ClinVar Miner

Submissions for variant NM_139276.3(STAT3):c.1852G>C (p.Gly618Arg)

dbSNP: rs2081548277
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001553660 SCV001774597 uncertain significance not specified 2021-07-16 criteria provided, single submitter clinical testing Variant summary: STAT3 c.1852G>C (p.Gly618Arg) results in a non-conservative amino acid change located in the SH2 domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251424 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.1852G>C have been reported in individuals affected with Hyper IgE Syndrome. However, somatic occurrences of this variant have been reported in individuals affected with various hematopoietic and lymphoid malignancies (Examples: 29386642, 22859607, 27203213, see COSMIC entry). The variant has been reported in a functional study to result in increased phosphorylated protein and a growth advantage to transduced cell lines or normal NK cells (Kucuk_2020). Two other variants affecting the same codon have been reported in HGMD in association with Hyper-IgE syndrome (p.Gly618Asp) and Immunodeficiency (p.Gly618Val). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
Institute of Human Genetics, University Hospital Muenster RCV002287502 SCV002577888 uncertain significance See cases 2021-12-21 criteria provided, single submitter clinical testing ACMG categories: PM1,PM2,PP3
Invitae RCV003771695 SCV004569386 uncertain significance Hyper-IgE recurrent infection syndrome 1, autosomal dominant; STAT3 gain of function 2023-08-24 criteria provided, single submitter clinical testing 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. Experimental studies have shown that this missense change affects STAT3 function (PMID: 25586472, 28356514, 34075200). 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. ClinVar contains an entry for this variant (Variation ID: 1192236). This missense change has been observed in individual(s) with STAT3-related conditions (PMID: 24797340, 33060403). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 618 of the STAT3 protein (p.Gly618Arg).
Clinical Genomics Labs, University Health Network RCV003320250 SCV004024455 pathogenic EBV-Positive Inflammatory Follicular Dendritic Cell Sarcoma 2023-08-09 no assertion criteria provided research

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