ClinVar Miner

Submissions for variant NM_033629.6(TREX1):c.829A>T (p.Lys277Ter) (rs1553820518)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000644051 SCV000765740 likely pathogenic Aicardi Goutieres syndrome 1; Vasculopathy, retinal, with cerebral leukodystrophy; Chilblain lupus erythematosus 2017-09-29 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the TREX1 gene (p.Lys277*). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 38 amino acids of the TREX1 protein. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with TREX1-related disease. Different truncating variants downstream from this codon (c.850dupA, c.858dupG, 830_833dup) have been reported in multiple individuals affected with retinal vasculopathy with cerebral leukodystrophy (HERNS syndrome) (PMID: 17660820, 26691497). Experimental studies have shown that these truncated proteins retain exonuclease activity but lose normal perinuclear localization (PMID: 17660820). This suggests that the C-terminal sequence is critical for TREX1 protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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