Total submissions: 9
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Kasturba Medical College, |
RCV001330236 | SCV006076495 | likely pathogenic | Aicardi-Goutieres syndrome 1 | criteria provided, single submitter | research | A known missense variant, c.667G>A in exon 2 of TREX1 was observed in homozygous state in Proband (Gavazzi et al., 2021; Abe et al., 2014). Sanger validation and segregation analysis revealed that the variant was present in homozygous state in the proband and heterozygous in his parents (Lab ID: mother-10214 and father-10215). This variant has been observed in heterozygous state in 41 individuals in gnomAD (v4.1.0) population database and absent in our in-house database of 3598 exomes. The variant is absent in homozygous state in gnomAD and in our in-house database. In-silico prediction tools (REVEL, CADD Phred) are consistent in predicting the variant to be damaging to the TREX1 protein function. The clinical and neuroimaging findings observed in the proband are in concordance with Aicardi-Goutieres syndrome 1, dominant and recessive. Thus, the above-mentioned variant in the homozygous state is the likely cause of the condition observed in proband. | |
| Fulgent Genetics, |
RCV005027489 | SCV005662010 | likely pathogenic | Aicardi-Goutieres syndrome 1; Chilblain lupus 1; Systemic lupus erythematosus; Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations | 2024-06-08 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV004701472 | SCV005205113 | uncertain significance | not specified | 2025-08-26 | criteria provided, single submitter | clinical testing | Variant summary: TREX1 c.667G>A (p.Ala223Thr) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 1.2e-05 in 251100 control chromosomes (gnomAD). c.667G>A has been observed in individuals affected with Aicardi-Goutieres Syndrome 1-AR (e.g., Crow_2015, Gavazzi_2022, Vanderver_2020, Abe_2014). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 24300241, 25604658, 34490982, 32877590). ClinVar contains an entry for this variant (Variation ID: 381689). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. |
| Genomic Medicine Center of Excellence, |
RCV001330236 | SCV004806846 | uncertain significance | Aicardi-Goutieres syndrome 1 | 2024-03-26 | criteria provided, single submitter | clinical testing | |
| Revvity Omics, |
RCV000433529 | SCV004236930 | uncertain significance | not provided | 2023-11-22 | criteria provided, single submitter | clinical testing | |
| 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. |
| Labcorp Genetics |
RCV001340342 | SCV001534148 | uncertain significance | Aicardi-Goutieres syndrome 1; Chilblain lupus 1; Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations | 2025-12-13 | 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, 32877590, 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. |
| 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]. |
| Gene |
RCV000433529 | SCV000521216 | likely pathogenic | not provided | 2025-12-29 | criteria provided, single submitter | clinical testing | Reported in multiple patients with Aicardi-Goutieres syndrome with a second variant, however parental testing was not performed to determine whether the variants were in cis or trans (PMID: 24300241, 33053223); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31475890, 33053223, 34426522, 31589614, 37357214, Puckelwartz2023[casereport], 35879334, 34490982, 32877590, 25604658, 24300241, 38003924) |