Submissions for variant NM_139276.2(STAT3):c.2228G>T (p.Gly743Val) (rs151033214)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000606915	SCV000725687	likely benign	not specified	2017-12-19	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae	RCV000707338	SCV000836430	uncertain significance	Hyper-IgE recurrent infection syndrome 1, autosomal dominant; STAT3 gain of function	2018-09-13	criteria provided, single submitter	clinical testing	This sequence change replaces glycine with valine at codon 743 of the STAT3 protein (p.Gly743Val). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and valine. This variant is present in population databases (rs151033214, ExAC 0.03%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with STAT3-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000768099	SCV000899001	uncertain significance	Hyper-IgE recurrent infection syndrome 1, autosomal dominant; Autoimmune disease, multisystem, infantile-onset, 1	2018-06-08	criteria provided, single submitter	clinical testing	STAT3 NM_139276.2 exon 23 p.Gly743Val (c.2228G>T): This variant has not been reported in the literature but is present in 34/126596 European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs151033214). This variant is present in ClinVar (Variation ID:514074). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.