Primary immunodeficiency or monogenic inflammatory bowel disease

Gene: TMEM173

Comment on publications: Additional evidence added to the publication list, provided by Abdelazeem Elhabyan. Comments from Abdelazeem Elhabyan: GenBank - https://www.ncbi.nlm.nih.gov/gene?term=(human%5BOrganism%5D)%20AND%20TMEM173%5BGene%20Name%5D) This gene encodes a five transmembrane protein that functions as a major regulator of the innate immune response to viral and bacterial infections. The encoded protein is a pattern recognition receptor that detects cytosolic nucleic acids and transmits signals that activate type I interferon responses.

Hypothesis:
This gene is involved in interferon 1 pathway which is directly related to viral innate immune response. Upregulation may be associated with a protective effect or autoinflammatory response with aggravating effect. This is to be determined by clinical trials.

Highest organ of expression is the lung in genbank (Pneumonia caused by corona) RPKM ,\mean is 37

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7069765/

Extracellular vesicles released by virally infected cells(HSV) that carry STING can induce protective effect against viral replication in neighbouring non infected cells
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6146713/

Virulent Poxviruses Inhibit DNA Sensing by Preventing STING Activation
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5923072/
The gene is involved in acute pancreatitis in mice
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6112120/

Created: 1 Apr 2020, 10:08 a.m. | Last Modified: 1 Apr 2020, 10:08 a.m.

Panel Version: 2.37

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

Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.

Created: 14 Oct 2020, 4:41 p.m. | Last Modified: 14 Oct 2020, 4:41 p.m.

Panel Version: 2.324

The following PubMed IDs were added to entity TMEM173: 25029335;25401470. These publications have been associated with OMIM phenotype MIM#615934, which is listed for this entity, by the autoinflammation subgroup of the Human Phenotype Ontology Immune Mediated Disorders Consortium (https://hpo-immune-mediated-disorders.groups.io/g/update) in August 2020.

Created: 13 Oct 2020, 9:36 a.m. | Last Modified: 13 Oct 2020, 9:36 a.m.

Panel Version: 2.208

Comment on mode of pathogenicity: In two publications (PMIDs 25029335 and 25401470) the variants have been shown to cause gain of function.

Created: 3 Jul 2018, 1:53 p.m.

Comment on publications: Added publications suggested by reviewer

Created: 3 Jul 2018, 1:51 p.m.

Comment on phenotypes: Added MIM number to STING-associated vasculopathy, infantile-onset

Created: 3 Jul 2018, 1:50 p.m.

In OMIM this gene is associated with STING-associated vasculopathy, infantile-onset. Evidence comes from two publications: Liu et al 2014 (PMID:25029335) and Jeremiah et al 2014 (PMID: 25401470). Liu et al report 6 unrelated patients with STING-associated vasculopathy with onset in infancy in which they identified 3 different de novo heterozygous missense mutations in the TMEM173 gene. The mutation in the first patient was found by whole-exome sequencing, and mutations in the subsequent patients were found by Sanger sequencing. One of the patients was somatic mosaic for the mutation. Studies in patient cells as well as transfection studies in HEK293T cells indicated that the mutations resulted in a gain of function. Jeremiah et al. report 3 affected members of a 3-generation French family of mixed European descent with SAVI identified a heterozygous missense mutation in the STING gene (V155M). In vitro functional expression assays showed that the mutation caused constitutive activation of the IFNB1 promoter, even in the absence of stimulation. More than 3 unrelated cases with plausible disease causing variants.

Created: 3 Jul 2018, 1:50 p.m.

Publications

• 25029335
• 25401470

Green List (high evidence)

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Publications

• 25029335
• 25401470

Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments

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

Added new-gene-name tag, new approved HGNC gene symbol for TMEM173 is STING1

Created: 6 Sep 2019, 4:14 p.m. | Last Modified: 6 Sep 2019, 4:14 p.m.

Panel Version: 1.54

Comment on list classification: Changed Amber to Green from external review comment and further publications to support gene-disease association

Created: 5 Jul 2018, 2:02 p.m.

Comment on mode of inheritance: updated MOI based on expert review and PMIDs 25029335 and 25401470

Created: 5 Jul 2018, 2:01 p.m.

OriginaI Metadata from IUIS classification table (February, 2018) downloaded 20180614. IUIS Genetic defect (original gene symbol in IUIS download): TMEM173 .PanelApp HGNC gene symbol check: TMEM173 . IUIS Disease: STING--associated vasculopathy, infantile-onset . IUIS Inheritance: AR .T cells: N/A, .B cells: N/A, .IUIS Other affected cells: N/A. IUIS Associated features: Skin vasculopathy, inflammatory lung disease, systemic autoinflammation and ICC, FCL. IUIS Major category: Autoinflammatory Disorders. IUIS Subcategory: Type 1 Interferonopathies

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, 12:01 p.m.

Original metadata downloaded from ESID Registry. ESID_Gene_original: STING (TMEM173), PanelApp HGNC gene symbol check: TMEM173, ESID classification: Main_category/ Sub_category/ PID_Diagnosis Diseases of immune dysregulation / Type 1 interferonopathies / Type 1 interferonopathies

Created: 17 Apr 2018, 12:29 p.m.

Original metadata supplied by GRID. GRID Gene Symbol HGNC PanelApp check: TMEM173, GRID_Gene_Symbol: TMEM173, GRID_Transcript_ENS_Community submitted: ENST00000330794, GRID_Transcript_RefSeq: NM_198282.3, GRID_Transcript_ENS_used_on_Production: ENST00000330794

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