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Primary immunodeficiency

Gene: PLCG2

Green List (high evidence)

PLCG2 (phospholipase C gamma 2)
EnsemblGeneIds (GRCh38): ENSG00000197943
EnsemblGeneIds (GRCh37): ENSG00000197943
OMIM: 600220, Gene2Phenotype
PLCG2 is in 6 panels

9 reviews

Eleanor Williams (Genomics England Curator)

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

Kimberly Gilmour (Great Ormond Street Hopsital)

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

Tracy Briggs (Manchester Genomic Medicine Centre)

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

Sarah Leigh (Genomics England Curator)

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.

Louise Daugherty (Genomics England Curator)

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.

Olivia Niblock (Genomics England Curator)

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.

Sophie Hambleton (Newcastle University)

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

Ellen McDonagh (Genomics England Curator)

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.

William Rae (University Hospital Southampton NHS Foundation Trust)

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

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Expert Review Green
  • Other
  • NHS GMS
  • North West GLH
  • London North GLH
  • IUIS Classification February 2018
  • Victorian Clinical Genetics Services
  • ESID Registry 20171117
  • GRID V2.0
  • GOSH PID v.8.0
  • A- or hypo-gammaglobulinaemia v1.25
Phenotypes
  • 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
OMIM
600220
Clinvar variants
Variants in PLCG2
Penetrance
None
Publications
Mode of Pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Panels with this gene

History Filter Activity

14 Oct 2020, Gel status: 3

Entity classified by Genomics England curator

Eleanor Williams (Genomics England Curator)

Gene: plcg2 has been classified as Green List (High Evidence).

13 Oct 2020, Gel status: 1

Added New Source, Set publications, Status Update

Eleanor Williams (Genomics England Curator)

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)

17 Sep 2019, Gel status: 3

Added New Source

Louise Daugherty (Genomics England Curator)

Source NHS GMS was added to PLCG2.

17 Sep 2019, Gel status: 3

Added New Source

Louise Daugherty (Genomics England Curator)

Source North West GLH was added to PLCG2.

17 Sep 2019, Gel status: 3

Added New Source

Louise Daugherty (Genomics England Curator)

Source London North GLH was added to PLCG2.

12 Jul 2018, Gel status: 4

Panel promoted to version 1.0

Louise Daugherty (Genomics England Curator)

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.

1 Jul 2018, Gel status: 4

Set penetrance

Louise Daugherty (Genomics England Curator)

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

26 Jun 2018, Gel status: 4

Added New Source

Louise Daugherty (Genomics England Curator)

IUIS Classification February 2018 was added to PLCG2. Panel: Primary immunodeficiency disorders

26 Jun 2018, Gel status: 4

Added New Source

Louise Daugherty (Genomics England Curator)

Victorian Clinical Genetics Services was added to PLCG2. Panel: Primary immunodeficiency disorders

13 Jun 2018, Gel status: 3

Entity classified by Genomics England curator

Louise Daugherty (Genomics England Curator)

Gene: plcg2 has been classified as Green List (High Evidence).

9 May 2018, Gel status: 3

Gene classified by Genomics England curator

Sarah Leigh (Genomics England Curator)

This gene has been classified as Green List (High Evidence).

9 May 2018, Gel status: 2

Set publications

Sarah Leigh (Genomics England Curator)

Publications for PLCG2 were set to 22236196; 23000145; 29538758

9 May 2018, Gel status: 2

Set Phenotypes

Sarah Leigh (Genomics England Curator)

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

20 Apr 2018, Gel status: 2

Set mode of pathogenicity

Louise Daugherty (Genomics England Curator)

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

20 Apr 2018, Gel status: 2

Set mode of pathogenicity

Louise Daugherty (Genomics England Curator)

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

17 Apr 2018, Gel status: 2

Added New Source, Set penetrance

Louise Daugherty (Genomics England Curator)

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

17 Apr 2018, Gel status: 2

Set penetrance

Louise Daugherty (Genomics England Curator)

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

17 Apr 2018, Gel status: 2

Added New Source, Set penetrance

Louise Daugherty (Genomics England Curator)

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

6 Apr 2018, Gel status: 2

Clear Sources

Louise Daugherty (Genomics England Curator)

PLCG2 Source: GOSH PID 20171178 was removed from gene: PLCG2

6 Apr 2018, Gel status: 2

Added New Source

Louise Daugherty (Genomics England Curator)

GOSH PID v.8.0 was added to PLCG2. Panel: Primary immunodeficiency disorders

29 Mar 2018, Gel status: 2

Added New Source, Set mode of inheritance

Louise Daugherty (Genomics England Curator)

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

29 Mar 2018, Gel status: 2

Added New Source

Louise Daugherty (Genomics England Curator)

PLCG2 was added to Primary immunodeficiency disorders panel. Sources: Expert Review Amber, A- or hypo-gammaglobulinaemia v1.25

29 Mar 2018, Gel status: 2

Created

Louise Daugherty (Genomics England Curator)

PLCG2 was created by Louise Daugherty