Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001553661 | SCV001774598 | uncertain significance | not specified | 2021-07-25 | criteria provided, single submitter | clinical testing | Variant summary: STAT3 c.1840A>C (p.Ser614Arg) results in a non-conservative amino acid change located in the SH2 domain (IPR000980) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251452 control chromosomes (gnomAD). 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.1840A>C have been reported in individuals affected with Hyper IgE Syndrome. However, it has been reported in various types of cancers including but not limited to peripheral T-Cell Lymphoma, anaplastic large cell lymphoma, chronic lymphoproliferative disorders of NK cells (CLPD-NKs) and T-cell large granular lymphocytic leukemia (T-LGL), Plasmablastic lymphoma (example: Abate_2016, Blombery_2016, Jerez_STAT3_LN_2012, Liu_STAT3_BCD_2020). The variant has also been reported in patients affected with Coeliac Disease(CeD)-Enteropathy-associated T-cell lymphoma (EATL) and Type II refractory celiac disease (Cording_2020). Several somatic occurrences of the variant have also been reported in the literature. (example: PMID: 24283217, 24345752, 25586472, 26192917, 27859003). It is not clear, whether the gain-of-function activity observed in such incidences would support a pathogenic role in Hyper IgE Syndrome as a germline variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Different variants affecting the same and nearby codons (example: p.S614G, p.S611I, p.K615E, p.G617E) have been reported in the HGMD database associated with Hyper-IgE syndrome/STAT3 deficiency, 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 |
RCV003771696 | SCV004587154 | uncertain significance | Hyper-IgE recurrent infection syndrome 1, autosomal dominant; STAT3 gain of function | 2024-04-23 | criteria provided, single submitter | clinical testing | This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 614 of the STAT3 protein (p.Ser614Arg). 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: 1192237). 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 with a negative 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. |
| Fulgent Genetics, |
RCV005014587 | SCV005646046 | uncertain significance | Hyper-IgE recurrent infection syndrome 1, autosomal dominant; STAT3-related early-onset multisystem autoimmune disease | 2024-04-26 | criteria provided, single submitter | clinical testing |