Submissions for variant NM_139276.3(STAT3):c.2147C>T (p.Thr716Met)

dbSNP: rs869312892

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	RCV000210415	SCV000266408	pathogenic	STAT3-related early-onset multisystem autoimmune disease	2014-10-30	criteria provided, single submitter	research	segregates with the phenotype in an affected family
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224259	SCV000281134	pathogenic	not provided	2014-10-03	criteria provided, single submitter	clinical testing
GeneDx	RCV000224259	SCV000566572	pathogenic	not provided	2021-09-01	criteria provided, single submitter	clinical testing	Observed in a patient and their parent with autoimmune enteropathy (Slowik et al., 2014); Published functional studies demonstrate variant results in a gain of function effect (Flanagan SE et al., 2014; Milner JD et al., 2015); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25359994, 30942636, 25038750, 31770611, 33046446, 28960754, 29330115, 26280891)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000653278	SCV000775157	pathogenic	Hyper-IgE recurrent infection syndrome 1, autosomal dominant; STAT3 gain of function	2024-08-13	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 716 of the STAT3 protein (p.Thr716Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autoimmune disease and early-onset polyautoimmunity (PMID: 25038750, 25359994, 29330115). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 224848). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects STAT3 function (PMID: 25038750, 25359994). For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000224259	SCV001246592	pathogenic	not provided	2021-09-01	criteria provided, single submitter	clinical testing
OMIM	RCV000210415	SCV000188612	pathogenic	STAT3-related early-onset multisystem autoimmune disease	2014-08-01	no assertion criteria provided	literature only
Clinical Genomics Laboratory, Stanford Medicine	RCV000210415	SCV001427091	pathogenic	STAT3-related early-onset multisystem autoimmune disease	2019-10-22	no assertion criteria provided	clinical testing	The p.Thr716Met variant has been previously reported in 5 unrelated individuals with clinical features of infantile-onset multisystem autoimmune disease 1 (ADMIO1) and co-segregated with disease in 1 affected relative (Flanagan et al., 2014; Slowik et al., 2014; Milner at al., 2015; Takagi et al., 2018; Besnard et al., 2018). This variant was identified de novo in this individual and has also been previously reported de novo in 1 additional individual (Flanagan et al., 2014). The p.Thr716Met was absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Functional studies suggest the p.Thr716Met variant causes increased transptional activity (Flanagan et al., 2014; Milner et al., 2015). Additionally, the STAT3 gene has fewer missense variants in the general population than expected. A low rate of missense variation may suggest that this gene is intolerant to missense variation. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.Thr716Met variant as pathogenic for ADMIO1 in an autosomal dominant manner based on the information above. [ACMG evidence codes used: PS2, PM2, PS3_moderate, PP2, PS4_supporting]