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Primary immunodeficiency

Gene: TCF3

Green List (high evidence)

TCF3 (transcription factor 3)
EnsemblGeneIds (GRCh38): ENSG00000071564
EnsemblGeneIds (GRCh37): ENSG00000071564
OMIM: 147141, Gene2Phenotype
TCF3 is in 3 panels

10 reviews

Arina Puzriakova (Genomics England Curator)

Added 'for-review' tag as the MOI has changed since previous sign-off of this panel (version 2.1) and requires review by the Specialist Test Group.
Created: 21 Oct 2020, 4:35 p.m. | Last Modified: 21 Oct 2020, 4:35 p.m.
Panel Version: 2.368

Ivone Leong (Genomics England Curator)

Comment on mode of inheritance: Updated MOI from Monoallelic to Both Monoallelic and biallelic based on expert review and evidence provided by Zornitza Stark (Australian Genomics).
Created: 15 Apr 2020, 2:26 p.m. | Last Modified: 15 Apr 2020, 2:26 p.m.
Panel Version: 2.62

Zornitza Stark (Australian Genomics)

Green List (high evidence)

Please note recent reports of bi-allelic variants associated with disease.
Created: 12 Apr 2020, 4:52 a.m. | Last Modified: 12 Apr 2020, 4:52 a.m.
Panel Version: 2.51

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

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)

Eleanor Williams (Genomics England Curator)

Comment on list classification: Sufficient number of cases for this gene to be rated green. Confirmed with Genomics England Clinical team.
Created: 19 Jun 2018, 8:54 a.m.
Asked for Genomics England clinical team input to decide if this gene should be green. Enough cases but in some only mutations in the TCF3 were looked for.
Created: 14 Jun 2018, 12:11 p.m.
As noted by Olivia Niblock, in the report from Boisson et al 2013 (PMID: 24216514), although 4 unrelated individuals with agammaglobulinemia (not from isolated populations or consanguineous families) all have a de novo missense mutation in the TCF3 gene (E555K) that appears to have a dominant negative effect, only 1 patient and their family underwent whole genome sequence analysis. One other patient is reported in Ben-Ali et al 2017 (PMID: 28532655) with severe hypogammaglobulinemia who was homozygous for a nonsense mutation p.Q270*. The first cousin parents were heterozygous for this variant. Ameratunga et al 2017 (PMID: 29114388) report a mother with a de novo TCF3 mutation in addition to an inherited C104R mutation of the TACI gene. The mother has severe CVID-like disorder and systemic lupus erythematosus (SLE). Her symptomatic son, who has inherited only the TCF3 mutation, but not the TACI gene mutation, has type 1 diabetes (T1D), synovitis, reduced IgG levels and IgA deficiency. In OMIM the TCF3 gene is associated with agammaglobulinemia. No data for this gene in gene2phenotype.
Created: 13 Jun 2018, 1:27 p.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): TCF3 .PanelApp HGNC gene symbol check: TCF3 . IUIS Disease: E47 transcription factor deficiency . IUIS Inheritance: AD .T cells: Nl numbers, low antigen specific memory CD4+, .B cells: N/A, .IUIS Other affected cells: N/A. IUIS Associated features: Recurrent bacterial infections. IUIS Major category: Predominantly Antibody Deficiencies. IUIS Subcategory: Severe Reduction in All Serum Immunoglobulin Isotypes with Profoundly Decreased or Absent B Cells, Agammaglobulinemia
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, 10:28 a.m.
Original metadata downloaded from ESID Registry. ESID_Gene_original: TCF3, PanelApp HGNC gene symbol check: TCF3, ESID classification: Main_category/ Sub_category/ PID_Diagnosis Predominantly antibody disorders / Agammaglobulinemias / Agammaglobulinemia
Created: 17 Apr 2018, 12:29 p.m.

Olivia Niblock (Genomics England Curator)

Comment on list classification: After literature research, while participants in a study in PMID: 24216514 all had the same variant, only one patient and their family had GWAS, highlighting variant in this gene. Another study in PMID 28532655 suggests a homozygous variant in an individual from a consanguineous family.
Created: 15 Aug 2017, 12:54 p.m.

Owen Siggs (Flinders University)

Green List (high evidence)

Four unrelated cases/families with same de novo missense variant (E555K). Suspected to be a dominant negative allele.
Created: 16 May 2017, 7:56 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Agammaglobulinemia

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

Details

Mode of Inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Sources
  • NHS GMS
  • North West GLH
  • London North GLH
  • Expert Review Green
  • IUIS Classification February 2018
  • Victorian Clinical Genetics Services
  • ESID Registry 20171117
  • A- or hypo-gammaglobulinaemia v1.25
Phenotypes
  • Agammaglobulinemia
  • Agammaglobulinemia 8, autosomal dominant, 616941
  • Primary immunodeficiency
  • Recurrent bacterial infections
  • Predominantly Antibody Deficiencies
Tags
for-review
OMIM
147141
Clinvar variants
Variants in TCF3
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

21 Oct 2020, Gel status: 3

Added Tag

Arina Puzriakova (Genomics England Curator)

Tag for-review tag was added to gene: TCF3.

15 Apr 2020, Gel status: 3

Set mode of inheritance

Ivone Leong (Genomics England Curator)

Mode of inheritance for gene: TCF3 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal

15 Apr 2020, Gel status: 3

Set publications

Ivone Leong (Genomics England Curator)

Publications for gene: TCF3 were set to 24216514; 28532655; 29114388

17 Sep 2019, Gel status: 3

Added New Source

Louise Daugherty (Genomics England Curator)

Source NHS GMS was added to TCF3.

17 Sep 2019, Gel status: 3

Added New Source

Louise Daugherty (Genomics England Curator)

Source North West GLH was added to TCF3.

17 Sep 2019, Gel status: 3

Added New Source

Louise Daugherty (Genomics England Curator)

Source London North GLH was added to TCF3.

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 TCF3 were set to Agammaglobulinemia, Agammaglobulinemia 8, autosomal dominant, 616941, Primary immunodeficiency, Recurrent bacterial infections, Predominantly Antibody Deficiencies

27 Jun 2018, Gel status: 4

Entity classified by Genomics England curator

Louise Daugherty (Genomics England Curator)

Gene: tcf3 has been classified as Green List (High Evidence).

26 Jun 2018, Gel status: 4

Added New Source

Louise Daugherty (Genomics England Curator)

IUIS Classification February 2018 was added to TCF3. 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 TCF3. Panel: Primary immunodeficiency disorders

19 Jun 2018, Gel status: 3

Entity classified by Genomics England curator

Eleanor Williams (Genomics England Curator)

Gene: tcf3 has been classified as Green List (High Evidence).

13 Jun 2018, Gel status: 2

Set publications

Eleanor Williams (Genomics England Curator)

Publications for gene: TCF3 were set to 24216514; 28532655; 29114388

24 Apr 2018, Gel status: 2

Set Phenotypes

Louise Daugherty (Genomics England Curator)

Phenotypes for TCF3 were set to Agammaglobulinemia; Agammaglobulinemia 8, autosomal dominant, 616941; Primary immunodeficiency

24 Apr 2018, Gel status: 2

Set Phenotypes

Louise Daugherty (Genomics England Curator)

Phenotypes for TCF3 were set to Agammaglobulinemia; Agammaglobulinemia 8, autosomal dominant, 616941; Primary immunodeficiency

20 Apr 2018, Gel status: 2

Set mode of pathogenicity

Louise Daugherty (Genomics England Curator)

Mode of pathogenicity for TCF3 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 TCF3. Panel: Primary immunodeficiency disorders Phenotypes for gene TCF3 were set to Agammaglobulinemia

29 Mar 2018, Gel status: 2

Added New Source

Louise Daugherty (Genomics England Curator)

TCF3 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)

TCF3 was created by Louise Daugherty