Primary immunodeficiency or monogenic inflammatory bowel disease
Gene: TLR3
agree with green geneCreated: 17 Sep 2019, 3:18 p.m. | Last Modified: 17 Sep 2019, 3:18 p.m.
Panel Version: 1.94
YES- this is covered on our targeted exomeCreated: 17 Sep 2019, 3:18 p.m. | Last Modified: 17 Sep 2019, 3:18 p.m.
Panel Version: 1.94
Comment on mode of pathogenicity: Only missense variants reported to dateCreated: 19 Jun 2018, 11:45 a.m.
Comment on publications: Added publication listing variantsCreated: 19 Jun 2018, 11:36 a.m.
Comment on list classification: There are plausible disease-causing mutations identified in more than 3 families. All variants reported to date are missense.Created: 19 Jun 2018, 11:32 a.m.
Changed penetrance to 'incomplete'Created: 19 Jun 2018, 11:30 a.m.
Added 'missense' tag as all variants reported so far in exons are missense.Created: 19 Jun 2018, 10:55 a.m.
In OMIM TLR3 is associated with {Encephalopathy, acute, infection-induced (herpes-specific), susceptibility to, 2} and {HIV1 infection, resistance to}. 10 independent cases of missense variants in TLR3 in patients with herpes simplex encephalitis are reported by Zhang et al. (2007) (PMID: 17872438), Guo et al. (2011) (PMID: 21911422), Lim et al. (2014) (PMID: 25339207) and Mork et al. (2015) (26513235). Patients show a mixture of 1 heterozygous mutation, compound heterozygous mutations and homozygous mutation. Some family members of the two patients reported by Zhang et al. (2007) were also heterozygous for the mutation found, were HSV-1 seropositive but had not suffered from HSE suggesting that the mutation confers an autosomal dominant predisposition to the disease with incomplete penetrance. Lim et al (2014) also report dominant negative and haploinsufficiency effects. A review of literature finds a report by Sironi et al (2017) (PMID: 28368532) which describe a HSE patient with a previously reported variant (p.Leu297Val) and another with an intronic variant c.−8 + 6T > C, rs765240183), located 6 nucleotides downstream from the donor splice site of the first noncoding exon. All variants reported so far in exons are missense. Not in Gene2Phenotype. This gene should be rated green as there plausible disease-causing mutations identified in 3 or more families.Created: 18 Jun 2018, 1:49 p.m.
Gene rating submitted by Kimberly Gilmour and Austen Worth on behalf of London North GLH for the GMS Immunology specialist test group. As discussed with the GMS Immunology Specialist Test Group during webex call 28th March 2019 and confirmed in follow up email 6th September the Specialist Test Group all agreed there is enough evidence to rate this gene Green.Created: 17 Sep 2019, 3:18 p.m. | Last Modified: 17 Sep 2019, 3:18 p.m.
Panel Version: 1.94
Gene rating submitted by Tracy Briggs, David Gokhale and Abigal Rousseau on behalf of North West GLH for the GMS Immunology specialist test group. As discussed with the GMS Immunology Specialist Test Group during webex call 28th March 2019 and confirmed in follow up email on 20th June the Specialist Test Group all agreed there is enough evidence to rate this gene Green.Created: 17 Sep 2019, 3:18 p.m. | Last Modified: 17 Sep 2019, 3:18 p.m.
Panel Version: 1.94
OriginaI Metadata from IUIS classification table (February, 2018) downloaded 20180614. IUIS Genetic defect (original gene symbol in IUIS download): TLR3 .PanelApp HGNC gene symbol check: TLR3 . IUIS Disease: TLR3 deficiency . IUIS Inheritance: AD or AR .T cells: N/A, .B cells: N/A, .IUIS Other affected cells: Central nervous system (CNS) resident cells and fibroblasts. IUIS Associated features: Herpes simplex virus 1 encephalitis (incomplete clinical penetrance for all etiologies listed here). IUIS Major category: Defects in Intrinsic and Innate Immunity. IUIS Subcategory: Herpes Simplex Encephalitis (HSE)Created: 2 Jul 2018, 10:35 a.m.
This gene was absent from the original PanelApp PID panel dataset (review April 2018). However it was listed in external expert immunodeficiency diagnostic gene list(s)
GOSH or GRID. In this combined PID panel, this gene has been rated as AMBER and needs further curational review to assess pertinence prior to v1.Created: 19 Apr 2018, 12:30 p.m.
Original metadata downloaded from ESID Registry. ESID_Gene_original: TLR3, PanelApp HGNC gene symbol check: TLR3, ESID classification: Main_category/ Sub_category/ PID_Diagnosis Defects in innate immunity / Herpetic encephalitis / Herpetic encephalitis (HSE)Created: 17 Apr 2018, 12:29 p.m.
Original metadata supplied by GRID. GRID Gene Symbol HGNC PanelApp check: TLR3, GRID_Gene_Symbol: TLR3, GRID_Transcript_ENS_Community submitted: ENST00000296795, GRID_Transcript_RefSeq: NM_003265.2, GRID_Transcript_ENS_used_on_Production: ENST00000296795Created: 17 Apr 2018, 12:12 p.m.
Source NHS GMS was added to TLR3.
Source North West GLH was added to TLR3.
Source London North GLH was added to TLR3.
2018-07-12 Louise Daugherty (Genomics England Curator) promoted panel to v1.0. Reviews were assessed, and panel was revised according to expert reviews and further in-house curation based on PanelApp guidelines. Previous panels (A- or hypo-gammaglobulinaemia, Congenital neutropaenia, Agranulocytosis, Combined B and T cell defect, Inherited complement deficiency and SCID panels) that were merged with this panel, were checked again for any changes/new reviews prior to versioning of this panel, these merged panels are now retired/made internal.
Phenotypes for gene TLR3 were set to Herpes simplex encephalitis, susceptibility to, 2, Herpetic encephalitis (HSE), Herpes simplex virus 1 encephalitis (incomplete clinical penetrance for all etiologies listed here), Defects in Intrinsic and Innate Immunity
Gene: tlr3 has been classified as Green List (High Evidence).
IUIS Classification February 2018 was added to TLR3. Panel: Primary immunodeficiency disorders
Victorian Clinical Genetics Services was added to TLR3. Panel: Primary immunodeficiency disorders
Mode of pathogenicity for gene: TLR3 was changed to Other - please provide details in the comments
Publications for gene: TLR3 were set to 21911422; 25339207; 25339207; 28368532
Mode of inheritance for gene: TLR3 was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Gene: tlr3 has been classified as Green List (High Evidence).
Source GRID V2.0 was removed from TLR3. Panel: Primary immunodeficiency disorders Source ESID Registry 20171117 was removed from TLR3. Panel: Primary immunodeficiency disorders Other was added to TLR3. Panel: Primary immunodeficiency disorders Phenotypes for gene TLR3 were set to Herpes simplex encephalitis, susceptibility to, 2, Herpetic encephalitis (HSE) Penetrance for gene TLR3 was set to Incomplete
This gene has been classified as Amber List (Moderate Evidence).
ESID Registry 20171117 was added to TLR3. Panel: Primary immunodeficiency disorders Phenotypes for gene TLR3 were set to Herpes simplex encephalitis, susceptibility to, 2, Herpetic encephalitis (HSE)
Phenotypes for gene TLR3 were set to Herpes simplex encephalitis, susceptibility to, 2
TLR3 was added to Primary immunodeficiency disorders panel. Sources: GRID V2.0
TLR3 was created by Louise Daugherty