ClinVar Miner

Submissions for variant NM_033629.6(TREX1):c.294dup (p.Cys99fs) (rs760594164)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Soonchunhyang University Bucheon Hospital,Soonchunhyang University Medical Center RCV000490271 SCV000267538 pathogenic Aicardi Goutieres syndrome 1 2016-03-18 criteria provided, single submitter reference population
Illumina Clinical Services Laboratory,Illumina RCV000375716 SCV000445020 likely benign TREX1-Related Disorders 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000806372 SCV000946366 pathogenic Aicardi Goutieres syndrome 1; Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations; Chilblain Lupus 2019-12-04 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the TREX1 gene (p.Cys99Metfs*3). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 216 amino acids of the TREX1 protein. This variant is present in population databases (rs760594164, ExAC 0.1%). This variant has been observed in homozygous and compound heterozygous individuals affected with Aicardi Gouti res syndrome (PMID: 24183309, 25582466). It has also been observed in the heterozygous state in a family affected with retinal vasculopathy with cerebral leukodystrophy (RVCL); however, in that family a homozygous variant in the NOTCH3 gene was found to segregate with the disease (PMID: 23602593). This variant is also known as c.294dup and c.294_295insA in the literature. ClinVar contains an entry for this variant (Variation ID: 225499). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV001008124 SCV001167880 likely pathogenic not provided 2018-08-20 criteria provided, single submitter clinical testing The c.294dupA variant in the TREX1 gene has been reported previously in either the homozygous or compound heterozygous state in individuals with Aicardi-Goutieres syndrome (Rice et al., 2013; Ji et al., 2014). This variant causes a frameshift starting with codon Cysteine 99, changes this amino acid to a Methionine residue, and creates a premature Stop codon at position 3 of the new reading frame, denoted p.Cys99MetfsX3. The c.294dupA variant is predicted to cause loss of normal protein function through protein truncation. The c.294dupA variant is observed in 22/18,860 alleles (0.12%) from individuals of East Asian background, and 22/275,440 global alleles (0.008%), in large population cohorts (Lek et al., 2016). We interpret c.294dupA as a likely pathogenic variant.

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