BEST1

Chr 11AD

bestrophin 1

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

NCBI Gene: 7439 ENSG00000167995 UniProt: O76090

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]

Primary Disease Associations & Inheritance

?Microcornea, rod-cone dystrophy, cataract, and posterior staphyloma 2MIM #193220

Bestrophinopathy, autosomal recessiveMIM #611809

Macular dystrophy, vitelliform, 2MIM #153700

Retinitis pigmentosa-50MIM #613194

Retinitis pigmentosa, concentricMIM #613194

VitreoretinochoroidopathyMIM #193220

385

ClinVar variants

109

Pathogenic / LP

0.00

pLI score

Active trials

Clinical Summary— BEST1

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Gene-Disease Validity (ClinGen)

BEST1-related dominant retinopathy · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡

Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

📋

ClinVar Variants

109 Pathogenic / Likely Pathogenic· 174 VUS of 385 total submissions

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Clinical Trials

6 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.

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?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.

0.62Z-score

OE missense 0.90 (0.82–0.99)

289 obs / 320.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.

LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.1.01 (0.69–1.49)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.90 (0.82–0.99)

0≤0.61.4

Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.91

0≤1.21.6

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

ClinVar Variant Classifications

385 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic56

Likely Pathogenic53

VUS174

Likely Benign62

Benign36

Conflicting4

Pathogenic

Likely Pathogenic

174

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	20	26	10	0	56
Likely Pathogenic	6	44	3	0	53
VUS	5	150	15	4	174
Likely Benign	1	10	25	26	62
Benign	1	4	28	3	36
Conflicting	—				4
Total	33	234	81	33	385

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

BEST1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

BEST1-related retinitis pigmentosa

definitive

ARUndeterminedAltered Gene Product Structure

Eye

G2P ↗

missense variantinframe deletioninframe insertion

BEST1-related microcornea, rod-cone dystrophy, cataract, and posterior staphyloma

definitive

ADUndeterminedAltered Gene Product Structure

Eye

G2P ↗

missense variantinframe deletioninframe insertion

BEST1-related macular dystrophy, vitelliform

definitive

ADLoss Of FunctionAbsent Gene Product

Eye

G2P ↗

BEST1-related bestrophinopathy

definitive

ARLoss Of FunctionAbsent Gene Product

Eye

G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

BESTROPHIN 1; BEST1

MIM #607854 · *

?Microcornea, rod-cone dystrophy, cataract, and posterior staphyloma 2

MIM #193220