Submissions for variant NM_033629.6(TREX1):c.58dup (p.Glu20fs)

dbSNP: rs78300695

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000114330	SCV000484428	pathogenic	Aicardi-Goutieres syndrome 1	2015-05-05	criteria provided, single submitter	clinical testing	This heterozygous duplication variant is predicted to create a substitution of a glutamic acid to a glycine at position 75 and cause a frameshift and premature truncation 82 amino acids downstream, NP_057465.1(TREX1): p.(Glu75Glyfs*82). This change is predicted to be disease-causing by in-silico models and is novel. It was identified in a patient with clinical features of AGS, and a second truncating mutation in trans.
Invitae	RCV001384732	SCV001584366	pathogenic	Aicardi-Goutieres syndrome 1; Chilblain lupus 1; Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations	2023-12-30	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu20Glyfs*82) in the TREX1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 295 amino acid(s) of the TREX1 protein. This variant is present in population databases (rs748398051, gnomAD 0.1%). This premature translational stop signal has been observed in individual(s) with autosomal recessive Aicardi-Goutieres syndrome and neurological features (PMID: 16845398, 25604658). This variant is also known as 58_59insG (E20fs). ClinVar contains an entry for this variant (Variation ID: 126390). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts a region of the TREX1 protein in which other variant(s) (p.Arg164*) have been determined to be pathogenic (PMID: 16845398, 25604658). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV001731376	SCV001984797	pathogenic	TREX1-Related Disorders	2020-10-28	criteria provided, single submitter	clinical testing	This frameshift variant is found in the only exon of TREX1, and frameshift variants located downstream of this variant have been reported as disease-causing variants in the Human Gene Mutation Database (PMID: 24183309, 20301648). This variant has been previously reported as a compound heterozygous and a homozygous change in patients with Aicardi-Goutieres syndrome (PMID: 16845398, 26182405, 28832562, 29453417). It is present in the heterozygous state in the gnomAD population database at a frequency of .013% (32/251392) and thus is presumed to be rare. Based on the available evidence, the c.28dup (p.Glu10GlyfsTer82) variant is classified as Pathogenic.
Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences	RCV000114330	SCV001994861	pathogenic	Aicardi-Goutieres syndrome 1		criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV003137626	SCV003823657	pathogenic	not provided	2023-12-25	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000114330	SCV003922196	pathogenic	Aicardi-Goutieres syndrome 1	2023-05-02	criteria provided, single submitter	curation	The homozygous p.Glu20GlyfsTer82 variant in TREX1 was identified by our study in one individual with Aicardi Goutieres syndrome. The p.Glu20GlyfsTer82 variant in TREX1 has been previously reported in 12 unrelated individuals with Aicardi Goutieres syndrome 1 (PMID: 26938784, PMID: 33235754, PMID: 25604658, PMID: 16845398) but has been identified in 0.1% (32/30616) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs770193197). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. Of these 12 previously reported unrelated individuals (PMID: 26938784, PMID: 33235754, PMID: 25604658, PMID: 16845398), 7 were homozygotes (PMID: 16845398, PMID: 25604658), 1 was a compound heterozygote who carried a likely pathogenic variant in trans (PMID: 26938784, ClinVar ID: 369666), and 2 were compound heterozygotes who carried pathogenic or likely pathogenic variants in unknown phase (PMID: 33235754, ClinVar Variation ID: 126384, 126392), which increases the likelihood that the p.Glu20GlyfsTer82 variant is pathogenic. This variant has also been reported in ClinVar (Variation ID: 126390) and has been interpreted as pathogenic by Invitae, Rady Children's Institute for Genomic Medicine, Murdoch Childrens Research Institute Victorian Clinical Genetics Services, GeneReviews, and Sanjay Gandhi Post Graduate Institute of Medical Sciences Department of Medical Genetics. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 20 and leads to a premature termination codon 82 amino acids downstream. This termination codon occurs within the last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. Loss of function of the TREX1 gene is an established disease mechanism in autosomal recessive Aicardi Goutieres syndrome 1. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Aicardi Goutieres syndrome 1. ACMG/AMP Criteria applied: PVS1_Strong, PM3_Strong (Richards 2015).
Lifecell International Pvt. Ltd	RCV000114330	SCV003924379	pathogenic	Aicardi-Goutieres syndrome 1		criteria provided, single submitter	clinical testing	A Homozygote Frameshift variant c.26_27insG in Exon 2 of the TREX1 gene that results in the amino acid substitution p.Glu10fs*82 was identified. The observed variant has a minor allele frequency of 0.00013% in gnomAD exomes and novel in gnomAD genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic [Variation ID: 126390]. The observed variant has been previously reported as a compound heterozygous and a homozygous mutation in patients with Aicardi-Goutieres syndrome (Dillon OJ, et.al., 2018). For these reasons, this variant has been classified as Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003905089	SCV004725028	pathogenic	TREX1-related condition	2023-12-24	criteria provided, single submitter	clinical testing	The TREX1 c.58dupG variant is predicted to result in a frameshift and premature protein termination (p.Glu20Glyfs*82). This variant (aka c.223dup, p.Glu75Glyfs*82) has been reported in the homozygous or compound heterozygous states in multiple individuals with Aicardi-Goutières syndrome (Crow et al. 2006. PubMed ID: 16845398; Crow et al. 2015. PubMed ID: 25604658. Table S1; Lim et al. 2015. PubMed ID: 26182405. Supplementary file 1; Dillon et al. 2018. PubMed ID: 29453417. Table S1). This variant is reported in 0.10% of alleles in individuals of South Asian descent in gnomAD. Frameshift variants in TREX1 are expected to be pathogenic. This variant is interpreted as pathogenic.
GeneReviews	RCV000114330	SCV000147897	pathogenic	Aicardi-Goutieres syndrome 1	2014-03-13	no assertion criteria provided	literature only