Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000689142 | SCV000816782 | pathogenic | STING-associated vasculopathy with onset in infancy | 2023-10-09 | 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 281 of the TMEM173 protein (p.Arg281Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with STING (stimulator of interferon genes)-associated vasculopathy with infantile onset (SAVI) (PMID: 28087229). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 568703). 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 not expected to disrupt TMEM173 protein function. Experimental studies have shown that this missense change affects TMEM173 function (PMID: 28087229). For these reasons, this variant has been classified as Pathogenic. |
| Centre for Mendelian Genomics, |
RCV001198467 | SCV001369401 | pathogenic | not provided | 2019-08-19 | criteria provided, single submitter | clinical testing | This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS2,PS3,PM2,PP3,PP5. |
| Hudson |
RCV000689142 | SCV001870389 | likely pathogenic | STING-associated vasculopathy with onset in infancy | 2021-08-10 | criteria provided, single submitter | research | ACMG codes:PS3, PS4M, PM2, PP5 |
| Center for Genomics, |
RCV000689142 | SCV004190173 | pathogenic | STING-associated vasculopathy with onset in infancy | 2023-06-28 | criteria provided, single submitter | clinical testing | This variant has been reported in the literature in at least five unrelated individuals with various features including interstitial lung disease, polyarthritis, arthralgia, elevated rheumatoid factor, and others (Melki 2017 PMID: 28087229; Karacan 2019 PMID: 30783801; Li 2020 PMID: 33014937; Nishida 2021 PMID: 33162473; Wang 2021 PMID: 33569478). The variant was shown to be de novo in two of the cases and was found to segregate with disease in at least four affected family members (Melki 2017 PMID: 28087229; Li 2020 PMID: 33014937; Wang 2021 PMID: 33569478). It is absent from gnomAD but has been submitted to ClinVar by multiple laboratories as pathogenic or likely pathogenic (Variation ID: 568703). In vitro functional studies have suggested that this variant results in constitutive activation of type I interferon signaling, consistent with a gain of function effect (Melki 2017 PMID: 28087229; Lin 2020 PMID: 32673614). Evolutionary conservation and computational prediction tools do not support a predicted pathogenic effect. However, the overwhelming evidence associated with this variant's clinical relevance is sufficient for this variant to be classified as pathogenic. |
| Gene |
RCV001198467 | SCV005079248 | pathogenic | not provided | 2024-04-24 | criteria provided, single submitter | clinical testing | Published functional studies demonstrate that this variant results in increased IFN-B activity and NF-kB activation (PMID: 28087229, 30038614); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 33162473, 33217613, 31230712, 30038614, 31144250, 32673614, 29870684, 29800647, 33014937, 33569478, 34134972, 27943079, 36648577, 36275728, 28087229, 30783801) |