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Primary immunodeficiency

Gene: CTPS1

Green List (high evidence)

CTPS1 (CTP synthase 1)
EnsemblGeneIds (GRCh38): ENSG00000171793
EnsemblGeneIds (GRCh37): ENSG00000171793
OMIM: 123860, Gene2Phenotype
CTPS1 is in 3 panels

5 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, 12:41 p.m. | Last Modified: 14 Oct 2020, 12:41 p.m.
Panel Version: 2.242
The following PubMed IDs were added to gene CTPS1 (OMIM gene MIM#123860): 24870241;29884857. These publications have been associated with the gene by the immunedysregulation 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

Sophie Hambleton (Newcastle University)

Green List (high evidence)

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

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): CTPS1 .PanelApp HGNC gene symbol check: CTPS1 . IUIS Disease: CTPS1 deficiency . IUIS Inheritance: AR .T cells: Increased activated T cells, .B cells: Nl/low , .IUIS Other affected cells: N/A. IUIS Associated features: Recurrent/chronic bacterial and viral infections (EBV, VZV), EBV lymphoproliferation, B-cell non-Hodgkin lymphoma. IUIS Major category: Diseases of Immune Dysregulation. IUIS Subcategory: Susceptibility to EBV and Lymphoproliferative Conditions
Created: 2 Jul 2018, 10:35 a.m.
Comment on list classification: Changed from Amber to Green after internal clinical review. Clinical consensus is that CTPS1 should be rated green, in view of meeting the threshold for numbers of cases but also some additional information pointing towards a deleterious effect from the variant (effect on splicing and expression pattern). This is considered further evidence for this gene, within the founder region. Consensus was sought in view of going against the current PanelApp founder variant rule.
Created: 8 Jun 2018, 8:32 a.m.
Past onto clinical team for further discussion. Our current PanelApp rules denote that for a founder mutation we cannot make these genes Green. There are exceptions to this rule (reviewed by clinical team) if there has been an additional pathogenic var. conformed/reported. In this instance there is currently only one mutation that gives rise to observed PID phenotype.
Created: 4 Jun 2018, 10 a.m.
From ClinVar : This variant is present in population databases (rs145092287, ExAC 0.02%). This variant has been reported to segregate with combined immunodeficiency in several families (PMID: 24870241, 27638562). ClinVar contains an entry for this variant (Variation ID: 140454). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant leads to skipping of exon 18 and reduced CTPS1 protein expression (PMID: 24870241). For these reasons, this variant has been classified as Pathogenic.
Created: 4 Jun 2018, 8:41 a.m.
Comment on publications: Added PMID: 27638562 (2016) report details two sisters with homozygous CTPS1 mutations, identified by exome sequencing. Similar to the previously published cases (Martin et al. 2014 PMID :24870241), these siblings, born to a non-consanguineous family, whose ancestors emigrated from Northern England, suffered from recurrent sino-pulmonary and viral infections, due to VZV and EBV.
Created: 4 Jun 2018, 8:39 a.m.
added found-effect tag
Created: 1 Jun 2018, 3:51 p.m.
from Genomics of Rare Immune Disorders (GRID) platform which is supported by Cambridge Biomedical Research centre/NHS East England NHS GMC : CTPS1 is associated to a type of SCID, with noted phenotype attributes via clinical review Prof T.W. Kuijpers: Patients develop Epstein-Barr Virus (EBV) driven Hemophagocytic Lymphohistiocytosis (HLH ). Severe EBV infection can be associated with immunodeficiencies that also predispose a patient to other viral infections PMID: 26424649.
Created: 1 Jun 2018, 3:24 p.m.
Only one variant has been reported (CTPS1, IVS17, G-C, -1 (rs145092287) NM_001905.2:c.1692-1G>C in the literature which seems to have a founder effect. from OMIM: 8 children from 5 families from the northwest region of England who manifested a combined deficiency of adaptive immunity Martin et al. (2014) PMID: 24870241 detected a homozygous G-to-C transversion at the -1 position of intron 17 of the CTPS1 gene (rs145092287) using whole-exome and confirmatory Sanger sequencing. The mutation was considered deleterious since CTPS1 protein expression could not be detected in lysates of EBV-transformed B cells and T-cell blasts from patients. All parents and unaffected sibs tested were heterozygous carriers. Sequencing of a cohort of 752 healthy individuals from the northwest of England gave an estimated frequency of homozygosity of 1 in 560,000. This frequency represented a more than 10-fold increase compared to the frequency estimated from available exome databases. Whole-exome sequencing data and analysis of polymorphic microsatellite markers in all patients revealed a common region of homozygosity of 1.1 Mb surrounding the mutation. These data indicated a founder effect.
Created: 1 Jun 2018, 3:19 p.m.
Comment on phenotypes: added phenotype from GRID/ BRIDGE PID project
Created: 1 Jun 2018, 2:12 p.m.
Comment on phenotypes: Added MIMid from OMIM and phenotype from Orphanet
Created: 1 Jun 2018, 2:04 p.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: 20 Apr 2018, 12:25 p.m.
Original metadata supplied by GRID. GRID Gene Symbol HGNC PanelApp check: CTPS1, GRID_Gene_Symbol: CTPS1, GRID_Transcript_ENS_Community submitted: ENST00000372621, GRID_Transcript_RefSeq: NM_001905.3, GRID_Transcript_ENS_used_on_Production: ENST00000372621
Created: 17 Apr 2018, 12:12 p.m.

Details

Mode of Inheritance
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • Other
  • NHS GMS
  • North West GLH
  • London North GLH
  • IUIS Classification February 2018
  • Victorian Clinical Genetics Services
  • GRID V2.0
Phenotypes
  • Immunodeficiency 24, 615897
  • Severe combined immunodeficiency due to CTPS1 deficiency
  • Patients develop Epstein-Barr Virus (EBV) driven Hemophagocytic Lymphohistiocytosis (HLH )
  • Recurrent/chronic bacterial and viral infections (EBV, VZV), EBV lymphoproliferation, B-cell non-Hodgkin lymphoma
  • Diseases of Immune Dysregulation
Tags
founder-effect
OMIM
123860
Clinvar variants
Variants in CTPS1
Penetrance
None
Publications
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: ctps1 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 CTPS1. Publications for gene CTPS1 were updated from 24870241; 26424649; 27638562; 17576681; 9536098 to 26424649; 17576681; 27638562; 9536098; 29884857; 24870241 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 CTPS1.

17 Sep 2019, Gel status: 3

Added New Source

Louise Daugherty (Genomics England Curator)

Source North West GLH was added to CTPS1.

17 Sep 2019, Gel status: 3

Added New Source

Louise Daugherty (Genomics England Curator)

Source London North GLH was added to CTPS1.

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 CTPS1 were set to Immunodeficiency 24, 615897, Severe combined immunodeficiency due to CTPS1 deficiency, Patients develop Epstein-Barr Virus (EBV) driven Hemophagocytic Lymphohistiocytosis (HLH ), Recurrent/chronic bacterial and viral infections (EBV, VZV), EBV lymphoproliferation, B-cell non-Hodgkin lymphoma, Diseases of Immune Dysregulation

26 Jun 2018, Gel status: 4

Added New Source

Louise Daugherty (Genomics England Curator)

IUIS Classification February 2018 was added to CTPS1. 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 CTPS1. Panel: Primary immunodeficiency disorders

13 Jun 2018, Gel status: 3

Entity classified by Genomics England curator

Louise Daugherty (Genomics England Curator)

Gene: ctps1 has been classified as Green List (High Evidence).

8 Jun 2018, Gel status: 3

Entity classified by Genomics England curator

Louise Daugherty (Genomics England Curator)

Gene: ctps1 has been classified as Green List (High Evidence).

4 Jun 2018, Gel status: 2

Set publications

Louise Daugherty (Genomics England Curator)

Publications for gene: CTPS1 were set to 24870241; 26424649; 27638562; 17576681; 9536098

4 Jun 2018, Gel status: 2

Set publications

Louise Daugherty (Genomics England Curator)

Publications for gene: CTPS1 were set to 24870241; 26424649; 27638562

1 Jun 2018, Gel status: 2

Set publications

Louise Daugherty (Genomics England Curator)

Publications for gene: CTPS1 were set to 24870241; 26424649

1 Jun 2018, Gel status: 2

Set Phenotypes

Louise Daugherty (Genomics England Curator)

Phenotypes for gene: CTPS1 were set to Immunodeficiency 24, 615897; Severe combined immunodeficiency due to CTPS1 deficiency; Patients develop Epstein-Barr Virus (EBV) driven Hemophagocytic Lymphohistiocytosis (HLH )

1 Jun 2018, Gel status: 2

Set Phenotypes

Louise Daugherty (Genomics England Curator)

Phenotypes for gene: CTPS1 were set to Immunodeficiency 24, 615897; Severe combined immunodeficiency due to CTPS1 deficiency; Patients develop Epstein-Barr Virus (EBV )-Induced Hemophagocytic Lymphohistiocytosis (HLH )

1 Jun 2018, Gel status: 2

Set publications

Louise Daugherty (Genomics England Curator)

Publications for gene: CTPS1 were set to 24870241

1 Jun 2018, Gel status: 2

Set Phenotypes

Louise Daugherty (Genomics England Curator)

Phenotypes for gene: CTPS1 were set to Immunodeficiency 24, 615897; Severe combined immunodeficiency due to CTPS1 deficiency

20 Apr 2018, Gel status: 2

Added New Source

Louise Daugherty (Genomics England Curator)

Expert Review Amber was added to CTPS1. Panel: Primary immunodeficiency disorders

17 Apr 2018, Gel status: 1

Set penetrance

Louise Daugherty (Genomics England Curator)

Phenotypes for gene CTPS1 were set to Immunodeficiency 24

17 Apr 2018, Gel status: 1

Added New Source

Louise Daugherty (Genomics England Curator)

CTPS1 was added to Primary immunodeficiency disorders panel. Sources: GRID V2.0

17 Apr 2018, Gel status: 1

Created

Louise Daugherty (Genomics England Curator)

CTPS1 was created by Louise Daugherty