ClinVar Genomic variation as it relates to human health
NM_033629.6(TREX1):c.290G>A (p.Arg97His)
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.
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(2); Likely pathogenic(2); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_033629.6(TREX1):c.290G>A (p.Arg97His)
Variation ID: 225498 Accession: VCV000225498.28
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p21.31 3: 48466945 (GRCh38) [ NCBI UCSC ] 3: 48508344 (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 May 25, 2017 Apr 15, 2024 Jan 29, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_033629.6:c.290G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_338599.1:p.Arg97His missense NM_130384.3:c.*1391G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
3 prime UTR NM_001271023.2:c.*1391G>A 3 prime UTR NM_007248.5:c.260G>A NP_009179.2:p.Arg87His missense NM_032166.4:c.*1391G>A 3 prime UTR NM_033629.3:c.290G>A NR_153405.1:n.3599G>A non-coding transcript variant NC_000003.12:g.48466945G>A NC_000003.11:g.48508344G>A NG_009820.2:g.6116G>A NG_033100.1:g.38916C>T NG_041782.1:g.25236G>A LRG_282:g.6116G>A LRG_282t1:c.290G>A LRG_282p1:p.Arg97His - Protein change
- R97H, R87H
- Other names
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- Canonical SPDI
- NC_000003.12:48466944:G:A
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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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0.00020 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00006
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
The Genome Aggregation Database (gnomAD) 0.00003
Exome Aggregation Consortium (ExAC) 0.00004
Trans-Omics for Precision Medicine (TOPMed) 0.00005
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 | ||
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HI score
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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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ATRIP | - | - |
GRCh38 GRCh37 |
- | 777 | |
ATRIP-TREX1 | - | - | - | GRCh38 | - | 764 |
TREX1 | - | - |
GRCh38 GRCh37 |
4 | 532 |
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. |
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Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Dec 8, 2021 | RCV000490435.3 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Oct 26, 2020 | RCV001093075.21 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 29, 2024 | RCV001853392.4 |
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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Likely pathogenic
(Mar 18, 2016)
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criteria provided, single submitter
Method: reference population
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Aicardi-Goutieres syndrome 1
Affected status: unknown
Allele origin:
germline
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Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center
Accession: SCV000267537.1
First in ClinVar: May 25, 2017 Last updated: May 25, 2017 |
Number of individuals with the variant: 1
Age: 40-69 years
Ethnicity/Population group: East Asian
Geographic origin: South Korean
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Likely pathogenic
(Dec 08, 2021)
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criteria provided, single submitter
Method: clinical testing
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Aicardi-Goutieres syndrome 1
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002050828.1
First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022 |
Comment:
Variant summary: TREX1 c.290G>A (p.Arg97His) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a damaging … (more)
Variant summary: TREX1 c.290G>A (p.Arg97His) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 249418 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in TREX1 causing Aicardi Goutieres Syndrome 1 (6e-05 vs ND), allowing no conclusion about variant significance. c.290G>A has been reported in the literature in individuals affected with Aicardi Goutieres Syndrome 1 (compound heterozygote, Olivieri_2013) or affected with cerebral lupus (homozygote, Ellyard_2014). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Ellyard_2014). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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Uncertain significance
(Oct 26, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV003823461.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 29, 2024)
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criteria provided, single submitter
Method: clinical testing
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Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations
Aicardi-Goutieres syndrome 1 Chilblain lupus 1
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV002123015.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 97 of the TREX1 protein (p.Arg97His). … (more)
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 97 of the TREX1 protein (p.Arg97His). This variant is present in population databases (rs200773268, gnomAD 0.02%). This missense change has been observed in individual(s) with autosomal recessive Aicardi-Goutieres syndrome and/or systemic lupus erythematosus (PMID: 3580372, 23918923, 25138095, 31130681, 34490615, 35803721). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 225498). 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. Experimental studies have shown that this missense change affects TREX1 function (PMID: 22367235, 25138095). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(May 01, 2018)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001249887.20
First in ClinVar: May 12, 2020 Last updated: Apr 15, 2024 |
Number of individuals with the variant: 1
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Child Neurology: Aicardi-Goutières Syndrome Presenting as Recurrent Ischemic Stroke. | Kuang SY | Neurology | 2022 | PMID: 35803721 |
Prevalence and clinical prediction of mitochondrial disorders in a large neuropediatric cohort. | van der Ven AT | Clinical genetics | 2021 | PMID: 34490615 |
Optimizing clinical exome design and parallel gene-testing for recessive genetic conditions in preconception carrier screening: Translational research genomic data from 14,125 exomes. | Capalbo A | PLoS genetics | 2019 | PMID: 31589614 |
Molecular Genetics and Interferon Signature in the Italian Aicardi Goutières Syndrome Cohort: Report of 12 New Cases and Literature Review. | Garau J | Journal of clinical medicine | 2019 | PMID: 31130681 |
Identification of a pathogenic variant in TREX1 in early-onset cerebral systemic lupus erythematosus by Whole-exome sequencing. | Ellyard JI | Arthritis & rheumatology (Hoboken, N.J.) | 2014 | PMID: 25138095 |
Assessment of interferon-related biomarkers in Aicardi-Goutières syndrome associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, and ADAR: a case-control study. | Rice GI | The Lancet. Neurology | 2013 | PMID: 24183309 |
Dysregulation of the immune system in Aicardi-Goutières syndrome: another example in a TREX1-mutated patient. | Olivieri I | Lupus | 2013 | PMID: 23918923 |
Inhibition of neuroblastoma cell growth by TREX1-mutated human lymphocytes. | Pulliero A | Oncology reports | 2012 | PMID: 22367235 |
Alterations in amounts and covalent modifications of low-molecular-weight chromosomal proteins in Chinese hamster ovary cells during polyamine depletion. | Palvimo J | Biochimica et biophysica acta | 1987 | PMID: 3580372 |
Text-mined citations for rs200773268 ...
HelpRecord last updated Apr 15, 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.