Submissions for variant NM_198282.4(STING1):c.575G>T (p.Gly192Val)

gnomAD frequency: 0.00019  dbSNP: rs201096097

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000539383	SCV000655349	uncertain significance	STING-associated vasculopathy with onset in infancy	2024-01-08	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 192 of the TMEM173 protein (p.Gly192Val). This variant is present in population databases (rs201096097, gnomAD 0.06%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with disorders of immunity (PMID: 35086391, 35482138). ClinVar contains an entry for this variant (Variation ID: 475208). 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.
CeGaT Center for Human Genetics Tuebingen	RCV001092019	SCV001248352	likely benign	not provided	2022-10-01	criteria provided, single submitter	clinical testing	STING1: BP4, BS2
Johns Hopkins Genomics, Johns Hopkins University	RCV000539383	SCV001548505	uncertain significance	STING-associated vasculopathy with onset in infancy	2021-03-29	criteria provided, single submitter	clinical testing	STING1 c.575G>T (rs201096097) is rare (<0.1%) in a large population dataset (gnomAD: 73/282854 total alleles; 0.03%; 1 homozygote) and has not been reported in the literature, to our knowledge. There is an entry for this variant in ClinVar (Variation ID: 475208). Of three bioinformatics tools queried, one predicts that the substitution would be possibly damaging, while two predict that it would be tolerated. The glycine at this position is conserved in most mammals, but not in the other species assessed. We consider the clinical significance of c.575G>T to be uncertain at this time.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002263800	SCV002542587	likely benign	Autoinflammatory syndrome	2022-01-31	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003905453	SCV004725800	uncertain significance	STING1-related disorder	2023-11-01	criteria provided, single submitter	clinical testing	The STING1 c.575G>T variant is predicted to result in the amino acid substitution p.Gly192Val. To our knowledge, this variant has not been reported in the literature in association with STING1 (TMEM173)-related disease but has been reported in individuals with early-onset systemic lupus erythematosus (Dasdemir et al. 2022. PubMed ID: 35086391), inborn errors of immunity (El Hawary et al. 2022. PubMed ID: 35482138), and autism spectrum disorder (Tuncay et al. 2023. PubMed ID: 37492102). This variant is reported in 0.065% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/5-138858039-C-A). Although we suspect that this variant may be benign, the clinical significance of this variant is uncertain at this time due to the absence of conclusive functional and genetic evidence.
Ambry Genetics	RCV004024307	SCV004958822	uncertain significance	Inborn genetic diseases	2021-12-03	criteria provided, single submitter	clinical testing	The c.575G>T (p.G192V) alteration is located in exon 6 (coding exon 4) of the TMEM173 gene. This alteration results from a G to T substitution at nucleotide position 575, causing the glycine (G) at amino acid position 192 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001092019	SCV001930839	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001092019	SCV001970883	likely benign	not provided		no assertion criteria provided	clinical testing