BEST1

Chr 11

bestrophin 1

Also known as: ARB, BEST, BMD, Best1V1Delta2, RP50, TU15B, VMD2

NCBI Gene: 7439 ENSG00000167995 UniProt: O76090

This gene encodes bestrophin-1, a calcium-activated chloride channel that transports chloride and bicarbonate ions across cell membranes and is essential for retinal pigment epithelium function. Mutations cause juvenile-onset vitelliform macular dystrophy (Best disease), adult-onset vitelliform macular dystrophy, retinitis pigmentosa, and other retinopathies with autosomal dominant inheritance. The gene is extremely intolerant to loss-of-function variants (pLI ~1.0), indicating that complete loss of protein function is likely incompatible with normal development.

GeneReviews ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtMacular dystrophy, vitelliform, 2

UniProtRetinitis pigmentosa 50

UniProtBestrophinopathy, autosomal recessive

UniProtVitreoretinochoroidopathy

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · BEST1-related dominant retinopathy · AD · ClinGen 2023

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.49

LOEUF

LOF*

Mechanism· G2P

📖

GeneReview available — BEST1

Authoritative clinical overview · Recommended first read

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Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.49LOEUF

pLI 0.000

Z-score -0.02

OE 1.01 (0.69–1.49)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.62Z-score

OE missense 0.90 (0.82–0.99)

289 obs / 320.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?1.01 (0.69–1.49)

0≤0.351.4

Missense OE?0.90 (0.82–0.99)

0≤0.61.4

Synonymous OE?0.91

0≤1.21.6

LoF obs/exp: 18 / 17.9Missense obs/exp: 289 / 320.1Syn Z: 0.80

Background carrier burden — how many people carry a rare variant somewhere in BEST1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 57

923 rare PASS variants

Rare truncating (LoF)

1 in 700

191 rare PASS variants

Rare synonymous (reference)

1 in 110

344 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for BEST1. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 73	1 in 750
South Asian	~43k	1 in 55	1 in 630
Remaining (unassigned)	~30k	1 in 53	1 in 410
European (Finnish)	~27k	1 in 150	1 in 1,700
Admixed American	~22k	1 in 54	1 in 1,100
African / African American	~21k	1 in 66	1 in 370
East Asian	~20k	1 in 56	1 in 570
Ashkenazi Jewish	~13k	1 in 150	1 in 460
Middle Eastern	~2,884	1 in 69	≈ 1 in 1,400

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 10 coding exons well covered in gnomAD exomes and genomes.? see exons ↓