Case: Proband (II-1), male, 56yo, Italian

DiseaseAssertion: VWD1 and Hemophilia A

FamilyInfo: Pedigree in Fig. 1 - Father had VWD1 and Mother had Hemophilia A - parents have normal or higher VWF levels, and normal FVIII/VWF:Ag ratios, as well as a normal bleeding score; 2 daughters carry F8 variant

ParentalGenotype(s): Paternal = NM_000552.4(VWF):c.4751A>G (p.Tyr1584Cys); Maternal = NM_000132.3(F8):c.2167G>A (p.Ala723Thr)

CasePresentingHPOs: HP:0012147, HP:0030129, HP:0030130, HP:0001892, HP:0000421, HP:0000978, HP:0004846, HP:0000225, HP:0005261, HP:0040242

(Reduced quantity of VWF, Impaired ristocetin cofactor assay activity, Impaired von Willebrand factor collagen binding activity, abnormal bleeding, epistaxis, Bruising susceptibility, Prolonged bleeding after surgery, bleeding gums, joint hemorrhage, muscle hemorrhage)

CaseHPOFreeText: blood group = 0, aPTT = 0.56sec, FVIII = 9.8 IU/dL, VWF:Ag = 43.2 IU/dL, VWF:CB = 35.6 IU/dL, VWF:Rco = 42.1 IU/dL, VWF:FVIIIB = 41.3 IU/dL, Platelet VWF:Ag = 58.2 IU/dL, bleeding score = 27

CaseNOTHPOs: HP:0011871

(Impaired RIPA)

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: PCR and direct sequencing of VWF and FVIII

PreviouslyPublished: NA

Gene: VWF

Variant: c.4751A>G (p.Tyr1584Cys)

HGVS: NM_000552.4(VWF):c.4751A>G (p.Tyr1584Cys)

ClinVarID: 310; https://www.ncbi.nlm.nih.gov/clinvar/variation/310/

CAID: NA

gnomAD: MAF = 0.004024 (519/128972 alleles, 4 homozygotes) in European (non-Finnish) population

MultipleGeneVariants:

Gene: F8

Variant: c.2167G>A (p.Ala723Thr)

HGVS: NM_000132.3(F8):c.2167G>A (p.Ala723Thr)

ClinVarID: 10246; https://www.ncbi.nlm.nih.gov/clinvar/variation/10246/

CAid: NA

gnomAD: MAF = 0.00005257 (1/19022 alleles, 1 hemizygote) in South Asian population

Case#: 01028, Age 8, Male, Blood type O+( Table S3)

Disease Assertion: VWD 1

FamilyInfo: Not listed

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding score 7, VWF:Ag: 21, VWF:RCo: 33, FVIII:C: 34, VWF:CB: 30

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

Protein Expression: N/A

CasePreviousTesting: 48,48 Access-Array amplification. NGS Molecular analysis was performed. Sanger sequencing was used to validate selected mutations.

Gene: VWF

Variant: NM_000552.4:c.4751A>G (p.Tyr1584Cys) and NM_000552.3:c.5312-19A>C

ClinVar: 310 and 806794

ClinVar1

ClinVar2

CAID: CA114162 and CA6402297 CAID1 CAID2

gnomAD: MAF of 0.004024 (519/128972 alleles) in the European (non-Finnish) population (CA114162). MAF of 0.002507 (26/10370 alleles) in the Ashkenazi Jewish population.

gnomAD1

gnomAD2