This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS2,PS3,PM2,PP3,PP5.
ClinVar Genomic variation as it relates to human health
NM_198282.4(STING1):c.842G>A (p.Arg281Gln)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(5)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic/Likely pathogenic
5
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_198282.4(STING1):c.842G>A (p.Arg281Gln)
Variation ID: 568703 Accession: VCV000568703.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 5q31.2 5: 139477433 (GRCh38) [ NCBI UCSC ] 5: 138857018 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Oct 10, 2018 Jul 23, 2024 Apr 24, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_198282.4:c.842G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_938023.1:p.Arg281Gln missense NM_001301738.2:c.759+837G>A intron variant NM_001367258.1:c.485G>A NP_001354187.1:p.Arg162Gln missense NC_000005.10:g.139477433C>T NC_000005.9:g.138857018C>T NG_034249.1:g.10358G>A LRG_1308:g.10358G>A LRG_1308t1:c.842G>A LRG_1308p1:p.Arg281Gln - Protein change
- R281Q, R162Q
- Other names
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- Canonical SPDI
- NC_000005.10:139477432:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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Trans-Omics for Precision Medicine (TOPMed) 0.00000
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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| STING1 | - | - |
GRCh38 GRCh38 GRCh37 |
267 | 350 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Oct 9, 2023 | RCV000689142.11 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Apr 24, 2024 | RCV001198467.3 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Aug 19, 2019)
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criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
unknown
|
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001369401.2
First in ClinVar: Jul 04, 2020 Last updated: Jul 04, 2020 |
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS2,PS3,PM2,PP3,PP5.
|
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Likely pathogenic
(Aug 10, 2021)
|
criteria provided, single submitter
Method: research
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STING-associated vasculopathy with onset in infancy
Affected status: yes
Allele origin:
maternal
|
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology
Study: AGHI WGS
Accession: SCV001870389.1 First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021 |
Comment:
ACMG codes:PS3, PS4M, PM2, PP5
Number of individuals with the variant: 1
Clinical Features:
High palate (present) , Long face (present) , Low-set ears (present) , Upslanted palpebral fissure (present) , Tetralogy of Fallot (present) , Prominent tragus (present) … (more)
High palate (present) , Long face (present) , Low-set ears (present) , Upslanted palpebral fissure (present) , Tetralogy of Fallot (present) , Prominent tragus (present) , Midface retrusion (present) (less)
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Pathogenic
(Jun 28, 2023)
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criteria provided, single submitter
Method: clinical testing
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STING-associated vasculopathy with onset in infancy
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago
Accession: SCV004190173.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
Comment:
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 … (more)
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. (less)
Zygosity: Single Heterozygote
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Pathogenic
(Oct 09, 2023)
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criteria provided, single submitter
Method: clinical testing
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STING-associated vasculopathy with onset in infancy
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000816782.6
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
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). … (more)
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. (less)
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Pathogenic
(Apr 24, 2024)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV005079248.1
First in ClinVar: Jul 23, 2024 Last updated: Jul 23, 2024 |
Comment:
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 … (more)
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) (less)
|
Comment:
Comment:
ACMG codes:PS3, PS4M, PM2, PP5
Comment:
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.
Comment:
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.
Comment:
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)
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS2,PS3,PM2,PP3,PP5.
Comment:
ACMG codes:PS3, PS4M, PM2, PP5
Comment:
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.
Comment:
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.
Comment:
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)
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Disease-associated mutations identify a novel region in human STING necessary for the control of type I interferon signaling. | Melki I | The Journal of allergy and clinical immunology | 2017 | PMID: 28087229 |
Text-mined citations for rs1561482476 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Sep 29, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.