Submissions for variant NM_139276.3(STAT3):c.1861T>G (p.Phe621Val)

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003050469	SCV003441917	likely pathogenic	Hyper-IgE recurrent infection syndrome 1, autosomal dominant; STAT3 gain of function	2022-07-21	criteria provided, single submitter	clinical testing	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. This sequence change replaces phenylalanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 621 of the STAT3 protein (p.Phe621Val). 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: 17881745). 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. Experimental studies have shown that this missense change affects STAT3 function (PMID: 22581330). This variant disrupts the p.Phe621 amino acid residue in STAT3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20093388, 23830147, 32944025, 34134972). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing.