Primary immunodeficiency or monogenic inflammatory bowel disease

Gene: PLCG2

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, 1:39 p.m. | Last Modified: 14 Oct 2020, 1:39 p.m.

Panel Version: 2.292

The following PubMed IDs were added to entity PLCG2: 23000145;22236196;25760457. These publications have been associated with OMIM phenotype MIM#614468, 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

Publications

• 23000145
• 22236196
• 25760457

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: Associated with relevant phenotypes in OMIM and as possible Gen2Phen gene. At least 3 large inframe deletion variants have been reported in unrelated Familial cold autoinflammatory syndrome 3 614468 cases. These deletions remove, the C-terminal Src-homology-2 (cSH2) domain, which is autoinhibitory and normally prevents constitutive enzymatic function, hence the deletions are gain of function (PMID 22236196). The missense variant (NM_002661, c.2120C>A, p.Ser707Tyr) also falls within the cSH2 domain, it does not result in loss of inhibition alone, but requires other stimulating factors also (PMID 23000145)

Created: 9 May 2018, 11:55 a.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): PLCG2 .PanelApp HGNC gene symbol check: PLCG2 . IUIS Disease: PLAID (PLCg2 associated antibody deficiency and immune dysregulation) or familial cold autoinflammatory syndrome 3 or APLAID (c2120A>C) . IUIS Inheritance: AD GOF .T cells: Very low, .B cells: N/A, .IUIS Other affected cells: B cells, NK, Mast cells. IUIS Associated features: Cold urticaria hypogammaglobulinemia, autoinflammation. IUIS Major category: Autoinflammatory Disorders. IUIS Subcategory: Defects Affecting the Inflammasome

Created: 2 Jul 2018, 10:35 a.m.

This gene was present in the original PanelApp PID panel dataset (review in April 2018) rated as Amber. The gene is present in the 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: 20 Apr 2018, 10:29 a.m.

Original metadata downloaded from ESID Registry. ESID_Gene_original: PLCG2, PanelApp HGNC gene symbol check: PLCG2, ESID classification: Main_category/ Sub_category/ PID_Diagnosis Autoinflammatory disorders / Other autoinflammatory diseases with known genetic defect / Other autoinflammatory diseases with known genetic defect

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

Original metadata supplied by GRID. GRID Gene Symbol HGNC PanelApp check: PLCG2, GRID_Gene_Symbol: PLCG2, GRID_Transcript_ENS_Community submitted: ENST00000359376, GRID_Transcript_RefSeq: NM_002661.4, GRID_Transcript_ENS_used_on_Production: ENST00000359376

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

Comment on list classification: Variants in this gene are certainly linked to immunodeficiency. From literature review, found 2 papers documenting variation in this gene being linked to hypo-gammaglobulinaemia, the first paper 22236196, citing 3 individuals being treated for hypo-gammaglobulinaemia, however not clear if these individuals are related.

Created: 15 Aug 2017, 1:17 p.m.

Comment on mode of pathogenicity: Gain of Function

Created: 15 Aug 2017, 1:09 p.m.

Green List (high evidence)

Disease alleles cause gain of phospholipase activity that may or may not be temperature-dependent

Created: 6 Jan 2017, 3:30 p.m.

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

It is a possible DD gene for Autoinflammation, antibody deficiency, and immune dysregulation syndrome-PLCG2 associated, and a possible DD gene for Familial cold autoinflammatory syndrome 3.

Created: 9 Sep 2016, 8:29 a.m.

Green List (high evidence)

Gain of function variants.

Created: 6 Sep 2016, 5:20 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Hypogammaglobulinaemia, cold induced urticaria, autoinflammatory

Publications

• PMID: 22236196, PMID: 23000145