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

dbSNP: rs2081548277

Total submissions: 4

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
Labcorp Genetics (formerly Invitae), Labcorp	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