Submissions for variant NM_007315.4(STAT1):c.1169T>G (p.Met390Arg)

dbSNP: rs1553494436

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000521523	SCV000620199	likely pathogenic	not provided	2017-08-18	criteria provided, single submitter	clinical testing	The c.1169 T>G variant in the STAT1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The c.1169 T>G variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). In-silico splice models predict that c.1169 T>G may create a cryptic splice donor site in exon 14 that could supplant the natural splice acceptor site. However, in the absence of RNA/functional studies, the actual effect of the c.1169 T>G change in this individual is unknown. If c.1169 T>G does not alter splicing, it will result in the M390R missense change. The M390R 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. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in the same residues (M390T, M390I) have been reported in unrelated individuals with STAT1-related disorders, supporting the functional importance of this region of the protein (Mizoguchi et al., 2014; Toubiana et al., 2016). We interpret c.1169 T>G as a likely pathogenic variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV005222994	SCV005863660	uncertain significance	Immunodeficiency 31B; Autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome; Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency	2024-12-13	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 390 of the STAT1 protein (p.Met390Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with STAT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 451487). 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 disruptive. 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.