Submissions for variant NM_033629.6(TREX1):c.797A>G (p.Glu266Gly)

gnomAD frequency: 0.00175  dbSNP: rs55999987

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000431072	SCV000114288	uncertain significance	not provided	2013-09-24	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000262094	SCV000445035	likely benign	Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000300719	SCV000445036	likely benign	Aicardi Goutieres syndrome	2016-06-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000082325	SCV000490863	uncertain significance	not specified	2016-09-28	criteria provided, single submitter	clinical testing	The E266G variant has not been published in association with Aicardi-Goutieres syndrome. However, the E266G variant has been published in association with systemic lupus erythematosus (SLE) (Namjou et al., 2011; Lee-Kirsch et al., 2007). Namjou et al., reports identifying the E266G variant in 5 patients of African decent diagnosed with SLE but not in ethnically matched controls (Namjou et al., 2011). This variant was also identified identified in members of the cohort of European decent but also within ethnically matched controls (Namjou et al., 2011). The NHLBI Exome Sequencing Project reports E266G was observed in 33/8600 (0.38%) alleles from individuals of European background, and the 1000 Genomes Project Consortium reports E266G was observed in 1/978 (0.1%) alleles from individuals of South Asian background. The E266G variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is not conserved. In silico analysis predicts this variant likely does not alter the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000431072	SCV000510785	uncertain significance	not provided	2017-02-09	criteria provided, single submitter	clinical testing	Converted during submission to Uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001082165	SCV000765744	benign	Aicardi-Goutieres syndrome 1; Chilblain lupus 1; Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations	2025-02-03	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000431072	SCV000844510	uncertain significance	not provided	2018-04-23	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000431072	SCV002496827	likely benign	not provided	2025-03-01	criteria provided, single submitter	clinical testing	TREX1: BP4, BS2
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000082325	SCV004242526	uncertain significance	not specified	2025-03-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000082325	SCV005883284	uncertain significance	not specified	2024-12-17	criteria provided, single submitter	clinical testing	Variant summary: TREX1 c.797A>G (p.Glu266Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0017 in 251436 control chromosomes, predominantly at a frequency of 0.0029 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in TREX1 causing Aicardi-Goutieres Syndrome 1-AR (0.0017 vs 0.011), allowing no conclusion about variant significance. c.797A>G has been reported in the literature in two unspecified individuals without primary infomration (Dineiro_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Aicardi-Goutieres Syndrome 1-AR. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 32483926). ClinVar contains an entry for this variant (Variation ID: 96242). Based on the evidence outlined above, the variant was classified as uncertain significance.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV005394348	SCV006053114	likely benign	Aicardi-Goutieres syndrome 1; Chilblain lupus 1; Systemic lupus erythematosus; Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations	2020-06-01	criteria provided, single submitter	research
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000082325	SCV001927336	benign	not specified		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000431072	SCV002035847	likely benign	not provided		no assertion criteria provided	clinical testing
Institute of Neurology, Charite University of Medicine	RCV002281915	SCV002571720	likely benign	Aicardi-Goutieres syndrome 1; Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations	2022-06-04	no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV004732658	SCV005351960	likely benign	TREX1-related disorder	2024-08-09	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).