Submissions for variant NM_033629.6(TREX1):c.667G>A (p.Ala223Thr)

gnomAD frequency: 0.00002  dbSNP: rs766785968

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000433529	SCV000521216	likely pathogenic	not provided	2016-12-01	criteria provided, single submitter	clinical testing	The A223T variant in the TREX1 gene has been reported in a patient with Aicardi-Goutieres syndrome with a second variant, however parental testing was not performed to determine whether the variants were in cis or trans (Abe et al., 2014). The A223T variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The A223T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals. The A223T variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
Baylor Genetics	RCV001330236	SCV001521859	uncertain significance	Aicardi-Goutieres syndrome 1	2020-06-09	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Invitae	RCV001340342	SCV001534148	uncertain significance	Aicardi-Goutieres syndrome 1; Chilblain lupus 1; Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations	2024-01-20	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 223 of the TREX1 protein (p.Ala223Thr). This variant is present in population databases (rs766785968, gnomAD 0.006%). This missense change has been observed in individuals with autosomal recessive Aicardi-Goutieres syndrome (PMID: 24300241, 34490982). ClinVar contains an entry for this variant (Variation ID: 381689). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
3billion	RCV001330236	SCV002012171	likely pathogenic	Aicardi-Goutieres syndrome 1	2021-10-02	criteria provided, single submitter	clinical testing	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with supporting evidence (ClinVar ID: VCV000194897.5, PS1_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000119, PM2). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
Revvity Omics, Revvity	RCV000433529	SCV004236930	uncertain significance	not provided	2023-11-22	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV001330236	SCV004806846	uncertain significance	Aicardi-Goutieres syndrome 1	2024-03-26	criteria provided, single submitter	clinical testing