NM_033629.6(TREX1):c.667G>A (p.Ala223Thr) AND multiple conditions

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Dec 13, 2025
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:: RCV001340342.6

Allele description [Variation Report for NM_033629.6(TREX1):c.667G>A (p.Ala223Thr)]

NM_033629.6(TREX1):c.667G>A (p.Ala223Thr)

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.667G>A (p.Ala223Thr)

Other names:

NM_016381.5:c.832G>A; NM_016381.3:c.832G>A

HGVS:

NC_000003.12:g.48467322G>A
NG_009820.2:g.6493G>A
NG_033100.1:g.38539C>T
NG_033100.2:g.42488C>T
NG_041782.1:g.25613G>A
NG_099340.1:g.383G>A
NM_001271022.2:c.*1768G>A
NM_001271023.2:c.*1768G>A
NM_007248.5:c.637G>A
NM_032166.4:c.*1768G>A
NM_033629.6:c.667G>AMANE SELECT
NM_130384.3:c.*1768G>AMANE SELECT
NP_009179.2:p.Ala213Thr
NP_338599.1:p.Ala223Thr
NP_338599.1:p.Ala223Thr
LRG_282t1:c.667G>A
LRG_282:g.6493G>A
LRG_282p1:p.Ala223Thr
NC_000003.11:g.48508721G>A
NM_033629.2:c.667G>A
NM_033629.3:c.667G>A
NM_033629.4:c.667G>A
NR_153405.1:n.3976G>A

Protein change:

A213T

Links:

dbSNP: rs766785968

Molecular consequence:

NM_001271022.2:c.*1768G>A - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_001271023.2:c.*1768G>A - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_032166.4:c.*1768G>A - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_130384.3:c.*1768G>A - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_007248.5:c.637G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_033629.6:c.667G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_153405.1:n.3976G>A - 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:: 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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001534148	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 13, 2025)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 24300241, 32877590, 34490982, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001534148

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 13, 2025)

germline

clinical testing

PubMed (4)
[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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A nationwide survey of Aicardi-Goutières syndrome patients identifies a strong association between dominant TREX1 mutations and chilblain lesions: Japanese cohort study.

Abe J, Nakamura K, Nishikomori R, Kato M, Mitsuiki N, Izawa K, Awaya T, Kawai T, Yasumi T, Toyoshima I, Hasegawa K, Ohshima Y, Hiragi T, Sasahara Y, Suzuki Y, Kikuchi M, Osaka H, Ohya T, Ninomiya S, Fujikawa S, Akasaka M, Iwata N, et al.

Rheumatology (Oxford). 2014 Mar;53(3):448-58. doi: 10.1093/rheumatology/ket372. Epub 2013 Dec 3.

PubMed [citation]

PMID:: 24300241

Janus Kinase Inhibition in the Aicardi-Goutières Syndrome.

Vanderver A, Adang L, Gavazzi F, McDonald K, Helman G, Frank DB, Jaffe N, Yum SW, Collins A, Keller SR, Lebon P, Meritet JF, Rhee J, Takanohashi A, Armangue T, Ulrick N, Sherbini O, Koh J, Peer K, Besnier C, Scher C, Boyle K, et al.

N Engl J Med. 2020 Sep 3;383(10):986-989. doi: 10.1056/NEJMc2001362. No abstract available.

PubMed [citation]

PMID:: 32877590
PMCID:: PMC7495410

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001534148.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 223 of the TREX1 protein (p.Ala223Thr). This variant is present in population databases (rs766785968, gnomAD 0.006%). This missense change has been observed in individuals with autosomal recessive Aicardi-Goutieres syndrome (PMID: 24300241, 32877590, 34490982). ClinVar contains an entry for this variant (Variation ID: 381689). 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.

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

Last Updated: Jul 6, 2026

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