Submissions for variant NM_033629.6(TREX1):c.290G>A (p.Arg97His)

gnomAD frequency: 0.00003  dbSNP: rs200773268

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	RCV000490435	SCV000267537	likely pathogenic	Aicardi-Goutieres syndrome 1	2016-03-18	criteria provided, single submitter	reference population
CeGaT Center for Human Genetics Tuebingen	RCV001093075	SCV001249887	pathogenic	not provided	2018-05-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000490435	SCV002050828	pathogenic	Aicardi-Goutieres syndrome 1	2024-06-24	criteria provided, single submitter	clinical testing	Variant summary: TREX1 c.290G>A (p.Arg97His) results in a non-conservative amino acid change located in the Exonuclease domain (IPR013520) of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 249418 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in TREX1 causing Aicardi Goutieres Syndrome 1, allowing no conclusion about variant significance. c.290G>A has been reported in the literature in multiple homozygous- and compound heterozygous individuals affected with Aicardi Goutieres Syndrome 1 (e.g. Ellyard_2014, Olivieri_2013, van der Ven_2021, Kuang_2022). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence, demonstrating decreased enzyme activity in an in vitro expression system and lymphocyte function changes in patient derived cells (Olivieri_2013, Pulliero_2012). The following publications have been ascertained in the context of this evaluation (PMID: 31589614, 25138095, 23918923, 22367235, 34490615, 35803721). ClinVar contains an entry for this variant (Variation ID: 225498). Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001853392	SCV002123015	pathogenic	Aicardi-Goutieres syndrome 1; Chilblain lupus 1; Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations	2024-01-29	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 97 of the TREX1 protein (p.Arg97His). This variant is present in population databases (rs200773268, gnomAD 0.02%). This missense change has been observed in individual(s) with autosomal recessive Aicardi-Goutieres syndrome and/or systemic lupus erythematosus (PMID: 3580372, 23918923, 25138095, 31130681, 34490615, 35803721). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 225498). 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: 22367235, 25138095). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV001093075	SCV003823461	uncertain significance	not provided	2020-10-26	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000490435	SCV005400308	likely pathogenic	Aicardi-Goutieres syndrome 1	2023-12-20	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely 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 generally associated with recessive disease, while dominant negative variants are associated with dominant disease (OMIM, PMID: 21937424). However, loss of function is the mechanism of disease associated with heterozygous C-terminal frameshift variants identified in individuals with retinal vasculopathy with cerebral leukodystrophy (OMIM). (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 (16 heterozygotes, 0 homozygotes). (SP) 0309 - Multiple alternative amino acid changes at the same position have been observed in gnomAD (v3) (highest allele count: 2 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. However, two alternative changes with higher Grantham scores, p.(Arg97Ser) and p.(Arg97Cys), have been reported once each as a VUS (ClinVar). (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported as a VUS and as likely pathogenic and pathogenic, with limited clinical information provided (ClinVar, LOVD). However, it has also been observed in two compound heterozygous individuals with Aicardi-Goutières syndrome (PMID: 35803721, PMID: 31130681), a homozygous individual with cerebral systemic lupus erthematosus (PMID: 25138095) and another homozygous individual with severe global developmental delay, leukodystrophy and cerebellar hypoplasia (PMID: 31056085). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Transfected cells demonstrated a 20-fold reduction in exonuclease activity compared to wildtype cells (PMID: 25138095). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign