Vitelliform macular dystrophy 2

Summary

Vitelliform macular dystrophy 2 (MONDO:0007931) is a disease caused by BEST1 (GenCC Definitive), with 5 cohort genes and 17 clinical trials. Top therapeutic interventions include dapagliflozin.

At a glance

• Prevalence: 1-9 / 100 000 (Europe) [Orphanet-validated]
• Causal gene: BEST1 (GenCC Definitive)
• Cohort genes: 5
• ClinVar variants: 150
• Phenotypes (HPO): 6
• Clinical trials: 17

Clinical features

Epidemiology

Prevalence records

4 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000		Europe	Validated
Point prevalence	1-5 / 10 000	20	Sweden	Validated
Point prevalence	1-9 / 100 000	1.5	Denmark	Validated
Prevalence at birth	1-9 / 100 000	1.5	Denmark	Validated

Signs & symptoms

Clinical features (HPO)

6 HPO clinical features (Orphanet curated; top 6 by frequency):

HPO ID	Term	Frequency
HP:0000505	Visual impairment	Very frequent (80-99%)
HP:0008028	Cystoid macular degeneration	Very frequent (80-99%)
HP:0012508	Metamorphopsia	Very frequent (80-99%)
HP:0000551	Color vision defect	Frequent (30-79%)
HP:0001123	Visual field defect	Occasional (5-29%)
HP:0001139	Choroideremia	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	vitelliform macular dystrophy 2
Mondo ID	MONDO:0007931
OMIM	153700
Orphanet	1243
SNOMED CT	763387005
UMLS	C2745945
MedGen	411553
GARD	0000182
NORD	853
Is cancer (heuristic)	no

Also known as: Best disease · Best macular dystrophy · Best Vitelliform Macular Dystrophy · BEST1 retinopathy · BMD · BVMD · early-onset vitelliform macular dystrophy · juvenile-onset vitelliform macular dystrophy · macular degeneration, polymorphic vitelline · macular dystrophy, vitelliform, 2 · macular dystrophy, vitelliform, type 2 · polymorphic vitelline macular degeneration · vitelliform macular dystrophy type 2 · vitelliform macular dystrophy, early-onset · vitelliform macular dystrophy, juvenile-onset · vitelliform macular dystrophy, type 2 · VMD2

Data availability: 150 ClinVar variants · 5 GenCC gene-disease records · 6 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › retinal disorder › retinal degeneration › macular degeneration › vitelliform macular dystrophy › vitelliform macular dystrophy 2

Related subtypes (1): adult-onset foveomacular vitelliform dystrophy

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

150 retrieved; paginated sample, class counts are floors:

40 pathogenic/likely pathogenic, 34 pathogenic, 26 uncertain significance, 22 conflicting classifications of pathogenicity, 15 likely pathogenic, 8 benign, 4 benign/likely benign, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1004951	NM_004183.4(BEST1):c.638A>G (p.Glu213Gly)	BEST1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1069280	NM_004183.4(BEST1):c.1552G>T (p.Glu518Ter)	BEST1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1074134	NM_004183.4(BEST1):c.1066C>T (p.Arg356Ter)	BEST1	Pathogenic	criteria provided, single submitter
143127	NM_004183.4(BEST1):c.763C>T (p.Arg255Trp)	BEST1	Pathogenic	criteria provided, multiple submitters, no conflicts
1466118	NM_004183.4(BEST1):c.79A>G (p.Ser27Gly)	BEST1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
162042	NM_004183.4(BEST1):c.172_173dup (p.Gln58fs)	BEST1	Pathogenic	criteria provided, single submitter
1685569	NM_004183.4(BEST1):c.737G>A (p.Ser246Asn)	BEST1	Pathogenic	criteria provided, single submitter
1709319	NM_004183.4(BEST1):c.17C>A (p.Thr6Lys)	BEST1	Pathogenic/Likely 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
265047	NM_004183.4(BEST1):c.874G>A (p.Glu292Lys)	BEST1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2727	NM_004183.4(BEST1):c.279G>C (p.Trp93Cys)	BEST1	Pathogenic	criteria provided, multiple submitters, no conflicts
2728	NM_004183.4(BEST1):c.253T>C (p.Tyr85His)	BEST1	Pathogenic	criteria provided, multiple submitters, no conflicts
2729	NM_004183.4(BEST1):c.896G>A (p.Gly299Glu)	BEST1	Pathogenic	criteria provided, multiple submitters, no conflicts
2730	NM_004183.4(BEST1):c.87C>G (p.Tyr29Ter)	BEST1	Pathogenic	criteria provided, single submitter
2731	NM_004183.4(BEST1):c.679T>A (p.Tyr227Asn)	BEST1	Pathogenic	criteria provided, multiple submitters, no conflicts
2732	NM_004183.4(BEST1):c.16A>C (p.Thr6Pro)	BEST1	Pathogenic	no assertion criteria provided
2733	NM_004183.4(BEST1):c.881TCA[1] (p.Ile295del)	BEST1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2734	NM_004183.4(BEST1):c.25G>A (p.Val9Met)	BEST1	Pathogenic	criteria provided, single submitter
2736	NM_004183.4(BEST1):c.436_437delinsAA (p.Ala146Lys)	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
2739	NM_004183.4(BEST1):c.1470_1471del (p.His490fs)	BEST1	Pathogenic	criteria provided, multiple submitters, no conflicts
2740	NM_004183.4(BEST1):c.422G>A (p.Arg141His)	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
2749	NM_004183.4(BEST1):c.680A>G (p.Tyr227Cys)	BEST1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
279701	NM_004183.4(BEST1):c.37C>T (p.Arg13Cys)	BEST1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
444256	NM_004183.4(BEST1):c.712del (p.Gln238fs)	BEST1	Pathogenic	criteria provided, multiple submitters, no conflicts
496689	NM_004183.4(BEST1):c.910G>A (p.Asp304Asn)	BEST1	Pathogenic	no assertion criteria provided
548451	NM_004183.4(BEST1):c.241G>A (p.Val81Met)	BEST1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
559498	NM_004183.4(BEST1):c.888C>G (p.Asn296Lys)	BEST1	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 22 · Orphanet: 22 · 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	vitelliform macular dystrophy 2	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
IMPG2	Orphanet:791	Retinitis pigmentosa
IMPG2	Orphanet:99000	Adult-onset foveomacular vitelliform dystrophy
FTH1	Orphanet:247790	FTH1-related iron overload
IMPG1	Orphanet:251287	Benign concentric annular macular dystrophy
IMPG1	Orphanet:791	Retinitis pigmentosa
IMPG1	Orphanet:99000	Adult-onset foveomacular vitelliform dystrophy
PRPH2	Orphanet:1872	Cone rod dystrophy
PRPH2	Orphanet:227796	Fundus albipunctatus
PRPH2	Orphanet:52427	Retinitis punctata albescens
PRPH2	Orphanet:75377	Central areolar choroidal dystrophy
PRPH2	Orphanet:791	Retinitis pigmentosa
PRPH2	Orphanet:827	Stargardt disease
PRPH2	Orphanet:99000	Adult-onset foveomacular vitelliform dystrophy
PRPH2	Orphanet:99001	Butterfly-shaped pigment dystrophy
PRPH2	Orphanet:99003	Multifocal pattern dystrophy simulating fundus flavimaculatus

Cohort genes → proteins

5 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
BEST1	HGNC:12703	ENSG00000167995	O76090	Bestrophin-1	gencc,clinvar
IMPG2	HGNC:18362	ENSG00000081148	Q9BZV3	Interphotoreceptor matrix proteoglycan 2	clinvar
FTH1	HGNC:3976	ENSG00000167996	P02794	Ferritin heavy chain	clinvar
IMPG1	HGNC:6055	ENSG00000112706	Q17R60	Interphotoreceptor matrix proteoglycan 1	clinvar
PRPH2	HGNC:9942	ENSG00000112619	P23942	Peripherin-2	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+).
IMPG2	Interphotoreceptor matrix proteoglycan 2	Chondroitin sulfate- and hyaluronan-binding proteoglycan involved in the organization of interphotoreceptor matrix; may participate in the maturation and maintenance of the light-sensitive photoreceptor outer segment.
FTH1	Ferritin heavy chain	Stores iron in a soluble, non-toxic, readily available form.
IMPG1	Interphotoreceptor matrix proteoglycan 1	Chondroitin sulfate-, heparin- and hyaluronan-binding protein.
PRPH2	Peripherin-2	Essential for retina photoreceptor outer segment disk morphogenesis, may also play a role with ROM1 in the maintenance of outer segment disk structure.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 4 · Druggable fraction: 0.2

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	2.4×	0.353
Other/Unknown	4	1.4×	0.353

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
BEST1	Other/Unknown	no		Bestrophin, Bestrophin-like
IMPG2	Other/Unknown	no		SEA_dom, EGF, SEA_dom_sf
FTH1	Enzyme (other)	yes	1.16.3.1	Ferritin, Ferritin_DPS_dom, Ferritin-like_diiron
IMPG1	Other/Unknown	no		SEA_dom, EGF, SEA_dom_sf
PRPH2	Other/Unknown	no		Peripherin/rom-1, Tetraspanin_EC2_sf, Peripherin/rom-1_CS

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)	0
broad (>20)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
male germ line stem cell (sensu Vertebrata) in testis	2
inferior olivary complex	1
lateral globus pallidus	1
pigmented layer of retina	1
pineal body	1
right uterine tube	1
nerve	1
stromal cell of endometrium	1
upper lobe of left lung	1
nucleus accumbens	1
secondary oocyte	1
hindlimb stylopod muscle	1
quadriceps femoris	1
vastus lateralis	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
IMPG2	81	tissue_specific	marker	right uterine tube, male germ line stem cell (sensu Vertebrata) in testis, pineal body
FTH1	292	ubiquitous	marker	stromal cell of endometrium, upper lobe of left lung, nerve
IMPG1	155	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, nucleus accumbens, secondary oocyte
PRPH2	176	tissue_specific	marker	quadriceps femoris, vastus lateralis, hindlimb stylopod muscle

Protein interactions among cohort

Intra-cohort edges: 5.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FTH1	2,729
PRPH2	1,234
BEST1	959
IMPG1	690
IMPG2	516

Intra-cohort edges

A	B	Sources
BEST1	IMPG1	string_interaction
BEST1	IMPG2	string_interaction
BEST1	PRPH2	string_interaction
IMPG1	PRPH2	string_interaction
IMPG2	PRPH2	string_interaction

Structural data

PDB: 3 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FTH1	P02794	147
BEST1	O76090	19
PRPH2	P23942	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
IMPG1	Q17R60	59.26
IMPG2	Q9BZV3	54.28

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. Enrichment computed across 5 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 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
visual perception	4	63.6×	3e-06	BEST1, IMPG2, IMPG1, PRPH2
detection of light stimulus involved in visual perception	2	259.3×	3e-04	BEST1, PRPH2
response to low light intensity stimulus	1	3370.4×	0.003	PRPH2
gamma-aminobutyric acid secretion, neurotransmission	1	1685.2×	0.004	BEST1
extracellular matrix organization	2	48.9×	0.004	IMPG2, IMPG1
transepithelial chloride transport	1	374.5×	0.010	BEST1
retina morphogenesis in camera-type eye	1	374.5×	0.010	IMPG2
glutamate secretion	1	337.0×	0.010	BEST1
photoreceptor cell outer segment organization	1	210.7×	0.013	PRPH2
protein heterooligomerization	1	210.7×	0.013	PRPH2
iron ion transport	1	177.4×	0.013	FTH1
regulation of calcium ion transport	1	160.5×	0.013	BEST1
negative regulation of ferroptosis	1	160.5×	0.013	FTH1
protein complex oligomerization	1	134.8×	0.015	BEST1
negative regulation of fibroblast proliferation	1	99.1×	0.019	FTH1
chloride transport	1	91.1×	0.019	BEST1
regulation of synaptic plasticity	1	51.9×	0.029	BEST1
retina development in camera-type eye	1	51.1×	0.029	PRPH2
intracellular iron ion homeostasis	1	48.9×	0.029	FTH1
chloride transmembrane transport	1	47.5×	0.029	BEST1
monoatomic ion transmembrane transport	1	41.6×	0.032	BEST1
protein maturation	1	32.7×	0.038	PRPH2
protein homooligomerization	1	24.4×	0.049	PRPH2
protein localization to plasma membrane	1	21.7×	0.052	PRPH2
intracellular protein localization	1	20.9×	0.052	IMPG2
immune response	1	9.4×	0.110	FTH1
negative regulation of cell population proliferation	1	8.4×	0.117	FTH1
cell adhesion	1	7.5×	0.127	PRPH2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 5 evidence-associated genes (20%) 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
IMPG2	0	0
FTH1	0	0
IMPG1	0	0
PRPH2	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: 5; 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	4	BEST1, IMPG2, IMPG1, PRPH2

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)
BEST1	0	—
IMPG2	0	—
FTH1	2	—
IMPG1	0	—
PRPH2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 17.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	14
PHASE4	1
PHASE3	1
PHASE1/PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05704088	PHASE4	COMPLETED	SGLT2 Inhibitors Between Reno Protective Effects and Impact on Bone and Mineral Disease Among Lupus Nephritis Patients
NCT05457530	PHASE3	WITHDRAWN	Doravirine and Weight Gain in Antiretroviral Naive
NCT07185256	PHASE1/PHASE2	RECRUITING	Safety and Tolerability of Subretinally Injected OPGx-BEST1 in Patients With Best Vitelliform Macular Dystrophy (BVMD) or Autosomal-Recessive Bestrophinopathy (ARB)
NCT02435940	Not specified	RECRUITING	Inherited Retinal Degenerative Disease Registry
NCT05102916	Not specified	RECRUITING	Swiss Registry for Neuromuscular Disorders
NCT05809635	Not specified	RECRUITING	Study of BEST1 Vitelliform Macular Dystrophy
NCT06491615	Not specified	RECRUITING	National Ophthalmic Genotyping and Phenotyping Network (eyeGENE (Registered Trademark)), Stage 3 - Expansion of DNA and Data Repositories for Rare Inherited Ophthalmic Diseases
NCT06581887	Not specified	RECRUITING	Defining Outcome Measures for Behavioural and Emotional Problems in Dystrophinopathies
NCT07298174	Not specified	NOT_YET_RECRUITING	Wide Field OCTA in Ocular Diseases
NCT00472745	Not specified	COMPLETED	The Effect of Weight Loss on Bone in Men
NCT02162953	Not specified	COMPLETED	Stem Cell Models of Best Disease and Other Retinal Degenerative Diseases.
NCT03225703	Not specified	UNKNOWN	The Effect of High Impact Exercise on Bone and Articular Cartilage in Post-menopausal Women
NCT03383861	Not specified	TERMINATED	Nutrition Status, BMD, and SSRIs
NCT03820895	Not specified	COMPLETED	Vitamin D Levels in Adolescent Idiopathic Scoliosis
NCT03866135	Not specified	COMPLETED	Bone Mineral Density, Disease Duration, and Activity in Ankylosing Spondylitis
NCT04427644	Not specified	COMPLETED	Body Mass Index and Obesity Surgery Mortality Risk Score in Perioperative Complications of Laparoscopic Sleeve Gastrectomy
NCT05258032	Not specified	UNKNOWN	Structural and Functional Characterization of Rare Ocular Diseases

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
DAPAGLIFLOZIN	4	1
CHEMBL4281478	0	1