Submissions for variant NM_033629.6(TREX1):c.868_885del (p.Pro290_Ala295del)

dbSNP: rs79318303

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000805420	SCV000945376	pathogenic	Aicardi-Goutieres syndrome 1; Chilblain lupus 1; Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations	2023-12-22	criteria provided, single submitter	clinical testing	This variant, c.868_885del, results in the deletion of 6 amino acid(s) of the TREX1 protein (p.Pro290_Ala295del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs776342560, gnomAD 0.03%). This variant has been observed in individual(s) with Aicardi Goutieres syndrome (PMID: 20131292, 24300241, 25582466, 28750028). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as c.859_876del18; p.Leu287_Gly292del. ClinVar contains an entry for this variant (Variation ID: 126393). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. For these reasons, this variant has been classified as Pathogenic.
Suma Genomics	RCV000114334	SCV001837624	likely pathogenic	Aicardi-Goutieres syndrome 1		criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV002262706	SCV002011144	pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
3billion	RCV000114334	SCV002521699	likely pathogenic	Aicardi-Goutieres syndrome 1	2022-05-22	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.006%). Inframe deletion located in a nonrepeat region: predicted to change the length of the protein and disrupt normal protein function. The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000126393 / PMID: 17846997). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
CeGaT Center for Human Genetics Tuebingen	RCV002262706	SCV002544809	likely pathogenic	not provided	2022-07-01	criteria provided, single submitter	clinical testing	TREX1: PM3:Strong, PM2, PM4
Fulgent Genetics, Fulgent Genetics	RCV002490761	SCV002797654	likely pathogenic	Aicardi-Goutieres syndrome 1; Chilblain lupus 1; Systemic lupus erythematosus; Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations	2022-03-29	criteria provided, single submitter	clinical testing
Pediatrics, Sichuan Provincial Hospital For Women And Children	RCV003153362	SCV003842196	pathogenic	Aicardi Goutieres syndrome		criteria provided, single submitter	research	The proband, male, 3 months old, was found to have widened lateral ventricles during the fetal period, had feeding difficulties after birth, did not gain weight, and was found to have microcephaly and nystagmus by physical examination. MRI revealed calcification in the skull, thrombocytopenia in blood routine, and elevated aminotransferase in liver function. During the follow-up observation period of more than 1 year, the patient developed recurrent chilblains and pneumonia and global development delay.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000114334	SCV003928643	pathogenic	Aicardi-Goutieres syndrome 1	2023-04-27	criteria provided, single submitter	clinical testing	Variant summary: TREX1 c.868_885del18 (p.Pro290_Ala295del), also referred to as c.859_876del18 (p.Leu287_Gly292del), results in an in-frame deletion that is predicted to remove six amino acids from the encoded protein. The variant allele was found at a frequency of 6.4e-05 in 251074 control chromosomes (gnomAD). c.868_885del18 has been reported in the literature in multiple individuals affected with Aicardi Goutieres Syndrome 1, including homozygous patients from at least three different families (e.g. Rice_2007, Ramantani_2010, Abe_2014, Crow_2015). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 24300241, 25604658, 20131292, 17846997). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all laboratories classified the variant as either pathogenic (n=2) or likely pathogenic (n=3). Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity	RCV002262706	SCV004238770	likely pathogenic	not provided	2023-04-07	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003935090	SCV004753932	pathogenic	TREX1-related condition	2024-02-19	criteria provided, single submitter	clinical testing	The TREX1 c.868_885del18 variant is predicted to result in an in-frame deletion (p.Pro290_Ala295del). This variant has been reported as causative in several patients with autosomal recessive Aicardi-Goutières syndrome (described as p.Pro290_Ala295del, Abe et al. 2014. PubMed ID: 24300241; Rice et al. 2007. PubMed ID: 17846997; Tise et al. 2021. PubMed ID: 33683010). This variant is reported in 0.026% of alleles in individuals of South Asian descent in gnomAD. This variant is interpreted as pathogenic.
GeneReviews	RCV000114334	SCV000147903	not provided	Aicardi-Goutieres syndrome 1		no assertion provided	literature only