Submissions for variant NM_198282.4(STING1):c.463G>A (p.Val155Met)

gnomAD frequency: 0.00003  dbSNP: rs587777610

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000481634	SCV000567423	pathogenic	not provided	2015-08-13	criteria provided, single submitter	clinical testing	The V155M substitution in the TMEM173 gene has been reported previously as both a de novo variant andin a family with multiple affected individuals showing variable clinical features consistent with SALVI (Liuet al., 2014; Jeremiah et al., 2014). Functional studies of the V155M variant indicate it results in gain offunction upregulation of type I interferon production (Jeremiah, et al., 2014). The V155M variant was notobserved in approximately 6,500 individuals of European and African American ancestry in the NHLBIExome Sequencing Project, indicating it is not a common benign variant in these populations. The V155Mvariant is a conservative amino acid substitution, which is at a position that is conserved, but Methioninehas been observed at this position in evolution. In silico analysis predicts this variant is probably damagingto the protein structure/function. Missense variants in nearby residues (V147L and N154S) have beenreported in the Human Gene Mutation Database in association with early onset vasculopathy (Stenson etal., 2014), supporting the functional importance of this region of the protein. We interpret V155M as a pathogenic variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000133401	SCV000774209	pathogenic	STING-associated vasculopathy with onset in infancy	2024-03-02	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 155 of the TMEM173 protein (p.Val155Met). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individual(s) with STING-associated vasculopathy (SAVI) and severe pulmonary disease (PMID: 25029335, 25401470, 27613991). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 143862). 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: 25029335, 25401470, 26235147, 28484079). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000133401	SCV000893691	pathogenic	STING-associated vasculopathy with onset in infancy	2018-10-31	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000481634	SCV003924252	pathogenic	not provided	2021-11-22	criteria provided, single submitter	clinical testing	TMEM173 NM_198282 exon 5 p.Val155Met (c.463G>A): This variant has been reported in the literature in at least 4 individuals with suspected STING related disease (early onset systemic inflammation, cutaneous vasculopathy and pulmonary inflammation), segregating with disease in 2 affected family members and identified as de novo in 2 individuals (Jeremiah 2014 PMID:25401470, Liu 2014 PMID:25029335, Picard 2016 PMID:27613991). This variant is present in 1/15300 African alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/). This variant is present in ClinVar (Variation ID:143862). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In vitro functional studies also predict that this variant will impact the protein, with authors proposing a gain of function mechanism (Jeremiah 2014 PMID:25401470, Liu 2014 PMID:25029335, Cerboni 2017 PMID:28484079). In summary, this variant is classified as pathogenic based on the data above.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000133401	SCV005400293	pathogenic	STING-associated vasculopathy with onset in infancy	2023-07-17	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with STING-associated vasculopathy, infantile-onset (MIM#615934). Missense variants were shown to result in reporter activation (PMID: 25029335). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Intrafamilial variability has been reported (PMID: 25401470). (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to methionine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3 and v2) <0.001 for a dominant condition (5 heterozygotes, 0 homozygotes). (SP) 0504 - Same amino acid change has been observed in placental mammals. (SB) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants, within the connecter helix loop (DECIPHER, PMID: 32673614). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as pathogenic, and observed in at least five unrelated individuals with an inflammatory syndrome or infantile onset interstitial lung disease. In four of these individuals, the variant was found to be de novo (ClinVar, PMID: 25029335, PMID: 25401470, PMID: 31705453). (SP) 0903 - This variant has limited evidence for segregation with disease. This variant segregated in three affected members of a single family with a familial inflammatory syndrome (PMID: 25401470). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Transfected cells showed elevated transcription of IFNB1 and other gene targets (PMID: 25029335, PMID: 25401470). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed, by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
CeGaT Center for Human Genetics Tuebingen	RCV000481634	SCV005890680	pathogenic	not provided	2025-02-01	criteria provided, single submitter	clinical testing	STING1: PM6:Strong, PP1:Strong, PM2, PS4:Moderate, PS3:Supporting
OMIM	RCV000133401	SCV000188474	pathogenic	STING-associated vasculopathy with onset in infancy	2014-12-01	no assertion criteria provided	literature only
Clinical Genetics Laboratory, University Hospital Schleswig-Holstein	RCV000133401	SCV002583394	pathogenic	STING-associated vasculopathy with onset in infancy	2022-02-01	no assertion criteria provided	clinical testing