Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Victorian Clinical Genetics Services, |
RCV004787079 | SCV005398071 | pathogenic | von Willebrand disease type 1 | 2024-09-21 | 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: 0103 - Dominant negative, gain of function and loss of function are known mechanisms of disease in this gene and are associated with von Willebrand disease (VWD) (OMIM, PMID: 30488424). (I) 0108 - This gene is associated with both recessive and dominant disease. VWD can be both dominantly and recessively inherited, and is categorised into six different types: 1 (MIM#193400), 2A, 2B, 2M, 2N (MIM#613554) and 3 (MIM#277480). (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID: 19372260). (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 19372260). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 (3 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. These variants have been reported many times as pathogenic (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been observed in multiple heterozygous individuals with type III von Willebrand disease, where almost all had a second variant identified in this gene. It has also been observed in several heterozygous individuals with type I or with low VWF levels (PMID: 23311757; PMID: 35343054, PMID: 23777763, PMID: 23355534). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |
| Mayo Clinic Laboratories, |
RCV004790635 | SCV005414054 | pathogenic | not provided | 2023-09-29 | criteria provided, single submitter | clinical testing | PM2_moderate, PS4_moderate, PVS1 |
| Prevention |
RCV004548906 | SCV004714249 | pathogenic | VWF-related disorder | 2023-12-15 | no assertion criteria provided | clinical testing | The VWF c.2438dupG variant is predicted to result in a frameshift and premature protein termination (p.Met814Hisfs*5). This variant has been reported to be causative for von Willebrand Disease (VWD) type 1 or type 3 (Starke et al. 2013. PubMed ID: 23355534; Bowman et al. 2013. PubMed ID: 23311757). This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Frameshift variants in VWF are expected to be pathogenic. This variant is interpreted as pathogenic. |