Disease: Von Willebrand Disease (VWD) type 1

Patient(s): 13 yo, female and 14 yo, female, both Italian

Variant: VWF NM_000552.5: c.820A>C p. (Thr274Pro)

Dominant negative effect

Heterozygous carrier

Variant located in the D1 domain on VWF

Phenotypes:

heterozygous carriers have no bleeding history

reduced VWF levels compatible with diagnosis of VWD type 1

increased FVIII:C/VWF:Ag ratio, suggests reduced VWF synthesis/secretion as possible phathophysiological mechanism

Normal VWFpp/VWF:Ag ratio

Modest alteration of multimeric pattern in plasma and platelet multimers

plasma VWF showed slight increase of LMWM and decrease of IMWM and HMWM

Platelet VWF showed quantitative decrease of IMWM, HMWM, and UL multimers

In silico analysis:

SIFT, ALIGN, GVD Polyphen 2.0, SNP&GO, Mutation Taster, Pmut all suggest damaging consequences.

PROVEAN and Effect suggest neutral effect

according to ACMG guidelines this variant was classified as pathogenic

Disease: Von Willebrand Disease (VWD)

Patient: 18 yo, Male, heterozygote

Variant: VWF NM_000552.5: c.5456_5842del p.(R1819_C1948delinsS)

Was not present in gnomAD when searched

Dominant negative effect

Phenotypes:

lower collagen-binding capacity

History of bleeding (epistaxis)

gum bleeding

cutaneous bruises

ADAMTS13 resistant

Family: Mother, father, sister are asymptomatic

Suggested as de novo, no picture found in patient's relative of the deletion, loss of A3 loop