Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000254755 | SCV000322343 | pathogenic | not provided | 2016-02-09 | criteria provided, single submitter | clinical testing | The S614G missense variant in the STAT3 gene has been reported previously in association with Hyper-IgE syndrome (Chandesris et al., 2012). The 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. S614G variant 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 substitution occurs at a position within the SH2 domain that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Functional studies have shown that fibroblasts and EBV-B cells with S614G show an impaired response to IL-6 (Kreins et al., 2015). Missense variants in nearby residues (R609G, S611G/I/N, G617E/V, G618D) have been reported in the Human Gene Mutation Database in association with HIES (Stenson et al., 2014), supporting the functional importance of this region of the protein. Additionally, a variant in the same residue, S614R, has been seen in a patient at GeneDx. |
| Labcorp Genetics |
RCV005222859 | SCV005863601 | uncertain significance | Hyper-IgE recurrent infection syndrome 1, autosomal dominant; STAT3 gain of function | 2024-03-21 | criteria provided, single submitter | clinical testing | This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 614 of the STAT3 protein (p.Ser614Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hyper IgE syndrome (PMID: 22751495). ClinVar contains an entry for this variant (Variation ID: 265440). 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 STAT3 protein function with a positive predictive value of 80%. 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. |