Primary immunodeficiency or monogenic inflammatory bowel disease
Gene: PLCG2Comment 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
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 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.
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 InflammasomeCreated: 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 defectCreated: 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: ENST00000359376Created: 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 FunctionCreated: 15 Aug 2017, 1:09 p.m.
Disease alleles cause gain of phospholipase activity that may or may not be temperature-dependentCreated: 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.
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
Phenotypes for gene: PLCG2 were changed from Autoinflammation, antibody deficiency, and immune dysregulation syndrome 614878; Familial cold autoinflammatory syndrome 3 614468; Hypogammaglobulinaemia, cold induced urticaria, autoinflammatory; Familial cold autoinflammatory syndrome 3; Other autoinflammatory diseases with known genetic defect; Cold urticaria hypogammaglobulinemia, autoinflammation; Autoinflammatory Disorders to Autoinflammation, antibody deficiency, and immune dysregulation syndrome, OMIM:614878; Familial cold autoinflammatory syndrome 3, OMIM:614468; Hypogammaglobulinaemia, cold induced urticaria, autoinflammatory
Gene: plcg2 has been classified as Green List (High Evidence).
Source Other was added to PLCG2. Publications for gene PLCG2 were updated from 22236196; 23000145; 29538758 to 23000145; 29538758; 25760457; 22236196 Rating Changed from Green List (high evidence) to Red List (low evidence)
Source NHS GMS was added to PLCG2.
Source North West GLH was added to PLCG2.
Source London North GLH was added to PLCG2.
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 PLCG2 were set to Autoinflammation, antibody deficiency, and immune dysregulation syndrome 614878, Familial cold autoinflammatory syndrome 3 614468, Hypogammaglobulinaemia, cold induced urticaria, autoinflammatory, Familial cold autoinflammatory syndrome 3, Other autoinflammatory diseases with known genetic defect, Cold urticaria hypogammaglobulinemia, autoinflammation, Autoinflammatory Disorders
IUIS Classification February 2018 was added to PLCG2. Panel: Primary immunodeficiency disorders
Victorian Clinical Genetics Services was added to PLCG2. Panel: Primary immunodeficiency disorders
Gene: plcg2 has been classified as Green List (High Evidence).
This gene has been classified as Green List (High Evidence).
Publications for PLCG2 were set to 22236196; 23000145; 29538758
Phenotypes for PLCG2 were set to Autoinflammation, antibody deficiency, and immune dysregulation syndrome 614878; Familial cold autoinflammatory syndrome 3 614468; Hypogammaglobulinaemia, cold induced urticaria, autoinflammatory; Familial cold autoinflammatory syndrome 3; Other autoinflammatory diseases with known genetic defect
Mode of pathogenicity for PLCG2 was changed to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Mode of pathogenicity for PLCG2 was changed to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
ESID Registry 20171117 was added to PLCG2. Panel: Primary immunodeficiency disorders Phenotypes for gene PLCG2 were set to Autoinflammation, antibody deficiency, and immune dysregulation syndrome, Familial cold autoinflammatory syndrome 3, Hypogammaglobulinaemia, cold induced urticaria, autoinflammatory, Familial cold autoinflammatory syndrome 3, Other autoinflammatory diseases with known genetic defect
Phenotypes for gene PLCG2 were set to Autoinflammation, antibody deficiency, and immune dysregulation syndrome, Familial cold autoinflammatory syndrome 3, Hypogammaglobulinaemia, cold induced urticaria, autoinflammatory, Familial cold autoinflammatory syndrome 3
GRID V2.0 was added to PLCG2. Panel: Primary immunodeficiency disorders Phenotypes for gene PLCG2 were set to Autoinflammation, antibody deficiency, and immune dysregulation syndrome, Familial cold autoinflammatory syndrome 3, Hypogammaglobulinaemia, cold induced urticaria, autoinflammatory, Familial cold autoinflammatory syndrome 3
PLCG2 Source: GOSH PID 20171178 was removed from gene: PLCG2
GOSH PID v.8.0 was added to PLCG2. Panel: Primary immunodeficiency disorders
GOSH PID 20171178 was added to PLCG2. Panel: Primary immunodeficiency disorders Model of inheritance for gene PLCG2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
PLCG2 was added to Primary immunodeficiency disorders panel. Sources: Expert Review Amber, A- or hypo-gammaglobulinaemia v1.25
PLCG2 was created by Louise Daugherty