Case: Row 17 in Supplemental Table 1. Found in 2 patients in the same family.

DiseaseAssertion: type 1 VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: FVIII:C/VWF:Ag = 2.3 (1.7-3.2); VWFpp/VWF:Ag = 3.0 (2.9-3.2)

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Genetic analysis was performed at the laboratory of hematology of the Radboud University Medical Center in Nijmegen. Ion semiconductor sequencing (Ion-Torrent) was used to analyze the VWF gene from peripheral blood obtained in EDTA tubes or from saliva samples. The 52 exons of VWF gene were analyzed including ±20 bp exon-intron boundaries. If no VWF gene variant was detected, multiplex ligation-dependent probe amplification (MLPA) analysis was performed to find large deletions or duplications. Thus, MLPA was performed in 183 patients (46.9%). All variants were confirmed with Sanger sequencing.

PreviouslyPublished:

Gene: VWF

Variant: 2435delC P812R fs*31

HGVS: VWF:c.2435del p.Pro812Argfs*31

ClinVarID: 303

CAID:

gnomAD: 0.00007187 (116 in 1613916) no homozygotes https://gnomad.broadinstitute.org/variant/12-6044297-CG-C?dataset=gnomad_r4

Case#: Elayaperumal_2018_V-270 , F, 1.5 y.o. (onset), origin in India

DiseaseAssertion: VWD type 3

FamilyInfo: consanguinity, no family history of bleeding

ParentalGenotype: not reported

CasePresentingHPOs:

CaseHPOFreeText: bleeding score of 3, VWF:Ag of 0, FVIII:C 6.2%

CaseNotHPOs:

CaseNotHPOFreeText:

CasePreviousTesting: not reported

GenotypingMethod: CSGE and Sanger sequencing of VWF gene only.

Gene: VWF

Variant: homozygous c.3656delC (p.Pro1219Leufs*34)

HGVS: NM_000552.3:c.3656delC

ClinVarID: not found

CAID:unable to register- system not processing 2/3/23

gnomAD: not found

MultipleGeneVariants: n/a

Gene: VWF

HGNCID: 12726

Case: 4 month old female

DiseaseAssertion: VWD type 3

FamilyInfo: both parents were sequenced ParentalGenotype(s): mother is VWF:c.2435delC carrier, father was negative

CasePresentingHPOs: HP:0011889 CaseHPOFreeRext: bleeding from injection site following vaccination administration CaseNOTHPOs: CaseNOTHPOFreeText: normal PT/PTT at 4 months. prolonged PTT, normal PT and platelet count upon repeat. Factor VIII levels <1%, VWF activity <15%

GenotypingMethod: unknown

Gene: VWF

Variant: c.2435delC in VWF gene, deletion in exon 6 of VWF gene

HGVS: NM_000552.5:c.2435del

ClinVarID: 303

gnomAD: 0.00007187 (116/1613916) https://gnomad.broadinstitute.org/variant/12-6044297-CG-C?dataset=gnomad_r4

Case:44‐year‐old male patient

DiseaseAssertion:type 3‐VWD patient

FamilyInfo:positive family hsiory: The proband and his sister both had low FVIII:C (1 IU/dL) and VWF:Ag (3 IU/dL) levels, confirming the diagnosis of type 3 VWD. His father had nearly normal levels of FVIII:C (58 IU/dL) and VWF:Ag (57 IU/dL). His daughter had type 1 VWD with decreased FVIII:C (46 IU/dL) and VWF:Ag (19 IU/dL)., NGS identified a heterozygous VWF c.2328delT (p.A778Lfs*23) frame shift mutation only in the proband and his sister

ParentalGenotype(s):VWF missense mutation, c.6521G > T (p.C2174F), was found heterozygous in father, but mother not tested

CasePresentingHPOs:BAT score=16, Arterial thrombosis=ischemic stroke, FVIII:C*=1, VWF:Ag=3, Proein S:58, Protein C:100, antithrombin III=106, activated protein C resistance:2.9. CaseHPOFreeRext: Complete blood count showed normocytic anemia (hemoglobin 74 g/L), normal white cell (and differential), and platelet counts. He had prolonged activated partial thromboplastin time (APTT) (89.4 s (s) [reference range (RR), 28.0–44.0 s]) with greatly decreased FVIII:C (1 IU/dL) and VWF:Ag (3 IU/dL) (Table 1). Abdominal ultrasound scanning revealed fatty liver, normal gallbladder, spleen, pancreas, and kidneys. Four hundred ml of virus inactivated fresh frozen plasma (FFP) was transfused, and his VWF:Ag increased to 6 IU/dL. On Day 2 after admission, the patient abruptly experienced numbness and weakness in his right limb.

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:n.a

GenotypingMethod:NGS

PreviouslyPublished: If applicable.

Gene: VWF

Variant:c.2328delT (p.A778Lfs*23) and c.6521G > T (p.C2174F)

HGVS:n.a.

ClinVarID:n.a.

CAID:n.a.

gnomAD: n.a.

PMID: unknown

Gene: VWF

HGNCID: 12726

Case: 2 year old female

DiseaseAssertion: type 3 VWD

FamilyInfo: 27 year old parents with no history of abnormal bleeding, non-consanguineous. Older brother (4 years old) with symptoms, younger brother asymptomatic.

ParentalGenotype(s): Mother is heterozygous for c.2345del variant. Father is heterozygous for exon 6 deletion.

CasePresentingHPOs: HP:0001934, HP:0000978, HP:0000225, HP:0001058, HP:0001058, HP:0012147, HP:0030132

CaseHPOFreeRext: reduced VWF activity

CaseNOTHPOs: HP:0001873, HP:0008151

CaseNOTHPOFreeText: reduced factor VIII

CasePreviousTesting: n/a

GenotypingMethod: unknown

PreviouslyPublished: n/a

Gene: VWF

Variant: compound heterozygous c2345delC in exon 18 and deletion in exon 6

HGVS: NM_000552.5:c.2435del p. (Pro812ArgfsTer31)

ClinVarID: 303

CAID:

gnomAD: 0.00007187 (11/1613916 alleles) https://gnomad.broadinstitute.org/variant/12-6044297-CG-C?dataset=gnomad_r4

Case#: Elayaperumal_2018_ , M, 4 y.o. (onset), origin in India

DiseaseAssertion: VWD type 3

FamilyInfo: Consanguinity, no family history

ParentalGenotype: not reported

CasePresentingHPOs:

CaseHPOFreeText: bleeding score of 14. VWF:Ag 0.83, FVlll:C of 1.9%.

CaseNotHPOs:

CaseNotHPOFreeText:

CasePreviousTesting: not reported

GenotypingMethod: CSGE and Sanger sequencing of VWF gene only.

Gene: VWF

Variant: homozygous c.757_770del

HGVS: NM_000552.3:c.757_770del (p.Thr253Cysfs*45)

ClinVarID: not found

CAID: CAR unable to parse. Error: unknown

gnomAD: not found

MultipleGeneVariants: not reported

Case: IP-2

DiseaseAssertion: VWD3

FamilyInfo: The mother reported no history of bleeding episodes and the laboratory data were in the border line of the normal range.

ParentalGenotype(s): mother is heterozygous for the p.Gln2551AlafsX16 in the VWF gene

CasePresentingHPOs: HP:0000421

CaseHPOFreeRext: VWF:Ag <6%, VWF:RCo <6% and FVIII:C 2%. Clinically, repetitive severe epistaxis and subcutaneous hematomas were observed.

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: Direct sequencing of exons 2–52 including exon/intron boundaries of the VWF gene

GenotypingMethod: multiple ligation‐dependent probe amplification (MLPA; using kit P011 and P012; MRC Holland, Amsterdam, the Netherlands) according to the manufacturer’s instructions. The PCR products were run on an ABI PRISM 3130XL sequencer with the GeneScan 500 LIZ size standard and analyzed using GeneMapper Software 5.0 (Applied Biosystems, Darmstadt, Germany).

PreviouslyPublished: NA

Gene: VWF

Variant: p.Gln2551AlafsX16

HGVS:

ClinVarID:

CAID:

gnomAD:

MultipleGeneVariants:

GeneName: VWF

Variant: whole gene deletion

ClinVarID or CAID:

gnomAD: