Adult-onset foveomacular vitelliform dystrophy

Summary

Adult-onset foveomacular vitelliform dystrophy (MONDO:0011979) is a disease with 4 cohort genes and 1 clinical trial.

At a glance

• Prevalence: Unknown (Europe)
• Cohort genes: 4
• ClinVar variants: 83
• Phenotypes (HPO): 9
• Clinical trials: 1

Clinical features

Signs & symptoms

Clinical features (HPO)

9 HPO clinical features (Orphanet curated; top 9 by frequency):

HPO ID	Term	Frequency
HP:0000478	Abnormality of the eye	Very frequent (80-99%)
HP:0000504	Abnormality of vision	Very frequent (80-99%)
HP:0000505	Visual impairment	Very frequent (80-99%)
HP:0007677	Vitelliform maculopathy	Very frequent (80-99%)
HP:0000551	Color vision defect	Frequent (30-79%)
HP:0001123	Visual field defect	Frequent (30-79%)
HP:0001139	Choroideremia	Frequent (30-79%)
HP:0007730	Iris hypopigmentation	Frequent (30-79%)
HP:0007899	Retinal nonattachment	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	adult-onset foveomacular vitelliform dystrophy
Mondo ID	MONDO:0011979
Orphanet	99000
ICD-11	558806410
SNOMED CT	232049001
UMLS	C1842914
MedGen	334280
GARD	0010909
Is cancer (heuristic)	no

Also known as: adult-onset foveomacular dystrophy · adult-onset foveomacular dystrophy with choroidal neovascularization · adult-onset vitelliform macular dystrophy · AOFMD · AVMD · foveomacular dystrophy, adult-onset, with choroidal neovascularization · foveomacular dystrophy, adult-onset; AOFMD · Gass disease · macular dystrophy, vitelliform, 3 · macular dystrophy, vitelliform, adult-onset · macular dystrophy, vitelliform, type 3 · pseudo-Best disease · pseudo-vitelliform macular dystrophy · VMD3

Data availability: 83 ClinVar variants · 4 GenCC gene-disease records.

Disease family

An umbrella term covering 4 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › retinal disorder › retinal degeneration › macular degeneration › vitelliform macular dystrophy › adult-onset foveomacular vitelliform dystrophy

Related subtypes (1): vitelliform macular dystrophy 2

Subtypes (4): vitelliform macular dystrophy 1, vitelliform macular dystrophy 4, vitelliform macular dystrophy 5, vitelliform macular dystrophy 3

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

83 retrieved; paginated sample, class counts are floors:

28 uncertain significance, 22 conflicting classifications of pathogenicity, 17 benign, 10 benign/likely benign, 2 pathogenic, 2 likely pathogenic, 2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
438671	NM_000322.5(PRPH2):c.636C>G (p.Ser212Arg)	PRPH2	Pathogenic	criteria provided, single submitter
599068	NM_000322.5(PRPH2):c.316_317del (p.Val106fs)	PRPH2	Pathogenic	no assertion criteria provided
98690	NM_000322.5(PRPH2):c.635G>C (p.Ser212Thr)	PRPH2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
98717	NM_000322.5(PRPH2):c.904G>T (p.Glu302Ter)	PRPH2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
975918	NM_000322.5(PRPH2):c.246_249del (p.Cys82fs)	PRPH2	Likely pathogenic	criteria provided, single submitter
992448	NM_000322.5(PRPH2):c.668T>C (p.Ile223Thr)	PRPH2	Likely pathogenic	no assertion criteria provided
255826	NM_000322.5(PRPH2):c.801C>T (p.Val267=)	PRPH2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
285861	NM_000322.5(PRPH2):c.367C>T (p.Arg123Trp)	PRPH2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
356743	NM_000322.5(PRPH2):c.*1687C>T	PRPH2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
356745	NM_000322.5(PRPH2):c.*1565G>A	PRPH2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
356761	NM_000322.5(PRPH2):c.*797G>A	PRPH2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
356775	NM_000322.5(PRPH2):c.*20C>T	PRPH2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
356776	NM_000322.5(PRPH2):c.1008C>T (p.Gly336=)	PRPH2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
356778	NM_000322.5(PRPH2):c.312C>T (p.Ile104=)	PRPH2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
356779	NM_000322.5(PRPH2):c.252C>T (p.Asp84=)	PRPH2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
498453	NM_000322.5(PRPH2):c.888C>T (p.Pro296=)	PRPH2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
846922	NM_000322.5(PRPH2):c.454A>G (p.Met152Val)	PRPH2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
908040	NM_000322.5(PRPH2):c.346G>T (p.Ala116Ser)	PRPH2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
908512	NM_000322.5(PRPH2):c.*1079G>A	PRPH2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
908960	NM_000322.5(PRPH2):c.955T>C (p.Phe319Leu)	PRPH2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
909688	NM_000322.5(PRPH2):c.*152G>A	PRPH2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
909882	NM_000322.5(PRPH2):c.852C>A (p.Arg284=)	PRPH2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
910496	NM_000322.5(PRPH2):c.*509G>A	PRPH2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
910955	NM_000322.5(PRPH2):c.44A>G (p.Lys15Arg)	PRPH2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
98658	NM_000322.5(PRPH2):c.249C>T (p.Tyr83=)	PRPH2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
98664	NM_000322.5(PRPH2):c.37C>T (p.Arg13Trp)	PRPH2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
98702	NM_000322.5(PRPH2):c.708C>T (p.Tyr236=)	PRPH2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
98721	NM_000322.5(PRPH2):c.938C>T (p.Pro313Leu)	PRPH2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
356744	NM_000322.5(PRPH2):c.*1580C>G	PRPH2	Uncertain significance	criteria provided, single submitter
356748	NM_000322.5(PRPH2):c.*1408G>C	PRPH2	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 58 · Orphanet: 21 · 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
IMPG1	Definitive	Autosomal dominant	vitelliform macular dystrophy 4	7
IMPG2	Definitive	Autosomal dominant	vitelliform macular dystrophy 5	8
PRPH2	Definitive	Autosomal dominant	hereditary macular dystrophy	21

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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
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
IMPG1	Orphanet:251287	Benign concentric annular macular dystrophy
IMPG1	Orphanet:791	Retinitis pigmentosa
IMPG1	Orphanet:99000	Adult-onset foveomacular vitelliform dystrophy

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PRPH2	HGNC:9942	ENSG00000112619	P23942	Peripherin-2	gencc,clinvar
BEST1	HGNC:12703	ENSG00000167995	O76090	Bestrophin-1	gencc
IMPG2	HGNC:18362	ENSG00000081148	Q9BZV3	Interphotoreceptor matrix proteoglycan 2	gencc
IMPG1	HGNC:6055	ENSG00000112706	Q17R60	Interphotoreceptor matrix proteoglycan 1	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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.
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.
IMPG1	Interphotoreceptor matrix proteoglycan 1	Chondroitin sulfate-, heparin- and hyaluronan-binding protein.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 4 · Druggable fraction: 0.0

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
Other/Unknown	4	1.8×	0.097

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PRPH2	Other/Unknown	no		Peripherin/rom-1, Tetraspanin_EC2_sf, Peripherin/rom-1_CS
BEST1	Other/Unknown	no		Bestrophin, Bestrophin-like
IMPG2	Other/Unknown	no		SEA_dom, EGF, SEA_dom_sf
IMPG1	Other/Unknown	no		SEA_dom, EGF, SEA_dom_sf

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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
male germ line stem cell (sensu Vertebrata) in testis	2
hindlimb stylopod muscle	1
quadriceps femoris	1
vastus lateralis	1
inferior olivary complex	1
lateral globus pallidus	1
pigmented layer of retina	1
pineal body	1
right uterine tube	1
nucleus accumbens	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PRPH2	176	tissue_specific	marker	quadriceps femoris, vastus lateralis, hindlimb stylopod muscle
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
IMPG1	155	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, nucleus accumbens, secondary oocyte

Protein interactions among cohort

Intra-cohort edges: 5.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
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: 2 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
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: 3. Enrichment computed across 4 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Stimuli-sensing channels	1	135.9×	0.016	BEST1
Ion channel transport	1	96.0×	0.016	BEST1
Transport of small molecules	1	25.1×	0.040	BEST1

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
visual perception	4	79.5×	5e-07	PRPH2, BEST1, IMPG2, IMPG1
detection of light stimulus involved in visual perception	2	324.1×	2e-04	PRPH2, BEST1
response to low light intensity stimulus	1	4213.0×	0.002	PRPH2
gamma-aminobutyric acid secretion, neurotransmission	1	2106.5×	0.002	BEST1
extracellular matrix organization	2	61.1×	0.002	IMPG2, IMPG1
transepithelial chloride transport	1	468.1×	0.007	BEST1
retina morphogenesis in camera-type eye	1	468.1×	0.007	IMPG2
glutamate secretion	1	421.3×	0.007	BEST1
photoreceptor cell outer segment organization	1	263.3×	0.008	PRPH2
protein heterooligomerization	1	263.3×	0.008	PRPH2
regulation of calcium ion transport	1	200.6×	0.010	BEST1
protein complex oligomerization	1	168.5×	0.011	BEST1
chloride transport	1	113.9×	0.015	BEST1
regulation of synaptic plasticity	1	64.8×	0.023	BEST1
retina development in camera-type eye	1	63.8×	0.023	PRPH2
chloride transmembrane transport	1	59.3×	0.023	BEST1
monoatomic ion transmembrane transport	1	52.0×	0.025	BEST1
protein maturation	1	40.9×	0.030	PRPH2
protein homooligomerization	1	30.5×	0.037	PRPH2
protein localization to plasma membrane	1	27.2×	0.039	PRPH2
intracellular protein localization	1	26.2×	0.039	IMPG2
cell adhesion	1	9.4×	0.103	PRPH2

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 4 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
PRPH2	0	0
BEST1	0	0
IMPG2	0	0
IMPG1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	4	PRPH2, BEST1, IMPG2, IMPG1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PRPH2	0	—
BEST1	0	—
IMPG2	0	—
IMPG1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT02162953	Not specified	COMPLETED	Stem Cell Models of Best Disease and Other Retinal Degenerative Diseases.