Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Victorian Clinical Genetics Services, |
RCV004788417 | SCV005400296 | uncertain significance | Aicardi-Goutieres syndrome 1 | 2023-07-17 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. 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 Retinal Vasculopathy with Cerebral Leukodystrophy (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) 0218 - Non-coding variant without known or predicted effect. (I) 0252 - This variant is homozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0508 - In silico predictions for abnormal splicing are conflicting. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable non-coding variants have previous evidence for pathogenicity. (I) 0807 - This variant has no previous evidence of pathogenicity in the literature. However, this variant was found to be biallelic in a research setting, in another individual with a typical Aicardi-Goutières syndrome phenotype (Professor Yanick Crow, personal communication). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1101 - Very strong and specific phenotype match for this individual. (SP) 1209 - This variant has been shown to be both maternally and paternally inherited (biallelic) (by Sanger sequencing segregation analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |