VCV002936991.1 - ClinVar

NM_033629.6(TREX1):c.522_523delinsTT (p.Arg174_Lys175delinsSerTer)

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.

(1)

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

criteria provided, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_033629.6(TREX1):c.522_523delinsTT (p.Arg174_Lys175delinsSerTer)

Variation ID: 2936991 Accession: VCV002936991.1

Type and length

Indel, 2 bp

Location

Cytogenetic: 3p21.31 3: 48467177-48467178 (GRCh38) [ NCBI UCSC ] 3: 48508576-48508577 (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	Feb 29, 2024	Feb 28, 2024	May 11, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_033629.6:c.522_523delinsTT MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_338599.1:p.Arg174_Lys175delinsSerTer	nonsense
NM_130384.3:c.1623_1624delinsTT MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		3 prime UTR
NM_001271022.2:c.1623_1624delinsTT		3 prime UTR
NM_001271023.2:c.1623_1624delinsTT		3 prime UTR
NM_007248.5:c.492_493delinsTT	NP_009179.2:p.Arg164_Lys165delinsSerTer	nonsense
NM_032166.4:c.1623_1624delinsTT		3 prime UTR
NR_153405.1:n.3831_3832delinsTT		non-coding transcript variant
NC_000003.12:g.48467177_48467178delinsTT
NC_000003.11:g.48508576_48508577delinsTT
NG_009820.2:g.6348_6349delinsTT
NG_033100.1:g.38683_38684delinsAA
NG_033100.2:g.42632_42633delinsAA
NG_041782.1:g.25468_25469delinsTT
NG_099340.1:g.238_239delinsTT
LRG_282:g.6348_6349delinsTT
LRG_282t1:c.522_523delinsTT	LRG_282p1:p.Arg174_Lys175delinsSerTer

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000003.12:48467176:GA:TT

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.

Links

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	785
ATRIP-TREX1	-	-	-	GRCh38	-	769
TREX1		-	-	GRCh38 GRCh37	4	536

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 Chilblain lupus 1 Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations	Pathogenic (1)	criteria provided, single submitter	May 11, 2023	RCV003791181.2

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.
Pathogenic (May 11, 2023)	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: SCV004584365.1 First in ClinVar: Feb 28, 2024 Last updated: Feb 28, 2024	Publications: PubMed (1) PubMed: 26938784 Comment: For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the TREX1 protein in which other variant(s) (p.Trp210* ) … (more) For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the TREX1 protein in which other variant(s) (p.Trp210* ) have been determined to be pathogenic (PMID: 26938784; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. This variant has not been reported in the literature in individuals affected with TREX1-related conditions. Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This sequence change creates a premature translational stop signal (p.Arg174_Lys175delinsSer*) in the TREX1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 141 amino acid(s) of the TREX1 protein. (less)

Comment:

For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the TREX1 protein in which other variant(s) (p.Trp210* ) have been determined to be pathogenic (PMID: 26938784; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. This variant has not been reported in the literature in individuals affected with TREX1-related conditions. Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This sequence change creates a premature translational stop signal (p.Arg174_Lys175delinsSer*) in the TREX1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 141 amino acid(s) of the TREX1 protein.

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
A prospective evaluation of whole-exome sequencing as a first-tier molecular test in infants with suspected monogenic disorders.	Stark Z	Genetics in medicine : official journal of the American College of Medical Genetics	2016	PMID: 26938784

Text-mined citations for this variant ...

Record last updated Sep 30, 2024

ClinVar Genomic variation as it relates to human health

NM_033629.6(TREX1):c.522_523delinsTT (p.Arg174_Lys175delinsSerTer)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...