Submissions for variant NM_033629.6(TREX1):c.308A>T (p.Asn103Ile)

gnomAD frequency: 0.00001  dbSNP: rs770158462

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001319122	SCV001509853	uncertain significance	Aicardi-Goutieres syndrome 1; Chilblain lupus 1; Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations	2024-01-12	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 103 of the TREX1 protein (p.Asn103Ile). This variant is present in population databases (rs770158462, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with TREX1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1019658). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003323855	SCV004029774	uncertain significance	not specified	2023-07-12	criteria provided, single submitter	clinical testing	Variant summary: TREX1 c.308A>T (p.Asn103Ile) results in a non-conservative amino acid change located in the Exonuclease, RNase T/DNA polymerase III domain (IPR013520) of the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 249844 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.308A>T in individuals affected with Aicardi Goutieres Syndrome 1 and no experimental evidence demonstrating its impact on protein function have been reported. One ClinVar submitter has assessed the variant since 2014, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV004531108	SCV004115503	uncertain significance	TREX1-related disorder	2022-12-01	criteria provided, single submitter	clinical testing	The TREX1 c.308A>T variant is predicted to result in the amino acid substitution p.Asn103Ile. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0087% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-48508362-A-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Ambry Genetics	RCV004034954	SCV004971194	uncertain significance	Inborn genetic diseases	2023-11-20	criteria provided, single submitter	clinical testing	The c.308A>T (p.N103I) alteration is located in exon 2 (coding exon 1) of the TREX1 gene. This alteration results from a A to T substitution at nucleotide position 308, causing the asparagine (N) at amino acid position 103 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.