ClinVar Miner

Submissions for variant NM_139276.3(STAT3):c.1003C>T (p.Arg335Trp)

dbSNP: rs193922716
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000030463 SCV000053133 likely pathogenic Hyper-IgE recurrent infection syndrome 1, autosomal dominant 2011-08-18 criteria provided, single submitter curation Converted during submission to Likely pathogenic.
GeneDx RCV000427432 SCV000521041 likely pathogenic not provided 2019-09-04 criteria provided, single submitter clinical testing Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 22581330, 22500887, 20159255, 18978467, 30081087, 18602572, 22030463)
Labcorp Genetics (formerly Invitae), Labcorp RCV000536459 SCV000656668 pathogenic Hyper-IgE recurrent infection syndrome 1, autosomal dominant; STAT3 gain of function 2024-03-18 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 335 of the STAT3 protein (p.Arg335Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hyper IgE syndrome (PMID: 18602572, 22030463; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 36783). 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%. For these reasons, this variant has been classified as Pathogenic.

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