ClinVar Miner

Submissions for variant NM_000215.4(JAK3):c.2680+89G>A

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen RCV002919224 SCV004102768 likely pathogenic T-B+ severe combined immunodeficiency due to JAK3 deficiency 2023-11-14 reviewed by expert panel curation The variant NM_000215.4(JAK3):c.2680+89G>A has been found in three individuals with T-B+NK- SCID. In three related consanguineous families, the disease phenotype segregated with the homozygous deep intronic variant in the proband, P3, and two affected relatives (PP1_moderate, PM3_supporting). In at least one of those patients, P3, with T-B+NK- SCID, whole exome sequencing was performed and STAT3 and STAT5 phosphorylation were found to be absent in B cells after stimulation with IL-21 (PMID:26769277, 3 points, PP4_moderate). The variant is absent from gnomAD (PM2_Supporting). Finally, the in silico predictor SpliceAI predicts that the deep intronic variant may impact splicing with a delta score of 0.30 (PP3). In summary, this variant meets criteria to be classified as Likely Pathogenic for autosomal recessive T-B+ severe combined immunodeficiency due to JAK3 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PP1_moderate, PM3_supporting, PP4_moderate, PP3, PM2_supporting (SCID VCEP Specifications Version 1).
Labcorp Genetics (formerly Invitae), Labcorp RCV002919224 SCV003262364 pathogenic T-B+ severe combined immunodeficiency due to JAK3 deficiency 2022-08-31 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Studies have shown that this variant results in partial intron inclusion and introduces a premature termination codon (PMID: 26769277). The resulting mRNA is expected to undergo nonsense-mediated decay. This variant has been observed in individual(s) with severe combined immune deficiency (PMID: 26769277). This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 19 of the JAK3 gene. It does not directly change the encoded amino acid sequence of the JAK3 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product.

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