ClinVar Miner

Submissions for variant NM_000215.4(JAK3):c.2280G>T (p.Met760Ile)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV002810364 SCV003197542 uncertain significance T-B+ severe combined immunodeficiency due to JAK3 deficiency 2022-05-24 criteria provided, single submitter clinical testing Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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. This variant has not been reported in the literature in individuals affected with JAK3-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 760 of the JAK3 protein (p.Met760Ile).
Neuberg Centre For Genomic Medicine, NCGM RCV002810364 SCV005060938 uncertain significance T-B+ severe combined immunodeficiency due to JAK3 deficiency criteria provided, single submitter clinical testing The missense c.2280G>T (p.Met760Ile) variant in the JAK3 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is reported with the allele frequency (0.0003%) in the gnomAD Exomes. It is submitted to ClinVar as Uncertain Significance. However, no details are available for independent assessment. The amino acid Methionine at position 760 is changed to a Isoleucine changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted as damaging by SIFT. The amino acid change p.Met760Ile in JAK3 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance.

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