Primary immunodeficiency or monogenic inflammatory bowel disease

Gene: CSF3R

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)

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): CSF3R .PanelApp HGNC gene symbol check: CSF3R . IUIS Disease: G-CSF receptor deficiency . IUIS Inheritance: AR .T cells: Profound depletion of CD4+ cells, .B cells: N/A, .IUIS Other affected cells: N. IUIS Associated features: N/A. IUIS Major category: Congenital defects of phagocyte number or function. IUIS Subcategory: Congenital Neutropenias

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

Comment on list classification: changed from Amber to Green after internal clinical review. The monoallelic form associated with neutrophilia is not relevant to this panel. However, there is a reference to three unrelated families with severe congenital neutropaenia and biallelic variants in OMIM, so rate Green

Created: 11 May 2018, 3:51 p.m.

Comment on publications: Three unrelated affecteds have been reported with Severe congenital neutropenia-7 caused by variants in CSF3R (PMID:24753537 (2104) , PMID:26324699 (2015). However, the main therapy of Severe congenital neutropenia (SCN) is the application of granulocyte colony stimulating factor (G-CSF). CSF3R gene mutation often occurs in the treatment process, and can lead to acute myeloid leukemia. (PMID: 29070147)

Created: 9 May 2018, 1:52 p.m.

Comment on mode of inheritance: Changed from monoallelic to biallelic inheritance as this instance represents Neutropenia, severe congenital, 7, autosomal recessive, 617014, which is relevant to this panel and not Hereditary neutrophilia, 617014 which was noted as being Autosomal dominant, the phenotype of which is not relevant to this panel

Created: 9 May 2018, 1:29 p.m.

Comment on phenotypes: Also reported gene-phenotype Neutrophilia, hereditary,162830 from OMIM PMID:19620628 Plo et al. (2009) who found a 3-generation family segregating autosomal dominant neutrophilia, sequenced the CSF3R gene and identified a heterozygous activating mutation.This phenotype is not relevant to the PID panel.

Created: 9 May 2018, 1:20 p.m.

Comment on phenotypes: From expert review it was noted that somatic mutations of this gene often occur following GCSF therapy for severe congenital neutropenia of alternative aetiology, but germline mutations of CSF3R are associated with neutrophilia rather than neutropenia. The germline mutations result in a phenotype that is not PID panel relevant.

Created: 9 May 2018, 12:55 p.m.

Associated in the ESID Registry to a PID Diagnosis of Phagocytic disorders Congenital neutropenia, but from the literature and expert reviews CSF3R germline mutations are associated to neutrophilia rather than neutropenia.

Created: 9 May 2018, 12:50 p.m.

This gene was present in the original PanelApp PID panel dataset (review in April 2018) rated as Red. 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, 12:25 p.m.

Original metadata downloaded from ESID Registry. ESID_Gene_original: CSF3R, PanelApp HGNC gene symbol check: CSF3R, ESID classification: Main_category/ Sub_category/ PID_Diagnosis Phagocytic disorders / Congenital neutropenia / Congenital neutropenia

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

Original metadata supplied by GRID. GRID Gene Symbol HGNC PanelApp check: CSF3R, GRID_Gene_Symbol: CSF3R, GRID_Transcript_ENS_Community submitted: ENST00000373103, GRID_Transcript_RefSeq: NM_156039.3, GRID_Transcript_ENS_used_on_Production: ENST00000373103

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

Publications

• 19620628

Green List (high evidence)

Comment when marking as ready: One expert reviewer suggested green and one red because germline variants in this gene associated with neurtophilia and not neutropenia. Associated with neurtophilia in OMIM. No disease association in G2P, and only found in 1/4 sources

Created: 24 May 2016, 8:03 p.m.

Red List (low evidence)

Agree there is good evidence that biallelic variation in this gene causes SCN

Created: 23 Oct 2019, 6:31 a.m. | Last Modified: 23 Oct 2019, 6:31 a.m.

Panel Version: 1.132

Somatic mutations of this gene often occur following GCSF therapy for severe congenital neutropenia of alternative aetiology, but germline mutations of CSF3R are associated with neutrophilia rather than neutropenia

Created: 19 Oct 2015, 10:35 p.m.