Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Illumina Laboratory Services, |
RCV000779412 | SCV000916025 | likely pathogenic | TREX1-Related Disorders | 2018-11-22 | criteria provided, single submitter | clinical testing | The TREX1 c.635delC (p.Pro212HisfsTer65) variant results in a frameshift and is predicted to result in premature termination of the protein. This variant is located in the last exon of the gene and may escape nonsense-mediated decay. The p.Pro212HisfsTer65 variant has been reported in three studies in which it is found in a total of three individuals including two with a diagnosis of Aicardi-Goutieres syndrome (Ramantani et al. 2010; Rice et al. 2013) and one individual with systemic lupus erythematosus (Lee-Kirsch et al. 2007). One of the subjects with Aicardi-Goutieres was homozygous for the p.Pro212HisfsTer65 variant and the second was compound heterozygous for the variant and a missense variant. The p.Pro212HisfsTer65 variant has not been reported in the literature in association with retinal vasculopathy with cerebral leukodystrophy. The variant was absent from 1612 healthy control subjects and is reported at a frequency of 0.000015 in the European (non-Finnish) population from the Exome Aggregation Consortium but this is based on one allele, in a region of good sequencing coverage, so the variant is presumed to be rare. Functional studies showed that, when overexpressed in HeLa cells, GFP tagged TREX1 p.Pro212HisfsTer65, , alters the subcellular distribution of TREX1 and might therefore interfere with its function (Lee-Kirsch et al. 2007). Based on the collective evidence the p.Pro212HisfsTer65 variant is classified as likely pathogenic for TREX-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. |
| Invitae | RCV003768447 | SCV004569653 | pathogenic | Aicardi-Goutieres syndrome 1; Chilblain lupus 1; Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations | 2023-10-10 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Pro212Hisfs*65) in the TREX1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 103 amino acid(s) of the TREX1 protein. This variant is present in population databases (rs756664985, gnomAD 0.0009%). This premature translational stop signal has been observed in individuals with Aicardi-Goutieres syndrome (PMID: 20131292, 27943079). This variant is also known as P212fsX276. ClinVar contains an entry for this variant (Variation ID: 632418). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects TREX1 function (PMID: 17660818). For these reasons, this variant has been classified as Pathogenic. |