Primary immunodeficiency or monogenic inflammatory bowel disease

Gene: CD247

The rating of this gene has been updated following NHS Genomic Medicine Service approval.

Created: 4 Mar 2022, 10:17 a.m. | Last Modified: 4 Mar 2022, 10:17 a.m.

Panel Version: 2.529

Comment on list classification: Changed rating to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).

Created: 20 Oct 2020, 2 p.m. | Last Modified: 20 Oct 2020, 2 p.m.

Panel Version: 2.336

The following PubMed IDs were added to gene CD247 (OMIM gene MIM#186780): 17170122. These publications have been associated with the gene by the immunodeficiencies 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

• 17170122

Comment on list classification: Promoted from Amber to Green after discussion with the Genomics England Clinical Team. An additional case was found (PMID: 26542031). Therefore, there is enough evidence to promote this gene to Green status.

Created: 18 May 2020, 10:11 a.m. | Last Modified: 18 May 2020, 10:11 a.m.

Panel Version: 2.171

I don't know

Please note there appear to be at least two other cases reported as pathogenic in ClinVar by clinical laboratories.

Created: 10 Jul 2018, 10:23 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Variants in this GENE are reported as part of current diagnostic practice

I don't know

Internal clinical team agree there is difficulty of distinguishing whether these are separate cases. As this gene has been reviewed recently with an immunology expert it was decided to keep this gene Amber until more robust evidence is published

Created: 21 Sep 2018, 11:54 a.m.

Additional external review added so this gene was reviewed again. There are two pathogenic germline variants in Clinvar, the first NM_198053.2(CD247):c.301C>T (p.Gln101Ter) pathogenic variant is the same variant reported in PMID:16672702. However, it is not clear if this is strong enough evidence for three unrelated cases, as there is not a clear indication based on the information supplied to ClinVar wether these are two different cases, or are the same.
To be referred to clinical team again, in view of green review (pers. comm with Zornitza Stark, VCGS) in addition to comment made in PanelApp 10 July 2018.
1) NM_198053.2(CD247):c.301C>T (p.Gln101Ter) reported from GeneDx clinical lab, no disorder associated but is the same pathogenic variant as reported in PMID:16672702
2) NM_198053.2(CD247):c.51dup (p.Ile18Aspfs) which is associated to Immunodeficiency due to defect in cd3-zeta reported from Invitae clinical lab

Created: 21 Sep 2018, 9:50 a.m.

OriginaI Metadata from IUIS classification table (February, 2018) downloaded 20180614. IUIS Genetic defect (original gene symbol in IUIS download): CD247 .PanelApp HGNC gene symbol check: CD247 . IUIS Disease: CD3z deficiency . IUIS Inheritance: AR .T cells: N/A, .B cells: Normal, .IUIS Other affected cells: N/A. IUIS Associated features: Nl NK, no g/d T cells. IUIS Major category: Immunodeficiencies affecting cellular and humoral immunity. IUIS Subcategory: T-B+ Severe Combined Immune Deficiency (SCID)

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

Comments after internal clinical review: It was thought best to keep rating as amber, unless there is expert opinion to support a green rating. PMID: 16672702 refers to a boy with germline and somatic variants as the cause for his T cell deficiency, so further evidence is needed in terms of cases and the mechanism of pathogenicity in order for us to be confident about what to report back.

Created: 11 May 2018, 3:42 p.m.

CD247 is on both the GRID and GOSH diagnostic panels for immunodeficiency. Kept as amber for external expert review input before versioning panel.

Created: 1 May 2018, 5:14 p.m.

Marin AV PMID: 27555457 (2017) described a new case that showed complete CD247 protein deficiency due to loss of the initiation codon. The immunologic phenotype of this new patient resembled that of 2 other previously reported cases of CD247 deficiency by Rieux-Laucat PMID: 16672702 (2006) and Roberts PMID: 17170122 (2007). In both pervious cases, CD3 expression low and CD3 expression high T cells were also identified. The first study Rieux-Laucat PMID: 16672702 (2006) reported 3 second-site somatic mutations in CD247 that partially rescued TCR expression but not function, as measured solely by anti-CD3–induced ZAP-70 phosphorylation. No molecular analysis for somatic mutations was reported for the second patient Roberts PMID: 17170122 (2007). Thus, the presence of revertants along with strongly reduced surface TCR expression is pathognomonic of CD247 deficiency (PMID:25688246 and https://doi.org/10.14785/lpsn-2014-0012). In conclusion, mild lymphopenia and functional revertant somatic mosaicism should not confound the fact that CD247 deficiency is a very severe condition that requires urgent transplantation, but easy to diagnose by intracellular flow cytometry or by the surface TCR phenotype of obligate carriers.

Created: 1 May 2018, 4:52 p.m.

Comment on phenotypes: added phenotype from orphanet T-B+ severe combined immunodeficiency due to CD3zeta (previous name for CD247)

Created: 1 May 2018, 4:13 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: CD3z, PanelApp HGNC gene symbol check: CD247, ESID classification: Main_category/ Sub_category/ PID_Diagnosis Combined immunodeficiencies / Atypical Severe Combined Immunodeficiency (Atypical SCID) / Atypical Severe Combined Immunodeficiency (Atypical SCID); Combined immunodeficiencies / Severe combined immunodeficiency (SCID) / Severe combined immunodeficiency (SCID)

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

Original metadata supplied by GRID. GRID Gene Symbol HGNC PanelApp check: CD247, GRID_Gene_Symbol: CD247, GRID_Transcript_ENS_Community submitted: ENST00000362089, GRID_Transcript_RefSeq: NM_198053.2, GRID_Transcript_ENS_used_on_Production: ENST00000362089

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

Red List (low evidence)

Green List (high evidence)

There are at least 2 separate published reports of SCID caused by biallelic mutations in this gene, in keeping with understanding of its role in T cell biology.

Created: 8 Apr 2020, 12:58 p.m. | Last Modified: 8 Apr 2020, 12:58 p.m.

Panel Version: 2.45

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
T-B+ SCID

Publications

• 16672702
• 17170122

Red List (low evidence)

Comment on list classification: Remain as red.

Created: 20 May 2016, 2:14 p.m.