Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and 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 | T-B+ severe combined immunodeficiency due to JAK3 deficiency | 2022-05-04 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 501 of the JAK3 protein (p.Gln501His). This variant is present in population databases (rs201283129, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with JAK3-related conditions. ClinVar contains an entry for this variant (Variation ID: 376114). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt JAK3 protein function. Experimental studies have shown that this missense change affects JAK3 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 |
RCV000436281 | SCV000505113 | likely pathogenic | Acute megakaryoblastic leukemia | 2014-12-26 | no assertion criteria provided | literature only | |
| Database of Curated Mutations |
RCV000419033 | SCV000505114 | likely pathogenic | Leukemoid reaction | 2016-05-13 | no assertion criteria provided | literature only |