Submissions for variant NM_007315.4(STAT1):c.722G>A (p.Arg241Gln)

gnomAD frequency: 0.00042  dbSNP: rs146273341

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000364320	SCV000425824	benign	Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000820516	SCV000961232	uncertain significance	Immunodeficiency 31B; Autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome; Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency	2024-12-10	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 241 of the STAT1 protein (p.Arg241Gln). This variant is present in population databases (rs146273341, gnomAD 0.1%). 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: 333286). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change affects STAT1 function (PMID: 30030262). 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.
New York Genome Center	RCV000364320	SCV001815744	likely benign	Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency	2020-08-14	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002521352	SCV003711815	uncertain significance	Inborn genetic diseases	2021-11-24	criteria provided, single submitter	clinical testing	The c.722G>A (p.R241Q) alteration is located in exon 9 (coding exon 7) of the STAT1 gene. This alteration results from a G to A substitution at nucleotide position 722, causing the arginine (R) at amino acid position 241 to be replaced by a glutamine (Q). Based on data from gnomAD, the A allele has an overall frequency of 0.03% (83/282854) total alleles studied. The highest observed frequency was 0.14% (49/35436) of Latino alleles. This amino acid position is not well conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). Functional analysis suggests that the p.R241Q alteration may lead to increased expression of STAT1 and have a gain-of-function effect impacting transcription of downstream targets (Carapito, 2018). This alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
GeneDx	RCV004777653	SCV005389772	uncertain significance	not provided	2024-04-29	criteria provided, single submitter	clinical testing	Identified in a patient with classic symptoms of mevalonate kinase deficiency who was homozygous for a MVK variant; her asymptomatic sibling was also homozygous for the MVK variant but was absent for the R241Q variant in the STAT1 gene (PMID: 30030262); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Functional studies showed R241Q responded two times more strongly than the wild-type allele after stimulation with IFN-gamma (PMID: 30030262); This variant is associated with the following publications: (PMID: 30030262, 35353336, 33917151)