rs72556554
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PP3PP5_Very_Strong
The NM_033629.6(TREX1):c.341G>A(p.Arg114His) variant causes a missense change. The variant allele was found at a frequency of 0.00051 in 1,613,086 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_033629.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| TREX1 | NM_033629.6 | c.341G>A | p.Arg114His | missense_variant | Exon 2 of 2 | ENST00000625293.3 | NP_338599.1 | |
| ATRIP | NM_130384.3 | c.*1442G>A | 3_prime_UTR_variant | Exon 13 of 13 | ENST00000320211.10 | NP_569055.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| TREX1 | ENST00000625293.3 | c.341G>A | p.Arg114His | missense_variant | Exon 2 of 2 | 6 | NM_033629.6 | ENSP00000486676.2 | ||
| ATRIP | ENST00000320211.10 | c.*1442G>A | 3_prime_UTR_variant | Exon 13 of 13 | 1 | NM_130384.3 | ENSP00000323099.3 |
Frequencies
GnomAD3 genomes 0.000302 AC: 46AN: 152154Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000208 AC: 52AN: 249654Hom.: 0 AF XY: 0.000185 AC XY: 25AN XY: 135264
GnomAD4 exome AF: 0.000531 AC: 776AN: 1460932Hom.: 0 Cov.: 31 AF XY: 0.000502 AC XY: 365AN XY: 726832
GnomAD4 genome 0.000302 AC: 46AN: 152154Hom.: 0 Cov.: 33 AF XY: 0.000283 AC XY: 21AN XY: 74316
ClinVar
Submissions by phenotype
not provided Pathogenic:10
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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) -
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PP3, PM3_very_strong, PS3 -
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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. -
TREX1: PM3:Very Strong, PM5, PM2:Supporting, PS3:Supporting -
Aicardi-Goutieres syndrome 1 Pathogenic:9
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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. -
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. -
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. -
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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. -
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 -
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TREX1-related disorder Pathogenic:2
This variant, also referred to as c.341G>A (p.Arg114His), has been previously reported as a compound heterozygous and homozygous change in patients with Aicardi-Goutières syndrome (PMID: 25604658, 16845398, 28089741). Functional studies demonstrated that the c.506G>A (p.Arg169His) variant results in a reduction of TREX1 endonuclease activity (PMID: 17293595). The c.506G>A (p.Arg169His) variant affects a highly conserved amino acid; however, in silico tools used to predict the effect of this variant on protein function yield discordant results. The c.506G>A (p.Arg169His) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.02% (61/281046), and is absent in the homozygous state, thus is presumed to be rare. Based on the available evidence, c.506G>A (p.Arg169His) is classified as Pathogenic. -
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. -
Chilblain lupus 1;C0796126:Aicardi-Goutieres syndrome 1;C1860518:Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations Pathogenic:2
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. -
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Inborn genetic diseases Pathogenic:1
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Systemic lupus erythematosus;C0024145:Chilblain lupus 1;C0796126:Aicardi-Goutieres syndrome 1;C1860518:Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations Pathogenic:1
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Chilblain lupus 1;C0796126:Aicardi-Goutieres syndrome 1;C0950123:Inborn genetic diseases Benign:1
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Systemic lupus erythematosus, susceptibility to Other:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at