ClinVar Miner

Submissions for variant NM_033629.6(TREX1):c.341G>A (p.Arg114His) (rs72556554)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Baylor Genetics RCV000850611 SCV000992844 pathogenic Aicardi Goutieres syndrome 1; Chilblain lupus 1; Vasculopathy, retinal, with cerebral leukodystrophy 2017-12-31 criteria provided, single submitter clinical testing
GeneDx RCV000256102 SCV000321979 pathogenic not provided 2018-06-21 criteria provided, single submitter clinical testing The R114H pathogenic variant in the TREX1 gene has been reported previously in the homozygous state, and in the heterozygous state in the presence of a second TREX1 variant, in multiple unrelated patients with Aicardi-Goutieres syndrome (Crow et al., 2006). The R114H variant is observed in 45/125740 (0.036%) alleles from individuals of non-Finnish European background, in large population cohorts and no individuals were reported to be homozygous (Lek et al., 2016). The R114H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Functional studies have demonstrated 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). We interpret R114H as a pathogenic variant.
GeneReviews RCV000004396 SCV000147889 pathogenic Aicardi Goutieres syndrome 1 2014-03-13 no assertion criteria provided literature only
Illumina Clinical Services Laboratory,Illumina RCV000388382 SCV000445023 benign Vasculopathy, retinal, with cerebral leukodystrophy 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,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.
Invitae RCV000691933 SCV000819732 pathogenic Aicardi Goutieres syndrome 1; Vasculopathy, retinal, with cerebral leukodystrophy; Chilblain Lupus 2018-12-26 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 114 of the TREX1 protein (p.Arg114His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs72556554, ExAC 0.02%). This variant has been observed in numerous individuals and families affected with Aicardi-Goutieres syndrome (PMID: 16845398, 28089741). This variant has also been observed in other TREX1-related conditions (PMID: 21270825, 27391121, 23881107). ClinVar contains an entry for this variant (Variation ID: 4179). Experimental studies have shown that this missense change disrupts the exonuclease activity of TREX1 (PMID: 16845398, 18805785, 17293595). For these reasons, this variant has been classified as Pathogenic.
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.
Laboratory for Molecular Medicine,Partners HealthCare 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.
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

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