Submissions for variant NM_000206.3(IL2RG):c.924G>A (p.Ser308=)

dbSNP: rs2092255386

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	RCV001236093	SCV004102793	likely pathogenic	X-linked severe combined immunodeficiency	2023-11-14	reviewed by expert panel	curation	The NM_000206.3(IL2RG):c.924G>A (p.Ser308=) synonymous variant occurs at the final nucleotide of exon 7 and is predicted to impact the splice consensus sequence (SpliceAI score 0.95; varSEAK -64.86 %, class 5; MaxEntScan 8.51-->2.69, -68% change) with loss of the donor splice site (PP3). The variant has been reported to segregate with X-SCID through 3 affected segregations. The mutation was confirmed by Sanger sequencing in patients 1 and 2 (maternal first cousins), as well as their mothers (PMID: 30850927; PP1). Patient 1 is a male (0.5pt) with atypical X-SCID, presenting with persistent cutaneous viral infection. There is a family history of SCID (0.5pt) and the patient was sequenced on a panel of 29 SCID causing genes (0.5pt). Phosphorylation of STAT5 after IL-2 stimulation in T cells exhibited a weaker response (1pt). Together these phenotypes and family history are highly specific for SCID due to gamma chain deficiency (2.5pt; PP4_moderate). Validation of a splicing defect was found in IL2RG mRNA analysis in patients 1 and 2 (PMID: 30850927). Skipping of exon 7 was detected which would cause a frameshift in exon 8 (the final exon) with a stop loss and elongation of the protein by 31 amino acids. Of note, products of non-spliced intron 7, other abnormal splicings, and even normal splicing were also detected (PM4). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as likely 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: PM2_supporting, PM4, PP1, PP3, PP4_moderate. (VCEP specifications version 1).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001236093	SCV001408805	uncertain significance	X-linked severe combined immunodeficiency	2019-07-17	criteria provided, single submitter	clinical testing	This sequence change affects codon 308 of the IL2RG mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the IL2RG protein. This variant also falls at the last nucleotide of exon 7 of the IL2RG coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant has been observed in a family affected with atypical X-Linked severe combined immunodeficiency (PMID: 30850927). 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 disrupts mRNA splicing (PMID: 30850927). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
CeGaT Center for Human Genetics Tuebingen	RCV001310729	SCV001500639	pathogenic	not provided	2020-11-01	criteria provided, single submitter	clinical testing