Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Illumina Laboratory Services, |
RCV000779411 | SCV000916024 | uncertain significance | Aicardi-Goutieres syndrome 1 | 2018-11-13 | criteria provided, single submitter | clinical testing | The TREX1 c.-26-1G>A variant occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. It was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018) and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score for this variant, it could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene and cDNA change. No publications were found based on this search. Due to the potential impact of splice acceptor variants and the lack of clarifying evidence, this variant is classified as a variant of uncertain significance but suspicious for pathogenicity for Aicardi-Goutieres Syndrome. |
Genomic Research Center, |
RCV000785138 | SCV000923700 | uncertain significance | TREX1-related disorder | 2023-10-09 | criteria provided, single submitter | clinical testing | |
Gene |
RCV003320742 | SCV004025585 | likely pathogenic | not provided | 2024-03-19 | criteria provided, single submitter | clinical testing | Observed with additional TREX1 variant(s) in patients with AicardiGoutieres syndrome, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (PMID: 35551623); Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: Oh2022[CaseReport], 37556020, 29159939, 35551623, 35532072) |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV003330948 | SCV004038361 | uncertain significance | not specified | 2023-08-07 | criteria provided, single submitter | clinical testing | Variant summary: TREX1 c.-26-1G>A alters a conserved nucleotide located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Three predict the variant weakens the canonical 3' splicing acceptor site. One predict the variant abolishes the canonical 3' splicing acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 7.6e-05 in 249970 control chromosomes. As the prevalence of Aicardi Goutieres Syndrome 1 attributed to TREX1 gene is unknown, this frequency does not allow conclusions about variant significance. c.-26-1G>A has been reported in the literature as a heterozygous genotype in an individual reportedly affected with Juvenile-onset systemic lupus erythematosus (jSLE) (example, Charras_2023) and annotated in a different transcript (NM_016381.5) as a missense variant of uncertain significance (c.139G>A, p.Gly47Ser) in compound heterozygosity with a different TREX1 variant (c.358_360dup, p.Asp120dup) in an individual with developmental delay and other clinical findings (example, Xiao_2018). These reports do not provide unequivocal conclusions about association of the variant with Aicardi Goutieres Syndrome 1. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 35532072, 29159939). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified the variant as pathogenic, one submitter classified the variant as benign, and a third submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. |
Prevention |
RCV000785138 | SCV005360764 | uncertain significance | TREX1-related disorder | 2024-08-28 | no assertion criteria provided | clinical testing | The TREX1 c.-26-1G>A variant is located in the 5' untranslated region. Using the canonical transcript (NM_033629) this variant is located upstream of the start codon (c.-26-1G>A) and is predicted to weaken a cryptic splice site based on available splicing prediction programs (Alamut Visual v1.6.1). However, the use of computer prediction programs is not equivalent to functional evidence. This variant has been reported in an individual undergoing sequencing for juvenile-onset systemic lupus erythematosus (described as "rs749323787", Charras et al. 2023. PubMed ID: 35532072). This variant is reported in 0.036% of alleles in individuals of South Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. |