Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Soonchunhyang University Bucheon Hospital, |
RCV000490435 | SCV000267537 | likely pathogenic | Aicardi-Goutieres syndrome 1 | 2016-03-18 | criteria provided, single submitter | reference population | |
Ce |
RCV001093075 | SCV001249887 | pathogenic | not provided | 2018-05-01 | criteria provided, single submitter | clinical testing | |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000490435 | SCV002050828 | likely pathogenic | Aicardi-Goutieres syndrome 1 | 2021-12-08 | criteria provided, single submitter | clinical testing | Variant summary: TREX1 c.290G>A (p.Arg97His) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 249418 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in TREX1 causing Aicardi Goutieres Syndrome 1 (6e-05 vs ND), allowing no conclusion about variant significance. c.290G>A has been reported in the literature in individuals affected with Aicardi Goutieres Syndrome 1 (compound heterozygote, Olivieri_2013) or affected with cerebral lupus (homozygote, Ellyard_2014). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Ellyard_2014). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. |
Invitae | RCV001853392 | SCV002123015 | pathogenic | Aicardi-Goutieres syndrome 1; Chilblain lupus 1; Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations | 2024-01-29 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 97 of the TREX1 protein (p.Arg97His). This variant is present in population databases (rs200773268, gnomAD 0.02%). This missense change has been observed in individual(s) with autosomal recessive Aicardi-Goutieres syndrome and/or systemic lupus erythematosus (PMID: 3580372, 23918923, 25138095, 31130681, 34490615, 35803721). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 225498). 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. Experimental studies have shown that this missense change affects TREX1 function (PMID: 22367235, 25138095). For these reasons, this variant has been classified as Pathogenic. |
Revvity Omics, |
RCV001093075 | SCV003823461 | uncertain significance | not provided | 2020-10-26 | criteria provided, single submitter | clinical testing |