ClinVar Miner

Submissions for variant NM_033629.6(TREX1):c.703dup (p.Val235fs) (rs1553820434)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000519088 SCV000617737 pathogenic not provided 2018-10-15 criteria provided, single submitter clinical testing The c.703dupG variant in the TREX1 gene has been reported previously in association with RVCL (DiFrancesco et al., 2015; Stam et al., 2016). The duplication causes a frameshift starting with codon Valine 235, changes this amino acid to a Glycine residue and creates a premature Stop codon at position 6 of the new reading frame, denoted p.Val235GlyfsX6. This variant is predicted to cause loss of normal protein function through protein truncation, as functional studies have shown that the c.703dupG variant results in the loss of a protein localization signal (Richards et al., 2007). The variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). In summary, we consider this variant to be pathogenic.
Invitae RCV000795266 SCV000934715 pathogenic Aicardi Goutieres syndrome 1; Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations; Chilblain Lupus 2018-12-19 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the TREX1 gene (p.Val235Glyfs*6). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 80 amino acids of the TREX1 protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in multiple families affected with retinal vasculopathy with cerebral leukodystrophy (PMID: 17660820, 27604306). ClinVar contains an entry for this variant (Variation ID: 449514). Experimental studies have shown that this frameshift change results in mislocalization of the TREX1 protein (PMID: 17660820). For these reasons, this variant has been classified as Pathogenic.

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