NM_033629.6(TREX1):c.598G>A (p.Asp200Asn) AND Aicardi-Goutieres syndrome 1, autosomal dominant

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Sep 16, 2011
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

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:: RCV000004402.3

Allele description [Variation Report for NM_033629.6(TREX1):c.598G>A (p.Asp200Asn)]

NM_033629.6(TREX1):c.598G>A (p.Asp200Asn)

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:

single nucleotide variant

Cytogenetic location:

3p21.31

Genomic location:

Preferred name:

NM_033629.6(TREX1):c.598G>A (p.Asp200Asn)

HGVS:

NC_000003.12:g.48467253G>A
NG_009820.2:g.6424G>A
NG_033100.1:g.38608C>T
NG_033100.2:g.42557C>T
NG_041782.1:g.25544G>A
NG_099340.1:g.314G>A
NM_001271022.2:c.*1699G>A
NM_001271023.2:c.*1699G>A
NM_007248.5:c.568G>A
NM_032166.4:c.*1699G>A
NM_033629.6:c.598G>AMANE SELECT
NM_130384.3:c.*1699G>AMANE SELECT
NP_009179.2:p.Asp190Asn
NP_338599.1:p.Asp200Asn
NP_338599.1:p.Asp200Asn
LRG_282t1:c.598G>A
AAK07616.1:p.Asp200Asn
LRG_282:g.6424G>A
LRG_282p1:p.Asp200Asn
NC_000003.11:g.48508652G>A
NM_033629.4:c.598G>A
NR_153405.1:n.3907G>A
Q9NSU2:p.Asp255Asn

Protein change:

D190N; ASP200ASN

Links:

UniProtKB: Q9NSU2#VAR_032940; OMIM: 606609.0006; dbSNP: rs78846775

Molecular consequence:

NM_001271022.2:c.*1699G>A - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_001271023.2:c.*1699G>A - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_032166.4:c.*1699G>A - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_130384.3:c.*1699G>A - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_007248.5:c.568G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_033629.6:c.598G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_153405.1:n.3907G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Aicardi-Goutieres syndrome 1, autosomal dominant
Identifiers:: MedGen: C3150315

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000024574	OMIM	no assertion criteria provided	Pathogenic (Sep 16, 2011)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 17357087, 21808053

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000024574

OMIM

no assertion criteria provided

Pathogenic
(Sep 16, 2011)

germline

literature only

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

Heterozygous mutations in TREX1 cause familial chilblain lupus and dominant Aicardi-Goutieres syndrome.

Rice G, Newman WG, Dean J, Patrick T, Parmar R, Flintoff K, Robins P, Harvey S, Hollis T, O'Hara A, Herrick AL, Bowden AP, Perrino FW, Lindahl T, Barnes DE, Crow YJ.

Am J Hum Genet. 2007 Apr;80(4):811-5. Epub 2007 Feb 19.

PubMed [citation]

PMID:: 17357087
PMCID:: PMC1852703

Dominant mutation of the TREX1 exonuclease gene in lupus and Aicardi-Goutieres syndrome.

Fye JM, Orebaugh CD, Coffin SR, Hollis T, Perrino FW.

J Biol Chem. 2011 Sep 16;286(37):32373-82. doi: 10.1074/jbc.M111.276287. Epub 2011 Aug 1.

PubMed [citation]

PMID:: 21808053
PMCID:: PMC3173215

Details of each submission

From OMIM, SCV000024574.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

In a child with a classic history of Aicardi-Goutieres syndrome (AGS1; 225750), who was born to nonconsanguineous Scottish parents, Rice et al. (2007) found heterozygosity for a missense mutation in the TREX1 gene: a 598G-A transition that resulted in a substitution of asparagine for aspartic acid at codon 200 (D200N). Both parents had a homozygous wildtype genotype at this position, suggesting a de novo occurrence. Differentiation of the maternal and paternal alleles was possible because of a frequently observed C-to-T SNP at position 531, which allowed the authors to demonstrate that the mutation has arisen on the maternal allele. A standard exonuclease assay indicated close-to-normal TREX1 enzymatic activity. Rice et al. (2007) hypothesized that the aspartic acid at position 200 of TREX1 represents one of 4 residues essential for coordinating 2 magnesium ions involved in DNA binding and catalysis, and that the D200N mutation represents a gain-of-function mutation conferring altered substrate specificity, DNA binding, or protein-protein interaction which would not be detected in a standard TREX1 exonuclease assay.

Fye et al. (2011) stated that asp18 and asp200 are the 2 aspartates that coordinate the divalent metal ion Mg(2+) at the TREX1 active site and contribute to DNA binding and catalysis. They found that homodimers of recombinant human TREX1 containing D200N or D18N (606609.0007) mutations had negligible nuclease activity against ssDNA and dsDNA compared with wildtype. Heterodimers of wildtype TREX1 with D18N or D200N TREX1 mutants had more modestly reduced ssDNA nuclease activity, but profoundly reduced dsDNA nuclease activity, compared with wildtype homodimers. Fye et al. (2011) concluded that the dominant phenotypes of asp18 and asp200 mutations relate predominantly to impaired dsDNA degradation and indicate that TREX1 dsDNA degradation activity is fundamental to the prevention of autoimmunity.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jul 6, 2026

ClinVar

Relating variation to medicine