ClinVar Miner

Submissions for variant NM_139276.3(STAT3):c.994C>T (p.His332Tyr)

dbSNP: rs2144827923
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CeGaT Center for Human Genetics Tuebingen RCV002276048 SCV002563409 pathogenic not provided 2022-07-01 criteria provided, single submitter clinical testing STAT3: PP1:Strong, PM2, PS4:Moderate, PP2, PP3, PP4
Labcorp Genetics (formerly Invitae), Labcorp RCV003096208 SCV003441919 pathogenic Hyper-IgE recurrent infection syndrome 1, autosomal dominant; STAT3 gain of function 2024-02-23 criteria provided, single submitter clinical testing This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 332 of the STAT3 protein (p.His332Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hyper IgE syndrome (PMID: 18706697). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1701323). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects STAT3 function (PMID: 22581330). For these reasons, this variant has been classified as Pathogenic.
Neuberg Centre For Genomic Medicine, NCGM RCV003339948 SCV004047473 likely pathogenic Hyper-IgE recurrent infection syndrome 1, autosomal dominant criteria provided, single submitter clinical testing The missense variant c.994C>T in STAT3 has been reported in heterozygous state in individuals affected with Hyper-IgE recurrent infection syndrome (Soltész B, Tóth B, Shabashova N, et al, 2013; Jiao, Hong et al., 2008). The p.His332Tyr variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. The amino acid change p.His332Tyr in STAT3 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid His at position 332 is changed to a Tyr changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Likely Pathogenic.

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