ClinVar Genomic variation as it relates to human health

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with TREX1-related conditions. Loss of function is generally associated with recessive disease, while dominant negative variants are associated with dominant disease (OMIM, PMID: 21937424). However, loss of function is the mechanism of disease associated with heterozygous C-terminal frameshift variants identified in individuals with vasculopathy, retinal, with cerebral leukoencephalopathy and systemic manifestations (MIM#192315) (OMIM). (I) 0108 - This gene is known to be associated with both recessive and dominant disease. Aicardi-Goutieres syndrome is predominantly a recessive condition; however, there have been rare cases of a dominant form of the disease reported (OMIM). (I) 0115 - Variants in this gene are known to have variable expressivity, with intrafamilial and interfamilial variability reported (PMID: 33516249). (I) 0208 - Variant is predicted to result in an elongated protein. (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - A downstream protein elongation change has been observed in gnomAD (v2) (4 heterozygotes, 0 homozygotes). (I) 0600 - Variant affects the annotated putative transmembrane helix (PMID: 27604306). Functional studies have shown the C-terminal region contains a perinuclear localization signal. However, the exact location of this signal and if this variant affects it, is unclear (PMID: 17660820). (I) 0704 - Other protein elongation variants comparable to the one identified in this case have limited previous evidence for pathogenicity. Two of these variants have been reported as likely pathogenic or pathogenic (ClinVar), and observed in families with hereditary endotheliopathy with retinopathy, nephropathy, and stroke (HERNS) (PMID: 17660820). Other further downstream elongation variants have been reported as VUS (ClinVar), and in a compound heterozygous individual with epilepsy (PMID: 29720203). (SP) 0803 - This variant has limited previous evidence of pathogenicity in an unrelated individual. This variant was observed in a single family with HERNS (PMID: 17660820; PMID: 27604306). (SP) 0906 - Segregation evidence for this variant is inconclusive. This variant has segregated with disease in three individuals from the same family; however, this is an insufficient number of meioses to establish pathogenicity (PMID: 17660820; PMID: 27604306). (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign