Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Victorian Clinical Genetics Services, |
RCV004788604 | SCV005399012 | uncertain significance | Aicardi-Goutieres syndrome 6 | 2024-10-08 | 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 Aicardi-Goutieres syndrome 6 (AGS 6; MIM#615010) and dyschromatosis symmetrica hereditarian (DSH; MIM#127400). The dominant negative mechanism has only been reported for a single variant, p.(Gly1007Arg), whereas all other variants have been reported with a loss of function mechanism (PMID: 23001123, 28561207, OMIM). (I) 0108 - This gene is associated with both recessive and dominant disease. AGS is predominantly a recessive condition, caused by variants found within isoform p150. The p.(Gly1007Arg) variant is the only dominantly-acting variant to cause AGS. DHS is a dominant condition caused by variants found within isoform p110 (PMID: 25456137, 23001123). (I) 0112 - The condition associated with this gene has incomplete penetrance. This variant p.(Gly1007Arg) has been reported in probands with unaffected parents (PMID: 28561207). (I) 0115 - Variants in this gene are known to have variable expressivity (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to isoleucine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |