ClinVar Miner

Submissions for variant NM_139276.3(STAT3):c.454C>T (p.Arg152Trp)

dbSNP: rs869312890
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Total submissions: 4
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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 RCV000210417 SCV000266405 pathogenic STAT3-related early-onset multisystem autoimmune disease 2014-10-30 criteria provided, single submitter research segregates with the phenotype in an affected family
Labcorp Genetics (formerly Invitae), Labcorp RCV000653281 SCV000775160 pathogenic Hyper-IgE recurrent infection syndrome 1, autosomal dominant; STAT3 gain of function 2024-04-22 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 152 of the STAT3 protein (p.Arg152Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with multi-organ autoimmune disease (PMID: 25359994). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 224846). 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 80%. Experimental studies have shown that this missense change affects STAT3 function (PMID: 25359994). For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn RCV000210417 SCV005387922 pathogenic STAT3-related early-onset multisystem autoimmune disease 2024-09-03 criteria provided, single submitter clinical testing
GeneDx RCV005055741 SCV005689875 pathogenic not provided 2024-08-05 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect with significantly increased STAT3 binding activity consistent with a gain of function mutation; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34128135, 31770611, 30092289, 34573280, 34134972, 33726816, 33057194, 36228738, 34390446, 37976116, 35982159, 15919823, 25359994)

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