ClinVar Miner

Submissions for variant NM_000215.3(JAK3):c.2773C>A (p.Arg925Ser) (rs149452625)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Blueprint Genetics RCV000480888 SCV000927429 uncertain significance not provided 2017-10-12 criteria provided, single submitter clinical testing
GeneDx RCV000480888 SCV000565084 likely pathogenic not provided 2015-11-10 criteria provided, single submitter clinical testing The R925S variant in the JAK3 gene has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The NHLBI Exome Sequencing Project and the 1000 Genomes Project Consortium report R925S was observed in approximately 0.1-0.2% of alleles from individuals of European background, indicating it may be a rare variant in this population. The variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties, and this substitution occurs at a position where amino acids with similar properties to Arginine are tolerated across species. However, functional studies have shown that R925S impairs both interaction with STAT5 and JAK3 and STAT5 phosphorylation (de Martino et al., 2013). Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Invitae RCV000525347 SCV000638324 uncertain significance Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-positive, NK cell-negative 2017-10-02 criteria provided, single submitter clinical testing This sequence change replaces arginine with serine at codon 925 of the JAK3 protein (p.Arg925Ser). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and serine. This variant is present in population databases (rs149452625, ExAC 0.2%), including 1 homozygous individual. This variant has been reported in individuals affected with T-cell acute lymphoblastic leukemia, and clear cell renal cancer (PMID: 25193870, 21868263). ClinVar contains an entry for this variant (Variation ID: 418267). Experimental studies have shown that while this missense change did not lead to transfomation of cell lines to cytokine-independent proliferation (PMID: 25193870), it did cause abnormal JAK3 and STAT5 phosphorylation and reduced JAK3/STAT5 interaction in patient-derived cells (PMID: 21868263). The clinical significance of these findings is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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