ClinVar Miner

Submissions for variant NM_033629.6(TREX1):c.52G>A (p.Asp18Asn) (rs121908117)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000323773 SCV000329899 pathogenic not provided 2016-02-26 criteria provided, single submitter clinical testing The D18N variant in the TREX1 gene has been reported multiple times in individuals with familial chilblain lupus and Aicardi-Goutieres syndrome. Reported individuals did not have a second identifiable TREX1 pathogenic variant (Lee-Kirsch et al., 2007; Haaxma et al., 2010; Yamashiro et al., 2013; Abe et al., 2013). The D18N variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The D18N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs within the exonuclease 1 domain, a region that is conserved across species and is critical for catalytic activity. Functional studies indicate that D18N forms heterodimers with wild type that are deficient at degrading double-stranded DNA and inhibit double-stranded DNA degradation activity of the TREX1 wild type enzyme, explaining the dominant phenotype seen with the D18N variant (Lehtinen et al., 2008; Lee-Kirsch et al., 2007). We interpret D18N as a pathogenic variant.
Invitae RCV000819829 SCV000960511 pathogenic Aicardi Goutieres syndrome 1; Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations; Chilblain Lupus 2019-02-04 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 18 of the TREX1 protein (p.Asp18Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in an individual affected with Aicardi-Goutieres syndrome (PMID: 20799324), and has been shown to segregate with chilblain lupus in several families (PMID: 17440703, 23989343, 22829693). ClinVar contains an entry for this variant (Variation ID: 4185). Experimental studies have shown that this missense change impairs enzyme activity with a dominant negative effect, and causes lupus-like inflammatory disease in knock-in mice (PMID: 17440703, 18805785, 25848017, 20871604). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000004404 SCV000024576 pathogenic Chilblain lupus 1 2011-09-16 no assertion criteria provided literature only
OMIM RCV000004405 SCV000024577 pathogenic Aicardi Goutieres syndrome 1, autosomal dominant 2011-09-16 no assertion criteria provided literature only
GeneReviews RCV000114329 SCV000147896 pathogenic Aicardi Goutieres syndrome 1 2014-03-13 no assertion criteria provided literature only

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