Submissions for variant NM_139276.3(STAT3):c.1261G>A (p.Gly421Arg)

dbSNP: rs869312888

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	RCV000210420	SCV000266403	pathogenic	STAT3-related early-onset multisystem autoimmune disease	2014-10-30	criteria provided, single submitter	research	segregates with the phenotype in an affected family
GeneDx	RCV000489679	SCV000577104	likely pathogenic	not provided	2017-04-11	criteria provided, single submitter	clinical testing	The G421R variant has been published previously in association with STAT3-related disorders (Milner et al., 2015; Khoury et al., 2017). The variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). G421R 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. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. In summary, we consider this variant to be likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001302951	SCV001492179	pathogenic	Hyper-IgE recurrent infection syndrome 1, autosomal dominant; STAT3 gain of function	2022-07-06	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects STAT3 function (PMID: 25359994). 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. ClinVar contains an entry for this variant (Variation ID: 224844). This missense change has been observed in individual(s) with clinical features of STAT3 gain of function associated autoimmune disease and/or Evans syndrome (PMID: 25359994, 30940614, 32531373, 32944025). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 421 of the STAT3 protein (p.Gly421Arg).
3billion	RCV001775103	SCV002011947	likely pathogenic	Hyper-IgE recurrent infection syndrome 1, autosomal dominant	2021-10-02	criteria provided, single submitter	clinical testing	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with supporting evidence (ClinVar ID: VCV000224844.3, PMID: 30940614 and 25359994, PS1_P). It is not observed in the gnomAD v2.1.1 dataset (PM2). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.653, 3Cnet: 0.951, PP3). Therefore, this variant is classified as likely pathogenic according to th recommendation of ACMG/AMP guideline.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV004545762	SCV004046136	likely pathogenic	STAT3-related disorder		criteria provided, single submitter	clinical testing	This variant has been previously reported as a heterozygous change in patients with Early-onset lymphoproliferation and autoimmunity, Immune dysregulation and Evans syndrome (PMID: 25359994, 30092289, 30940614). Flow cytometry analysis of peripheral blood mononuclear cells from a patient showed delayed phosphorylation compared with healthy controls (PMID: 25359994). It is absent from the gnomAD population database and thus is presumed to be rare. The c.1261G>A (p.Gly421Arg) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.1261G>A (p.Gly421Arg) variant is classified as Likely Pathogenic.