Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001388678 | SCV001589752 | pathogenic | X-linked severe combined immunodeficiency | 2020-10-03 | 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. For these reasons, this variant has been classified as Pathogenic. 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). 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. Disruption of this splice site has been observed in individual(s) with severe combined immunodeficiency (SCID) (PMID: 10794430, Invitae). This variant is not present in population databases (ExAC no frequency). |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001388678 | SCV002103403 | likely pathogenic | X-linked severe combined immunodeficiency | 2022-02-22 | criteria provided, single submitter | clinical testing | Variant summary: IL2RG c.758-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 3 acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 144980 control chromosomes (gnomAD). c.758-2A>G has been reported in the literature in at least one individual affected with X-Linked Severe Combined Immunodeficiency (van Oers_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One ClinVar submitter (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. |