Submissions for variant NM_000206.3(IL2RG):c.982C>T (p.Arg328Ter)

dbSNP: rs1064793347

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000483975	SCV000565878	likely pathogenic	not provided	2017-11-02	criteria provided, single submitter	clinical testing	The R328X nonsense variant in the IL2RG gene has been reported previously in association with immune deficiency (Chien et al., 2015; de Oliveira et al., 2015; Gallo et al., 2016); however, many of these individuals were presented in abstracted case reports and detailed information is not available. The variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). R328X results in truncation of the final 42 amino acids and is not predicted to result in nonsense-mediated decay. No downstream nonsense or missense variants have been reported in the Human Gene Mutation Database (Stenson et al., 2014). In summary, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586219	SCV000695978	likely pathogenic	X-linked severe combined immunodeficiency	2016-08-19	criteria provided, single submitter	clinical testing	Variant summary: The IL2RG c.982C>T (p.Arg328X) variant results in a premature termination codon, predicted to cause a truncated or absent IL2RG protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant is absent in 80559 control chromosomes. This variant has been reported in two brothers with a late-onset and atypical presentation of the disease via a conference abstract. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as likely pathogenic until more information becomes available.
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV001090163	SCV001190359	pathogenic	Combined immunodeficiency, X-linked	2020-03-06	criteria provided, single submitter	clinical testing	A hemizygous nonsense variation in exon 8 of the IL2RG gene that results in a stop codon and premature truncation of the protein at codon 328 was detected. The observed variant c.982C>T (p.Arg328Ter) has previously been reported in a patient affected with severe combined immunodeficiency (Luk ADW. et al., 2017). The variant has not been reported in the 1000 genomes and ExAC databases. The in silico prediction of the variant is damaging by MutationTaster2. The reference codon is conserved across mammals. In summary, the variant meets our criteria to be classified as pathogenic.
Invitae	RCV000586219	SCV002135270	pathogenic	X-linked severe combined immunodeficiency	2022-06-27	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the C-terminus of the IL2RG protein. Other variant(s) that disrupt this region (p.Leu329Argfs*3) have been observed in individuals with IL2RG-related conditions (PMID: 10794430). This suggests that this may be a clinically significant region of the protein. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Experimental studies have shown that this premature translational stop signal affects IL2RG function (PMID: 31799703). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 418656). This premature translational stop signal has been observed in individuals with severe combined immunodeficiency (SCID), atypical SCID, or other immunodeficiency phenotypes (PMID: 28747913, 30622570, 30778380, 31799703, 32499645). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg328*) in the IL2RG gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 42 amino acid(s) of the IL2RG protein.
GeneReviews	RCV000586219	SCV001775478	not provided	X-linked severe combined immunodeficiency		no assertion provided	literature only	Observed in 2 brothers with atypical X-SCID