Submissions for variant NM_139276.3(STAT3):c.1361T>C (p.Leu454Pro)

gnomAD frequency: 0.00003  dbSNP: rs748564923

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003772187	SCV004571885	uncertain significance	Hyper-IgE recurrent infection syndrome 1, autosomal dominant; STAT3 gain of function	2023-11-14	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 454 of the STAT3 protein (p.Leu454Pro). This variant is present in population databases (rs748564923, gnomAD 0.008%). This variant has not been reported in the literature in individuals affected with STAT3-related conditions. ClinVar contains an entry for this variant (Variation ID: 1328318). 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%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV001795750	SCV002035546	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001795750	SCV002038426	uncertain significance	not provided		no assertion criteria provided	clinical testing