Immunodeficiency 83, susceptibility to viral infections

Summary

Immunodeficiency 83, susceptibility to viral infections (MONDO:0800187) is a disease caused by TLR3 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: TLR3 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 20

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	immunodeficiency 83, susceptibility to viral infections
Mondo ID	MONDO:0800187
OMIM	613002
UMLS	C2751803
MedGen	416638
Is cancer (heuristic)	no

Also known as: IMD83

Data availability: 20 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease susceptibility › inherited disease susceptibility › encephalitis, acute, infection-induced, susceptibility to › immunodeficiency 83, susceptibility to viral infections

Related subtypes (6): encephalopathy, acute, infection-induced, susceptibility to, 4, encephalopathy, acute, infection-induced (herpes-specific), susceptibility to, 10, encephalitis, acute, infection (viral)-induced, susceptibility to, 11, encephalopathy, acute, infection-induced, susceptibility to, 9, encephalopathy, acute, infection-induced (herpes-specific), susceptibility to, 8, encephalitis, acute, infection-induced, susceptibility to, 12

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

20 retrieved; paginated sample, class counts are floors:

10 uncertain significance, 4 risk factor, 3 conflicting classifications of pathogenicity, 1 benign, 1 benign/likely benign, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
495312	NM_003265.2(TLR3):c.[2228G>A;2432G>T]		risk factor	no assertion criteria provided
1177576	NM_003265.3(TLR3):c.2039C>T (p.Pro680Leu)	TLR3	risk factor	no assertion criteria provided
495310	NM_003265.3(TLR3):c.2236G>T (p.Glu746Ter)	TLR3	risk factor	no assertion criteria provided
495313	NM_003265.3(TLR3):c.1079T>C (p.Leu360Pro)	TLR3	risk factor	no assertion criteria provided
1002005	NM_003265.3(TLR3):c.2599C>T (p.Arg867Ter)	TLR3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
495314	NM_003265.3(TLR3):c.889C>G (p.Leu297Val)	TLR3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
842830	NM_003265.3(TLR3):c.1987G>A (p.Glu663Lys)	TLR3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1177575	NM_003265.3(TLR3):c.597A>T (p.Leu199Phe)	TLR3	Uncertain significance	criteria provided, multiple submitters, no conflicts
2153676	NM_003265.3(TLR3):c.2394del (p.Phe798fs)	TLR3	Uncertain significance	criteria provided, multiple submitters, no conflicts
2585561	NM_003265.3(TLR3):c.1873G>T (p.Val625Phe)	TLR3	Uncertain significance	criteria provided, single submitter
3242191	NM_003265.3(TLR3):c.2077dup (p.Thr693fs)	TLR3	Uncertain significance	criteria provided, single submitter
4071520	NM_003265.3(TLR3):c.2658_2661dup (p.Ala888fs)	TLR3	Uncertain significance	criteria provided, single submitter
569628	NM_003265.3(TLR3):c.176C>A (p.Thr59Asn)	TLR3	Uncertain significance	criteria provided, multiple submitters, no conflicts
570922	NM_003265.3(TLR3):c.554C>T (p.Ala185Val)	TLR3	Uncertain significance	criteria provided, multiple submitters, no conflicts
652556	NM_003265.3(TLR3):c.2384C>T (p.Ala795Val)	TLR3	Uncertain significance	criteria provided, multiple submitters, no conflicts
6662	NM_003265.3(TLR3):c.1660C>T (p.Pro554Ser)	TLR3	Uncertain significance	criteria provided, multiple submitters, no conflicts
956119	NM_003265.3(TLR3):c.109T>C (p.Cys37Arg)	TLR3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1170782	NM_003265.3(TLR3):c.2224C>T (p.Leu742Phe)	TLR3	Benign	criteria provided, single submitter
41472	NM_003265.3(TLR3):c.1234C>T (p.Leu412Phe)	TLR3	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
495311	NM_003265.3(TLR3):c.2600G>A (p.Arg867Gln)	TLR3	Likely benign	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
TLR3	Strong	Autosomal dominant	immunodeficiency 83, susceptibility to viral infections	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TLR3	Orphanet:1930	Herpes simplex virus encephalitis

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TLR3	HGNC:11849	ENSG00000164342	O15455	Toll-like receptor 3	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TLR3	Toll-like receptor 3	Key component of innate and adaptive immunity.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TLR3	Other/Unknown	no		TIR_dom, Cys-rich_flank_reg_C, Leu-rich_rpt

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
jejunal mucosa	1
palpebral conjunctiva	1
placenta	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TLR3	232	ubiquitous	marker	jejunal mucosa, palpebral conjunctiva, placenta

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TLR3	4,305

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TLR3	O15455	20

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
TLR3 deficiency - HSE	1	11420.0×	8e-04	TLR3
UNC93B1 deficiency - HSE	1	5710.0×	8e-04	TLR3
TICAM1 deficiency - HSE	1	5710.0×	8e-04	TLR3
TRAF3 deficiency - HSE	1	3806.7×	9e-04	TLR3
TLR3-mediated TICAM1-dependent programmed cell death	1	1903.3×	0.001	TLR3
TICAM1,TRAF6-dependent induction of TAK1 complex	1	1038.2×	0.002	TLR3
Regulation of TBK1, IKKε-mediated activation of IRF3, IRF7 upon TLR3 ligation	1	951.7×	0.002	TLR3
Trafficking and processing of endosomal TLR	1	815.7×	0.002	TLR3
TICAM1-dependent activation of IRF3/IRF7	1	815.7×	0.002	TLR3
RIP-mediated NFkB activation via ZBP1	1	671.8×	0.002	TLR3
TICAM1, RIP1-mediated IKK complex recruitment	1	601.0×	0.002	TLR3
Toll Like Receptor 3 (TLR3) Cascade	1	193.6×	0.006	TLR3
RSV-host interactions	1	156.4×	0.006	TLR3

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
type III interferon production	1	16852.0×	0.002	TLR3
positive regulation of type III interferon production	1	8426.0×	0.002	TLR3
regulation of dendritic cell cytokine production	1	5617.3×	0.002	TLR3
response to dsRNA	1	5617.3×	0.002	TLR3
detection of virus	1	4213.0×	0.002	TLR3
inflammatory response to wounding	1	2106.5×	0.003	TLR3
necroptotic signaling pathway	1	2106.5×	0.003	TLR3
hyperosmotic response	1	1685.2×	0.003	TLR3
activation of NF-kappaB-inducing kinase activity	1	1685.2×	0.003	TLR3
toll-like receptor 3 signaling pathway	1	1123.5×	0.004	TLR3
cellular response to exogenous dsRNA	1	1053.2×	0.004	TLR3
positive regulation of macrophage cytokine production	1	732.7×	0.004	TLR3
positive regulation of interferon-alpha production	1	648.1×	0.004	TLR3
microglial cell activation	1	624.1×	0.004	TLR3
toll-like receptor signaling pathway	1	601.9×	0.004	TLR3
negative regulation of osteoclast differentiation	1	543.6×	0.004	TLR3
positive regulation of cytokine production involved in inflammatory response	1	543.6×	0.004	TLR3
cellular response to interferon-beta	1	526.6×	0.004	TLR3
response to exogenous dsRNA	1	526.6×	0.004	TLR3
positive regulation of interferon-beta production	1	391.9×	0.005	TLR3
positive regulation of interleukin-12 production	1	391.9×	0.005	TLR3
positive regulation of chemokine production	1	374.5×	0.005	TLR3
extrinsic apoptotic signaling pathway	1	306.4×	0.006	TLR3
JNK cascade	1	271.8×	0.007	TLR3
positive regulation of interleukin-8 production	1	244.2×	0.007	TLR3
cellular response to xenobiotic stimulus	1	240.7×	0.007	TLR3
positive regulation of type II interferon production	1	224.7×	0.007	TLR3
cellular response to mechanical stimulus	1	216.1×	0.007	TLR3
cellular response to type II interferon	1	208.1×	0.007	TLR3
cellular response to virus	1	200.6×	0.007	TLR3

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TLR3	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
TLR3	55	Binding:52, Functional:3

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	TLR3

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
TLR3	55	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.