Primary immunodeficiency or monogenic inflammatory bowel disease

Gene: TLR3

Green List (high evidence)

agree with green gene

Created: 17 Sep 2019, 3:18 p.m. | Last Modified: 17 Sep 2019, 3:18 p.m.

Panel Version: 1.94

Green List (high evidence)

YES- this is covered on our targeted exome

Created: 17 Sep 2019, 3:18 p.m. | Last Modified: 17 Sep 2019, 3:18 p.m.

Panel Version: 1.94

Green List (high evidence)

Comment on mode of pathogenicity: Only missense variants reported to date

Created: 19 Jun 2018, 11:45 a.m.

Comment on publications: Added publication listing variants

Created: 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.

Green List (high evidence)

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: ENST00000296795

Created: 17 Apr 2018, 12:12 p.m.