Submissions for variant NM_000206.3(IL2RG):c.43C>T (p.Gln15Ter)

dbSNP: rs1057517747

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	RCV001251321	SCV004102799	pathogenic	X-linked severe combined immunodeficiency	2023-11-14	reviewed by expert panel	curation	The NM_000206.3(IL2RG):c.43C>T (p.Gln15Ter) nonsense variant occurs in exon 1 of 8 and, therefore, may result in NMD (PVS1). Male (0.5pt) X-SCID patient with T-B+NK+ subset (ALC of 66/mm3 with 3% CD3+, 39% CD19+, and 36% CD56+); Diagnostic criteria for SCID met (very low CD3+ T cells and this variant is Likely Pathogenic without considering PP4) 0.5pt. Total is 1pt; PP4 met (PMID: 18615703). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for X-linked T-B+ severe combined immunodeficiency due to gamma chain deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: PVS1, PM2_supporting, PP4. (VCEP specifications version 1).
GeneDx	RCV000412822	SCV000490563	pathogenic	not provided	2015-04-01	criteria provided, single submitter	clinical testing	To our knowledge, the Q15X variant has neither been published as a pathogenic variant, nor reported as a benign polymorphism. It was not not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The Q15X nonsense variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Although this variant has not been reported in the literature, to our knowledge, we interpret it as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001251321	SCV001426873	likely pathogenic	X-linked severe combined immunodeficiency	2020-07-23	criteria provided, single submitter	clinical testing	Variant summary: IL2RG c.43C>T (p.Gln15X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 183451 control chromosomes (gnomAD). The variant c.43C>T (also known as 57C>T), has been reported in the literature in a male patient affected with X-Linked Severe Combined Immunodeficiency (Mustillo_2008). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.