GeneBe

BEST1

protein-coding

bestrophin 1, the group of Bestrophins

Gene summary

This gene encodes a member of the bestrophin gene family. This small gene family is characterized by proteins with a highly conserved N-terminus with four to six transmembrane domains. Bestrophins may form chloride ion channels or may regulate voltage-gated L-type calcium-ion channels. Bestrophins are generally believed to form calcium-activated chloride-ion channels in epithelial cells but they have also been shown to be highly permeable to bicarbonate ion transport in retinal tissue. Mutations in this gene are responsible for juvenile-onset vitelliform macular dystrophy (VMD2), also known as Best macular dystrophy, in addition to adult-onset vitelliform macular dystrophy (AVMD) and other retinopathies. Alternative splicing results in multiple variants encoding distinct isoforms.[provided by RefSeq, Nov 2008]

Previous symbols:
  • VMD2

MANE transcript

NM_004183.4

Inheritance

AD, AR

ClinVar variants

P:388U:324B:134

Top phenotype

Vitreoretinochoroidopathy

gnomAD constraint

pLI —, LoF o/e 1.01

Max pathogenic AF

—

Genomic locus

chr11:61,950,063-61,965,515

External References & Databases

Ensembl (ENSG00000167995)NCBI Gene (7439)OMIM (607854)HGNC:12703GenCCUniProt (O76090)AlphaFoldClinVar (BEST1)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~15.5 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

adult-onset foveomacular vitelliform dystrophySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011979

Submitter: Orphanet

vitelliform macular dystrophy 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007931

Submitter: PanelApp Australia

retinitis pigmentosaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019200

Submitter: G2P

autosomal dominant vitreoretinochoroidopathyDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008662

Submitter: G2P

retinitis pigmentosa 50LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0013175

Submitter: Ambry Genetics

vitelliform macular dystrophy 2DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007931

Submitter: Ambry Genetics

retinitis pigmentosaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019200

Submitter: Orphanet

autosomal dominant vitreoretinochoroidopathySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008662

Submitter: Orphanet

MRCS syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0016979

Submitter: Orphanet

autosomal recessive bestrophinopathySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012733

Submitter: Orphanet

autosomal dominant vitreoretinochoroidopathySTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008662

Submitter: Labcorp Genetics (formerly Invitae)

vitelliform macular dystrophy 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007931

Submitter: Labcorp Genetics (formerly Invitae)

autosomal recessive bestrophinopathyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012733

Submitter: Ambry Genetics

autosomal recessive bestrophinopathySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012733

Submitter: Labcorp Genetics (formerly Invitae)

retinitis pigmentosa 50STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013175

Submitter: Labcorp Genetics (formerly Invitae)

autosomal dominant vitreoretinochoroidopathyMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0008662

Submitter: Ambry Genetics

BEST1-related dominant retinopathyDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0700238

Submitter: ClinGen

*BEST1* (also referred to in the literature as *VMD2* or *TU15B*) was first reported in relation to autosomal dominant inheritance of Best vitelliform macular dystrophy (BVMD) in 1998 (Petrukhin et al., PMID: 9662395). Disease-causing *BEST1* mutations are also associated with autosomal dominant vitreoretinochoroidopathy (ADVIRC) and autosomal recessive bestrophinopathy (ARB). Per criteria outlined by the ClinGen Lumping & Splitting Working Group, the phenotype of cases diagnosed with vitelliform macular dytrophy or other forms of BEST1-related dominant retinopathy has been found to represent a distinct disease entity from cases diagnosed with vitreoretinochoroidopathy (AD) or bestrophinopathy (AR). Therefore, this curation has focused on BEST1-related dominant retinopathy, while the gene will undergo separate curations for BEST1-related vitreoretinochoroidopathy and BEST1-related recessive retinopathy. This curation has included twenty variants (17 missense, 1 in-frame deletion, 1 nonsense and 1 frameshift) that have been reported in twenty probands in nine publications (PMIDs: 10331951, 16754206, 9700209, 10617923, 14517959, 27193166, 10854112, 25082885, 31836750). Segregation data have also been scored from three families showing co-segregation of *BEST1* with BVMD (PMID: 10617923, PMID: 9700209, PMID: 16754206). The mechanism of pathogenicity appears to be dominant negative, primarily through mislocalization of the BEST1 protein and a reduction in anion conductance in the RPE. This gene-disease association is also supported by experimental evidence that *BEST1* mRNA and BEST1 protein expression are restricted to the RPE layer of the retina (PMID: 9700209 and PMID: 29022597). Two functional alteration experiments, one conducted in patient cells and one conducted in HEK-293 cells, show that *BEST1* mutations result in mislocalization of the mature protein in the cell and strongly reduced anion permeability (PMID: 21878505, PMID: 32111077). A *BEST1* (+/W93C) knock-in mouse model was shown to recapitulate many of the features of BVMD seen in human patients, including an abnormal LP luminance-response function, accumulation of lipofuscin in RPE cells, and the formation of fluid- and debris-filled retinal detachments (PMID: 20053664). In summary, *BEST1* is definitively associated with BEST1-related dominant retinopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time without the emergence of contradictory evidence. This classification was approved by the ClinGen Retina GCEP on August 3rd, 2023 (SOP Version 9).

vitelliform macular dystrophy 2SUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007931

Submitter: Orphanet

autosomal recessive bestrophinopathySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012733

Submitter: PanelApp Australia

autosomal dominant vitreoretinochoroidopathySTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008662

Submitter: PanelApp Australia

vitelliform macular dystrophy 2DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007931

Submitter: G2P

autosomal recessive bestrophinopathyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012733

Submitter: G2P

nanophthalmiaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0005514

Submitter: Orphanet

Clinical Genomic Database (CGD)

VitreoretinochoroidopathyAD

Manifestation: Ophthalmologic

Intervention: Ophthalmologic; Pharmacogenomic

Rationale: Findings such as glaucoma and retinal detachment have been described, and surveillance and early treatment (eg, direct laser photocoagulation and anti-vascular endothelial growth factors for choroidal neovascularization and hemorrhage), as well as preventive measures, may be beneficial; Agents that may contribute to glaucoma, as well as smoking, should be avoided

Refs: 13546939; 838599; 7065944; 6689931; 8431155; 9662395; 10453731; 10331951; 10854112; 10737974; 11585313; 12543751; 15452077; 16458719; 16678511; 17698758; 17591911; 18179881; 18611979; 19853238; 20057903; 20301346; 20375334; 20847757; 21192766; 21320969; 22422030; 22584882; 22633354; 23290749; 23572118; 23765342; 23823511; 24345323Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to BEST1 variants in ClinVar

25 Conditions Cataloged
not providedTotal: 836
BEST1-related disorderTotal: 264
Retinal dystrophyTotal: 157
Vitelliform macular dystrophy 2Total: 132
not specifiedTotal: 90
Autosomal recessive bestrophinopathyTotal: 65
Autosomal dominant vitreoretinochoroidopathyTotal: 52
Inborn genetic diseasesTotal: 51

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004183.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
1
clinvar
13
clinvar
113
clinvar
3
clinvar
 130
missense
87
clinvar
213
clinvar
300
clinvar
17
clinvar
1
clinvar
 618
nonsense
11
clinvar
13
clinvar
4
clinvar
 28
start loss
1
clinvar
 1
frameshift
27
clinvar
15
clinvar
3
clinvar
 45
splice donor/acceptor (+/-2bp)
8
clinvar
12
clinvar
4
clinvar
 24
Total1332553241304846

Highest pathogenic variant AF is 0.0002857187

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 24 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_004183.4RefSeqNP_004174.110MANE Select
ENST00000378043.9EnsemblENSP00000367282.410MANE Select
NM_001139443.3RefSeqNP_001132915.18Standard
NM_001300786.2RefSeqNP_001287715.18Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Stimuli-sensing channels
  • Ion channel transport
  • Transport of small molecules

Biological Process

  • chloride transport
  • visual perception
  • bicarbonate transport
  • transepithelial chloride transport
  • ion transmembrane transport

Molecular Function

  • intracellular calcium activated chloride channel activity
  • chloride channel activity
  • bicarbonate transmembrane transporter activity
  • identical protein binding

Cellular Component

  • cytosol
  • plasma membrane
  • membrane
  • integral component of membrane
  • basolateral plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000449131
Coding exons
8
Length
15695
Individuals with no LoFs
125713
Homozygous LoFs
0
Heterozygous LoFs
35
Defined
125748
p
0.000139
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense0.6172893200.9030.00001783952
Missense (PolyPhen)74103.350.716051255
Synonymous0.8041221340.9120.000007941181
Loss of Function-0.02331817.91.018.53e-7181

Population LoF Frequency

PopulationCAFp-valueStatus
African0.0000620.000062rare
Latino/Admixed American0.000170.00017rare
Ashkenazi Jewish00.0absent
East Asian0.000380.00038rare
Finnish0.0000460.000046rare
European (Non-Finnish)0.000150.00015rare
South Asian0.0000340.000033rare
Other0.000330.00033rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Forms calcium-sensitive chloride channels. Highly permeable to bicarbonate. {ECO:0000269|PubMed:11904445, ECO:0000269|PubMed:12907679, ECO:0000269|PubMed:18400985}.;
Disease
DISEASE: Macular dystrophy, vitelliform, 2 (VMD2) [MIM:153700]: An autosomal dominant form of macular degeneration that usually begins in childhood or adolescence. VMD2 is characterized by typical 'egg-yolk' macular lesions due to abnormal accumulation of lipofuscin within and beneath the retinal pigment epithelium cells. Progression of the disease leads to destruction of the retinal pigment epithelium and vision loss. {ECO:0000269|PubMed:10331951, ECO:0000269|PubMed:10394929, ECO:0000269|PubMed:10453731, ECO:0000269|PubMed:10682987, ECO:0000269|PubMed:10798642, ECO:0000269|PubMed:11241846, ECO:0000269|PubMed:11449320, ECO:0000269|PubMed:12187431, ECO:0000269|PubMed:12324875, ECO:0000269|PubMed:13129869, ECO:0000269|PubMed:14517959, ECO:0000269|PubMed:15176385, ECO:0000269|PubMed:18400985, ECO:0000269|PubMed:18766995, ECO:0000269|PubMed:19357557, ECO:0000269|PubMed:21330666, ECO:0000269|PubMed:9662395, ECO:0000269|PubMed:9700209}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Retinitis pigmentosa 50 (RP50) [MIM:613194]: A retinal dystrophy belonging to the group of pigmentary retinopathies. Retinitis pigmentosa is characterized by retinal pigment deposits visible on fundus examination and primary loss of rod photoreceptor cells followed by secondary loss of cone photoreceptors. Patients typically have night vision blindness and loss of midperipheral visual field. As their condition progresses, they lose their far peripheral visual field and eventually central vision as well. {ECO:0000269|PubMed:19853238}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Bestrophinopathy, autosomal recessive (ARB) [MIM:611809]: A retinopathy characterized by loss of central vision, an absent electro-oculogram light rise, and electroretinogram anomalies. {ECO:0000269|PubMed:18179881, ECO:0000269|PubMed:19853238, ECO:0000269|PubMed:21330666, ECO:0000269|PubMed:26200502, ECO:0000269|PubMed:26720466}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Vitreoretinochoroidopathy, autosomal dominant (ADVIRC) [MIM:193220]: A disorder characterized by vitreoretinochoroidal dystrophy. The clinical presentation is variable. VRCP may be associated with cataract, nanophthalmos, microcornea, shallow anterior chamber, and glaucoma. {ECO:0000269|PubMed:15452077}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.157

Intolerance Scores

LoFtool
0.0103
RVIS EVS
-0.22
RVIS percentile EVS
37.66

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.827

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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