Disease: Von-willebrand Disease (Type 1)

Study: additional evaluation to interpret pathogenicity of a common VWF variant.

Note: 244 healthy controls from general population to compare to the patient cohorts. Study performed with subjects from across Canada.

Patients: 58 subjects with only the specified variant below were recruited from two cohort studies

Variant: VWF NM_000552.5 c:4751A>G p.(Y1584C)

According to this publication: using the rules of ACMG/AMP guidelines concluded the variant is LIKELY PATHOGENIC

CADD score (26)

AlphaMissense metric score (0.5865- Likely pathogenic)

Variant identified in 14% of index cases for Canadian type 1 VWD, in ClinVar databases is shown as conflicting interpretation of pathogenicity

Present in gnomAD, 1000 genomes, and UK BioBank with pop prevalence of 0.08%-0.27%. Highest prevalence is 0.43% in European Non-Finnish Population. Absent in East Asian and middle Eastern populations.

Cites a VWF mouse model for this variant that shows no change in protein clearance, decreased VWF antigen levels and mild reduction in multimers.