ClinVar Miner

Submissions for variant NM_000206.2(IL2RG):c.758-1G>A (rs886042051)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000393951 SCV000330891 pathogenic not provided 2016-10-17 criteria provided, single submitter clinical testing The c.758-1 G>A splice site variant in the IL2RG gene destroys the canonical splice acceptor site in intron 5. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. The variant was 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. Although this pathogenic variant has not been previously reported to our knowledge, we consider it to be pathogenic.
Invitae RCV000553796 SCV000637251 pathogenic X-linked severe combined immunodeficiency 2019-01-05 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 5 of the IL2RG gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). Disruption of this splice site has been observed in an individual affected with severe combined immunodeficiency (PMID: 10794430). ClinVar contains an entry for this variant (Variation ID: 280937). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in IL2RG are known to be pathogenic (PMID: 9058718, 10794430). For these reasons, this variant has been classified as Pathogenic.

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