BBS1
protein-codingBardet-Biedl syndrome 1, the group of BBSome
Gene summary
Mutations in this gene have been observed in patients with the major form (type 1) of Bardet-Biedl syndrome. The encoded protein may play a role in eye, limb, cardiac and reproductive system development. [provided by RefSeq, Jul 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~23.0 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:1040043
Submitter: ClinGen
The *BBS1* gene was first reported in relation to Bardet-Biedl syndrome in a 2002 study of affected individuals with a combination of retinal and extraocular features (PMID: 12118255). Subsequent publications have established that cases diagnosed with Bardet-Biedl syndrome 1 exhibit retinal disease as the most penetrant feature, characterized by retinal dystrophy, pigmentary retinopathy, reduced visual acuity, night blindness, peripheral visual field constriction, reduced or absent rod and cone electroretinogram responses, attenuation of retinal blood vessels, optic disc pallor, and/or nystagmus. These phenotypes are generally accompanied by diverse extraocular features such as obesity, polydactyly, renal abnormalities including cysts, hypoplastic external genitalia in males, and/or intellectual disability. More recent publications have revealed that the spectrum of disease also includes cases diagnosed with juvenile onset retinitis pigmentosa, in which most or all extraocular features are absent (PMID: 23847139, PMID: 27032803). Per criteria outlined by the ClinGen Lumping & Splitting Working Group, the mode of inheritance (autosomal recessive) and molecular mechanism (biallelic *BBS1* loss of function) have been found to be consistent among patients diagnosed with either Bardet-Biedl syndrome 1 (MIM# 209900) or retinitis pigmentosa, while the phenotypic variability between cases appears to represent a spectrum of disease rather than separate disease entities. Therefore, cases caused by inherited biallelic *BBS1* variants have been lumped into a single disease entity, referred to as BBS1-related ciliopathy. Nine suspected disease-causing variants have been scored as part of this curation (one nonsense, two frameshift, four affecting splicing, one missense, and one large insertion-deletion resulting in a frameshift), which have been collectively reported in twelve probands in five publications (PMID: 12118255, PMID: 23847139, PMID: 33169370, PMID: 19797195, PMID: 27032803). All of the probands scored in this curation harbored biallelic *BBS1* variants. The mechanism of pathogenicity appears to be biallelic loss of BBS1 function conferred by null and/or hypomorphic variants. Only one relatively small family was found in the literature with at least three affected members (PMID: 33169370), and segregation evidence did not contribute to the scoring of this curation. This gene-disease association is also supported by biochemical evidence that *BBS1* encodes a component of the BBSome, a protein complex that functions in ciliogenesis and intraflagellar transport (PMID: 22072986). BBS1 co-immunoprecipitates with BBS4 (PMID: 17574030), and the genes encoding other BBSome components have similarly been asserted in connection with various monogenic forms of Bardet-Biedl syndrome, including *BBS2* (PMID: 11285252), *ARL6* (PMID: 15258860), *BBS4* (PMID: 11381270), *BBS5* (PMID: 15137946), *MKKS* (PMID: 10973238, PMID: 10973251), *BBS7* (PMID: 12567324), and *TTC8* (PMID: 14520415). *Chlamydomonas* with partial deletion of *BBS1* are unable to perform light-responsive movement (PMID: 20038682), while *Zbbs1* knockdown in zebrafish disrupts ciliary beat frequency and triggers cyst formation in the pronephritic kidney (PMID: 24069149). Biallelic disruption of *Bbs1* in mice has been studied in ciliated tissues of the brain, where it causes cilia to aberrantly accumulate or exclude various G-protein-coupled receptors (PMID: 36699005). Homozygous knock-in of a missense variant from human patients into mouse *Bbs1* recapitulates both retinal and syndromic features from the human disease state, including abnormal dark-adapted electroretinogram, photoreceptor layer loss on optical coherence tomography, obesity, and male reproductive abnormalities (PMID: 18032602). In summary, *BBS1* is definitively associated with BBS1-related ciliopathy. This has been repeatedly demonstrated in both research and diagnostic settings, and has been upheld over time without the emergence of contradictory evidence, leading to a Definitive classification. This classification was approved by the ClinGen Retina Gene Curation Expert Panel on December 7th, 2023 (SOP Version 10).
Inheritance Pattern: AR
Disease ID:MONDO:0008854
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0008854
Submitter: Myriad Women's Health
Inheritance Pattern: AR
Disease ID:MONDO:0008854
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0008854
Submitter: Natera
Inheritance Pattern: AR
Disease ID:MONDO:0008854
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0008854
Submitter: Genomics England PanelApp
Inheritance Pattern: AR
Disease ID:MONDO:0008854
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0015229
Submitter: Orphanet
Clinical Genomic Database (CGD)
Manifestation: Cardiovascular; Craniofacial; Gastrointestinal; Genitourinary; Endocrine; Musculoskeletal; Neurologic; Ophthalmologic; Renal
Intervention: Cardiovascular; Endocrine
Rationale: Individuals have been described with congenital heart anomalies, and awareness may enable early diagnosis and management; Medical management of obesity with melanocortin-4 receptor (MC4R) agonist (setmelanotide) may be beneficial
Comments: Variants may modify the severity of BBS and related disorders due to variants in other BBS-associated genes
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to BBS1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_024649.5. 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.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 2 | 15 | 276 | 1 | 294 | |
| missense | 3 | 24 | 315 | 12 | 1 | 355 |
| nonsense | 23 | 23 | 46 | |||
| start loss | 4 | 3 | 7 | |||
| frameshift | 44 | 49 | 3 | 96 | ||
| splice donor/acceptor (+/-2bp) | 12 | 48 | 4 | 64 | ||
| Total | 86 | 149 | 337 | 288 | 2 | 862 |
Highest pathogenic variant AF is 0.0026775205
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_078925.3 | 17 | MANE Select | |
| Ensembl | ENSP00000317469.7 | 17 | MANE Select | |
| Ensembl | ENSP00000377563.2 | 13 | Standard | |
| Ensembl | ENSP00000377563.2 | 13 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| bbs1 | Danio rerio | Structure: pancreatic B cell Quality: increased area abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- BBSome-mediated cargo-targeting to cilium
- Cargo trafficking to the periciliary membrane
- Cilium Assembly
- Organelle biogenesis and maintenance
Biological Process
- retina homeostasis
- visual perception
- sensory perception of smell
- Golgi to plasma membrane protein transport
- photoreceptor cell maintenance
Molecular Function
- RNA polymerase II repressing transcription factor binding
- patched binding
- smoothened binding
- protein binding
Cellular Component
- centrosome
- cytosol
- axoneme
- BBSome
- ciliary basal body
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000318312
- Coding exons
- 17
- Length
- 23022
- Individuals with no LoFs
- 125670
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 78
- Defined
- 125748
- p
- 0.000310
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.156 | 335 | 343 | 0.976 | 0.0000223 | 3790 |
| Missense (PolyPhen) | 87 | 93.871 | 0.9268 | 1060 | ||
| Synonymous | -0.0290 | 146 | 146 | 1.00 | 0.00000912 | 1262 |
| Loss of Function | 1.64 | 23 | 33.2 | 0.692 | 0.00000194 | 358 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00025 | 0.00025 | rare |
| Latino/Admixed American | 0.00029 | 0.00029 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00011 | 0.00011 | rare |
| Finnish | 0.00097 | 0.00097 | rare |
| European (Non-Finnish) | 0.00026 | 0.00025 | rare |
| South Asian | 0.00036 | 0.00036 | rare |
| Other | 0.00033 | 0.00033 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: The BBSome complex is thought to function as a coat complex required for sorting of specific membrane proteins to the primary cilia. The BBSome complex is required for ciliogenesis but is dispensable for centriolar satellite function. This ciliogenic function is mediated in part by the Rab8 GDP/GTP exchange factor, which localizes to the basal body and contacts the BBSome. Rab8(GTP) enters the primary cilium and promotes extension of the ciliary membrane. Firstly the BBSome associates with the ciliary membrane and binds to RAB3IP/Rabin8, the guanosyl exchange factor (GEF) for Rab8 and then the Rab8-GTP localizes to the cilium and promotes docking and fusion of carrier vesicles to the base of the ciliary membrane. The BBSome complex, together with the LTZL1, controls SMO ciliary trafficking and contributes to the sonic hedgehog (SHH) pathway regulation. Required for proper BBSome complex assembly and its ciliary localization (PubMed:17574030, PubMed:22072986). Plays a role in olfactory cilium biogenesis/maintenance and trafficking (By similarity). {ECO:0000250|UniProtKB:Q3V3N7, ECO:0000269|PubMed:17574030, ECO:0000269|PubMed:22072986}.;
- Disease
- DISEASE: Bardet-Biedl syndrome 1 (BBS1) [MIM:209900]: A syndrome characterized by usually severe pigmentary retinopathy, early- onset obesity, polydactyly, hypogenitalism, renal malformation and mental retardation. Secondary features include diabetes mellitus, hypertension and congenital heart disease. Bardet-Biedl syndrome inheritance is autosomal recessive, but three mutated alleles (two at one locus, and a third at a second locus) may be required for clinical manifestation of some forms of the disease. {ECO:0000269|PubMed:12118255, ECO:0000269|PubMed:12524598, ECO:0000269|PubMed:12567324, ECO:0000269|PubMed:12677556, ECO:0000269|PubMed:12920096, ECO:0000269|PubMed:15770229, ECO:0000269|PubMed:21052717, ECO:0000269|PubMed:21344540}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Intolerance Scores
- LoFtool
- 0.166
- RVIS EVS
- -0.26
- RVIS percentile EVS
- 34.88
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- S
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.568
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Low | Low |
| Primary Immunodeficiency | Medium | Low | Medium |
| Cancer | Low | Low | Low |