ClinVar Miner

Submissions for variant NM_139276.2(STAT3):c.2147C>T (p.Thr716Met) (rs869312892)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000210415 SCV000266408 pathogenic Autoimmune disease, multisystem, infantile-onset, 1 2014-10-30 criteria provided, single submitter research segregates with the phenotype in an affected family
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000224259 SCV000281134 pathogenic not provided 2014-10-03 criteria provided, single submitter clinical testing
GeneDx RCV000224259 SCV000566572 pathogenic not provided 2016-06-14 criteria provided, single submitter clinical testing The T716M substitution was initially reported as a de novo variant in a patient with early-onset polyautoimmunity and has subsequently been described in multiple other individuals with autoimmune enteropathy (Flanagan et al., 2014; Milner et al., 2014). In vitro functional studies indicate that T716M is a gain-of-function variant leading to altered regulatory T cells and cytokine signaling (Flanagan et al., 2014; Milner et al., 2014). T716M was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. It is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. Therefore, we interpret T716M a pathogenic variant.
Invitae RCV000653278 SCV000775157 pathogenic Hyper-IgE recurrent infection syndrome 1, autosomal dominant; STAT3 gain of function 2018-12-07 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 716 of the STAT3 protein (p.Thr716Met). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to be de novo in an individual affected with early-onset polyautoimmunity (PMID: 25038750). It has also been reported in unrelated individuals with autoimmune disease (PMID: 25359994, 29330115). ClinVar contains an entry for this variant (Variation ID: 224848). Experimental studies have shown that this missense change is a gain-of-function variant leading to increased STAT3 activity (PMID: 25038750, 25359994). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000210415 SCV000188612 pathogenic Autoimmune disease, multisystem, infantile-onset, 1 2014-08-01 no assertion criteria provided literature only

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