Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Victorian Clinical Genetics Services, |
RCV004788360 | SCV005400149 | pathogenic | Cataract 5 multiple types | 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 cataract 5 multiple types (MONDO:0007290). (I) 0108 - This gene is associated with both recessive and dominant disease. Variants associated with autosomal dominant disease are located in the DNA-binding domain, while variants associated with autosomal recessive disease are truncating variants throughout the protein, or missense variants located within the hydrophobic repeat (HR-A/B) domain and downstream of the hydrophobic repeat (DHR) domain (PMIDs: 31815953, 24045990). (I) 0205 - Variant is predicted to result in a truncated protein with less than 1/3 of the protein sequence affected. Premature termination codons in this gene are known to escape nonsense-mediated decay (PMID: 24045990). (SP) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 (1 heterozygote, 0 homozygotes). (SP) 0601 - Variant partially truncates the well-established functional DHR domain, a region with negative regulatory activity and containing the second activation domain (PMID: 24045990). (I) 0703 - Other downstream truncating variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. A splice variant, c.1327+4A>G, shown to produce an out of frame protein, p.(Met419Glyfs*29), has been observed as homozygous in one large consanguineous family with cataracts (PMID: 15277496). p.(Leu436*) has been observed as compound heterozygous with a splice variant in an individual with congenital cataracts (PMID: 33923544). (SP) 0803 - This variant has limited previous evidence of pathogenicity in an unrelated individual. This variant has been observed as homozygous in several members of a large consanguineous family with cataracts (PMID: 19014451). (SP) 0901 - This variant has strong evidence for segregation with disease. This variant segregated with autosomal recessive disease in one consanguineous family with cataracts. The variant was observed as homozygous in all eight affected family members, and was either absent or heterozygous in all unaffected family members that were tested (PMID: 19014451). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Transfection and western blot studies have shown that this variant creates a stable protein of the expected truncated size, and a luciferase assay has shown this variant produces a protein with significantly decreased transactiviation potential compared to wild type protein (PMID: 24045990). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |