GeneBe

TLR7

protein-coding

toll like receptor 7, the group of Toll like receptors

Gene summary

The protein encoded by this gene is a member of the Toll-like receptor (TLR) family which plays a fundamental role in pathogen recognition and activation of innate immunity. TLRs are highly conserved from Drosophila to humans and share structural and functional similarities. The human TLR family comprises 11 members. They recognize pathogen-associated molecular patterns (PAMPs) that are expressed on infectious agents, and mediate the production of cytokines necessary for the development of effective immunity. For the recognition of structural components in foreign microorganisms, the various TLRs exhibit different patterns of expression as well; in this way for example, TLR-3, -7, and -8 are essential in the recognition of single-stranded RNA viruses. TLR7 senses single-stranded RNA oligonucleotides containing guanosine- and uridine-rich sequences from RNA viruses, a recognition occuring in the endosomes of plasmacytoid dendritic cells and B cells. This gene is predominantly expressed in lung, placenta, and spleen, and is phylogenetically related and lies in close proximity to another family member, TLR8, on chromosome X. [provided by RefSeq, Aug 2020]

MANE transcript

NM_016562.4

Inheritance

XL

ClinVar variants

P:8U:216B:142

Top phenotype

Immunodeficiency 74, COVID-19 related, X-linked

gnomAD constraint

pLI —, LoF o/e 0.1

Max pathogenic AF

—

Genomic locus

chrX:12,867,072-12,890,361

External References & Databases

Ensembl (ENSG00000196664)NCBI Gene (51284)OMIM (300365)HGNC:15631GenCCUniProt (Q9NYK1)AlphaFoldClinVar (TLR7)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~23.3 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

systemic lupus erythematosusSUPPORTIVE

Inheritance Pattern: Unknown

Disease ID:MONDO:0007915

Submitter: Orphanet

systemic lupus erythematosus 17MODERATE

Inheritance Pattern: XL

Disease ID:MONDO:0859083

Submitter: PanelApp Australia

immunodeficiency 74, COVID-19-related, X-linkedMODERATE

Inheritance Pattern: XL

Disease ID:MONDO:0026767

Submitter: PanelApp Australia

systemic lupus erythematosus 17MODERATE

Inheritance Pattern: XL

Disease ID:MONDO:0859083

Submitter: Baylor College of Medicine Research Center

immunodeficiency 74, COVID-19-related, X-linkedLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0026767

Submitter: Labcorp Genetics (formerly Invitae)

systemic lupus erythematosus 17MODERATE

Inheritance Pattern: XL

Disease ID:MONDO:0859083

Submitter: ClinGen

The *TLR7* (Toll-like receptor 7) gene encodes a viral RNA sensor (PMID:35477763) that plays a key role in the recognition of pathogen-derived single-stranded RNA (ssRNA), which is integral to the innate immune response to viral infections. TLR7 can also recognize self-derived ssRNA, which may underlie the association of gain-of-function mutations in this gene with systemic lupus erythematosus (SLE) (PMID:38324161). *TLR7* was first reported in relation to X-linked dominant SLE in 2022 (Brown et al., PMID:35477763). Genetic evidence reviewed in the curation of this gene-disease relationship included 6 probands with 4 unique heterozygous variants. The molecular mechanism of disease is gain of function: only rare missense variants with *in vitro* functional evidence of gain of function have been reported (PMID: 35477763, 38753439, 38324161). No loss of function variants have been reported in individuals with SLE (ClinVar, literature review). Genetic evidence that was not scored include one study that reported association of *TLR7* copy number gain with SLE (PMID:20525845); however, this finding has not been replicated. In addition, common variants in *TLR7* are associated with increased risk of SLE and/or SLE-related phenotypes in cases compared to healthy controls (PMID: 33272962, 20733074, 36439744, 33650302), but these associations have not been replicated in genome-wide association studies. The gene-disease relationship is also supported by experimental evidence including biochemical function, function alterations and animal model data. SLE patients with *TLR7* variants display increased NFkB activity and B cell alterations typical for lupus (PMID: 38753439, 38324161, 35477763). A knock-in animal model of the p.Y264H variant recapitulates lupus-like phenotypes in mice (PMID: 35477763). In summary, there is **moderate** evidence supporting the relationship between TLR7 and X-linked dominant systemic lupus erythematosus. This classification was approved by the ClinGen Monogenic Systemic and Incomplete Lupus Erythematosus GCEP on the meeting date October 11, 2024 (SOP Version 11).

Clinical Genomic Database (CGD)

Immunodeficiency 74, COVID-19 related, X-linkedXL

Manifestation: Allergy/Immunology/Infectious

Intervention: Allergy/Immunology/Infectious

Rationale: Individuals with Immunodeficiency 74, COVID-19 related, X-linked, may demonstrate susceptibility to severe COVID-19, and awareness may allow preventative measures (such as adhering to practices to reduce the chance of infection); Individuals with Systemic lupus erythematosus have been described as benefiting from medical management (eg, with prednisone, azathioprine, mycophenolate, rituximab, immunoglobulins, Etanercept)

Refs: 32706371; 35477763Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TLR7 variants in ClinVar

7 Conditions Cataloged
not providedTotal: 298
not specifiedTotal: 64
Systemic lupus erythematosus 17Total: 6
TLR7-related disorderTotal: 5
Immunodeficiency 74, COVID-19-related, X-linkedTotal: 5
Systemic lupus erythematosusTotal: 3
See casesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_016562.4. 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.

EffectPLPVUSLBBSum
synonymous
8
clinvar
127
clinvar
7
clinvar
 142
missense
4
clinvar
195
clinvar
7
clinvar
1
clinvar
 207
nonsense
7
clinvar
 7
start loss
0
frameshift
1
clinvar
3
clinvar
3
clinvar
 7
splice donor/acceptor (+/-2bp)
3
clinvar
 3
Total532161348366
Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 3 of 3 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_016562.4RefSeqNP_057646.12MANE Select
ENST00000380659.4EnsemblENSP00000370034.32MANE Select
ENST00001132251.1EnsemblENSP00000811150.12Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Influenza A - Homo sapiens (human)
  • Toll-like receptor signaling pathway - Homo sapiens (human)
  • Measles - Homo sapiens (human)
  • Regulation of toll-like receptor signaling pathway
  • Toll-like Receptor Signaling

Biological Process

  • microglial cell activation
  • regulation of protein phosphorylation
  • toll-like receptor signaling pathway
  • MyD88-dependent toll-like receptor signaling pathway
  • immune response

Molecular Function

  • double-stranded RNA binding
  • single-stranded RNA binding
  • transmembrane signaling receptor activity
  • drug binding
  • signaling pattern recognition receptor activity

Cellular Component

  • Golgi membrane
  • cytoplasm
  • lysosome
  • endosome
  • endoplasmic reticulum

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000380659
Coding exons
2
Length
23298
Individuals with no LoFs
125735
Homozygous LoFs
4
Heterozygous LoFs
5
Defined
125744
p
0.0000358
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense3.012053680.5580.00002616976
Missense (PolyPhen)42127.940.328282454
Synonymous-0.5271571491.050.00001092020
Loss of Function3.80220.70.09680.00000143428

Population LoF Frequency

PopulationCAFp-valueStatus
African0.0000770.000062rare
Latino/Admixed American0.0000370.000029rare
Ashkenazi Jewish0.000270.00020rare
East Asian00.0absent
Finnish00.0absent
European (Non-Finnish)0.0000240.000018rare
South Asian0.000170.000098rare
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Key component of innate and adaptive immunity. TLRs (Toll-like receptors) control host immune response against pathogens through recognition of molecular patterns specific to microorganisms. TLR7 is a nucleotide-sensing TLR which is activated by single-stranded RNA. Acts via MYD88 and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response (By similarity). {ECO:0000250, ECO:0000269|PubMed:18250417}.;

Recessive Scores

pRec
0.287

Intolerance Scores

LoFtool
0.271
RVIS EVS
-0.4
RVIS percentile EVS
26.85

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
N
Indispensability score
0.122

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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