Submissions for variant NM_033629.6(TREX1):c.23dup (p.Pro10fs)

dbSNP: rs781731683

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001225792	SCV001398084	pathogenic	Aicardi-Goutieres syndrome 1; Chilblain lupus 1; Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations	2022-10-27	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Pro10Alafs*92) in the TREX1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 305 amino acid(s) of the TREX1 protein. This variant is present in population databases (rs781731683, gnomAD 0.02%). 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: 953494). 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.
New York Genome Center	RCV001291770	SCV001480387	likely pathogenic	Aicardi-Goutieres syndrome 1	2020-05-04	criteria provided, single submitter	clinical testing	The c.23dup (p.Pro10AlafsTer92) variant identified in the TREX1 gene is a single nucleotide duplication resulting in a frameshift of the protein at amino acid 10/315 (coding exon 2/2). This is predicted to lead to the premature termination of the protein approximately 92 amino acids downstream of the variant. This variant is absent from gnomAD (v3.0) suggesting it is not a common benign variant in the populations represented in this database. This variant is absent from ClinVar and to our current knowledge has not been reported in affected individuals in the literature, although frameshift and nonsense variants downstream have been reported in both autosomal recessive and autosomal dominant TREX1 associated disorders (PMID:25731743; PMID:25604658; PMID:31130681). Given its deleterious nature and absence in population databases, the c.23dup (p.Pro10AlafsTer92) variant identified in the TREX1 gene is reported here as Likely Pathogenic.
New York Genome Center	RCV001291771	SCV001480388	likely pathogenic	Chilblain lupus 1	2020-05-04	criteria provided, single submitter	clinical testing	The c.23dup (p.Pro10AlafsTer92) variant identified in the TREX1 gene is a single nucleotide duplication resulting in a frameshift of the protein at amino acid 10/315 (coding exon 2/2). This is predicted to lead to the premature termination of the protein approximately 92 amino acids downstream of the variant. This variant is absent from gnomAD (v3.0) suggesting it is not a common benign variant in the populations represented in this database. This variant is absent from ClinVar and to our current knowledge has not been reported in affected individuals in the literature, although frameshift and nonsense variants downstream have been reported in both autosomal recessive and autosomal dominant TREX1 associated disorders (PMID:25731743; PMID:25604658; PMID:31130681). Given its deleterious nature and absence in population databases, the c.23dup (p.Pro10AlafsTer92) variant identified in the TREX1 gene is reported here as Likely Pathogenic.
GeneDx	RCV002462846	SCV002757319	uncertain significance	not provided	2022-05-13	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation, as the last 305 amino acids are replaced with 91 different amino acids, and other loss-of-function variants have been reported downstream in HGMD; Has not been previously published as pathogenic or benign to our knowledge