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.

Disease: Dystrophic epidermolysis bullosa (DEB) pruriginosa *Note: A novel vwf variant was found in this patient with these other variants in COL7A1 gene

Patient(s): 17 YO Korean male

Variant: VWF NM_000552.5: c.3310C>T p. (R1101W) Located in exon 26

Hadn't been reported previously Variant found to be inherited in trans from family analysis

According to the paper, they have classified with with ACMG guidelines as likely pathogenic.

Reasoning: Variant absent in the Korea Ref Genome Database and Allele Freq = 0.00086% in gnomAD (Evidence: PM2)

Variant detected in trans with another well-known pathologic variant (c.5797C>T) (Evidence: PM3)

Multiple missense variants are known to be pathogenic in RDEB (Evidence: PP2)

Various computational in silico predictive programs reported the variant as pathogenic (Evidence PP3)

Disease: Von-willebrand Disease (Type 2A)

Patient: 50 yo female

Variant: VWF NM_000552.5 c:4232_4249del p.(Val411_Ile416del), Exon 28, heterozygous variant

According to this paper, ACMG-AMP guidelines for interpreting this variant resulted in classification of likely pathogenic

Phenotypes: increased bruising, fatigue, recurrent sinusitis, menorrhagia, neutropenia, anaemia. Reduction in high-molecular-weight multimers

Family: segregation analysis showed two affected family members had the variant and two unaffected family members did not have variant.

Note: Patient also has diagnosed Acute Myeloid Leukaemia (AML) NM_000546.6(TP53):c704A>G p.(Asn235Ser), listed as VUS and found by NGS