ClinVar Miner

Submissions for variant NM_000206.3(IL2RG):c.854G>A (p.Arg285Gln)

dbSNP: rs111033617
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000010709 SCV001210090 pathogenic X-linked severe combined immunodeficiency 2023-10-13 criteria provided, single submitter clinical testing This sequence change affects codon 285 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 6, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with X-linked severe combined immunodeficiency (PMID: 7557965, 9058718, 21184155, 22039266). This variant is also known as c.868G>A (p.R285Q). ClinVar contains an entry for this variant (Variation ID: 10026). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Neuberg Centre For Genomic Medicine, NCGM RCV000010709 SCV002072941 pathogenic X-linked severe combined immunodeficiency criteria provided, single submitter clinical testing The missense variant p.R285Q in IL2RG (NM_000206.3) has been previusly reported in affected individuals (Lee PP et al; Jones AM et al). It falls at the last nucleotide of exon 6 of the IL2RG coding sequence, which is part of the consensus splice site for this exon. Splicing predictions predict a damaging effect though the same has not been proved by functional studies. The variant is submitted to ClinVar as Pathogenic. It is novel (not in any individuals) in gnomAD Exomes. The p.R285Q variant is novel (not in any individuals) in 1000 Genomes. There is a small physicochemical difference between arginine and glutamine, which is not likely to impact secondary protein structure as these residues share similar properties. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV003231098 SCV003930243 pathogenic not provided 2023-05-30 criteria provided, single submitter clinical testing RNA studies from a male with this variant demonstrate aberrant splicing with skipping of exon 6 (Kanai et al., 1999); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32993535, 35874699, 9150740, 7557965, 10071190, 10444186, 31031743, 11129345, 33628209, 21184155)
OMIM RCV000010709 SCV000030935 pathogenic X-linked severe combined immunodeficiency 1997-05-01 no assertion criteria provided literature only

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