Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Victorian Clinical Genetics Services, |
RCV002470362 | SCV002767148 | pathogenic | Exudative vitreoretinopathy 1 | 2023-07-16 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with exudative vitreoretinopathy 1 (MIM#133780). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. There is a large degree of intrafamilial variability, and asymptomatic heterozygous individuals have been reported (OMIM, PMID: 19324841). (I) 0200 - Variant is predicted to result in a missense amino acid change from tyrosine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0601 - Variant is located in the well-established functional cysteine-rich domain, which is required for interaction with the ligand Norrin (PMID:15035989, PMID:26227961). (SP) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individuals. This variant was reported in a family with familial exudative vitreoretinopathy (PMID:21177847). (SP) 0902 - This variant has moderate evidence for segregation with disease. This variant segregated with the disease in 5 members of a family with familial exudative vitreoretinopathy, and was absent in an unaffected family member (PMID:21177847). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. In HEK293 human cell lines, this variant was unable to bind its ligand Norrin and activate downstream signalling (PMID:21177847). (SP) 1102 - Strong phenotype match for this individual. (SP) 1205 - This variant has been shown to be maternally inherited (by Sanger analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |