VCV000522920.40 - ClinVar

NM_033629.6(TREX1):c.218C>T (p.Pro73Leu)

Germline

Classification

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.

(8)

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.

Conflicting classifications of pathogenicity
Likely pathogenic(1); Uncertain significance(5)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_033629.6(TREX1):c.218C>T (p.Pro73Leu)

Variation ID: 522920 Accession: VCV000522920.40

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3p21.31 3: 48466873 (GRCh38) [ NCBI UCSC ] 3: 48508272 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	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	Apr 29, 2018	Nov 24, 2024	Nov 12, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_033629.6:c.218C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_338599.1:p.Pro73Leu	missense
NM_130384.3:c.*1319C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		3 prime UTR
NM_001271022.2:c.*1319C>T		3 prime UTR
NM_001271023.2:c.*1319C>T		3 prime UTR
NM_007248.5:c.188C>T	NP_009179.2:p.Pro63Leu	missense
NM_032166.4:c.*1319C>T		3 prime UTR
NM_033629.2:c.218C>T
NR_153405.1:n.3527C>T		non-coding transcript variant
NC_000003.12:g.48466873C>T
NC_000003.11:g.48508272C>T
NG_009820.2:g.6044C>T
NG_033100.1:g.38988G>A
NG_033100.2:g.42937G>A
NG_041782.1:g.25164C>T
NG_099339.1:g.816C>T
LRG_282:g.6044C>T
LRG_282t1:c.218C>T	LRG_282p1:p.Pro73Leu

... more HGVS ... less HGVS

Protein change

P73L, P63L

Other names

Canonical SPDI

NC_000003.12:48466872:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD) 0.00001

Exome Aggregation Consortium (ExAC) 0.00002

The Genome Aggregation Database (gnomAD), exomes 0.00002

Trans-Omics for Precision Medicine (TOPMed) 0.00002

Links

ClinGen: CA2376601 dbSNP: rs755919767 VarSome

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
Gene	OMIM	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.
ATRIP		-	-	GRCh38 GRCh37	1	788
ATRIP-TREX1	-	-	-	GRCh38	-	772
TREX1		-	-	GRCh38 GRCh37	4	539

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.
Aicardi-Goutieres syndrome 1	Conflicting interpretations of pathogenicity (3)	criteria provided, conflicting classifications	Jun 18, 2019	RCV000626116.9
Aicardi-Goutieres syndrome 1 Chilblain lupus 1 Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations Systemic lupus erythematosus	Uncertain significance (1)	criteria provided, single submitter	Oct 31, 2018	RCV000764509.3
Aicardi-Goutieres syndrome 1 Chilblain lupus 1 Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations	Uncertain significance (1)	criteria provided, single submitter	Jan 14, 2024	RCV001219467.6
not provided	Uncertain significance (3)	criteria provided, multiple submitters, no conflicts	Nov 12, 2024	RCV000656254.26

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.
Uncertain significance (Oct 31, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Systemic lupus erythematosus Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations Aicardi-Goutieres syndrome 1 Chilblain lupus 1 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000895588.1 First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Likely pathogenic (Jun 18, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Aicardi-Goutieres syndrome 1 Affected status: unknown Allele origin: germline	Johns Hopkins Genomics, Johns Hopkins University Accession: SCV000992375.1 First in ClinVar: Sep 13, 2019 Last updated: Sep 13, 2019	Comment: This TREX1 variant (rs755919767) is rare (<0.1%) in large population datasets (gnomAD: 6/250524 total alleles; 0.0024%; no homozygotes) and has not been reported in the … (more) This TREX1 variant (rs755919767) is rare (<0.1%) in large population datasets (gnomAD: 6/250524 total alleles; 0.0024%; no homozygotes) and has not been reported in the literature, to our knowledge. There are conflicting interpretations of the pathogenicity of this variant in ClinVar. Two submitters classified it as a variant of uncertain clinical significance and one as pathogenic. Two bioinformatic tools queried predict that this substitution would be probably damaging/deleterious, and the proline residue at this position is evolutionarily conserved in mammals. This variant is considered to be likely pathogenic. (less)
Uncertain significance (Dec 18, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Aicardi-Goutieres syndrome 1 Affected status: yes Allele origin: inherited	Genomic Research Center, Shahid Beheshti University of Medical Sciences Accession: SCV000746743.2 First in ClinVar: Apr 29, 2018 Last updated: Dec 11, 2022	Age: 0-9 years Sex: male Geographic origin: Iran
Uncertain significance (Jan 14, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	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	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001391408.4 First in ClinVar: Jul 16, 2020 Last updated: Feb 28, 2024	Publications: PubMed (1) PubMed: 34440436 Comment: This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 73 of the TREX1 protein (p.Pro73Leu). … (more) This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 73 of the TREX1 protein (p.Pro73Leu). This variant is present in population databases (rs755919767, gnomAD 0.01%). This missense change has been observed in individual(s) with increased CSF interferon alpha (PMID: 34440436). ClinVar contains an entry for this variant (Variation ID: 522920). 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. 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. (less)
Uncertain significance (Feb 01, 2019)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001153941.27 First in ClinVar: Feb 03, 2020 Last updated: Oct 20, 2024	Number of individuals with the variant: 1
Uncertain significance (Nov 12, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001997054.3 First in ClinVar: Nov 06, 2021 Last updated: Nov 24, 2024	Comment: Reported in two patients with atypical cerebral palsy and one patient with thrombocytopenia, glaucoma, nystagmus an increased CSF interferon alpha (PMID: 34440436, 34540776); In silico … (more) Reported in two patients with atypical cerebral palsy and one patient with thrombocytopenia, glaucoma, nystagmus an increased CSF interferon alpha (PMID: 34440436, 34540776); 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: 34540776, 34440436) (less)
Pathogenic (Sep 26, 2016)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes Accession: SCV000778215.1 First in ClinVar: Jun 04, 2018 Last updated: Jun 04, 2018
Uncertain significance (-)	no assertion criteria provided Method: clinical testing	Aicardi-Goutieres syndrome 1 (Autosomal recessive inheritance) Affected status: yes Allele origin: inherited	Myelin Disorders Clinic-Children's Medical Center/Medical Genetics Lab-Tarbiat Modares University, Children's Medical Center, Pediatrics Center of Excellence, Accession: SCV001334141.1 First in ClinVar: Jun 18, 2020 Last updated: Jun 18, 2020	Sex: female

Comment:

This TREX1 variant (rs755919767) is rare (<0.1%) in large population datasets (gnomAD: 6/250524 total alleles; 0.0024%; no homozygotes) and has not been reported in the literature, to our knowledge. There are conflicting interpretations of the pathogenicity of this variant in ClinVar. Two submitters classified it as a variant of uncertain clinical significance and one as pathogenic. Two bioinformatic tools queried predict that this substitution would be probably damaging/deleterious, and the proline residue at this position is evolutionarily conserved in mammals. This variant is considered to be likely pathogenic.

Comment:

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 73 of the TREX1 protein (p.Pro73Leu). This variant is present in population databases (rs755919767, gnomAD 0.01%). This missense change has been observed in individual(s) with increased CSF interferon alpha (PMID: 34440436). ClinVar contains an entry for this variant (Variation ID: 522920). 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. 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.

Comment:

Reported in two patients with atypical cerebral palsy and one patient with thrombocytopenia, glaucoma, nystagmus an increased CSF interferon alpha (PMID: 34440436, 34540776); 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: 34540776, 34440436)

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Utility of Gene Panels for the Diagnosis of Inborn Errors of Metabolism in a Metabolic Reference Center.	Barbosa-Gouveia S	Genes	2021	PMID: 34440436

Text-mined citations for rs755919767 ...

These 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 Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_033629.6(TREX1):c.218C>T (p.Pro73Leu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs755919767 ...