Ser)	CLRN1	Pathogenic	criteria provided, single submitter
30574	NM_174878.3(CLRN1):c.461T>G (p.Leu154Trp)	CLRN1-AS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2357	NM_206933.4(USH2A):c.11864G>A (p.Trp3955Ter)	USH2A	Pathogenic	criteria provided, multiple submitters, no conflicts
1185681	NM_174878.3(CLRN1):c.697T>C (p.Ter233Arg)	CLRN1	Likely pathogenic	no assertion criteria provided
1511878	NM_174878.3(CLRN1):c.253+1G>A	CLRN1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3024084	NM_174878.3(CLRN1):c.341del (p.Val114fs)	CLRN1	Likely pathogenic	no assertion criteria provided
3588695	NM_174878.3(CLRN1):c.569G>A (p.Trp190Ter)	CLRN1	Likely pathogenic	criteria provided, single submitter
3588696	NM_174878.3(CLRN1):c.64dup (p.Leu22fs)	CLRN1	Likely pathogenic	criteria provided, single submitter
3601045	NM_174878.3(CLRN1):c.118T>C (p.Cys40Arg)	CLRN1	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · 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
CLRN1	Definitive	Unknown	Usher syndrome type 3	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CLRN1	Orphanet:231183	Usher syndrome type 3
CLRN1	Orphanet:791	Retinitis pigmentosa
USH2A	Orphanet:231178	Usher syndrome type 2
USH2A	Orphanet:791	Retinitis pigmentosa

Cohort genes → proteins

3 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CLRN1	HGNC:12605	ENSG00000163646	P58418	Clarin-1	gencc,clinvar
USH2A	HGNC:12601	ENSG00000042781	O75445	Usherin	clinvar
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.
USH2A	Usherin	Involved in hearing and vision as member of the USH2 complex.

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
Antibody/Immunoglobulin	1	9.7×	0.199
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CLRN1	Other/Unknown	no		Clarin
USH2A	Antibody/Immunoglobulin	yes		Laminin_G, LE_dom, FN3_dom
SIAH2-AS1	Other/Unknown	no

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
buccal mucosa cell	2
adrenal tissue	1
right adrenal gland	1
right adrenal gland cortex	1
male germ line stem cell (sensu Vertebrata) in testis	1
right lobe of liver	1
oocyte	1
secondary oocyte	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
USH2A	30	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, right lobe of liver, 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
USH2A	2,332
CLRN1	727
SIAH2-AS1	0

Intra-cohort edges

A	B	Sources
CLRN1	USH2A	string_interaction

Structural data

PDB: 0 · AlphaFold-only: 2 · No structure: 1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CLRN1	P58418	90.74
USH2A	O75445

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 3 evidence-associated genes (0 with Reactome annotation).

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
sensory perception of light stimulus	2	1872.4×	4e-06	CLRN1, USH2A
photoreceptor cell maintenance	2	358.6×	6e-05	CLRN1, USH2A
sensory perception of sound	2	100.9×	5e-04	CLRN1, USH2A
visual perception	2	79.5×	6e-04	CLRN1, USH2A
maintenance of animal organ identity	1	1685.2×	0.001	USH2A
inner ear receptor cell differentiation	1	1685.2×	0.001	USH2A
equilibrioception	1	1203.7×	0.002	CLRN1
hair cell differentiation	1	1053.2×	0.002	USH2A
inner ear auditory receptor cell differentiation	1	601.9×	0.003	USH2A
auditory receptor cell stereocilium organization	1	421.3×	0.004	CLRN1
positive regulation of lamellipodium assembly	1	300.9×	0.005	CLRN1
establishment of protein localization	1	216.1×	0.006	USH2A
cell motility	1	200.6×	0.006	CLRN1
establishment of localization in cell	1	80.2×	0.013	USH2A
actin filament organization	1	59.3×	0.017	CLRN1

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 3 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
CLRN1	0	0
USH2A	0	0
SIAH2-AS1	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	2	CLRN1, SIAH2-AS1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
CLRN1	0	—
USH2A	0	—
SIAH2-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.