Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001381941 | SCV001580518 | pathogenic | Aicardi-Goutieres syndrome 1; Chilblain lupus 1; Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations | 2024-01-19 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Cys42*) in the TREX1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 273 amino acid(s) of the TREX1 protein. This variant is present in population databases (no rsID available, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with TREX1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1069943). This variant disrupts a region of the TREX1 protein in which other variant(s) (p.Cys99Metfs*3) have been determined to be pathogenic (PMID: 24183309, 25582466). 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. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV002282536 | SCV002570980 | likely pathogenic | Aicardi-Goutieres syndrome 1 | 2022-07-18 | criteria provided, single submitter | clinical testing | Variant summary: TREX1 c.123_125dupATG (p.Cys42X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic in ClinVar (e.g. c.703dup (p.Val235fs), c.212_213del (p.Val71fs)). The variant was absent in 251290 control chromosomes (gnomAD). To our knowledge, no occurrence of c.123_125dupATG in individuals affected with Aicardi Goutieres Syndrome 1 and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted an assessment for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. |