Submissions for variant NM_139276.3(STAT3):c.832C>T (p.Arg278Cys)

dbSNP: rs1555566945

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000523018	SCV000618534	uncertain significance	not provided	2018-07-12	criteria provided, single submitter	clinical testing	The R278C variant in the STAT3 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The R278C variant is not observed in large population cohorts (Lek et al., 2016). The R278C variant 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. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret R278C as a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000811844	SCV000952131	likely pathogenic	Hyper-IgE recurrent infection syndrome 1, autosomal dominant; STAT3 gain of function	2023-11-29	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 278 of the STAT3 protein (p.Arg278Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of STAT3-related conditions (PMID: 30443250). ClinVar contains an entry for this variant (Variation ID: 450010). 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%. This variant disrupts the p.Arg278 amino acid residue in STAT3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28579554). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.