ClinVar Miner

Submissions for variant NM_000206.2(IL2RG):c.956_957AG[1] (p.Leu321fs)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000815773 SCV000956243 pathogenic X-linked severe combined immunodeficiency 2018-09-19 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the IL2RG gene (p.Leu321Alafs*6). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 50 amino acids of the IL2RG protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with severe combined immunodeficiency (PMID: 8027558). Experimental studies have shown that this frameshift change, p.Leu321Alafs*6, compromises proper IL-2 signal transduction (PMID: 8027558). This variant disrupts the C terminal region the interleukin receptor common gamma chain, which is critical for proper association with Jak3 (PMID: 7973658, 7973659). Deletions affecting this intracellular region of the protein have been shown to lead to defects in signal transduction, including loss of ability to induce c-myc, c-fos, and c-jun expression (PMID: 7683423). For these reasons, this variant has been classified as Pathogenic.

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