TTC8
protein-codingtetratricopeptide repeat domain 8, the group of BBSome|Tetratricopeptide repeat domain containing
Gene summary
This gene encodes a protein that has been directly linked to Bardet-Biedl syndrome. The primary features of this syndrome include retinal dystrophy, obesity, polydactyly, renal abnormalities and learning disabilities. Experimentation in non-human eukaryotes suggests that this gene is expressed in ciliated cells and that it is involved in the formation of cilia. A mutation in this gene has also been implicated in nonsyndromic retinitis pigmentosa. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~56.9 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0013274
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0005308
Submitter: Natera
Inheritance Pattern: AR
Disease ID:MONDO:0014436
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0014436
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0014436
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0013274
Submitter: LiferaOmics
Genetic evidence – Published PMID: 26195043 – Family 1 – one proband. Case-level (AR homozygous/bi-allelic; non-LOF start = 0.1; no consanguinity deduction applied [not reported]) = 0.1; Segregation = 0; Case-control = 0 Family 1 total = 0.1 PMID: 25999674 – Family 2 – one proband. Variant: c.1363C>A; p.Gln455Lys (homozygous). Case-level (AR homozygous; non-LOF start = 0.1; no consanguinity deduction applied [not reported]) = 0.1; Segregation = 0; Case-control = 0 Family 2 total = 0.1 PMID: 30718709 – Family 3 – one proband. Case-level (AR Compound heterozygous/ non-LOF and another pLOF; each variant evaluated independently); no consanguinity deduction applied [not reported]) = 1.6; Segregation = 0; Case-control = 0 Family 3 total = 1.6 PMID: 20451172 – Family 4 – 4 affected siblings, Segregation (9 members) Case-level (AR homozygous; pLOF, consanguinity) Family 4 total= 2 Published genetic evidence total = 3.8/ 12 Genetic evidence – Our cases Family 1 – one proband (consanguineous parents; variant class treated as non-LOF pending stronger evidence). Case-level (AR homozygous; non-LOF start = 0.1) = 0.1; Segregation = 0; Case-control = 0 Family 1 total = 0.1 Family 2 – one proband (homozygous canonical splice NM_144596.3:c.115-2A>G; non-consanguineous). Case-level (AR predicted null default = 1.5; no consanguinity deduction applied [non-consanguineous]) = 1.5; Segregation = 0; Case-control = 0 Family 2 total = 1.5 Our cases genetic evidence total = 2.0 / 12 Total genetic evidence (published AR + our cases) 3.8 (published) + 1.6 (our cases) = 5.4 / 12 Experimental evidence – Published Experimental evidence total = PMID: 20451172 demonstrates that exon 2A of TTC8 is retina/photoreceptor-specific and that the IVS1-2A>G splice-site variant results in aberrant splicing of the retina-specific transcript (+0.5 expression evidence; +0.5 functional alteration evidence) PMID: 25776555 shows photoreceptor-specific missplicing caused by the IVS1-2A>G variant, leading to a frameshift and loss of TTC8 protein specifically in photoreceptors, providing mechanistic explanation for nonsyndromic RP (+1.0 functional alteration evidence)=1.5 0 / 6 Overall score Genetic evidence = 5.4 Experimental evidence = 1.5 Overall score = 6.9 / 18
Inheritance Pattern: AR
Disease ID:MONDO:1040049
Submitter: ClinGen
*TTC8* was first reported in relation to autosomal recessive Bardet-Biedl syndrome (BBS) in 2003 (Ansley et al., PMID: 14520415). BBS is a rare genetically heterogeneous ciliopathy, characterized by rod-cone dystrophy, polydactyly, obesity, genital anomalies, renal anomalies, and intellectual disabilities. *TTC8* variants have also been asserted in relation to non-syndromic cases diagnosed as retinitis pigmentosa (PMID: 20451172, PMID: 26195043). Per criteria outlined by the ClinGen Lumping & Splitting Working Group, the mode of inheritance (autosomal recessive) and molecular mechanism (biallelic *TTC8* loss of function) have been found to be consistent among patients diagnosed with either Bardet-Biedl syndrome 8 (MIM# 615985) or retinitis pigmentosa 51 (MIM# 613464), while the phenotypic variability between cases appears to represent a spectrum of disease rather than separate disease entities. Therefore, cases caused by inherited biallelic *TTC8* variants have been lumped into a single disease entity, referred to as TTC8-related ciliopathy. This curation includes four variants (three disrupting splicing and one frameshift) that have been reported in five probands in three publications (PMIDs: 14520415, 16308660, 19797195). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be biallelic loss-of-function. This gene-disease association is also supported by expression studies from Ansley et. al. showing that *TTC8* is expressed in the basal body of cilium, as BBS is known to be caused by dysfunction of primary cilia (PMID: 14520415). Co-immunoprecipitation experiments show that TTC8 protein co-localizes with PCM1 and BBS4, which are encoded by two genes that have previously been implicated in BBS. Finally, two *Ttc8* knockout mouse models by Kretschmer et. al. and Dilan et. al. show that absence of the Ttc8 protein in mice results in rapid and severe retinal degeneration as seen in human BBS patients (PMIDs: 30901771, 29126234). In summary, *TTC8* is definitively associated with autosomal recessive TTC8-related ciliopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Retina GCEP on June 6, 2024 (SOP Version 10).
Inheritance Pattern: AR
Disease ID:MONDO:0014436
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0013274
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0014436
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0019200
Submitter: Orphanet
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: The condition can involve congenital cardiac anomalies, and awareness may allow early management; Medical management of obesity with melanocortin-4 receptor (MC4R) agonist (setmelanotide) may be beneficial
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to TTC8 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_144596.4. 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.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 1 | 8 | 106 | 115 | ||
| missense | 1 | 1 | 314 | 11 | 327 | |
| nonsense | 8 | 13 | 2 | 23 | ||
| start loss | 1 | 5 | 6 | |||
| frameshift | 10 | 26 | 36 | |||
| splice donor/acceptor (+/-2bp) | 6 | 20 | 8 | 34 | ||
| Total | 25 | 62 | 337 | 117 | 0 | 541 |
Highest pathogenic variant AF is 0.000055149885
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_653197.2 | 15 | MANE Select | |
| Ensembl | ENSP00000370031.2 | 15 | MANE Select | |
| RefSeq | NP_001275710.1 | 15 | Standard | |
| RefSeq | NP_001275711.1 | 9 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| ttc8 | Danio rerio | Structure: pharyngeal arch 3-7 Quality: aplastic abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Olfactory bulb development and olfactory learning
- BBSome-mediated cargo-targeting to cilium
- Cargo trafficking to the periciliary membrane
- Cilium Assembly
- Organelle biogenesis and maintenance
Biological Process
- protein transport
- establishment of anatomical structure orientation
- sensory processing
- cilium assembly
- non-motile cilium assembly
Molecular Function
- RNA polymerase II repressing transcription factor binding
- protein binding
Cellular Component
- centrosome
- cytosol
- cilium
- BBSome
- ciliary basal body
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000380656
- Coding exons
- 15
- Length
- 53839
- Individuals with no LoFs
- 125720
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 28
- Defined
- 125748
- p
- 0.000111
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -0.0790 | 282 | 278 | 1.01 | 0.0000145 | 3379 |
| Missense (PolyPhen) | 157 | 163.45 | 0.96054 | 1995 | ||
| Synonymous | 1.58 | 82 | 102 | 0.801 | 0.00000559 | 949 |
| Loss of Function | 2.69 | 15 | 31.2 | 0.481 | 0.00000143 | 387 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00012 | 0.00012 | rare |
| Latino/Admixed American | 0.00012 | 0.00012 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00011 | 0.00011 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.00013 | 0.00013 | rare |
| South Asian | 0.00016 | 0.00016 | rare |
| Other | 0 | 0.0 | absent |
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. {ECO:0000269|PubMed:17574030, ECO:0000269|PubMed:22072986}.;
- Disease
- DISEASE: Bardet-Biedl syndrome 8 (BBS8) [MIM:615985]: 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:14520415, ECO:0000269|PubMed:16308660}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.201
Intolerance Scores
- LoFtool
- 0.651
- RVIS EVS
- 0.33
- RVIS percentile EVS
- 73.54
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.272
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |