Autosomal dominant vitreoretinochoroidopathy

Summary

Autosomal dominant vitreoretinochoroidopathy (MONDO:0008662) is a disease caused by BEST1 (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: (Worldwide) [Orphanet-validated]
• Causal gene: BEST1 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 56

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		3	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Europe	Not yet validated

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal dominant vitreoretinochoroidopathy
Mondo ID	MONDO:0008662
MeSH	C536352
OMIM	193220
Orphanet	3086
DOID	DOID:0111569
ICD-11	96951767
SNOMED CT	711162004
UMLS	C3888099
MedGen	854768
GARD	0005507
Is cancer (heuristic)	no

Also known as: ADVIRC · vitreoretinochoroidopathy · vitreoretinochoroidopathy dominant · VRCP · VRCP autosomal dominant

Data availability: 56 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › disorder of orbital region › eye disorder › vitreous body disorder › vitreous disorder › vitreous syneresis › vitreoretinal degeneration › BEST1-related vitreoretinochoroidopathy › autosomal dominant vitreoretinochoroidopathy

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

56 retrieved; paginated sample, class counts are floors:

15 uncertain significance, 12 conflicting classifications of pathogenicity, 10 pathogenic/likely pathogenic, 8 benign, 5 pathogenic, 3 benign/likely benign, 3 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
143127	NM_004183.4(BEST1):c.763C>T (p.Arg255Trp)	BEST1	Pathogenic	criteria provided, multiple submitters, no conflicts
2039113	NM_004183.4(BEST1):c.508C>T (p.Gln170Ter)	BEST1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2737	NM_004183.4(BEST1):c.728C>T (p.Ala243Val)	BEST1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2738	NM_004183.4(BEST1):c.140G>A (p.Arg47His)	BEST1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2741	NM_004183.4(BEST1):c.598C>T (p.Arg200Ter)	BEST1	Pathogenic	criteria provided, multiple submitters, no conflicts
2744	NM_004183.4(BEST1):c.256G>A (p.Val86Met)	BEST1	Pathogenic	criteria provided, multiple submitters, no conflicts
2751	NM_004183.4(BEST1):c.704T>C (p.Val235Ala)	BEST1	Pathogenic	no assertion criteria provided
632163	NM_004183.4(BEST1):c.1415del (p.Leu472fs)	BEST1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
812233	NM_004183.4(BEST1):c.908A>T (p.Asp303Val)	BEST1	Pathogenic	criteria provided, single submitter
931891	NM_004183.4(BEST1):c.1444del (p.Glu482fs)	BEST1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
99695	NM_004183.4(BEST1):c.240C>A (p.Phe80Leu)	BEST1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
99725	NM_004183.4(BEST1):c.584C>T (p.Ala195Val)	BEST1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
99726	NM_004183.4(BEST1):c.602T>C (p.Ile201Thr)	BEST1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
99735	NM_004183.4(BEST1):c.652C>T (p.Arg218Cys)	BEST1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
99766	NM_004183.4(BEST1):c.889C>T (p.Pro297Ser)	BEST1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1705627	NM_004183.4(BEST1):c.684C>A (p.Asp228Glu)	BEST1	Likely pathogenic	criteria provided, single submitter
3382257	NM_004183.4(BEST1):c.488T>G (p.Met163Arg)	BEST1	Likely pathogenic	criteria provided, single submitter
852739	NM_004183.4(BEST1):c.682G>C (p.Asp228His)	BEST1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1487156	NM_004183.4(BEST1):c.56G>A (p.Arg19His)	BEST1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
289316	NM_004183.4(BEST1):c.495G>A (p.Pro165=)	BEST1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
305118	NM_004183.4(BEST1):c.152+6G>T	BEST1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
305121	NM_004183.4(BEST1):c.699A>G (p.Pro233=)	BEST1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
305122	NM_004183.4(BEST1):c.813C>T (p.Leu271=)	BEST1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
305123	NM_004183.4(BEST1):c.954C>G (p.Ser318=)	BEST1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
386501	NM_004183.4(BEST1):c.1054G>A (p.Ala352Thr)	BEST1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
877569	NM_004183.4(BEST1):c.822C>T (p.Pro274=)	BEST1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
878549	NM_004183.4(BEST1):c.482-15C>T	BEST1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
878590	NM_004183.4(BEST1):c.991C>T (p.Arg331Trp)	BEST1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
878688	NM_004183.4(BEST1):c.*45T>C	BEST1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
99732	NM_004183.4(BEST1):c.637-6C>T	BEST1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 22 · Orphanet: 8 · 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
BEST1	Definitive	Autosomal dominant	autosomal dominant vitreoretinochoroidopathy	22

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
BEST1	Orphanet:1243	Best vitelliform macular dystrophy
BEST1	Orphanet:139455	Autosomal recessive bestrophinopathy
BEST1	Orphanet:263347	MRCS syndrome
BEST1	Orphanet:3086	Autosomal dominant vitreoretinochoroidopathy
BEST1	Orphanet:35612	Nanophthalmos
BEST1	Orphanet:791	Retinitis pigmentosa
BEST1	Orphanet:99000	Adult-onset foveomacular vitelliform dystrophy
FTH1	Orphanet:247790	FTH1-related iron overload

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
BEST1	HGNC:12703	ENSG00000167995	O76090	Bestrophin-1	gencc,clinvar
FTH1	HGNC:3976	ENSG00000167996	P02794	Ferritin heavy chain	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
BEST1	Bestrophin-1	Ligand-gated anion channel that allows the movement of anions across cell membranes when activated by calcium (Ca2+).
FTH1	Ferritin heavy chain	Stores iron in a soluble, non-toxic, readily available form.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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
Enzyme (other)	1	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
BEST1	Other/Unknown	no		Bestrophin, Bestrophin-like
FTH1	Enzyme (other)	yes	1.16.3.1	Ferritin, Ferritin_DPS_dom, Ferritin-like_diiron

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
inferior olivary complex	1
lateral globus pallidus	1
pigmented layer of retina	1
nerve	1
stromal cell of endometrium	1
upper lobe of left lung	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
BEST1	209	ubiquitous	marker	pigmented layer of retina, lateral globus pallidus, inferior olivary complex
FTH1	292	ubiquitous	marker	stromal cell of endometrium, upper lobe of left lung, nerve

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FTH1	2,729
BEST1	959

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FTH1	P02794	147
BEST1	O76090	19

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. 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
Scavenging by Class A Receptors	1	300.5×	0.020	FTH1
Iron uptake and transport	1	173.0×	0.020	FTH1
Golgi Associated Vesicle Biogenesis	1	100.2×	0.023	FTH1
Stimuli-sensing channels	1	68.0×	0.026	BEST1
Ion channel transport	1	48.0×	0.029	BEST1
Transport of small molecules	1	12.6×	0.085	BEST1
Neutrophil degranulation	1	11.5×	0.085	FTH1

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
gamma-aminobutyric acid secretion, neurotransmission	1	4213.0×	0.004	BEST1
transepithelial chloride transport	1	936.2×	0.007	BEST1
glutamate secretion	1	842.6×	0.007	BEST1
iron ion transport	1	443.5×	0.007	FTH1
regulation of calcium ion transport	1	401.2×	0.007	BEST1
negative regulation of ferroptosis	1	401.2×	0.007	FTH1
protein complex oligomerization	1	337.0×	0.007	BEST1
detection of light stimulus involved in visual perception	1	324.1×	0.007	BEST1
negative regulation of fibroblast proliferation	1	247.8×	0.007	FTH1
chloride transport	1	227.7×	0.007	BEST1
regulation of synaptic plasticity	1	129.6×	0.011	BEST1
intracellular iron ion homeostasis	1	122.1×	0.011	FTH1
chloride transmembrane transport	1	118.7×	0.011	BEST1
monoatomic ion transmembrane transport	1	104.0×	0.012	BEST1
visual perception	1	39.8×	0.028	BEST1
immune response	1	23.5×	0.045	FTH1
negative regulation of cell population proliferation	1	21.1×	0.047	FTH1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 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
BEST1	0	0
FTH1	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
FTH1	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
FTH1	1.16.3.1	ferroxidase

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	1	FTH1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	BEST1

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)
BEST1	0	—
FTH1	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.