Submissions for variant NM_033629.6(TREX1):c.341G>A (p.Arg114His)

gnomAD frequency: 0.00030  dbSNP: rs72556554

Total submissions: 26

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000004396	SCV000245673	pathogenic	Aicardi-Goutieres syndrome 1	2015-02-10	criteria provided, single submitter	clinical testing	The p.Arg114His variant in TREX1 has been reported in at least 23 homozygous and 11 compound heterozygous individuals with Aicardi-Goutieres syndrome (Crow 2006, Crow 2015). This variant has been identified in 0.06% (5/8600) of European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs72556554). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In vitro studies suggest that the p.Arg114His variant may lead to a reduction in TREX1 endonuclease activity (de Silva 2007 Lehtinen 2008); however, these types of assays may not accurately reflect biological function. In summary, this variant meets our criteria to be classified as pathogenic for Aicardi-Goutieres syndrome in an autosomal recessive manner.
GeneDx	RCV000256102	SCV000321979	pathogenic	not provided	2022-03-24	criteria provided, single submitter	clinical testing	Published functional studies demonstrate the mutant homozygous and compound heterozygous R114H protein has dysfunctional exonuclease activity when compared to the wild type protein (de Silva et al., 2007; Orebaugh et al., 2011; Lehtinen et al., 2008); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 17293595, 18805785, 18045533, 16845398, 23881107, 27391121, 26182405, 28089741, 29239743, 17660818, 17846997, 20131292, 31980526, 34426522, 30219631, 33504652, 21937424, 21270825)
Illumina Laboratory Services, Illumina	RCV000388382	SCV000445023	benign	Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.
Illumina Laboratory Services, Illumina	RCV000004396	SCV000445024	pathogenic	Aicardi-Goutieres syndrome 1	2017-04-27	criteria provided, single submitter	clinical testing	The TREX1 c.341G>A (p.Arg114His) missense variant, also referred to as c.506G>A (p.Arg169His), has been identified in 25 individuals with Aicardi-Goutieres syndrome, including in a homozygous state in 20 individuals and in a compound heterozygous state in five individuals (Crow et al. 2006; Rice et al. 2007). Control data are unavailable for this variant, which is reported at a frequency of 0.00068 in the African-American population of the Exome Sequencing Project. Expression analysis revealed no detectable TREX1 activity in any of the individuals with p.Arg114His (Crow et al. 2006). A study by Orebaugh et al. (2011) found that compound heterozygous individuals for the p.Arg114His variant and the p.Asp201ins variant displayed reduced enzyme activity, but activity was not as diminished as in those homozygous for the p.Arg114His variant. The same study also implicated heterozygous TREX1 variants (in particular p.Arg114His) as a risk allele for systemic lupus erythematosus, which was confirmed by Lehtinen et al. (2008). Based on the collective evidence, the p.Arg114His variant is classified as pathogenic for Aicardi-Goutieres syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000004396	SCV000538069	pathogenic	Aicardi-Goutieres syndrome 1	2015-07-10	criteria provided, single submitter	clinical testing	The c.341G>A (p.Arg114His) missense variant in the TREX1 gene has been previously reported in affected individuals and is known to represent ~50% of the AGS-associated genotypes (Orebaugh et al. 2011). This variant results in a 50-fold reduction in enzyme activity and is localized to the dimer interface of the protein and is important for dimer stabilization (de Silva et al. 2007). This p.Arg114His variant has been reported at very low frequency in the control population databases (Exome Sequencing Project [ESP], and ExAc, and not reported in 1000 Genomes) and has been predicted as deleterious by computational algorithms. In addition, it has been described as pathogenic in ClinVar (OMIM and GeneReviews). Therefore, this collective evidence supports the classification of the c.341G>A (p.Arg114His) as a heterozygous pathogenic variant for Aicardi-Goutieres syndrome 1.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000850611	SCV000819732	pathogenic	Aicardi-Goutieres syndrome 1; Chilblain lupus 1; Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 114 of the TREX1 protein (p.Arg114His). This variant is present in population databases (rs72556554, gnomAD 0.04%). This missense change has been observed in individuals with Aicardi-Goutieres syndrome (PMID: 16845398, 28089741). ClinVar contains an entry for this variant (Variation ID: 4179). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects TREX1 function (PMID: 16845398, 17293595, 18805785). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000850611	SCV000992844	pathogenic	Aicardi-Goutieres syndrome 1; Chilblain lupus 1; Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations	2017-12-31	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000256102	SCV001146239	pathogenic	not provided	2018-10-04	criteria provided, single submitter	clinical testing	The best available variant frequency is uninformative because it is below the disease allele frequency. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Damaging to protein function(s) relevant to disease mechanism. Moderate co-segregation with disease. However, available data lack unaffected family members.
CeGaT Center for Human Genetics Tuebingen	RCV000256102	SCV001249888	pathogenic	not provided	2024-01-01	criteria provided, single submitter	clinical testing	TREX1: PM3:Very Strong, PM5, PM2:Supporting, PS3:Supporting
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000004396	SCV001251826	likely pathogenic	Aicardi-Goutieres syndrome 1	2020-05-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001266495	SCV001444670	pathogenic	Inborn genetic diseases	2018-05-16	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000004396	SCV001527277	pathogenic	Aicardi-Goutieres syndrome 1	2024-01-09	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000256102	SCV002022421	pathogenic	not provided	2022-01-19	criteria provided, single submitter	clinical testing
AiLife Diagnostics, AiLife Diagnostics	RCV000256102	SCV002502628	pathogenic	not provided	2022-03-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000004396	SCV003934066	pathogenic	Aicardi-Goutieres syndrome 1	2023-05-18	criteria provided, single submitter	clinical testing	Variant summary: TREX1 c.341G>A (p.Arg114His) results in a non-conservative amino acid change located in the Exonuclease, RNase T/DNA polymerase III (IPR013520) of the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00021 in 249654 control chromosomes. c.341G>A has been reported in the literature in multiple individuals affected with Aicardi Goutieres Syndrome 1 (example: Rice_2007). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (example: Lehtinen_2008). The following publications have been ascertained in the context of this evaluation (PMID: 18805785, 17846997). 15 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, classifying the variant as pathogenic (n=10), likely pathogenic (n=1), or likely benign (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000004396	SCV005399140	pathogenic	Aicardi-Goutieres syndrome 1	2022-09-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with TREX1-related conditions. Loss of function is associated with recessive disease while dominant negative variants are associated with dominant disease (OMIM, PMID: 21937424). (I) 0108 - This gene is known to be associated with both recessive and dominant disease. Aicardi-Goutieres syndrome is predominantly a recessive condition, however there have been rare cases of a dominant form of the disease reported (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (61 heterozygotes, 0 homozygotes). (SP) 0309 - Multiple alternative amino acid changes at the same position have been observed in gnomAD (v2) (highest allele count: 67 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated DnaQ-like 3’-5’ exonuclease domain (NCBI). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic and likely pathogenic by multiple clinical laboratories in ClinVar and observed as homozygous and compound heterozygous in individuals with Aicardi-Goutieres syndrome (ClinVar, PMIDs: 29859840, 31130681). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Variant homodimers displayed a 23-fold reduction in enzyme activity (PMID: 21937424). (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Mayo Clinic Laboratories, Mayo Clinic	RCV000256102	SCV005413584	pathogenic	not provided	2024-08-01	criteria provided, single submitter	clinical testing	PP3, PM3_very_strong, PS3
OMIM	RCV000004396	SCV000024568	pathogenic	Aicardi-Goutieres syndrome 1	2007-10-01	no assertion criteria provided	literature only
OMIM	RCV000004397	SCV000024569	risk factor	Systemic lupus erythematosus, susceptibility to	2007-10-01	no assertion criteria provided	literature only
GeneReviews	RCV000004396	SCV000147889	pathogenic	Aicardi-Goutieres syndrome 1	2014-03-13	no assertion criteria provided	literature only
Clinical Genetics, Academic Medical Center	RCV000256102	SCV002034593	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000256102	SCV002035102	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000256102	SCV002035288	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000256102	SCV002037949	pathogenic	not provided		no assertion criteria provided	clinical testing
Institute of Neurology, Charite University of Medicine	RCV002281693	SCV002571718	likely benign	Aicardi-Goutieres syndrome 1; Chilblain lupus 1; Inborn genetic diseases	2022-06-04	no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV004540989	SCV004774370	pathogenic	TREX1-related disorder	2023-11-09	no assertion criteria provided	clinical testing	The TREX1 c.341G>A variant is predicted to result in the amino acid substitution p.Arg114His. This variant is also reported as c.341G>A, p.Arg114His in an alternative transcript (NM_ 033629.4). This variant has been reported in the compound heterozygous and homozygous state in many individuals with Aicardi-Goutieres syndrome (Crow et al. 2006. PubMed ID: 16845398; Rice et al. 2007. PubMed ID: 17846997; Tumienė et al. 2017. PubMed ID: 28089741; Crow et al. 2015. PubMed ID: 25604658). The c.506G>A variant is the most common recessive, pathogenic TREX1 variant and has been functionally characterized to have reduced enzyme activity (Crow et al. 2015. PubMed ID: 25604658; Orebaugh et al. 2011. PubMed ID: 21937424). This variant is reported in 0.037% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-48508395-G-A). In summary, the c.506G>A variant is pathogenic for autosomal recessive TREX1-related disorders.