TLR5
protein-codingtoll like receptor 5, the group of Toll like receptors
Gene summary
This gene encodes a member of the toll-like receptor (TLR) family, which plays a fundamental role in pathogen recognition and activation of innate immune responses. These receptors recognize distinct pathogen-associated molecular patterns that are expressed on infectious agents. The protein encoded by this gene recognizes bacterial flagellin, the principal component of bacterial flagella and a virulence factor. The activation of this receptor mobilizes the nuclear factor NF-kappaB, which in turn activates a host of inflammatory-related target genes. Mutations in this gene have been associated with both resistance and susceptibility to systemic lupus erythematosus, and susceptibility to Legionnaire disease.[provided by RefSeq, Dec 2009]
- SLEB1
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~33.9 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: Unknown
Disease ID:MONDO:0011138
Submitter: ClinGen
The *TLR5* (Toll-Like Receptor 5) gene encodes a pattern recognition receptor that recognizes bacterial flagellin. When flagellin is detected, NF-kappaB is mobilized, which then activates inflammation-related factors (Hayashi et al., PMID: 11323673). *TLR5* was first reported in relation to systemic lupus erythematosus (SLE) in 2005 (Hawn et al., PMID: 16027372). Genetic evidence reviewed during the curation of this gene-disease relationship included one proband who also carried a *de novo* gain of function *PIK3CD* variant in addition to the TLR5 p.Tyr108His variant (Hou et al., PMID: 36810668). A patient with a non-SLE-related phenotype carried a maternally inherited microdeletion that included parts of *TLR5* (Jun et al., PMID: 23542665). Linkage studies originally identified an association between the 1q41-1q42 region (which includes *TLR5*) and susceptibility to SLE. A case-control study (Hawn et al., PMID: 16027372) found a protective association between the common stop codon polymorphism c.1147C>T in *TLR5* and risk of developing SLE. There have since been four additional case-control studies in 2007, 2009, 2015, and 2017 that have found no significant associations between healthy controls and patients with SLE for this variant (PMIDs: 17516623, 19473567, 26221343, 28763101). Experimental evidence is limited to the common c.1174C>T variant. In isolated blood cells, impaired cytokine production in response to flagellin was found in c.1174C>T heterozygotes compared to controls. The authors hypothesized that the c.1174C>T variant provides protection from developing SLE by decreasing the production of proinflammatory cytokines (Hawn et al., PMID: 16027372). One study found increased expression of *TLR5* in the kidneys of lupus nephritis patients both at the protein and mRNA levels (Elloumi et al., PMID: 28763101). In summary, there is **limited** evidence to support the relationship between *TLR5* and systemic lupus erythematosus. This classification was approved by the ClinGen Monogenic Systemic and Incomplete Lupus Erythematosus GCEP on the meeting date February 12, 2025 (SOP Version 11).
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to TLR5 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_003268.6. 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 | 4 | 3 | 7 | |||
| missense | 100 | 15 | 3 | 118 | ||
| nonsense | 1 | 1 | ||||
| start loss | 0 | |||||
| frameshift | 1 | 1 | 2 | |||
| splice donor/acceptor (+/-2bp) | 1 | 1 | ||||
| Total | 0 | 1 | 103 | 19 | 6 | 129 |
Highest pathogenic variant AF is 6.840488e-7
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_003259.2 | 1 | MANE Select | |
| Ensembl | ENSP00000496355.1 | 1 | MANE Select | |
| RefSeq | NP_001424468.1 | 1 | Standard | |
| RefSeq | NP_001424553.1 | 1 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Salmonella infection - Homo sapiens (human)
- Legionellosis - Homo sapiens (human)
- Inflammatory bowel disease (IBD) - Homo sapiens (human)
- Toll-like receptor signaling pathway - Homo sapiens (human)
- Pathogenic Escherichia coli infection - Homo sapiens (human)
Biological Process
- MyD88-dependent toll-like receptor signaling pathway
- inflammatory response
- positive regulation of interleukin-8 production
- positive regulation of toll-like receptor signaling pathway
- toll-like receptor 5 signaling pathway
Molecular Function
- transmembrane signaling receptor activity
- interleukin-1 receptor binding
Cellular Component
- plasma membrane
- integral component of membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000540964
- Coding exons
- 1
- Length
- 33877
- Individuals with no LoFs
- 112631
- Homozygous LoFs
- 459
- Heterozygous LoFs
- 12658
- Defined
- 125748
- p
- 0.0536
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.392 | 407 | 430 | 0.947 | 0.0000215 | 5688 |
| Missense (PolyPhen) | 102 | 117.92 | 0.86498 | 1695 | ||
| Synonymous | -0.326 | 178 | 173 | 1.03 | 0.00000884 | 1683 |
| Loss of Function | 0.206 | 20 | 21.0 | 0.951 | 0.00000109 | 289 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.027 | 0.026 | notable |
| Latino/Admixed American | 0.022 | 0.022 | notable |
| Ashkenazi Jewish | 0.029 | 0.029 | notable |
| East Asian | 0.028 | 0.028 | notable |
| Finnish | 0.047 | 0.047 | notable |
| European (Non-Finnish) | 0.062 | 0.062 | notable |
| South Asian | 0.10 | 0.10 | notable |
| Other | 0.050 | 0.051 | notable |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Participates in the innate immune response to microbial agents. Mediates detection of bacterial flagellins. Acts via MYD88 and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response. {ECO:0000269|PubMed:11323673}.;
- Disease
- DISEASE: Systemic lupus erythematosus 1 (SLEB1) [MIM:601744]: A chronic, relapsing, inflammatory, and often febrile multisystemic disorder of connective tissue, characterized principally by involvement of the skin, joints, kidneys and serosal membranes. It is of unknown etiology, but is thought to represent a failure of the regulatory mechanisms of the autoimmune system. The disease is marked by a wide range of system dysfunctions, an elevated erythrocyte sedimentation rate, and the formation of LE cells in the blood or bone marrow. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.266
Intolerance Scores
- LoFtool
- 0.654
- RVIS EVS
- 1.65
- RVIS percentile EVS
- 96.21
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.974
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |