Submissions for variant NM_198282.4(STING1):c.841C>T (p.Arg281Trp)

gnomAD frequency: 0.00001  dbSNP: rs750077345

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001041670	SCV001205296	uncertain significance	STING-associated vasculopathy with onset in infancy	2023-10-23	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 281 of the TMEM173 protein (p.Arg281Trp). This variant is present in population databases (rs750077345, gnomAD 0.004%). This missense change has been observed in individual(s) with clinical features of infantile-onset STING-associated vasculopathy (PMID: 30919572, 32673614, 33488593, 36275728). ClinVar contains an entry for this variant (Variation ID: 839824). 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 TMEM173 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects TMEM173 function (PMID: 32673614). This variant disrupts the p.Arg281 amino acid residue in TMEM173. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28087229). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
GeneDx	RCV001593208	SCV001823939	pathogenic	not provided	2022-12-15	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33488593, 32673614, 36275728, 30919572)
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002264151	SCV002543066	uncertain significance	Autoinflammatory syndrome	2017-01-31	criteria provided, single submitter	clinical testing
Department of Human Genetics, Hannover Medical School	RCV001041670	SCV002568456	pathogenic	STING-associated vasculopathy with onset in infancy	2022-08-31	criteria provided, single submitter	clinical testing