Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000255561 | SCV000321792 | pathogenic | not provided | 2016-02-01 | criteria provided, single submitter | clinical testing | The G589S pathogenic variant in the JAK3 gene has been reported previously in the homozygous state in association with Severe Combined Immunodeficiency (SCID) (Roberts et al., 2004; Pasic et al., 2014). The G589S variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. G589S is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This variant is located in the conserved JH2 domain of the JAK3 protein, and in vitro functional studies showed that this variant disrupts the normal catalytic functions of the protein (Roberts et al., 2004). |
| Labcorp Genetics |
RCV003509521 | SCV004297955 | pathogenic | T-B+ severe combined immunodeficiency due to JAK3 deficiency | 2023-06-25 | criteria provided, single submitter | clinical testing | This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 589 of the JAK3 protein (p.Gly589Ser). This missense change has been observed in individual(s) with severe combined immunodeficiency (PMID: 14615376, 33040328). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects JAK3 function (PMID: 14615376). 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 expected to disrupt JAK3 protein function. ClinVar contains an entry for this variant (Variation ID: 265205). |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV004782333 | SCV005395272 | likely pathogenic | Severe combined immunodeficiency disease | 2024-09-20 | criteria provided, single submitter | clinical testing | Variant summary: JAK3 c.1765G>A (p.Gly589Ser) results in a non-conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.1765G>A has been reported in the literature in homozygous and compound heterozygous individuals affected with Severe Combined Immunodeficiency (El Hawary_2021, El Hawary_2022). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in abrogation of JAK3 kinase activity (Roberts_2004). The following publications have been ascertained in the context of this evaluation (PMID: 33040328, 35482138, 14615376). ClinVar contains an entry for this variant (Variation ID: 265205). Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| Genome Sciences Centre, |
RCV000585756 | SCV000693666 | uncertain significance | Adenoid cystic carcinoma | 2018-02-01 | no assertion criteria provided | research |