ClinVar Miner

Submissions for variant NM_000215.3(JAK3):c.1503G>T (p.Gln501His) (rs201283129)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV001174965 SCV001338447 uncertain significance not specified 2020-04-06 criteria provided, single submitter clinical testing Variant summary: JAK3 c.1503G>T (p.Gln501His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251496 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1503G>T in individuals affected with Severe Combined Immunodeficiency Syndrome has been reported although it has been reported in patients with AML (example, Sato_2008, Yamashita_2010). Two publications report experimental evidence evaluating an impact on protein function, however, none of these studies allows convincing conclusions about the variant effect in relation to the established mechanism of SCID (Sato_2008, Yamashita_2010). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant in germline state to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV001204387 SCV001375592 uncertain significance Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-positive, NK cell-negative 2019-10-19 criteria provided, single submitter clinical testing This sequence change replaces glutamine with histidine at codon 501 of the JAK3 protein (p.Gln501His). The glutamine residue is weakly conserved and there is a small physicochemical difference between glutamine and histidine. This variant is present in population databases (rs201283129, ExAC 0.02%). This variant has been observed in a cell line derived from a patient with acute megakaryoblastic leukemia of Down syndrome (PMID: 18397343). ClinVar contains an entry for this variant (Variation ID: 376114). This variant has been reported to affect JAK3 protein function (PMID: 18397343). 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.
Database of Curated Mutations (DoCM) RCV000436281 SCV000505113 likely pathogenic Acute megakaryoblastic leukemia 2014-12-26 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000419033 SCV000505114 likely pathogenic Leukemoid Reaction 2016-05-13 no assertion criteria provided literature only

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