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

for - quote - the more you come into contact with people who are different then you, the less likely it is that you will be threatened by them - adjacency - finding commonality - shared humanity - Deep Humanity - Common Human Denominators - from TED Talk - Can curiosity heal division? - Scott Shigeoka - 2024 Dec

Kai Kupferschmidt. (2021, December 1). If you’re curious how likely #omicron is to have spread from South Africa or Botswana to different places, @DirkBrockmann and colleagues have done some interesting calculations based on the world aviation network from 08/2021 You can see that US seems a very likely destination https://t.co/OSnZ6ZNble [Tweet]. @kakape. https://twitter.com/kakape/status/1466107074585239568

Kai Kupferschmidt. (2021, December 1). @DirkBrockmann That percentage number tells you “how likely an infected passenger from South Africa or Botswana travels to each country and exits the airport there”. So: “0.9% in Germany means that out of 1000 such individuals, 9 are expected to have Germany as their final destination.” [Tweet]. @kakape. https://twitter.com/kakape/status/1466107478807097354

reasonable: "a plausible explanation"

Of course.

Wed Mar 29 2017 09:49:00 GMT-0400 (Eastern Daylight Time)

Tue Mar 28 2017 08:08:27 GMT-0400 (Eastern Daylight Time)

Mon Mar 27 2017 09:12:13 GMT-0400 (EDT)