Usher syndrome type 2C

Summary

Usher syndrome type 2C (MONDO:0011558) is a disease caused by ADGRV1 (GenCC Strong), with 6 cohort genes.

At a glance

• Causal gene: ADGRV1 (GenCC Strong)
• Cohort genes: 6
• ClinVar variants: 676

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Usher syndrome type 2C
Mondo ID	MONDO:0011558
MeSH	C536492
OMIM	605472
DOID	DOID:0110839
NCIT	C153174
UMLS	C2931213
MedGen	419359
GARD	0008497
Is cancer (heuristic)	no

Also known as: USH2C · Usher syndrome, type 2C · Usher syndrome, type 2C, autosomal recessive, digenic dominant · Usher syndrome, type 2C, GPR98/PDZD7 digenic, autosomal recessive, digenic dominant · USHER syndrome, type IIC · Usher syndrome, type IIC, GPR98/PDZD7 digenic, autosomal recessive, digenic dominant

Data availability: 676 ClinVar variants · 4 GenCC gene-disease records · 1 cell line.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › Usher syndrome › Usher syndrome type 2 › Usher syndrome type 2C

Related subtypes (2): Usher syndrome type 2A, Usher syndrome type 2D

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

600 retrieved; paginated sample, class counts are floors:

220 conflicting classifications of pathogenicity, 100 uncertain significance, 74 benign, 66 benign/likely benign, 56 likely pathogenic, 46 pathogenic, 33 pathogenic/likely pathogenic, 5 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1065641	NM_032119.4(ADGRV1):c.14972+1G>T	ADGRV1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1067661	NM_032119.4(ADGRV1):c.1239-1G>T	ADGRV1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1075638	NM_032119.4(ADGRV1):c.2612del (p.Gly871fs)	ADGRV1	Pathogenic	criteria provided, multiple submitters, no conflicts
1075639	NM_032119.4(ADGRV1):c.14404C>T (p.Arg4802Ter)	ADGRV1	Pathogenic	criteria provided, multiple submitters, no conflicts
1185591	NM_032119.4(ADGRV1):c.12829C>T (p.Arg4277Ter)	ADGRV1	Pathogenic	criteria provided, multiple submitters, no conflicts
1371066	NM_032119.4(ADGRV1):c.11547_11550del (p.Ile3849fs)	ADGRV1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1385369	NM_032119.4(ADGRV1):c.14854dup (p.His4952fs)	ADGRV1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
143159	NM_032119.4(ADGRV1):c.15736C>T (p.Arg5246Ter)	ADGRV1	Pathogenic	criteria provided, multiple submitters, no conflicts
143160	NM_032119.4(ADGRV1):c.7006C>T (p.Arg2336Ter)	ADGRV1	Pathogenic	criteria provided, multiple submitters, no conflicts
1446555	NM_032119.4(ADGRV1):c.14971C>T (p.Arg4991Ter)	ADGRV1	Pathogenic	criteria provided, multiple submitters, no conflicts
1447059	NM_032119.4(ADGRV1):c.6610C>T (p.Gln2204Ter)	ADGRV1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1458724	NM_032119.4(ADGRV1):c.8875C>T (p.Arg2959Ter)	ADGRV1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
179121	NM_032119.4(ADGRV1):c.17303_17315del (p.Gly5768fs)	ADGRV1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
179305	NM_032119.4(ADGRV1):c.12631C>T (p.Arg4211Ter)	ADGRV1	Pathogenic	criteria provided, multiple submitters, no conflicts
1878513	NM_032119.4(ADGRV1):c.6077dup (p.Tyr2026Ter)	ADGRV1	Pathogenic	criteria provided, single submitter
1967432	NM_032119.4(ADGRV1):c.6491-1G>A	ADGRV1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1969864	NM_032119.4(ADGRV1):c.4371dup (p.Thr1458fs)	ADGRV1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2125215	NM_032119.4(ADGRV1):c.3364dup (p.Ser1122fs)	ADGRV1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
228353	NM_032119.4(ADGRV1):c.7129C>T (p.Arg2377Ter)	ADGRV1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2445626	NC_000005.10:g.90118339_90119245del	ADGRV1	Pathogenic	criteria provided, single submitter
265623	NM_032119.4(ADGRV1):c.10213C>T (p.Arg3405Ter)	ADGRV1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
266014	NM_032119.4(ADGRV1):c.7606G>T (p.Glu2536Ter)	ADGRV1	Pathogenic	no assertion criteria provided
2702915	NM_032119.4(ADGRV1):c.17960G>A (p.Trp5987Ter)	ADGRV1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2734742	NM_032119.4(ADGRV1):c.14455_14456del (p.Arg4819fs)	ADGRV1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2734743	NM_032119.4(ADGRV1):c.17386C>T (p.Gln5796Ter)	ADGRV1	Pathogenic	criteria provided, multiple submitters, no conflicts
2818627	NM_032119.4(ADGRV1):c.461C>A (p.Ser154Ter)	ADGRV1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2852958	NM_032119.4(ADGRV1):c.12542del (p.Pro4181fs)	ADGRV1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2867641	NM_032119.4(ADGRV1):c.4571C>G (p.Ser1524Ter)	ADGRV1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3004368	NM_032119.4(ADGRV1):c.2437C>T (p.Arg813Ter)	ADGRV1	Pathogenic	criteria provided, multiple submitters, no conflicts
3008485	NM_032119.4(ADGRV1):c.3908dup (p.Leu1303fs)	ADGRV1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 12 · Orphanet: 9 · 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
ADGRV1	Definitive	Autosomal recessive	Usher syndrome type 2	8
PDZD7	Limited	Unknown	Usher syndrome type 2C	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ADGRV1	Orphanet:231178	Usher syndrome type 2
ADGRV1	Orphanet:36387	Genetic epilepsy with febrile seizure plus
PDZD7	Orphanet:231178	Usher syndrome type 2
FRAS1	Orphanet:2052	Fraser syndrome
FRAS1	Orphanet:93100	Renal agenesis, unilateral
CRYGC	Orphanet:1377	Cataract-microcornea syndrome
CRYGC	Orphanet:441452	Early-onset lamellar cataract
CRYGC	Orphanet:98984	Pulverulent cataract
CRYGC	Orphanet:98991	Early-onset nuclear cataract

Cohort genes → proteins

6 cohort genes, 6 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	6

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ADGRV1	HGNC:17416	ENSG00000164199	Q8WXG9	Adhesion G-protein coupled receptor V1	gencc,clinvar
PDZD7	HGNC:26257	ENSG00000186862	Q9H5P4	PDZ domain-containing protein 7	gencc,clinvar
FRAS1	HGNC:19185	ENSG00000138759	Q86XX4	Extracellular matrix organizing protein FRAS1	clinvar
CNKSR1	HGNC:19700	ENSG00000142675	Q969H4	Connector enhancer of kinase suppressor of ras 1	clinvar
CRYGC	HGNC:2410	ENSG00000163254	P07315	Gamma-crystallin C	clinvar
WDR36	HGNC:30696	ENSG00000134987	Q8NI36	WD repeat-containing protein 36	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ADGRV1	Adhesion G-protein coupled receptor V1	G-protein coupled receptor which has an essential role in the development of hearing and vision.
PDZD7	PDZ domain-containing protein 7	In cochlear developing hair cells, essential in organizing the USH2 complex at stereocilia ankle links.
FRAS1	Extracellular matrix organizing protein FRAS1	Involved in extracellular matrix organization.
CNKSR1	Connector enhancer of kinase suppressor of ras 1	May function as an adapter protein or regulator of Ras signaling pathways.
CRYGC	Gamma-crystallin C	Crystallins are the dominant structural components of the vertebrate eye lens.
WDR36	WD repeat-containing protein 36	Part of the small subunit (SSU) processome, first precursor of the small eukaryotic ribosomal subunit.

Protein-family classification

Druggable: 1 · Difficult: 3 · Unknown: 2 · Druggable fraction: 0.17

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	3	8.6×	0.010
GPCR	1	4.0×	0.339
Other/Unknown	2	0.6×	0.936

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ADGRV1	GPCR	yes		GPCR_2_secretin-like, Calx_beta, EPTP
PDZD7	Scaffold/PPI	no		PDZ, PDZ_sf, PDZD7_HN-like
FRAS1	Other/Unknown	no		EGF, VWF_dom, Calx_beta
CNKSR1	Scaffold/PPI	no		PDZ, SAM, PH_domain
CRYGC	Other/Unknown	no		Beta/gamma_crystallin, G_crystallin-like, Beta/Gamma-Crystallin
WDR36	Scaffold/PPI	no		WD40_rpt, WDR36/Utp21_C, WD40/YVTN_repeat-like_dom_sf

Expression context

Cohort genes with no expression data: 0.

5 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)	1
broad (>20)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
left adrenal gland	1
right adrenal gland	1
right adrenal gland cortex	1
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
germinal epithelium of ovary	1
parietal pleura	1
renal medulla	1
gastrocnemius	1
hindlimb stylopod muscle	1
right lobe of thyroid gland	1
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1
testis	1
calcaneal tendon	1
deltoid	1
tibialis anterior	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ADGRV1	196	broad	marker	right adrenal gland cortex, right adrenal gland, left adrenal gland
PDZD7	178	broad	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
FRAS1	212	ubiquitous	marker	germinal epithelium of ovary, parietal pleura, renal medulla
CNKSR1	253	broad	marker	hindlimb stylopod muscle, gastrocnemius, right lobe of thyroid gland
CRYGC	15	tissue_specific	yes	male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad, testis
WDR36	249	ubiquitous	marker	calcaneal tendon, tibialis anterior, deltoid

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
WDR36	3,290
FRAS1	2,552
CRYGC	2,111
ADGRV1	1,658
PDZD7	1,317
CNKSR1	762

Intra-cohort edges

A	B	Sources
ADGRV1	PDZD7	intact, string_interaction

Structural data

PDB: 4 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
WDR36	Q8NI36	3
PDZD7	Q9H5P4	2
CNKSR1	Q969H4	1
CRYGC	P07315	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ADGRV1	Q8WXG9
FRAS1	Q86XX4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 12. Enrichment computed across 6 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
EGR2 and SOX10-mediated initiation of Schwann cell myelination	1	122.8×	0.020	ADGRV1
Signaling by high-kinase activity BRAF mutants	1	105.7×	0.020	CNKSR1
MAP2K and MAPK activation	1	95.2×	0.020	CNKSR1
Signaling by RAF1 mutants	1	92.8×	0.020	CNKSR1
Signaling by moderate kinase activity BRAF mutants	1	84.6×	0.020	CNKSR1
Paradoxical activation of RAF signaling by kinase inactive BRAF	1	84.6×	0.020	CNKSR1
Signaling downstream of RAS mutants	1	84.6×	0.020	CNKSR1
rRNA modification in the nucleus and cytosol	1	62.4×	0.023	WDR36
Signaling by BRAF and RAF1 fusions	1	56.8×	0.023	CNKSR1
Major pathway of rRNA processing in the nucleolus and cytosol	1	20.6×	0.057	WDR36
Nervous system development	1	14.3×	0.074	ADGRV1
Developmental Biology	1	4.8×	0.194	ADGRV1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
inner ear receptor cell differentiation	2	1123.5×	4e-05	ADGRV1, PDZD7
detection of mechanical stimulus involved in sensory perception of sound	2	312.1×	3e-04	ADGRV1, PDZD7
visual perception	3	39.8×	4e-04	ADGRV1, CRYGC, WDR36
establishment of protein localization	2	144.0×	7e-04	ADGRV1, PDZD7
metanephros morphogenesis	1	702.2×	0.008	FRAS1
sensory perception of sound	2	33.6×	0.008	ADGRV1, PDZD7
maintenance of animal organ identity	1	561.7×	0.009	ADGRV1
sensory perception of light stimulus	1	312.1×	0.012	ADGRV1
auditory receptor cell development	1	312.1×	0.012	PDZD7
self proteolysis	1	255.3×	0.013	ADGRV1
nervous system process	1	200.6×	0.015	ADGRV1
cell communication	1	140.4×	0.017	FRAS1
auditory receptor cell stereocilium organization	1	140.4×	0.017	PDZD7
inner ear receptor cell stereocilium organization	1	140.4×	0.017	ADGRV1
skin development	1	73.9×	0.028	FRAS1
embryonic limb morphogenesis	1	66.9×	0.028	FRAS1
positive regulation of bone mineralization	1	65.3×	0.028	ADGRV1
lens development in camera-type eye	1	62.4×	0.028	CRYGC
inner ear development	1	62.4×	0.028	ADGRV1
photoreceptor cell maintenance	1	59.8×	0.028	ADGRV1
morphogenesis of an epithelium	1	57.3×	0.028	FRAS1
roof of mouth development	1	41.3×	0.037	FRAS1
ribosomal small subunit biogenesis	1	38.0×	0.039	WDR36
cellular response to calcium ion	1	33.4×	0.042	ADGRV1
cell surface receptor protein tyrosine kinase signaling pathway	1	29.0×	0.046	CNKSR1
establishment of localization in cell	1	26.8×	0.048	PDZD7
rRNA processing	1	23.6×	0.051	WDR36
anatomical structure morphogenesis	1	23.2×	0.051	FRAS1
regulation of protein stability	1	21.0×	0.055	ADGRV1
cell-cell adhesion	1	16.9×	0.065	ADGRV1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 6

Druggability breadth: 3 of 6 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ADGRV1	0	0
PDZD7	0	0
FRAS1	0	0
CNKSR1	0	0
CRYGC	0	0
WDR36	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
CNKSR1	12	Binding:12
CRYGC	9	Binding:9
WDR36	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 6; 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	ADGRV1
E	Difficult family or no structure, no drug	5	PDZD7, FRAS1, CNKSR1, CRYGC, WDR36

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ADGRV1	0	—
PDZD7	0	—
FRAS1	0	—
CNKSR1	12	—
CRYGC	9	—
WDR36	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.