COVID-19 researchGene: CD247
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
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.
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Comment on list classification: Remain as red.
Created: 20 May 2016, 2:14 p.m.
Source Expert Review Green was added to CD247. Added phenotypes ?Immunodeficiency 25; T-B+ severe combined immunodeficiency due to CD3zeta; Immunodeficiency 25, 610163; Atypical Severe Combined Immunodeficiency (Atypical SCID); Nl NK, no g/d T cells; Immunodeficiencies affecting cellular and humoral immunity; T-B+ SCID; Severe combined immunodeficiency (SCID) for gene: CD247 Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
gene: CD247 was added gene: CD247 was added to Viral susceptibility. Sources: ESID Registry 20171117,Victorian Clinical Genetics Services,GRID V2.0,GOSH PID v.8.0,SCID v1.6,IUIS Classification February 2018,Expert Review Amber Mode of inheritance for gene: CD247 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CD247 were set to 26690594; 17170122; 16672702; 25688246; 27555457; https://doi.org/10.14785/lpsn-2014-0012 Phenotypes for gene: CD247 were set to ?Immunodeficiency 25; T-B+ severe combined immunodeficiency due to CD3zeta; Immunodeficiency 25, 610163; Atypical Severe Combined Immunodeficiency (Atypical SCID); Nl NK, no g/d T cells; Immunodeficiencies affecting cellular and humoral immunity; T-B+ SCID; Severe combined immunodeficiency (SCID)