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NM_033629.6(TREX1):c.858dup (p.Leu287fs) AND multiple conditions

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Sep 1, 2022
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV001971387.4

Allele description [Variation Report for NM_033629.6(TREX1):c.858dup (p.Leu287fs)]

NM_033629.6(TREX1):c.858dup (p.Leu287fs)

Genes:
ATRIP:ATR interacting protein [Gene - OMIM - HGNC]
ATRIP-TREX1:ATRIP-TREX1 readthrough [Gene]
TREX1:three prime repair exonuclease 1 [Gene - OMIM - HGNC]
Variant type:
Duplication
Cytogenetic location:
3p21.31
Genomic location:
Preferred name:
NM_033629.6(TREX1):c.858dup (p.Leu287fs)
HGVS:
  • NC_000003.12:g.48467513dup
  • NG_009820.2:g.6684dup
  • NG_033100.1:g.38351dup
  • NG_033100.2:g.42300dup
  • NG_041782.1:g.25804dup
  • NG_099340.1:g.574dup
  • NM_001271022.2:c.*1959dup
  • NM_001271023.2:c.*1959dup
  • NM_007248.5:c.828dup
  • NM_032166.4:c.*1959dup
  • NM_033629.6:c.858dupMANE SELECT
  • NM_130384.3:c.*1959dupMANE SELECT
  • NP_009179.2:p.Leu277fs
  • NP_338599.1:p.Leu287Alafs
  • NP_338599.1:p.Leu287fs
  • LRG_282t1:c.858dup
  • LRG_282:g.6684dup
  • LRG_282p1:p.Leu287fs
  • NC_000003.11:g.48508908_48508909insG
  • NC_000003.11:g.48508912dup
  • NM_033629.4:c.858dup
  • NR_153405.1:n.4167dup
Protein change:
L277fs
Links:
dbSNP: rs2107265977
NCBI 1000 Genomes Browser:
rs2107265977
Molecular consequence:
  • NM_001271022.2:c.*1959dup - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
  • NM_001271023.2:c.*1959dup - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
  • NM_032166.4:c.*1959dup - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
  • NM_130384.3:c.*1959dup - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
  • NM_007248.5:c.828dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_033629.6:c.858dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NR_153405.1:n.4167dup - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:
Aicardi-Goutieres syndrome 1
Synonyms:
CREE ENCEPHALITIS; ENCEPHALOPATHY, FAMILIAL INFANTILE, WITH INTRACRANIAL CALCIFICATION AND CHRONIC CEREBROSPINAL FLUID LYMPHOCYTOSIS; PSEUDOTOXOPLASMOSIS SYNDROME
Identifiers:
MONDO: MONDO:0009165; MedGen: C0796126; Orphanet: 51; OMIM: 225750
Name:
Chilblain lupus 1 (CHBL1)
Identifiers:
MONDO: MONDO:0012500; MedGen: C0024145; OMIM: 610448
Name:
Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCLS)
Synonyms:
Vasculopathy, retinal, with cerebral leukodystrophy; Cerebroretinal vasculopathy, hereditary; Retinopathy, vascular, with cerebral and renal involvement and Raynaud and migraine phenomena
Identifiers:
MONDO: MONDO:0008641; MedGen: C1860518; Orphanet: 3421; Orphanet: 63261; Orphanet: 71291; OMIM: 192315

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV002261531Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Likely pathogenic
(Sep 1, 2022)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

C-terminal truncations in human 3'-5' DNA exonuclease TREX1 cause autosomal dominant retinal vasculopathy with cerebral leukodystrophy.

Richards A, van den Maagdenberg AM, Jen JC, Kavanagh D, Bertram P, Spitzer D, Liszewski MK, Barilla-Labarca ML, Terwindt GM, Kasai Y, McLellan M, Grand MG, Vanmolkot KR, de Vries B, Wan J, Kane MJ, Mamsa H, Schäfer R, Stam AH, Haan J, de Jong PT, Storimans CW, et al.

Nat Genet. 2007 Sep;39(9):1068-70. Epub 2007 Jul 29.

PubMed [citation]
PMID:
17660820

Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations.

Stam AH, Kothari PH, Shaikh A, Gschwendter A, Jen JC, Hodgkinson S, Hardy TA, Hayes M, Kempster PA, Kotschet KE, Bajema IM, van Duinen SG, Maat-Schieman MLC, de Jong PTVM, de Smet MD, de Wolff-Rouendaal D, Dijkman G, Pelzer N, Kolar GR, Schmidt RE, Lacey J, Joseph D, et al.

Brain. 2016 Nov 1;139(11):2909-2922. doi: 10.1093/brain/aww217. No abstract available.

PubMed [citation]
PMID:
27604306
PMCID:
PMC5091044
See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002261531.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this frameshift affects TREX1 function (PMID: 17660820). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 1477050). This frameshift has been observed in individuals with retinal vasculopathy with cerebral leukodystrophy (PMID: 27604306; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change results in a frameshift in the TREX1 gene (p.Leu287Alafs*38). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 28 amino acid(s) of the TREX1 protein and extend the protein by 9 additional amino acid residues.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024