Submissions for variant NM_139276.3(STAT3):c.1234A>T (p.Thr412Ser)

dbSNP: rs1567713850

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005056543	SCV000920266	pathogenic	Hyper-IgE recurrent infection syndrome 1, autosomal dominant	2024-11-13	criteria provided, single submitter	clinical testing	Variant summary: STAT3 c.1234A>T (p.Thr412Ser) results in a conservative amino acid change located in the DNA-binding domain (IPR013801) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 252044 control chromosomes. c.1234A>T has been reported in the literature in an individual and at least 2 members of a family affected with Hyper IgE Syndrome where it was shown to co-segregate with disease (de Beaucoudrey 2008, Chandesris 2012, Powers 2009). These data indicate that the variant is likely to be associated with disease. Some of these reports also presented experimental evidence about the variant impact, measuring low levels of memory B-cells with high serum IgE levels in a patient, as well as demonstrating decreased STAT3 phosphorylation, nuclear translocation, DNA-binding and transactivation activity in response to stimulation in patient derived LCLs (Chandesris 2012) or showed significantly decreased transcriptional activity in Luciferase assays in vitro (e.g. Asano_2021). The following publications have been ascertained in the context of this evaluation (PMID: 18591412, 22751495, 19483664, 34137790). ClinVar contains an entry for this variant (Variation ID: 633433). Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001045489	SCV001209343	uncertain significance	Hyper-IgE recurrent infection syndrome 1, autosomal dominant; STAT3 gain of function	2019-11-27	criteria provided, single submitter	clinical testing	This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with autosomal dominant hyper-IgE syndrome (PMID: 22751495, 28098554). ClinVar contains an entry for this variant (Variation ID: 633433). 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. This sequence change replaces threonine with serine at codon 412 of the STAT3 protein (p.Thr412Ser). The threonine residue is moderately conserved and there is a small physicochemical difference between threonine and serine.