Submissions for variant NM_033629.6(TREX1):c.914A>G (p.Tyr305Cys)

gnomAD frequency: 0.00012  dbSNP: rs370504038

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Center for Human Genetics Tuebingen	RCV000762114	SCV000892372	uncertain significance	not provided	2024-02-01	criteria provided, single submitter	clinical testing	TREX1: PS4:Supporting, BP4
Invitae	RCV001246998	SCV001420394	uncertain significance	Aicardi-Goutieres syndrome 1; Chilblain lupus 1; Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations	2024-01-23	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 305 of the TREX1 protein (p.Tyr305Cys). This variant is present in population databases (rs370504038, gnomAD 0.02%). This missense change has been observed in individual(s) with systemic lupus erythematosus or early-onset cerebrovascular disease (PMID: 17660818, 21270825, 23881107). ClinVar contains an entry for this variant (Variation ID: 624024). 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.
GeneDx	RCV000762114	SCV002549222	uncertain significance	not provided	2022-01-14	criteria provided, single submitter	clinical testing	Observed in the heterozygous state in individuals with TREX1-related phenotypes (Pelzer N et al., 2013; Lee-Kirsch MA et al., 2007; Namjou B et al., 2011); Functional studies indicate the variant has a detrimental effect on ubiquitination, but exonuclease function was not affected; additional studies are needed to confirm the the effect of this sequence change (Orebaugh CD et al., 2013); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23881107, 23979357, 34426522, 17660818, 21270825, 18583934)
PreventionGenetics, part of Exact Sciences	RCV003413551	SCV004115315	uncertain significance	TREX1-related condition	2023-06-27	criteria provided, single submitter	clinical testing	The TREX1 c.914A>G variant is predicted to result in the amino acid substitution p.Tyr305Cys. This variant was reported in an individual with systemic lupus erythematosus (Table S2, Lee-Kirsch et al. 2007. PubMed ID: 17660818; Namjou et al. 2011. PubMed ID: 21270825) or early-onset cerebrovascular disease (Pelzer et al. 2013. PubMed ID: 23881107; Mönkäre et al. 2022. PubMed ID: 35307828). However, this variant is reported in 0.023% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-48508968-A-G). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Myllykangas group, University of Helsinki	RCV002051725	SCV001983992	uncertain significance	Vascular dementia	2021-10-01	no assertion criteria provided	research
Institute of Neurology, Charite University of Medicine	RCV002282361	SCV002571716	likely pathogenic	Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; Vascular dementia	2022-06-04	no assertion criteria provided	research