Submissions for variant NM_033629.6(TREX1):c.144dup (p.Thr49fs)

dbSNP: rs748914604

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000512682	SCV000334385	pathogenic	not provided	2015-08-14	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000512682	SCV000609101	pathogenic	not provided	2021-03-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000512682	SCV001167817	likely pathogenic	not provided	2018-11-28	criteria provided, single submitter	clinical testing	The c.144dupC variant in the TREX1 gene has been reported previously in association with Aicardi-Goutieres syndrome (Crow et al., 2015). The c.144dupC variant causes a frameshift starting with codon Threonine 49, changes this amino acid to a Histidine residue, and creates a premature Stop codon at position 53 of the new reading frame, denoted p.Thr49HisfsX53. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.144dupC variant is not observed in large population cohorts (Lek et al., 2016). We interpret c.144dupC as a likely pathogenic variant.
Centogene AG - the Rare Disease Company	RCV001251136	SCV001426635	pathogenic	Aicardi-Goutieres syndrome 1		criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000512682	SCV002020289	likely pathogenic	not provided	2021-09-24	criteria provided, single submitter	clinical testing
Invitae	RCV001859564	SCV002233165	pathogenic	Aicardi-Goutieres syndrome 1; Chilblain lupus 1; Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Thr49Hisfs*53) in the TREX1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 266 amino acid(s) of the TREX1 protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with clinical features of autosomal recessive Aicardi-Goutieres syndrome (PMID: 25604658). ClinVar contains an entry for this variant (Variation ID: 282766). This variant disrupts a region of the TREX1 protein in which other variant(s) (p.Arg164*) have been determined to be pathogenic (PMID: 16845398, 25604658). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin	RCV001251136	SCV002574826	pathogenic	Aicardi-Goutieres syndrome 1	2022-09-22	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002494829	SCV002796178	likely pathogenic	Aicardi-Goutieres syndrome 1; Chilblain lupus 1; Systemic lupus erythematosus; Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations	2022-02-07	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001251136	SCV003922197	likely pathogenic	Aicardi-Goutieres syndrome 1	2023-05-02	criteria provided, single submitter	curation	The homozygous p.Thr49HisfsTer53 variant in TREX1 was identified by our study in one individual with Aicardi Goutieres syndrome. The p.Thr49HisfsTer53 variant in TREX1 has been previously reported in 4 unrelated individuals with Aicardi Goutieres syndrome 1 (PMID: 25604658, PMID: 33099809, PMID: 32860008) but has been identified in 0.007% (1/15274) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs748914604). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. Of these 4 previously reported unrelated individuals (PMID: 25604658, PMID: 33099809, PMID: 32860008), 2 were homozygotes, which increases the likelihood that the p.Thr49HisfsTer53 variant is pathogenic. This variant has also been reported in ClinVar (Variation ID: 282766) and has been interpreted as pathogenic or likely pathogenic by multiple submitters. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 49 and leads to a premature termination codon 53 amino acids downstream. This termination codon occurs within the last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. Loss of function of the TREX1 gene is an established disease mechanism in autosomal recessive Aicardi Goutieres syndrome 1. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive Aicardi Goutieres syndrome 1. ACMG/AMP Criteria applied: PVS1_Strong, PM2_Supporting, PM3 (Richards 2015).
PreventionGenetics, part of Exact Sciences	RCV003909938	SCV004726361	pathogenic	TREX1-related condition	2024-01-12	criteria provided, single submitter	clinical testing	The TREX1 c.144dupC variant is predicted to result in a frameshift and premature protein termination (p.Thr49Hisfs*53). This variant has been reported in the homozygous state or with a second TREX1 variant in individuals with Aicardi-Goutières syndrome (see, for example, Crow et al 2015. PubMed ID: 25604658; Table S3, Rice et al. 2016. PubMed ID: 27943079; described as c.137_138insC, Wu et al. 2021. PubMed ID: 33996686). This variant is reported in 0.011% of alleles in individuals of Latino descent in gnomAD; however, the quality of this data is questionable and should be treated with caution. Frameshift variants in TREX1 are expected to be pathogenic. This variant is interpreted as pathogenic.