ClinVar Genomic variation as it relates to human health

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.

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.

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).

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.

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0104 - Dominant Negative is a mechanism of disease for this gene, where heterodimers with wildtype protein result in impaired function (OMIM). (N) 0108 - This gene is known to be associated with both recessive and dominant disease. Aicardi-Goutieres syndrome is predominantly a recessive condition, however there have been rare cases of a dominant form of the disease reported (OMIM). (N) 0204 - Variant is predicted to result in a truncated protein with more than 1/3 of the protein affected (exon 2 of 2). (P) 0252 - Variant is homozygous (testing performed by Perkin Elmer). (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (32 heterozygotes, 0 homozygotes). (P) 0701 - Comparable variants have very strong previous evidence for pathogenicity. Many pathogenic truncating variants have been reported downstream (ClinVar). (P) 0801 – Very strong previous evidence of pathogenicity in unrelated individuals. This variant has been previously reported in patients with Aicardi-Goutieres syndrome (ClinVar, PMID: 25604658). (P) 1205 - Variant is biallelic. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign

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.