Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV003441720 | SCV004167796 | pathogenic | not provided | 2023-04-27 | criteria provided, single submitter | clinical testing | Published functional studies demonstrate a damaging effect on endothelial cell differentiation and tyrosine phosphorylation (Suzuki et al., 2005); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 15904433, 11553610, 10835628, 11114740, 21490960, 27177310, 23074044, 19296866, 15102829, 11427983, 15389531, 15561887) |
| Victorian Clinical Genetics Services, |
RCV000017647 | SCV005086514 | pathogenic | Hereditary lymphedema type I | 2023-07-17 | 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 congenital heart defects 7, multiple types (MIM#618780) and lymphatic malformation 1 (MIM#153100). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID: 23074044, 30232381). (I) 0115 - Variants in this gene are known to have variable expressivity. Variable expressivity has been reported for the lymphatic malformation phenotype (PMID: 23074044). There is also a patient reported with a recurrent frameshift variant who has both tetralogy of Fallot and lymphoedema (PMID: 30232381). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to arginine. (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 protein tryosine kinase domain, and affects the kinase motif that is a critical part of the ATP-binding site (DECIPHER, PMID: 10835628). (SP) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been identified in four families with lymphoedema (PMIDs: 10835628, 15904433, 19002718, 24167460). (SP) 0902 - This variant has moderate evidence for segregation with disease. This variant has been shown to segregate with disease across several generations of two different families (PMIDs: 10835628, 15904433). In one of these families the variant was also identified in two unaffected individuals; however, incomplete penetrance is established for this gene. (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. This variant has been shown to decrease tyrosine-kinase activity causing poor activation of downstream signalling cascades (PMID: 10835628). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |
| OMIM | RCV000017647 | SCV000037924 | pathogenic | Hereditary lymphedema type I | 2000-06-01 | no assertion criteria provided | literature only |