Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001365482 | SCV001561755 | uncertain significance | Primary immunodeficiency with post-measles-mumps-rubella vaccine viral infection | 2022-09-07 | criteria provided, single submitter | clinical testing | This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 489 of the STAT2 protein (p.Pro489Arg). This variant is present in population databases (rs138681270, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with STAT2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1056621). 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 STAT2 protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. |
| Neuberg Centre For Genomic Medicine, |
RCV001365482 | SCV005073878 | uncertain significance | Primary immunodeficiency with post-measles-mumps-rubella vaccine viral infection | criteria provided, single submitter | clinical testing | The observed missense c.1466C>G (p.Pro489Arg) variant in STAT2 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Pro489Arg variant is present with an allele frequency of 0.02% in gnomAD exomes database. This variant has been submitted to the ClinVar database as Uncertain Significance. Multiple lines of computational evidence predict a damaging effect on protein structure and function for this variant (Sift - damaging; Polyphen - probably damaging; Mutation Taster - disease causing). The amino acid change p.Pro489Arg in STAT2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Pro at position 489 is changed to a Arg changing protein sequence and it might alter its composition and physico-chemical properties. Additional studies will be required to prove the pathogenicity of this variant. For these reasons, this variant has been classified as a Variant of Uncertain Significance (VUS). |