Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ce |
RCV001200220 | SCV001371123 | pathogenic | not provided | 2020-06-01 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001526946 | SCV001737716 | uncertain significance | not specified | 2023-04-20 | criteria provided, single submitter | clinical testing | Variant summary: STAT3 c.1940A>T (p.Asn647Ile) results in a non-conservative amino acid change located in the Src homology 2 (SH2) domain (IPR000980) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251490 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 occurrences of c.1940A>T have been reported in individuals affected with Hyper IgE Syndrome. However, it has been frequently reported as a somatic mutation in individuals affected with various types of hematopoietic and lymphoid malignancies (Example: Garcia-Reyero_2021, Liu_2019, deAraujo_2019, Lim_2019, Jerez_2012, Oishi_2023) and has been reported as a common mutation in T-Cell Large Granular Lymphocytic Leukemia and NK leukemias (NCCN Guidelines). The variant has also been reported in patients affected with Type I Enteropathy Associated T cell Lymphoma (EATL) and Type II refractory celiac disease (Moffitt_2017, Cording_2020). These reports however, do not provide unequivocal conclusions about association of the variant with Hyper IgE Syndrome. At least one functional study report that in cell culture, the variant resulted in increased levels of phosphorylated STAT3 upon stimulation with Oncostatin M or various concentrations of IL-6 demonstrating that it is a gain-of-function mutation (Chandrasekaran_2016). It is not clear however, whether this gain-of-function activity would support a pathogenic role in Hyper IgE Syndrome as a germline variant. One ClinVar submitter (evaluation after 2014) cites the variant as pathogenic. In addition, different variants affecting the same and/or nearby codons (example: p.N647D, p.N646K, p.E652K) have been reported in the HGMD database associated with Hyper-IgE syndrome, suggesting this region may be clinically significant. Based on the evidence outlined above, the variant was classified as uncertain significance for Hyper IgE Syndrome until additional information becomes available to determine its role in the Hyper IgE syndrome. |
| Labcorp Genetics |
RCV003770227 | SCV004589843 | uncertain significance | Hyper-IgE recurrent infection syndrome 1, autosomal dominant; STAT3 gain of function | 2023-04-05 | criteria provided, single submitter | clinical testing | This sequence change replaces asparagine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 647 of the STAT3 protein (p.Asn647Ile). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with STAT3-related conditions. ClinVar contains an entry for this variant (Variation ID: 932423). 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 STAT3 protein function. Experimental studies have shown that this missense change affects STAT3 function (PMID: 27345172). 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. |