PMID: 28987708

Gene: VWF

HGNCID: 12726

Case: P7, M/41

DiseaseAssertion: VWD2A

FamilyInfo: Positive family history, no details provided.

ParentalGenotype: NA

CaseHPOFreeText: The bleeding score was 7, aPTT was 36 seconds, FVIII:C was 36%, VWF:RCo was not determined, and VWF:Ag was 25 IU/dL. The VWF:RCo/VWF:Ag ratio was not applicable. The VWF multimer pattern showed a mild loss of high molecular weight multimers, RIPA was 4 ohms, and the platelet count was 301 × 10⁹/L.

CasePreviousTesting: NA

GenotypingMethod: Direct sequencing of all exons, flanking intronic sequences, and the promoter of VWF was performed.

Gene: VWF

Variant: c.4789C>T, p.R1597W — heterozygous

HGVS: NM_000552.5(VWF):c.4789C>T (p.Arg1597Trp)

ClinVar: 285

CAID: CA114117

gnomAD: https://gnomad.broadinstitute.org/variant/chr12-6018629-G-A?dataset=gnomad_r4

Case: P1, M/5

DiseaseAssertion: VWD1

FamilyInfo: No

ParentalGenotype: NA

CaseHPOFreeText: The bleeding score was 0, aPTT was 41 seconds, FVIII:C was 60%, VWF:RCo was 22 IU/dL, and VWF:Ag was 27 IU/dL, resulting in a VWF:RCo/VWF:Ag ratio of 0.8. RIPA was nearly absent, VWF multimer analysis was not tested, and the platelet count was 250 × 10⁹/L.

CasePreviousTesting: NA

GenotypingMethod: Direct sequencing of all exons, flanking intronic sequences, and the promoter of VWF was performed.

Gene: VWF

Variant: c.6579G>C, p.W2193C — heterozygous

HGVS: NM_000552.5(VWF):c.6579G>C (p.Trp2193Cys)

ClinVar:

CAID: CA383490665

gnomAD: absent from gnomad v4.1.0

Case: P22, F/5

DiseaseAssertion: VWD2A

FamilyInfo: Positive family history, no details provided.

ParentalGenotype: NA

CaseHPOFreeText: The bleeding score was 3, aPTT was 43 seconds, FVIII:C was 47%, VWF:RCo was 122 IU/dL, and VWF:Ag was 20 IU/dL, with a VWF:RCo/VWF:Ag ratio of 0.1. RIPA was normal, VWF multimer analysis was 2, and platelet count was 270 × 10⁹/L.

CasePreviousTesting: NA

GenotypingMethod: Direct sequencing of all exons, flanking intronic sequences, and the promoter of VWF was performed.

Gene: VWF

Variant: c.4825G>A, p.G1609R — heterozygous

HGVS: NM_000552.5(VWF):c.4825G>A (p.Gly1609Arg)

ClinVar: 100395

CAID: CA228665

gnomAD: https://gnomad.broadinstitute.org/variant/chr12-6018593-C-T?dataset=gnomad_r4

Case: P21, F/5

DiseaseAssertion: VWD2M

FamilyInfo: Positive family history, no details provided.

ParentalGenotype: NA

CaseHPOFreeText: The bleeding score was 2, aPTT was 53 seconds, FVIII:C was 30%, and VWF:RCo was 25 IU/dL. The VWF:RCo/VWF:Ag ratio indicated a mild loss of high molecular weight multimers. RIPA was 4, VWF multimer analysis was 301, and platelet count was not specified.

CasePreviousTesting: NA

GenotypingMethod: Direct sequencing of all exons, flanking intronic sequences, and the promoter of VWF was performed.

Gene: VWF

Variant: c.4121G>T, p.R1374L — heterozygous

HGVS: NM_000552.5(VWF):c.4121G>T (p.Arg1374Leu)

ClinVar: 100331

CAID: CA228543

gnomAD: https://gnomad.broadinstitute.org/variant/chr12-6019297-C-A?dataset=gnomad_r4

PMID: 31240882

Gene: VWF

HGNCID: 12726

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

PMID: 29165738

Gene: VWF

HGNC: 12726 (type 1)

Note: Insufficient Evidence due to lack of variant information. This paper designates variants as only "missense, deletion, etc" and lacks specific neucleotide changes. All probands with identifiable variants in this paper were from other PMIDs, which were confirmed to be previously curated or added to the list to be curated.

Case#: F3, II:1

DiseaseAssertion: Type 2 VWD

CaseHPOFreeText: all mutimers present, VWF:Ag = 45; VWF:RCo = 38; VWF:GPIbM = 45; 0.84; 1.00; 1.19

CasePreviousTesting: Not clearly described

Gene: VWF

Variant: p.[P1266L];[=]

HGVS: NM_000552.5(VWF):c.3797C>T (p.Pro1266Leu)

CAID: CA114170

gnomAD: https://gnomad.broadinstitute.org/variant/12-6019621-G-A?dataset=gnomad_r4

Case#: F13, I:1

DiseaseAssertion: Type 2 VWD

CaseHPOFreeText: complete loss of high MWM, VWF:Ag = 69; VWF:RCo = 50; VWF:GPIbM = 71; 0.72; 1.04; 1.43

CasePreviousTesting: Not clearly described

Gene: VWF

Variant: p.[R1341Q];[=]

HGVS: c.4022G>A (p.Arg1341Gln)

CAID: CA114129

gnomAD: https://gnomad.broadinstitute.org/variant/12-6019396-C-T?dataset=gnomad_r4

Case#: F3, I:1

DiseaseAssertion: Type 2 VWD

CaseHPOFreeText: all mutimers present, VWF:Ag = 60; VWF:RCo = 57; VWF:GPIbM = 59; 0.95; 0.98; 1.03

CasePreviousTesting: Not clearly described

Gene: VWF

Variant: p.[P1266L];[=]

HGVS: NM_000552.5(VWF):c.3797C>T (p.Pro1266Leu)

CAID: CA114170

gnomAD: https://gnomad.broadinstitute.org/variant/12-6019621-G-A?dataset=gnomad_r4

Case#: F2, II:1

DiseaseAssertion: Type 2 VWD

CaseHPOFreeText: all mutimers present, VWF:Ag = 68; VWF:RCo = 66; VWF:GPIbM = 61; 0.97; 0.90; 0.93

CasePreviousTesting: Not clearly described

Gene: VWF

Variant: p.[P1266L];[=]

HGVS: NM_000552.5(VWF):c.3797C>T (p.Pro1266Leu)

CAID: CA114170

gnomAD: https://gnomad.broadinstitute.org/variant/12-6019621-G-A?dataset=gnomad_r4

Case#: F12, II:1

DiseaseAssertion: Type 2 VWD

CaseHPOFreeText: complete loss of high MWM, VWF:Ag = 52; VWF:RCo = 18; VWF:GPIbM = 52; 0.34; 1.00; 2.92

CasePreviousTesting: Not clearly described

Gene: VWF

Variant: p.[R1341Q];[=]

HGVS: c.4022G>A (p.Arg1341Gln)

CAID: CA114129

gnomAD: https://gnomad.broadinstitute.org/variant/12-6019396-C-T?dataset=gnomad_r4

Case#: F2, I:1

DiseaseAssertion: Type 2 VWD

CaseHPOFreeText: all mutimers present, VWF:Ag = 30; VWF:RCo = 29; VWF:GPIbM = 24; 0.97; 0.81; 0.84

CasePreviousTesting: Not clearly described

Gene: VWF

Variant: p.[P1266L];[=]

HGVS: NM_000552.5(VWF):c.3797C>T (p.Pro1266Leu)

CAID: CA114170

gnomAD: https://gnomad.broadinstitute.org/variant/12-6019621-G-A?dataset=gnomad_r4

Case#: F11, I:1

DiseaseAssertion: Type 2 VWD

CaseHPOFreeText: complete loss of high MWM, VWF:Ag = 35; VWF:RCo = 5; VWF:GPIbM = 27; 0.14; 0.78; 5.44

CasePreviousTesting: Not clearly described

Gene: VWF

Variant: p.[R1306W];[=]

HGVS: c.3916C>T (p.Arg1306Trp)

CAID: CA114123

gnomAD: absent from gnomad v4.1.0

PMID: 26206100

Gene: VWF

HGNCID: 12726

Case#: F1, II:1

DiseaseAssertion: Type 2 VWD

CaseHPOFreeText: all mutimers present, VWF:Ag = 58; VWF:RCo = 54; VWF:GPIbM = 51; 0.94; 0.89; 0.95

CasePreviousTesting: Not clearly described

Gene: VWF

Variant: p.[V1229G; N1231T; P1266L]; [=]

HGVS: NM_000552.5(VWF):c.3686T>G (p.Val1229Gly), NM_000552.5(VWF):c.3797C>T (p.Pro1266Leu)

CAID: CA228433, CA114170

Case#: F10, II:3

DiseaseAssertion: Type 2 VWD

CaseHPOFreeText: complete loss of high MWM, VWF:Ag = 53; VWF:RCo = 13; VWF:GPIbM = 37; 0.25; 0.69; 2.82

CasePreviousTesting: Not clearly described

Gene: VWF

Variant: p.[R1306W];[=]

HGVS: c.3916C>T (p.Arg1306Trp)

CAID: CA114123

gnomAD: absent from gnomad v4.1.0

Case: IP #11 in type 2B VWD sub-cohort

DiseaseAssertion: type 2B VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032370 - blood group A

CaseHPOFreeRext: VWF:Ag [IU/dL] = 77; VWF:Ac [IU/dL] = 50; FVIII:C [IU/dL] = 82

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.3922C>A p.Arg1308Ser

HGVS:

ClinVarID: not found

CAID: CA383506203

gnomAD: absent

Case: IP #51 (also in row 21 table 6)

DiseaseAssertion: type 2A (IIA) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032442 - blood group O

CaseHPOFreeRext: VWF:Ag [IU/dL] = 27; VWF:Ac [IU/dL] = 8; FVIII:C [IU/dL] = 55

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.4811T>A p.Val1604Asp

HGVS:

ClinVarID: not found

CAID: CA383499144

gnomAD: absent

Case: 4

DiseaseAssertion: type 2A VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: VWF:Ag [IU/dL] = 64; VWF:Ac [IU/dL] = 39; FVIII:C [IU/dL] = 104

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.1681_1684dup p.Leu562Argfs

HGVS:

ClinVarID: not found

CAID: absent

gnomAD: absent

MultipleGeneVariants:

Gene: VWF

Variant: c.5278G > A p.Val1760Ile

CAID: CA228708

gnomAD: 0.001050 (1695 in 1614194) 4 homozygotes https://gnomad.broadinstitute.org/variant/12-6016549-C-T?dataset=gnomad_r4

Case: IP #41 in type U VWD sub-cohort

DiseaseAssertion: unclassified (A/1) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032442 - blood group O

CaseHPOFreeRext: VWF:Ag [IU/dL] = 37; VWF:Ac [IU/dL] = 32; FVIII:C [IU/dL] = 103

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.6981T>G

HGVS:

ClinVarID: not found

CAID: CA383492037

gnomAD: absent

Case: IP #14

DiseaseAssertion: type 2A (IIE) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032370 - blood group A

CaseHPOFreeRext: VWF:Ag [IU/dL] = 11; VWF:Ac [IU/dL] = 5; FVIII:C [IU/dL] = 21

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.3362G>T p.Arg1121Met

HGVS:

ClinVarID: not found

CAID: CA383511879

gnomAD: absent

Gene:VWF

HGNCID:12726

PMID33550910

Case:38-year-old woman from Saudi Arabia

DiseaseAssertion:VWD type 2B

FamilyInfo:Mother and brother suffered from epistaxis (no genotypes). Two sons and one daughter: both sons carry the same mutation, but only one presents with minimal epistaxis.

ParentalGenotype(s):Not available

CasePresentingHPOs:HP:0001934, HP:0004846, HP:0011871

CaseNOTHPOs:HP:0000421, HP:0000132

CaseNOTHPOFreeText:multiple dental extractions without bleeding complications

CaseHPOFreeRext:RIPA (+) Rist 0.5 mg/mL

CasePreviousTesting:No

GenotypingMethod:NGS

Gene:VWF

Variant:c.4136 G>T (p. R1379 L)

HGVS:NC_000012.12:g.6019282C>A

ClinVarID:

CAID:CA383504438

gnomAD:

Case: Patient 40, Family S (Table 1.), F/38, Afro-Caribbean

DiseaseAssertion: Indeterminant

FamilyInfo: Patient 39 (F/76, Afro-Caribbean), Patient 41 (M/63, Afro-Caribbean) and Patient 52 (F/48, Afro Caribbean) also from Family S. (Table 1.)

ParentalGenotype(s): NA

CasePresentingHPOs:

CaseHPOFreeRext: BAT = 0, FVIII:C (IU/dL) = 88, VWF:Ag (IU/dL) = 132, VWF:Act (IU/dL) = 35

CaseNOTHPOs:

CaseNOTHPOFreeText: Blood group B+

CasePreviousTesting:

GenotypingMethod: All samples were analyzed by captured-based high throughput sequencing which was performed with a custom-design of the VWF gene provided by Twist BioScience (San Francisco, USA). It comprised all 52 exons, intronic flanking regions, promoter and 3’UTR region of the VWF gene. Libraries were prepared by using the Twist NGS target enrichment solution (Twist BioScience) according to the manufacturer protocol. Samples were analyzed on a NovaSeq 6000 sequencer (Illumina) with a median read depth of 2500X by using the 300-cycle S1 NovaSeq 6000seq reagent kit with 150-bp paired-end reads. The raw data were analyzed with Mutect21 and Vardict2 tools. The inhouse NGSreport software (CHU Lille) was used for data visualization, sequences check and conservation of variants with high quality metrics. In some cases, patients genomic DNA was screened for sequence variations (large deletions, insertions and duplications) by Multiplex Ligation-dependent Probe Amplification (MCR Holland).

PreviouslyPublished: NA

Gene: VWF

Variant: c.4414G > C p.(Asp1472His)

HGVS: NM_000552.5:c.4414G>C (p.Asp1472His)

ClinVarID: 256679

CAID: CA6402534

gnomAD: MAF of 0.5076 (38011/74882 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6019004-C-G?dataset=gnomad_r4

Variant: c.4628C > G p.(Ser1543Cys)

HGVS: NM_000552.5:c.4628C>G (p.Ser1543Cys)

ClinVarID: 4533008

CAID: CA383500651

gnomAD:

Case: Patient 34, Family P (Table 1.), F/67, Afro-Caribbean

DiseaseAssertion: VWD2A (IIE)/2N

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs:

CaseHPOFreeRext: BAT = 7, FVIII:C (IU/dL) = 11, VWF:Ag (IU/dL) = 23, VWF:Act (IU/dL) = 19

CaseNOTHPOs:

CaseNOTHPOFreeText: Blood group A+

CasePreviousTesting:

GenotypingMethod: All samples were analyzed by captured-based high throughput sequencing which was performed with a custom-design of the VWF gene provided by Twist BioScience (San Francisco, USA). It comprised all 52 exons, intronic flanking regions, promoter and 3’UTR region of the VWF gene. Libraries were prepared by using the Twist NGS target enrichment solution (Twist BioScience) according to the manufacturer protocol. Samples were analyzed on a NovaSeq 6000 sequencer (Illumina) with a median read depth of 2500X by using the 300-cycle S1 NovaSeq 6000seq reagent kit with 150-bp paired-end reads. The raw data were analyzed with Mutect21 and Vardict2 tools. The inhouse NGSreport software (CHU Lille) was used for data visualization, sequences check and conservation of variants with high quality metrics. In some cases, patients genomic DNA was screened for sequence variations (large deletions, insertions and duplications) by Multiplex Ligation-dependent Probe Amplification (MCR Holland).

PreviouslyPublished: NA

Gene: VWF

Variant: c.1530G > A, p.(Val510 =) p.

HGVS: NM_000552.5:c.1530G>A (p.Val510=)

ClinVarID:

CAID: CA6403368

gnomAD: MAF of 0.00002198 (2/91004 alleles) in South Asian population https://gnomad.broadinstitute.org/variant/chr12-6062957-C-T?dataset=gnomad_r4

Variant: c.1892C > T, p.(Ala631Val)

HGVS: NM_000552.5:c.1892C>T (p.Ala631Val)

ClinVarID: 422844

CAID: CA6403245

gnomAD: MAF of 0.001908 (137/71810 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6056910-G-A?dataset=gnomad_r4

Variant: c.2220G > A, p.(Met740Ile)

HGVS: NM_000552.5:c.2220G>A (p.Met740Ile)

ClinVarID: 100206

CAID: CA201316

gnomAD: MAF of 0.1816 (13626/75022 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6046784-C-T?dataset=gnomad_r4

Variant: c.2451T > A, p.(His817Gln)

HGVS: NM_000552.5:c.2451T>A (p.His817Gln)

ClinVarID: 100224

CAID: CA228345

gnomAD: MAF of 0.1150 (8626/75016 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6036483-A-T?dataset=gnomad_r4

Variant: c.2561G>A, p.(Arg854Gln)

HGVS: NM_000552.5:c.2561G>A (p.Arg854Gln)

ClinVarID: 296

CAID: CA114139

gnomAD: MAF of 0.005974 (17050/1180026 alleles) in European (non-Finnish) population https://gnomad.broadinstitute.org/variant/chr12-6034812-C-T?dataset=gnomad_r4

Variant: c.3445T > C, p.(Cys1149Arg)

HGVS: NM_000552.5:c.3445T>C (p.Cys1149Arg)

ClinVarID: 309

CAID: CA228410

gnomAD: MAF of 0.000003160 (1/316464 alleles) in European (non-Finnish) population https://gnomad.broadinstitute.org/variant/chr12-6022833-A-G?dataset=gnomad_r4

Variant: c.4414G > C p.(Asp1472His)

HGVS: NM_000552.5:c.4414G>C (p.Asp1472His)

ClinVarID: 256679

CAID: CA6402534

gnomAD: MAF of 0.5076 (38011/74882 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6019004-C-G?dataset=gnomad_r4

Variant: c.6554G > A, p.(Arg2185Gln)

HGVS: NM_000552.5:c.6554G>A (p.Arg2185Gln)

ClinVarID: 100443

CAID: CA228748

gnomAD: MAF of 0.1927 (14427/74878 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-5993906-C-T?dataset=gnomad_r4

Case: Patient 24, Family I (Table 1.), F/92, Afro-Caribbean

DiseaseAssertion: VWD2A (IIE)

FamilyInfo: Patient 13 (F/65, Afro-Caribbean), Patient 21 (F/97, Afro-Caribbean), Patient 22 (F/67, Afro-Caribbean), Patient 23 (F/86, Afro-Caribbean), Patient 25 (F/62, Afro-Carribean) also from Family I. (Table 1.)

ParentalGenotype(s): NA

CasePresentingHPOs:

CaseHPOFreeRext: BAT =3, FVIII:C (IU/dL) = 61, VWF:Ag (IU/dL) = 30, VWF:Act (IU/dL) = 29

CaseNOTHPOs:

CaseNOTHPOFreeText: Blood group B+

CasePreviousTesting:

GenotypingMethod: All samples were analyzed by captured-based high throughput sequencing which was performed with a custom-design of the VWF gene provided by Twist BioScience (San Francisco, USA). It comprised all 52 exons, intronic flanking regions, promoter and 3’UTR region of the VWF gene. Libraries were prepared by using the Twist NGS target enrichment solution (Twist BioScience) according to the manufacturer protocol. Samples were analyzed on a NovaSeq 6000 sequencer (Illumina) with a median read depth of 2500X by using the 300-cycle S1 NovaSeq 6000seq reagent kit with 150-bp paired-end reads. The raw data were analyzed with Mutect21 and Vardict2 tools. The inhouse NGSreport software (CHU Lille) was used for data visualization, sequences check and conservation of variants with high quality metrics. In some cases, patients genomic DNA was screened for sequence variations (large deletions, insertions and duplications) by Multiplex Ligation-dependent Probe Amplification (MCR Holland).

PreviouslyPublished: NA

Gene: VWF

Variant: c.1530G > A, p.(Val510 =) p.

HGVS: NM_000552.5:c.1530G>A (p.Val510=)

ClinVarID:

CAID: CA6403368

gnomAD: MAF of 0.00002198 (2/91004 alleles) in South Asian population https://gnomad.broadinstitute.org/variant/chr12-6062957-C-T?dataset=gnomad_r4

Variant: c.1892C > T, p.(Ala631Val)

HGVS: NM_000552.5:c.1892C>T (p.Ala631Val)

ClinVarID: 422844

CAID: CA6403245

gnomAD: MAF of 0.001908 (137/71810 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6056910-G-A?dataset=gnomad_r4

Variant: c.2220G > A, p.(Met740Ile)

HGVS: NM_000552.5:c.2220G>A (p.Met740Ile)

ClinVarID: 100206

CAID: CA201316

gnomAD: MAF of 0.1816 (13626/75022 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6046784-C-T?dataset=gnomad_r4

Variant: c.2451T > A, p.(His817Gln)

HGVS: NM_000552.5:c.2451T>A (p.His817Gln)

ClinVarID: 100224

CAID: CA228345

gnomAD: MAF of 0.1150 (8626/75016 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6036483-A-T?dataset=gnomad_r4

Variant: c.3258C > T, p.(Tyr1086 =)

HGVS: NM_000552.5:c.3258C>T (p.Tyr1086=)

ClinVarID: 256664

CAID: CA6402788

gnomAD: MAF of 0.1284 (9131/71128 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6023752-G-A?dataset=gnomad_r4

Variant: c.3445T > C, p.(Cys1149Arg)

HGVS: NM_000552.5:c.3445T>C (p.Cys1149Arg)

ClinVarID: 309

CAID: CA228410

gnomAD: MAF of 0.000003160 (1/316464 alleles) in European (non-Finnish) population https://gnomad.broadinstitute.org/variant/chr12-6022833-A-G?dataset=gnomad_r4

Variant: c.4414G > C p.(Asp1472His)

HGVS: NM_000552.5:c.4414G>C (p.Asp1472His)

ClinVarID: 256679

CAID: CA6402534

gnomAD: MAF of 0.5076 (38011/74882 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6019004-C-G?dataset=gnomad_r4

Variant: c.6554G > A, p.(Arg2185Gln)

HGVS: NM_000552.5:c.6554G>A (p.Arg2185Gln)

ClinVarID: 100443

CAID: CA228748

gnomAD: MAF of 0.1927 (14427/74878 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-5993906-C-T?dataset=gnomad_r4

Case: Patient 20, Family M (Table 1.), M/80, Afro-Caribbean

DiseaseAssertion: VWD2A (IIE)

FamilyInfo: Patient 62 (F/42, Afro-Caribbean) also in Family M. (Table 1.)

ParentalGenotype(s): NA

CasePresentingHPOs:

CaseHPOFreeRext: BAT =10, FVIII:C (IU/dL) = NA, VWF:Ag (IU/dL) = 12, VWF:Act (IU/dL) = 10

CaseNOTHPOs:

CaseNOTHPOFreeText: Blood group O+

CasePreviousTesting:

GenotypingMethod: All samples were analyzed by captured-based high throughput sequencing which was performed with a custom-design of the VWF gene provided by Twist BioScience (San Francisco, USA). It comprised all 52 exons, intronic flanking regions, promoter and 3’UTR region of the VWF gene. Libraries were prepared by using the Twist NGS target enrichment solution (Twist BioScience) according to the manufacturer protocol. Samples were analyzed on a NovaSeq 6000 sequencer (Illumina) with a median read depth of 2500X by using the 300-cycle S1 NovaSeq 6000seq reagent kit with 150-bp paired-end reads. The raw data were analyzed with Mutect21 and Vardict2 tools. The inhouse NGSreport software (CHU Lille) was used for data visualization, sequences check and conservation of variants with high quality metrics. In some cases, patients genomic DNA was screened for sequence variations (large deletions, insertions and duplications) by Multiplex Ligation-dependent Probe Amplification (MCR Holland).

PreviouslyPublished: NA

Gene: VWF

Variant: c.1530G > A, p.(Val510 =) p.

HGVS: NM_000552.5:c.1530G>A (p.Val510=)

ClinVarID:

CAID: CA6403368

gnomAD: MAF of 0.00002198 (2/91004 alleles) in South Asian population https://gnomad.broadinstitute.org/variant/chr12-6062957-C-T?dataset=gnomad_r4

Variant: c.1892C > T, p.(Ala631Val)

HGVS: NM_000552.5:c.1892C>T (p.Ala631Val)

ClinVarID: 422844

CAID: CA6403245

gnomAD: MAF of 0.001908 (137/71810 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6056910-G-A?dataset=gnomad_r4

Variant: c.2220G > A, p.(Met740Ile)

HGVS: NM_000552.5:c.2220G>A (p.Met740Ile)

ClinVarID: 100206

CAID: CA201316

gnomAD: MAF of 0.1816 (13626/75022 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6046784-C-T?dataset=gnomad_r4

Variant: c.2451T > A, p.(His817Gln)

HGVS: NM_000552.5:c.2451T>A (p.His817Gln)

ClinVarID: 100224

CAID: CA228345

gnomAD: MAF of 0.1150 (8626/75016 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6036483-A-T?dataset=gnomad_r4

Variant: c.3445T > C, p.(Cys1149Arg)

HGVS: NM_000552.5:c.3445T>C (p.Cys1149Arg)

ClinVarID: 309

CAID: CA228410

gnomAD: MAF of 0.000003160 (1/316464 alleles) in European (non-Finnish) population https://gnomad.broadinstitute.org/variant/chr12-6022833-A-G?dataset=gnomad_r4

Variant: c.4414G > C p.(Asp1472His)

HGVS: NM_000552.5:c.4414G>C (p.Asp1472His)

ClinVarID: 256679

CAID: CA6402534

gnomAD: MAF of 0.5076 (38011/74882 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6019004-C-G?dataset=gnomad_r4

Variant: c.6554G > A, p.(Arg2185Gln

HGVS: NM_000552.5:c.6554G>A (p.Arg2185Gln)

ClinVarID: 100443

CAID: CA228748

gnomAD: MAF of 0.1927 (14427/74878 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-5993906-C-T?dataset=gnomad_r4

Case: Patient 50, Family X (Table 1.), F/47, Afro-Caribbean

DiseaseAssertion: VWD1

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs:

CaseHPOFreeRext: BAT = 10, FVIII:C (IU/dL) = 72, VWF:Ag (IU/dL) = 22, VWF:Act (IU/dL) = 28

CaseNOTHPOs:

CaseNOTHPOFreeText: Blood group O+

CasePreviousTesting:

GenotypingMethod: All samples were analyzed by captured-based high throughput sequencing which was performed with a custom-design of the VWF gene provided by Twist BioScience (San Francisco, USA). It comprised all 52 exons, intronic flanking regions, promoter and 3’UTR region of the VWF gene. Libraries were prepared by using the Twist NGS target enrichment solution (Twist BioScience) according to the manufacturer protocol. Samples were analyzed on a NovaSeq 6000 sequencer (Illumina) with a median read depth of 2500X by using the 300-cycle S1 NovaSeq 6000seq reagent kit with 150-bp paired-end reads. The raw data were analyzed with Mutect21 and Vardict2 tools. The inhouse NGSreport software (CHU Lille) was used for data visualization, sequences check and conservation of variants with high quality metrics. In some cases, patients genomic DNA was screened for sequence variations (large deletions, insertions and duplications) by Multiplex Ligation-dependent Probe Amplification (MCR Holland).

PreviouslyPublished: NA

Gene: VWF

Variant: c.3686T > G, p.(Val1229Gly)

HGVS: NM_000552.5(:c.3686T>G (p.Val1229Gly)

ClinVarID: 100274

CAID: CA228433

gnomAD: MAF of 0.01604 (1200/74796 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6019732-A-C?dataset=gnomad_r4

Variant: c.3692A > C, p.(Asn1231Thr)

HGVS: NM_000552.5:c.3692A>C (p.Asn1231Thr)

ClinVarID: 100275

CAID: CA228435

gnomAD: MAF of 0.01203 (900/74802 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/12-6019726-T-G?dataset=gnomad_r4

Variant: c.4414G > C p.(Asp1472His)

HGVS: NM_000552.5:c.4414G>C (p.Asp1472His)

ClinVarID: 256679

CAID: CA6402534

gnomAD: MAF of 0.5076 (38011/74882 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6019004-C-G?dataset=gnomad_r4

Case: Patient 10, Family G (Table 1.), M/22, Afro-Caribbean

DiseaseAssertion: VWD2A (IIE)

FamilyInfo: Patient 16 (F/58, Afro-Caribbean) and Patient 17 (F/79, Afro-Caribbean) also from Family G. (Table 1.)

ParentalGenotype(s): NA

CasePresentingHPOs:

CaseHPOFreeRext: BAT =1, FVIII:C (IU/dL) = 26, VWF:Ag (IU/dL) = 15, VWF:Act (IU/dL) = 4

CaseNOTHPOs:

CaseNOTHPOFreeText: Blood group O+

CasePreviousTesting:

GenotypingMethod: All samples were analyzed by captured-based high throughput sequencing which was performed with a custom-design of the VWF gene provided by Twist BioScience (San Francisco, USA). It comprised all 52 exons, intronic flanking regions, promoter and 3’UTR region of the VWF gene. Libraries were prepared by using the Twist NGS target enrichment solution (Twist BioScience) according to the manufacturer protocol. Samples were analyzed on a NovaSeq 6000 sequencer (Illumina) with a median read depth of 2500X by using the 300-cycle S1 NovaSeq 6000seq reagent kit with 150-bp paired-end reads. The raw data were analyzed with Mutect21 and Vardict2 tools. The inhouse NGSreport software (CHU Lille) was used for data visualization, sequences check and conservation of variants with high quality metrics. In some cases, patients genomic DNA was screened for sequence variations (large deletions, insertions and duplications) by Multiplex Ligation-dependent Probe Amplification (MCR Holland).

PreviouslyPublished: NA

Gene: VWF

Variant: c.1530G > A, p.(Val510 =) p.

HGVS: NM_000552.5:c.1530G>A (p.Val510=)

ClinVarID:

CAID: CA6403368

gnomAD: MAF of 0.00002198 (2/91004 alleles) in South Asian population https://gnomad.broadinstitute.org/variant/chr12-6062957-C-T?dataset=gnomad_r4

Variant: c.1892C > T, p.(Ala631Val)

HGVS: NM_000552.5:c.1892C>T (p.Ala631Val)

ClinVarID: 422844

CAID: CA6403245

gnomAD: MAF of 0.001908 (137/71810 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6056910-G-A?dataset=gnomad_r4

Variant: c.2220G > A, p.(Met740Ile)

HGVS: NM_000552.5:c.2220G>A (p.Met740Ile)

ClinVarID: 100206

CAID: CA201316

gnomAD: MAF of 0.1816 (13626/75022 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6046784-C-T?dataset=gnomad_r4

Variant: c.2451T > A, p.(His817Gln)

HGVS: NM_000552.5:c.2451T>A (p.His817Gln)

ClinVarID: 100224

CAID: CA228345

gnomAD: MAF of 0.1150 (8626/75016 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6036483-A-T?dataset=gnomad_r4

Variant: c.3445T > C, p.(Cys1149Arg)

HGVS: NM_000552.5:c.3445T>C (p.Cys1149Arg)

ClinVarID: 309

CAID: CA228410

gnomAD: MAF of 0.000003160 (1/316464 alleles) in European (non-Finnish) population https://gnomad.broadinstitute.org/variant/chr12-6022833-A-G?dataset=gnomad_r4

Variant: c.4414G > C p.(Asp1472His)

HGVS: NM_000552.5:c.4414G>C (p.Asp1472His)

ClinVarID: 256679

CAID: CA6402534

gnomAD: MAF of 0.5076 (38011/74882 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6019004-C-G?dataset=gnomad_r4

Variant: c.6554G > A, p.(Arg2185Gln)

HGVS: NM_000552.5:c.6554G>A (p.Arg2185Gln)

ClinVarID: 100443

CAID: CA228748

gnomAD: MAF of 0.1927 (14427/74878 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-5993906-C-T?dataset=gnomad_r4

Case: Patient 27, Family N (Table 1.), M/20, Afro-Caribbean

DiseaseAssertion: VWD2A (IIE)

FamilyInfo: Patient 26 (F/58, Afro-Caribbean) also in Family N. (Table 1.)

ParentalGenotype(s): NA

CasePresentingHPOs:

CaseHPOFreeRext: BAT =2, FVIII:C (IU/dL) = 18, VWF:Ag (IU/dL) = 18, VWF:Act (IU/dL) = 6

CaseNOTHPOs:

CaseNOTHPOFreeText: Blood group O+

CasePreviousTesting:

GenotypingMethod: All samples were analyzed by captured-based high throughput sequencing which was performed with a custom-design of the VWF gene provided by Twist BioScience (San Francisco, USA). It comprised all 52 exons, intronic flanking regions, promoter and 3’UTR region of the VWF gene. Libraries were prepared by using the Twist NGS target enrichment solution (Twist BioScience) according to the manufacturer protocol. Samples were analyzed on a NovaSeq 6000 sequencer (Illumina) with a median read depth of 2500X by using the 300-cycle S1 NovaSeq 6000seq reagent kit with 150-bp paired-end reads. The raw data were analyzed with Mutect21 and Vardict2 tools. The inhouse NGSreport software (CHU Lille) was used for data visualization, sequences check and conservation of variants with high quality metrics. In some cases, patients genomic DNA was screened for sequence variations (large deletions, insertions and duplications) by Multiplex Ligation-dependent Probe Amplification (MCR Holland).

PreviouslyPublished: NA

Gene: VWF

Variant: c.1530G > A, p.(Val510 =)

HGVS: NM_000552.5:c.1530G>A (p.Val510=)

ClinVarID:

CAID: CA6403368

gnomAD: MAF of 0.00002198 (2/91004 alleles) in South Asian population https://gnomad.broadinstitute.org/variant/chr12-6062957-C-T?dataset=gnomad_r4

Variant: c.1892C > T, p.(Ala631Val)

HGVS: NM_000552.5:c.1892C>T (p.Ala631Val)

ClinVarID: 422844

CAID: CA6403245

gnomAD: MAF of 0.001908 (137/71810 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6056910-G-A?dataset=gnomad_r4

Variant: c.2220G > A, p.(Met740Ile)

HGVS: NM_000552.5:c.2220G>A (p.Met740Ile)

ClinVarID: 100206

CAID: CA201316

gnomAD: MAF of 0.1816 (13626/75022 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6046784-C-T?dataset=gnomad_r4

Variant: c.2451T > A, p.(His817Gln)

HGVS: NM_000552.5:c.2451T>A (p.His817Gln)

ClinVarID: 100224

CAID: CA228345

gnomAD: MAF of 0.1150 (8626/75016 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6036483-A-T?dataset=gnomad_r4

Variant: c.2510C > A, p.(Ala837Asp)

HGVS: NM_000552.5:c.2510C>A (p.Ala837Asp)

ClinVarID: 993127

CAID: CA6403049

gnomAD: MAF of 0.02329 (1748/75040 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6036424-G-T?dataset=gnomad_r4

Variant: c.3445T > C, p.(Cys1149Arg)

HGVS: NM_000552.5:c.3445T>C (p.Cys1149Arg)

ClinVarID: 309

CAID: CA228410

gnomAD: MAF of 0.000003160 (1/316464 alleles) in European (non-Finnish) population https://gnomad.broadinstitute.org/variant/chr12-6022833-A-G?dataset=gnomad_r4

Variant: c.4414G > C p.(Asp1472His)

HGVS: NM_000552.5:c.4414G>C (p.Asp1472His)

ClinVarID: 256679

CAID: CA6402534

gnomAD: MAF of 0.5076 (38011/74882 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6019004-C-G?dataset=gnomad_r4

Variant: c.5173C > T, p.(Pro1725Ser)

HGVS: NM_000552.5:c.5173C>T (p.Pro1725Ser)

ClinVarID: 619937

CAID: CA6402355

gnomAD: MAF of 0.02447 (1836/75022 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6016654-G-A?dataset=gnomad_r4

Variant: c.6554G > A, p.(Arg2185Gln)

HGVS: NM_000552.5:c.6554G>A (p.Arg2185Gln)

ClinVarID: 100443

CAID: CA228748

gnomAD: MAF of 0.1927 (14427/74878 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-5993906-C-T?dataset=gnomad_r4

Case: Patient 36, Family R (Table 1.), M/22, Afro-Caribbean

DiseaseAssertion: VWD2A (IIE)

FamilyInfo: Patient 37 (M/20, Afro-Caribbean) and Patient 38 (F/51, Afro-Caribbean) also from Family R. (Table 1.)

ParentalGenotype(s): NA

CasePresentingHPOs:

CaseHPOFreeRext: BAT = 1, FVIII:C (IU/dL) = 28, VWF:Ag (IU/dL) = 15, VWF:Act (IU/dL) = 10

CaseNOTHPOs:

CaseNOTHPOFreeText: Blood group O+

CasePreviousTesting:

GenotypingMethod: All samples were analyzed by captured-based high throughput sequencing which was performed with a custom-design of the VWF gene provided by Twist BioScience (San Francisco, USA). It comprised all 52 exons, intronic flanking regions, promoter and 3’UTR region of the VWF gene. Libraries were prepared by using the Twist NGS target enrichment solution (Twist BioScience) according to the manufacturer protocol. Samples were analyzed on a NovaSeq 6000 sequencer (Illumina) with a median read depth of 2500X by using the 300-cycle S1 NovaSeq 6000seq reagent kit with 150-bp paired-end reads. The raw data were analyzed with Mutect21 and Vardict2 tools. The inhouse NGSreport software (CHU Lille) was used for data visualization, sequences check and conservation of variants with high quality metrics. In some cases, patients genomic DNA was screened for sequence variations (large deletions, insertions and duplications) by Multiplex Ligation-dependent Probe Amplification (MCR Holland).

PreviouslyPublished: NA

Gene: VWF

Variant: c.1530G > A, p.(Val510 =) p.

HGVS: NM_000552.5:c.1530G>A (p.Val510=)

ClinVarID:

CAID: CA6403368

gnomAD: MAF of 0.00002198 (2/91004 alleles) in South Asian population https://gnomad.broadinstitute.org/variant/chr12-6062957-C-T?dataset=gnomad_r4

Variant: c.1892C > T, p.(Ala631Val)

HGVS: NM_000552.5:c.1892C>T (p.Ala631Val)

ClinVarID: 422844

CAID: CA6403245

gnomAD: MAF of 0.001908 (137/71810 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6056910-G-A?dataset=gnomad_r4

Variant: c.2220G > A, p.(Met740Ile)

HGVS: NM_000552.5:c.2220G>A (p.Met740Ile)

ClinVarID: 100206

CAID: CA201316

gnomAD: MAF of 0.1816 (13626/75022 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6046784-C-T?dataset=gnomad_r4

Variant: c.2451T > A, p.(His817Gln)

HGVS: NM_000552.5:c.2451T>A (p.His817Gln)

ClinVarID: 100224

CAID: CA228345

gnomAD: MAF of 0.1150 (8626/75016 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6036483-A-T?dataset=gnomad_r4

Variant: c.3445T > C, p.(Cys1149Arg)

HGVS: NM_000552.5:c.3445T>C (p.Cys1149Arg)

ClinVarID: 309

CAID: CA228410

gnomAD: MAF of 0.000003160 (1/316464 alleles) in European (non-Finnish) population https://gnomad.broadinstitute.org/variant/chr12-6022833-A-G?dataset=gnomad_r4

Variant: c.4414G > C p.(Asp1472His)

HGVS: NM_000552.5:c.4414G>C (p.Asp1472His)

ClinVarID: 256679

CAID: CA6402534

gnomAD: MAF of 0.5076 (38011/74882 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6019004-C-G?dataset=gnomad_r4

Variant: c.6554G > A, p.(Arg2185Gln)

HGVS: NM_000552.5:c.6554G>A (p.Arg2185Gln)

ClinVarID: 100443

CAID: CA228748

gnomAD: MAF of 0.1927 (14427/74878 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-5993906-C-T?dataset=gnomad_r4

Case: Croatian adult patient

DiseaseAssertion: VWD1

FamilyInfo: No variant detected in a family member

ParentalGenotype(s): Not specified

CasePresentingHPOs: HP:0001892, HP:0011890, HP:0000132, HP:0002239, HP:0000790, HP:0001342

CaseHPOFreeText: Reduced VWF:Ag of 48.5%, VWF:GPIbM of 36.6% and VWF:CBA of 32.4%. Normal FVIII:C of 104%. Normal multimer distribution.

CaseNOTHPOs: Not specified

CaseNOTHPOFreeText: Normal multimer size distribution (tested in Agarose gel).

CasePreviousTesting: Not reported

GenotypingMethod: Illumina NGS, custom designed panel covering all 52 exons as well as intronic flanking regions and promoter region of VWF gene.

PreviouslyPublished: None

Gene: VWF

Variant: c.6504C>A

HGVS: NM_000552.4:c.6504C>A (p.Cys2168Ter)

ClinVarID: Not available

CAID: CA383491048

gnomAD: Not available

Case: Croatian adult patient

DiseaseAssertion: VWD1

FamilyInfo: Not specified

ParentalGenotype(s): Not specified

CasePresentingHPOs: HP:0001892, HP:0011890, HP:0000132, HP:0002239, HP:0000790, HP:0001342

CaseHPOFreeText: Reduced VWF:Ag of 27.2%, VWF:GPIbM of 28.7%, FVIII:C of 43% and VWF:CBA of 18%. Normal multimer distribution.

CaseNOTHPOs: Not specified

CaseNOTHPOFreeText: Normal multimer size distribution (tested in Agarose gel).

CasePreviousTesting: Not reported

GenotypingMethod: Illumina NGS, custom designed panel covering all 52 exons as well as intronic flanking regions and promoter region of VWF gene.

PreviouslyPublished: None

Gene: VWF

Variant: c.6596G>A

HGVS: NM_000552.4:c.6596G>A (p.Cys2199Tyr)

ClinVarID: Not available

CAID: CA383490627

gnomAD: Not available

Case: Croatian adult patient

DiseaseAssertion: VWD3

FamilyInfo: Not specified

ParentalGenotype(s): Not specified

CasePresentingHPOs: HP:0001892, HP:0011890, HP:0000132, HP:0002239, HP:0000790, HP:0001342

CaseHPOFreeText: <4.0% VWF:Ag, <4.0% VWF:GPIbM, 5% FVIII:C and <1% VWF:CBA.

CaseNOTHPOs: Not specified

CaseNOTHPOFreeText: Not specified.

CasePreviousTesting: Not reported

GenotypingMethod: Illumina NGS, custom designed panel covering all 52 exons as well as intronic flanking regions and promoter region of VWF gene.

PreviouslyPublished: None

Gene: VWF

Variant: c.571T>C

HGVS: NM_000552.4:c.571T>C (p.Trp191Arg)

ClinVarID: Not available

CAID: CA383514932

gnomAD: Not available

Case: T3-3, male, 27yo

DiseaseAssertion: VWD3

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeText: Blood type: A+, bleeding score = 29, VWF:Ag (IU/mL) = 0.02; VWF:RCo (IU/mL) = 0.04; FVIII:C (IU/mL) = 0.01

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: qRT-PCR

PreviouslyPublished:

Gene: VWF

Variant 1: c.3939G>A (p.Trp1313Ter)

HGVS: NM_000552.5:c.3939G>A (p.Trp1313Ter)

ClinVarID: n/a

CAID: CA383506120; https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA383506120

gnomAD: absent

Variant 2: c.5842+1G>C

HGVS: NM_000552.5:c.5842+1G>C

ClinVarID: n/a

CAID: CA383492977; https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA383492977

gnomAD: absent

Case: T1-1, female, 33yo

DiseaseAssertion: VWD1

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeText: Blood type: O+, bleeding score = 4, VWF:Ag (IU/mL) = 0.27; VWF:RCo (IU/mL) = 0.19; FVIII:C (IU/mL) = 0.53

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: qRT-PCR

PreviouslyPublished:

Gene: VWF

Variant: c.1897T>C (.Cys633Arg)

HGVS: NM_000552.5:c.1897T>C (.Cys633Arg)

ClinVarID: n/a

CAID: CA383496953; https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA383496953

gnomAD: absent

Case: 2N, female, 33yo

DiseaseAssertion: VWD2N

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeText: Blood type: A, bleeding score = 8, VWF:Ag (IU/mL) = 0.97; VWF:RCo (IU/mL) = 1.20; FVIII:C (IU/mL) = 0.44

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: qRT-PCR

PreviouslyPublished:

Gene: VWF

Variant 1: c.2561G>A (p.Arg854Gln)

Variant 2: unknown

HGVS: NM_000552.5(VWF):c.2561G>A (p.Arg854Gln)

ClinVarID: 296; https://www.ncbi.nlm.nih.gov/clinvar/variation/296/?new_evidence=false

CAID:

gnomAD: MAF = 0.005692 in European (Finnish) population; 2 homozygotes

Case: P35, Chinese, female, 60yo

DiseaseAssertion: VWD3

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type O blood, bleeding score = 20; VWF:Ag (%) = 1.5, VWF:RCo (%) = 1.3, FVIII:C (%) = 3.1, VWF:CB (%) = 1.1, VWFpp (%) = 1.3, VWF:RCo/VWF:Ag = 0.9, VWF:CB/VWF:Ag = 0.7, VWFpp/VWF:Ag = 0.9, FVIII:C/VWF:Ag = 2.1

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.5870delA - unregistered variant

HGVS: NA

ClinVarID: NA

CAID: NA

gnomAD: NA

Case: P68, Chinese, female, 12yo

DiseaseAssertion: VWD2A

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type A blood, bleeding score = 6; VWF:Ag (%) = 14.1, VWF:RCo (%) = 1.3, FVIII:C (%) = 42.3, VWF:CB (%) = 7.3, VWFpp (%) = 16.9, VWF:RCo/VWF:Ag = 0.1, VWF:CB/VWF:Ag = 0.5, VWFpp/VWF:Ag = 1.2, FVIII:C/VWF:Ag = 3.0

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.3830A>G (p.Asp1277Gly)

HGVS: NM_000552.5:c.3830A>G (p.Asp1277Gly)

ClinVarID: NA

CAID: CA383506912; http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA383506912

gnomAD: absent

Case: P86, Chinese, female, 20yo

DiseaseAssertion: VWD3

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type O blood, bleeding score = 14; VWF:Ag (%) = 0.5, VWF:RCo (%) = <0.5, FVIII:C (%) = 5.7, VWF:CB (%) = <0.5, VWFpp (%) = <0.5`, VWF:RCo/VWF:Ag = NA, VWF:CB/VWF:Ag = NA, VWFpp/VWF:Ag = NA, FVIII:C/VWF:Ag = 11.4

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.322A>T (p.Arg108Ter)

HGVS: NM_000552.5:c.322A>T (p.Arg108Ter)

ClinVarID: NA

CAID: CA383519152; http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA383519152

gnomAD: absent

Variant: Exons 6–16 del - unregistered variant

HGVS:

ClinVarID:

CAID:

gnomAD:

Case: 2A-3

DiseaseAssertion: VWD2A

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: AcuStar RCo/Ag = 0.33; AcuStar CB/Ag = 0.08; ELISA CB/Ag = 0.25

CaseHPOFreeText:

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: not described

PreviouslyPublished: PMID: 1537829

Gene: VWF

Variant: c.4789C>T (p.Arg1597Trp)

HGVS: NM_000552.5(VWF):c.4789C>T (p.Arg1597Trp)

ClinVarID: 285; https://www.ncbi.nlm.nih.gov/clinvar/variation/285/?new_evidence=false

CAID:

gnomAD: absent

Case: 11, M, 48, Italian

DiseaseAssertion: VWD type 3

FamilyInfo: Consanguinity: yes

ParentalGenotype: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: VWF:Ag (U/dl): <1, Bleeding symptoms: Mild

CaseNotHPOs: n/a

CaseNotHPOFreeText: Anti-VWF alloantibodies: no

CasePreviousTesting: n/a

Gene: VWF

Variant:

6182delT (FS), Exon 36, Homozygous

Case: 1, F, 38, Italian

DiseaseAssertion: VWD type 3

FamilyInfo: Consanguinity: no

ParentalGenotype: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: VWF:Ag (U/dl): <1, Bleeding symptoms: Severe

CaseNotHPOs: n/a

CaseNotHPOFreeText: Anti-VWF alloantibodies: no

CasePreviousTesting: n/a

Gene: VWF

Variant:

276delT (FS), Exon 4

2157delA (FS), Exon 16

Homozygous

Case: 40, M, 26, Indian

DiseaseAssertion: VWD type 3

FamilyInfo: Consanguinity: No

ParentalGenotype: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: VWF:Ag (U/dl): <1, Bleeding symptoms: Mild

CaseNotHPOs: n/a

CaseNotHPOFreeText: Anti-VWF alloantibodies: no

CasePreviousTesting: n/a

Gene: VWF

Variant:

5053+1G→A (intronic), Exon 28

7294delGT (FS), Exon 43

Compound Heterozygous

Note: The article assumed that 5053+1G→A causes a frameshift mutation. No potential splice site mutation was confirmed at the mRNA level; “Splice Site Prediction program” found all mutations likely to disrupt normal splicing. No possible splice site mutation could be identified on 100 chromosomes from a group of 50 normal subjects with same genetic background as patients, excluding the possibility that these mutations represent common polymorphisms.

Case: 16, F, 16, Iranian

DiseaseAssertion: VWD type 3

FamilyInfo: Consanguinity: Yes

ParentalGenotype: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: VWF:Ag (U/dl): 1, Bleeding symptoms: Severe

CaseNotHPOs: n/a

CaseNotHPOFreeText: Anti-VWF alloantibodies: no

CasePreviousTesting: n/a

Gene: VWF

Variant:

1093C→T (Arg365X), Exon 9, Homozygous

Case: 34, M, 15, Indian

DiseaseAssertion: VWD type 3

FamilyInfo: Consanguinity: No

ParentalGenotype: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: VWF:Ag (U/dl): <1, Bleeding symptoms: Mild

CaseNotHPOs: n/a

CaseNotHPOFreeText: Anti-VWF alloantibodies: no

CasePreviousTesting: n/a

Gene: VWF

Variant:

7300C→T (Arg2434X), Exon 43, Homozygous

Note: It is possible that the homozygous zygosity was detected from a PCR artifact (e.g. presence of a large gene deletion or point mutation that prevents amplification); different sets of primers were used, providing conformation and excluding the possibility for a PCR artifact due to point mutation.

PMID: 19687512

Gene: VWF

HGNCID: 12726

PMID: 28789675

Gene: VWF

HGNCID: 12726

Article Information:

PMID: 31320553

Gene: VWF

HGNCID: 12726

Case: Proband 1 (P1)

DiseaseAssertion: VWD III

FamilyInfo:

Father

Asp141Asn impaired multimerization of von Willebrand factor; reduced oxidoreductase activity

VWF are retained in the ER and fail to be transported to the Golgi

APTT ratio (seconds): 1.09

PT ratio (seconds): 1.15

TT ratio (seconds): 1.24

VWF: Ag (IU/dL): 48.4

VWF:RCo (IU/dL): 50.2

FVIII:C (IU/dL): 73.5

BS: 0

Mother

Gly39Arg impaired multimerization of von Willebrand factor; reduced oxidoreductase activity

VWF are retained in the ER and fail to be transported to the Golgi

APTT ratio (seconds): 1.12

PT ratio (seconds): 1.05

TT ratio (seconds): 0.91

VWF: Ag (IU/dL): 30.3

VWF:RCo (IU/dL): 36.4

FVIII:C (IU/dL): 50.6

BS: 1

ParentalGenotype: n/a

Father: Asp141Asn, Heterozygous

Mother: Gly39Arg, Heterozygous

CasePresentingHPOs: n/a

CaseHPOFreeText:

Asp141Asn and Gly39Arg impaired multimerization; reduced oxidoreductase activity; undetectable von Willebrand factor (VWF) multimer

VWF are retained in the ER and fail to be transported to the Golgi

APTT ratio (seconds): 2.24

PT ratio (seconds): 1.07

TT ratio (seconds): 0.97

VWF: Ag (IU/dL): 1.0

VWF:RCo (IU/dL): 2.3

FVIII:C (IU/dL): 2.0

BS: 6

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

Gene: VWF

Variant:

Asp141Asn

Gly39Arg

Compound heterozygous

PMID: 36324358

Gene: SLC4A1

HGNCID: 12726

Case: 14, F, 2 years, Indian

DiseaseAssertion: VWD type 3

FamilyInfo: Consanguinity: yes, family history of disease

ParentalGenotype: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: FVIII:C: (U/dl): 3, VWF:Ag (U/dl): 2.6, Bleeding Score: 6

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

Gene: VWF

Variant:

c.5335C>T (p.Arg1779*), Exon 31, Heterozygous

Case: 5, F, 49 years, Indian

DiseaseAssertion: VWD type 3

FamilyInfo: Consanguinity: no, family history of disease

ParentalGenotype: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: FVIII:C: (U/dl): <1, VWF:Ag (U/dl): <1, Bleeding Score: 13

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

Gene: VWF

Variant:

c.1093C>T (p.Arg365*), Exon 9, Homozygous

Case: 7, F, 4 years, Indian

DiseaseAssertion: VWD type 3

FamilyInfo: Consanguinity: yes, no family history of disease

ParentalGenotype: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: FVIII:C: (U/dl): <1, VWF:Ag (U/dl): <1, Bleeding Score: 24

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

Gene: VWF

Variant:

c.1117C>T (p.Arg373*), Exon 10, Homozygous

Case: 51, F, 22 years, Indian

DiseaseAssertion: VWD type 3

FamilyInfo: no family history of disease, Consanguinity: no

ParentalGenotype: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: FVIII:C: (U/dl): <1, VWF:Ag (U/dl): 4.8, Bleeding Score: 9

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

Gene: VWF

Variant:

c.3379+1G>A, Exon 25

Heterozygous

Case: 46, F, 5 years, Indian

DiseaseAssertion: VWD type 3

FamilyInfo: family history of disease, Consanguinity: no

ParentalGenotype: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: FVIII:C: (U/dl): 2.5, VWF:Ag (U/dl): 3.4, Bleeding Score: 32

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

Gene: VWF

Variant:

c.3686T>G (p.Val1229Gly), Exon 28

c.3692A>C (p.Asn1231Thr), Exon 28

c.3789G>A (p.Ser1263Ser), Exon 28

c.3797C>T (p.Pro1266Leu), Exon 28

c.3835G>A (p.Val1279Ile), Exon 28

c.3862C>G (p.Leu1288Val), Exon 28

Heterozygous

Case: 67, M, 13 years, Indian

DiseaseAssertion: VWD type 3

FamilyInfo: family history of disease, Consanguinity: yes

ParentalGenotype: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: FVIII:C: (U/dl): <1, VWF:Ag (U/dl): 2.6, Bleeding Score: 7

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

Gene: VWF

Variant:

c.3686T>G (p.Val1229Gly), Exon 28

c.3692A>C (p.Asn1231Thr), Exon 28

c.3931C>T (p.Gln1311*), Exon 28

Homozygous

Case: 24, F, 0.8 years, Indian

DiseaseAssertion: VWD type 3

FamilyInfo: Consanguinity: yes, no family history of disease

ParentalGenotype: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: FVIII:C: (U/dl): 2.4, VWF:Ag (U/dl): 2, Bleeding Score: 3

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

Gene: VWF

Variant:

c.1693C>T (p.Gln565*), Exon 14, Homozygous

Case: 85, F, 6 years, Indian

DiseaseAssertion: VWD type 3

FamilyInfo: no family history of disease, Consanguinity: yes

ParentalGenotype: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: FVIII:C: (U/dl): <1, VWF:Ag (U/dl): 2, Bleeding Score: 2

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

Gene: VWF

Variant:

c.4578G>T (p.Gln1526His), Exon 28

Heterozygous

Case: 32, M, 18 years, Indian

DiseaseAssertion: VWD type 3

FamilyInfo: no family history of disease, Consanguinity: no

ParentalGenotype: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: FVIII:C: (U/dl): 3.2, VWF:Ag (U/dl): <1, Bleeding Score: 12

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

Gene: VWF

Variant:

c.2908delC (p.Leu970del), Exon 22, Homozygous

Case: 30, M, 1.1 years, Indian

DiseaseAssertion: VWD type 3

FamilyInfo: Consanguinity: yes, no family history of disease

ParentalGenotype: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: FVIII:C: (U/dl): <1, VWF:Ag (U/dl): <1, Bleeding Score: 4

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

Gene: VWF

Variant:

c.3931C>T (p.Gln1311*), Exon 28, Homozygous

Case: 11, F, 13 years, Indian

DiseaseAssertion: VWD type 3

FamilyInfo: Consanguinity: no, no family history of disease

ParentalGenotype: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: FVIII:C: (U/dl): 1, VWF:Ag (U/dl): 2.3, Bleeding Score: 11

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

Gene: VWF

Variant:

c.5335C>T (p.Arg1779*), Exon 31, Homozygous

Case:n.a.

DiseaseAssertion:VWD 2A/M

FamilyInfo:n.a.

ParentalGenotype(s):n.a.

CasePresentingHPOs:n.a.

CaseHPOFreeRext:n.a.

CaseNOTHPOs:n.a.

CaseNOTHPOFreeText:n.a.

CasePreviousTesting:n.a.

GenotypingMethod: n.a.

PreviouslyPublished: If applicable. n.a.

Gene:VWF

Variant: c.4120C > T

HGVS: NM_000552.5:c.4120C>T

ClinVarID:n.a.

CAID:n.a.

gnomAD:n.a.

Case: n.a.

DiseaseAssertion: VWD 2A/M

FamilyInfo:n.a.

ParentalGenotype(s):n.a.

CasePresentingHPOs:n.a.

CaseHPOFreeRext:n.a.

CaseNOTHPOs:n.a.

CaseNOTHPOFreeText:n.a.

CasePreviousTesting:n.a.

GenotypingMethod:n.a.

PreviouslyPublished: If applicable. n.a.

Gene:VWF

Variant:NM_000552.5(VWF):c.3943C>T (p.Arg1315Cys)

HGVS:NM_000552.5:c.3943C>T

ClinVarID:100310

CAID:n.a.

gnomAD:n.a.

PMID: 28756118

Gene: VWF

HGNCID: 12726

Case: T112, M, 48

DiseaseAssertion: VWD type 3

FamilyInfo: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: Bleeding Score: 4 (Kruskal–Wallis followed by Mann–Whitney U post-hoc testing Post-hoc testing ), VWF:Ag (IU/ml): 0.04, VWF:RCo (IU/ml): 0.04, FVIII:C (IU/ml): 0.08

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

Gene: VWF

Variant:

c.8418_8419insTCCC (p.Ser2807 fs), Exon 52, Homozygous

Note: ELISA-based assay for detecting alloantibodies, genomic analysis via sequencing of leukocytes for the VWF gene including exons 1-52 and about 1.5 km of VWF promoter, PCR amplification for variant confirmation, SALSA-MLPAVWF assay evaluation for partial/total gene deletions when sequencing did not reveal pathogenic explanation

Case: T032, F, 19

DiseaseAssertion: VWD type 3

FamilyInfo: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: Bleeding Score: 13(Kruskal–Wallis followed by Mann–Whitney U post-hoc testing Post-hoc testing ), VWF:Ag (IU/ml): 0.01, VWF:RCo (IU/ml): 0.00, FVIII:C (IU/ml) : 0.01

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

Gene: VWF

Variant:

c.3379 + 1 G>A, Exon 25, Heterozygous

Note: ELISA-based assay for detecting alloantibodies, genomic analysis via sequencing of leukocytes for the VWF gene including exons 1-52 and about 1.5 km of VWF promoter, PCR amplification for variant confirmation, SALSA-MLPAVWF assay evaluation for partial/total gene deletions when sequencing did not reveal pathogenic explanation

Case: T121, M, 62

DiseaseAssertion: VWD type 3

FamilyInfo: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: Bleeding Score: 7 (Kruskal–Wallis followed by Mann–Whitney U post-hoc testing Post-hoc testing ), VWF:Ag (IU/ml): 0.02, VWF:RCo (IU/ml): 0.05, FVIII:C (IU/ml): 0.06

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

Gene: VWF

Variant:

c.7399C>T (p.Gln2467*), Exon 43

c.8418_8419insTCCC (p.Ser2807 fs), Exon 52

Compound heterozygous

Note: ELISA-based assay for detecting alloantibodies, genomic analysis via sequencing of leukocytes for the VWF gene including exons 1-52 and about 1.5 km of VWF promoter, PCR amplification for variant confirmation, SALSA-MLPAVWF assay evaluation for partial/total gene deletions when sequencing did not reveal pathogenic explanation

Case: T085, M, 17

DiseaseAssertion: VWD type 3

FamilyInfo: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: Bleeding Score: 23 (Kruskal–Wallis followed by Mann–Whitney U post-hoc testing Post-hoc testing ), VWF:Ag (IU/ml): 0.04, VWF:RCo (IU/ml): 0.03, FVIII:C (IU/ml): 0.01

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

Gene: VWF

Variant:

c.1926G>A (p.Trp642*), Exon 15

c.2438dupG (p.Gly813 fs), Exon 18

Compound heterozygous

Note: ELISA-based assay for detecting alloantibodies, genomic analysis via sequencing of leukocytes for the VWF gene including exons 1-52 and about 1.5 km of VWF promoter, PCR amplification for variant confirmation, SALSA-MLPAVWF assay evaluation for partial/total gene deletions when sequencing did not reveal pathogenic explanation

PMID: 29115006

Gene: VWF

HGNCID: 12726

Case: Patient C

DiseaseAssertion: VWD2N

FamilyInfo: Family 2

ParentalGenotype(s):

CasePresentingHPOs: HP:0012147, HP:0030129, HP:0030130, HP:0011871

CaseHPOFreeText: PTsec = 38.0, FVIII U/dL = 37.6, FVIII ratio = 0.26, VWF:Ag U/dL = 146.2, VWF:FVIIIB U/dL = 34.0, VWF:FVIIIB ratio = 0.20, VWF:CB U/dL = 157.5, VWF:RCo U/dL = 137.4, RIPA % = 87.9, PlatVWF:Ag U/dL = 102.7

CaseNOTHPOs:

CaseNOTHPOFreeText: n/a

CasePreviousTesting: n/a

GenotypingMethod: "Genetic analysis was performed on exons 17-20 of the VWF gene as previously described" (PMID: 12393698)

PreviouslyPublished: n/a

Gene: VWF

Variant: c.2561G>A (p.Arg854Gln); homozygous

HGVS: NM_000552.5(VWF):c.2561G>A (p.Arg854Gln)

ClinVarID: 296; https://www.ncbi.nlm.nih.gov/clinvar/variation/296/?new_evidence=false

CAID: n/a

gnomAD: MAF (European, Finnish) = 0.005692; https://gnomad.broadinstitute.org/variant/12-6143978-C-T

PMID: 28236847

Gene: VWF

HGNCID: 12726

Case#: 07003, Age 29, Female, Blood Type O+ (Table S3)

Disease Assertion: VWD1

FamilyInfo: The patient is the only member of Family#0703.

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: VWF:Ag: 25, VWF:RCo:24.9, FVIII:C: 50, VWF:CB:28

CaseNotHPOs: N/A

CaseNotHPOFreeText: Bleeding Score 5

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.5170+10C>T and NM_000552.4:c.8254-5T>G

ClinVar: 100418 ClinVar1

CAID: CA228702 and CA923726359 CAID1 CAID2

gnomAD: MAF of 0.01298 (326/ 25116 alleles) in the European (Finnish) population (CA228702).

gnomAD1

Case#: 35011, Age 46, Male, Blood Type O+ (Table S3)

Disease Assertion: VWD 1

FamilyInfo: The patient is one of 3 members of Family#3505. All have VWD type 1 and patient# 35013 has an additional intronic variant that the other two family members don't have.

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: VWF:Ag: 18, VWF:RCo: 14, FVIII:C: 42, VWF:CB: 12

CaseNotHPOs: N/A

CaseNotHPOFreeText: Bleeding Score 2

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.5198T>C (p.Leu1733Pro) and NM_000552.4(VWF):c.6187C>T (p.Pro2063Ser)

ClinVar: 100436 ClinVar

CAID: CA383496267 and CA202650 CAID1 CAID2

gnomAD: MAF of 0.04854 (1486/30616 alleles) in the South Asian population (CA202650). gnomAD

Case#: 05008, Age 30, Male, Blood Type A+ (Table S3)

Disease Assertion: VWD1

FamilyInfo: Patient is the only member of Family #0507

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding Score 2, VWF:Ag: 5.8, VWF:RCo:5, FVIII:C: 7.4, VWF:CB:6.1

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.3614G>A (p.Arg1205His)

ClinVar: 308 ClinVar

CAID: CA114160 CAID

gnomAD: N/A

Case#: 01025, Age 54, Male, Blood type AB- (Table S3)

Disease Assertion: VWD 1

FamilyInfo: Not listed

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding score 5, VWF:Ag: 27, VWF:RCo: 36, FVIII:C: 45, VWF:CB: 25

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: Not determined

ClinVar: N/A

CAID: N/A

gnomAD: N/A

Case#: 16001, Age 50, Female, Blood Type A+

Disease Assertion: VWD 1

FamilyInfo: The patient is one of two members of Family#1616. Both patients have the same variants. (Patient#16002)

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding Score 7, VWF:Ag:21, VWF:RCo: 16, FVIII:C:108, VWF:CB:20

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.1110-26T>A (p.=) and NM_000552.4:c.5695T>C (p.Cys1899Arg)

ClinVar: N/A

CAID: CA6403542 and CA6402177 CAID1 CAID2

gnomAD: MAF of 0.008911 (222/ 24914 alleles) in the African Population ( CA6403542). MAF of 0.00006892 (1/14510 alleles) in the African population (CA6402177)

gnomAD1 gnomAD2

Case#: 22001, Age 41, Female, Blood Type O+ (Table S3)

Disease Assertion: VWD 1

FamilyInfo: The patient is the only member of Family# 2201.

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding Score 14, VWF:Ag:18, VWF:RCo:17.5, FVIII:C: 35, VWF:CB: 17

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.5170+10C>T (p.=) and NM_000552.4(VWF):c.7730-1G>C (p.=)

ClinVar: 100418 and 100485 ClinVar1 ClinVar2

CAID: CA228702 and CA228816 CAID1 CAID2

gnomAD: 0.01298 (326/25116 alleles) in the European (Finnish) population. (CA228702) gnomAD

Case#: 01019, Age 52, Female, Blood Type O+ (Table S3)

Disease Assertion: VWD 1

FamilyInfo: 3 other family members tested. All 3 had the same VWD type and variation type. (Family 0111)

Parental Genotype: not listed

CasePresentingHPOs:

CaseHPOFreeText: Bleeding Score 12, VWF:Ag: 17, VWF:RCo: 21, FVIII:C: 49, VWF:CB: 20

CaseNotHPOs:

CaseNotHPOFreeText:

Protein Expression:

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.3223-7_3236dup (p.Pro1079_Tyr1080insLeuGlnValAspProGluPr)

ClinVar: N/A

CAID: CA1139532066

gnomAD: N/A

Case#: 37002, Age 42, Female, Blood Type O+ (Table S3)

Disease Assertion: VWD 1

FamilyInfo: The patient is the only member of Family# 3702

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: VWF:Ag: 36, VWF:RCo: 35, FVIII:C:49, VWF:CB: 27

CaseNotHPOs: N/A

CaseNotHPOFreeText: Bleeding Score 3

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.324-2_326dup (p.Ser110GlufsTer13)

ClinVar: N/A

CAID: CA1139532196 CAID

gnomAD:N/A

Case#: 01006, Age 39, Female, Blood type O+ (Table S3)

Disease Assertion: VWD type 1

FamilyInfo: Not listed

Parental Genotype: Not listed

CasePresentingHPOs:

CaseHPOFreeText: Bleeding score 11, VWF:Ag: 27, VWF:RCo: 32, FVIII:C: 72, VWF:CB: 33

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.7730-56C>T

ClinVar: N/A

CAID: CA232280547

CAID

gnomAD: N/A

Case#: 05012, Age 10, Female, Blood Type O+ (Table S3)

Disease Assertion: VWD1

FamilyInfo: Patient is the only member of Family# 0511.

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText:Bleeding Score 4, VWF:Ag: 15, VWF:RCo:12.3, FVIII:C: 45, VWF:CB: 25

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.2119T>C

ClinVar: N/A

CAID: CA383494546 CAID

gnomAD: N/A

Case#: 13018, Age 5, Male, Blood type not determined (TableS3)

Disease Assertion: VWD 1

FamilyInfo: The patient is the only member of Family#1314.

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding Score 0, VWF:Ag:18, VWF:RCo:21, FVIII:C:39, VWF:CB: 15

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.4238C>T (p.Pro1413Leu)

ClinVar: 100342 ClinVar

CAID: CA228565 CAID

gnomAD: MAF of 0.00003266 ( 1/30616 alleles) in the South Asian population. gnomAD

Case#: Elayaperumal_2018_V-289 , F, 3 y.o. (onset), origin in India

DiseaseAssertion: VWD type 3

FamilyInfo: consanguinity, positive family history

ParentalGenotype: not reported

CasePresentingHPOs:

CaseHPOFreeText: Bleeding score 14, VWF:Ag of 0, FVIII:C 1.7%

CaseNotHPOs:

CaseNotHPOFreeText:

CasePreviousTesting: not reported

GenotypingMethod: CSGE and Sanger sequencing of VWF gene only.

Gene: VWF

Variant: homozygous c.311_312delAG

HGVS: NM_000552.3:c.311_312delAG (p.Gln104ArgfsTer19)

ClinVarID: 1065296

CAID: CA690612114

gnomAD: not found

MultipleGeneVariants:

Case: VWD type 2M patients

DiseaseAssertion: VWD 2M

FamilyInfo: Patients with 2M genetics variant in A3 or A1 domain of VWF

ParentalGenotypes(s):

CasePresentingHPOs:

CaseHPOFreeText: bleeding score= 5, VWF:Ag ratio = 0.32,VWF collagen(VWF:CB/VWF:AG)=0.80. A3 domain VWF:ACT(0.45,1.03) and VWF:CB(0.45,0.63)

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

Gene: VWF

Variant:

HGVS:

ClinVar:

CAID:

gnomAD:

Case: 2 year old male at the time of genetic diagnosis, initially presenting with abnormal gait

DiseaseAssertion: Clinical exome sequencing showed the recurrent VWA1 founder mutation

FamilyInfo: no family history of neurological or musculoskeletal conditions

CasePresentingHPOs: HP:0001288 (abnormal gait), HP:0002359 (frequent falls), HP:0003701 (proximal muscle weakness)

CaseHPOFreeText: Gower's sign

Gene: VWA1

Variant: c.62_71dup (p.Gly25ArgfsTer74) (maternally inherited)

HGVS: NM_022834.5:c.62_71dup

ClinVar: 830327

gnomad: does not exist in database

MultipleGeneVariants: novel paternally inherited missense variant, c.212T>C (p.Leu71Pro)

PMID: 31423628

Gene: VWF

HGNC: 12726

PMID: 28696025

Gene: VWF

HGNCID: 12726

Case: Patient 21 (Family H), male, 40yo

DiseaseAssertion: VWD2B

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0030132, HP:0030129, HP:0030130, HP:0011871, HP:0012147

(Absence of large von Willebrand factor multimers, impaired ristocetin cofactor assay activity, Impaired von Willebrand factor collagen binding activity, Impaired RIPA, Reduced quantity of VWF)

CaseHPOFreeText: blood group A, Platelet count x103/μl = 158, PFA 100 sec = >300, SPA % = NA, MADR mg/mL = 0.45, VWF:Ag U/dL = 32.5, VWF:CB U/dL = 14.7, VWF:CB ratio = 0.45, VWF:RCo U/dL = 18.7, VWF:RCo ratio = 0.59, Platelet VWF U/dL = 130, FVIII U/dL = 39.0, BAT F/M = NA

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: Sequencing of exon 28 of VWF

PreviouslyPublished: NA

Gene: VWF

Variant: c.3916C>T (p.Arg1306Trp)

HGVS: NM_000552.4(VWF):c.3916C>T (p.Arg1306Trp)

ClinVarID: 288; https://www.ncbi.nlm.nih.gov/clinvar/variation/288/

CAID: NA

gnomAD: absent

Case: Patient 13 (Family C), male, 37yo

DiseaseAssertion: VWD2B

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0030132, HP:0030129, HP:0030130, HP:0011871, HP:0012147

(Absence of large von Willebrand factor multimers, impaired ristocetin cofactor assay activity, Impaired von Willebrand factor collagen binding activity, Impaired RIPA, Reduced quantity of VWF)

CaseHPOFreeText: blood group O, Platelet count x103/μl = 132, PFA 100 sec = >300, SPA % = 0, MADR mg/mL = 0.6, VWF:Ag U/dL = 51.9, VWF:CB U/dL = 10.6, VWF:CB ratio = 0.20, VWF:RCo U/dL = 25.2, VWF:RCo ratio = 0.48, Platelet VWF U/dL = 133.4, FVIII U/dL = 34.5, BAT F/M = 17

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: Sequencing of exon 28 of VWF

PreviouslyPublished: NA

Gene: VWF

Variant: c.3922C>T (p.Arg1308Cys)

HGVS: NM_000552.4(VWF):c.3922C>T (p.Arg1308Cys)

ClinVarID: 289; https://www.ncbi.nlm.nih.gov/clinvar/variation/289/

CAID: NA

gnomAD: absent

Case: Patient 15 (Family C), female, 14yo

DiseaseAssertion: VWD2B

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0030132, HP:0030129, HP:0030130, HP:0011871, HP:0012147

(Absence of large von Willebrand factor multimers, impaired ristocetin cofactor assay activity, Impaired von Willebrand factor collagen binding activity, Impaired RIPA, Reduced quantity of VWF)

CaseHPOFreeText: blood group O, Platelet count x103/μl = 126, PFA 100 sec = >300, SPA % = 0, MADR mg/mL = 0.45, VWF:Ag U/dL = 35.0, VWF:CB U/dL = 4.0, VWF:CB ratio = 0.11, VWF:RCo U/dL = 12.7, VWF:RCo ratio = 0.38, Platelet VWF U/dL = 141, FVIII U/dL = 46.0, BAT F/M = 6

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: Sequencing of exon 28 of VWF

PreviouslyPublished: NA

Gene: VWF

Variant: c.3922C>T (p.Arg1308Cys)

HGVS: NM_000552.4(VWF):c.3922C>T (p.Arg1308Cys)

ClinVarID: 289; https://www.ncbi.nlm.nih.gov/clinvar/variation/289/

CAID: NA

gnomAD: absent

PMID: 33556167

Gene: VWF

HGNCID: 12726

Proband: FB_II:3, male age unknown

Family details: parents are unaffected heterozygotes, VWF:Ag on the low end of reference range

Labs: prolonged bleeding time (15min), reduced VWF:Ag (0.09 IU/mL), FVIII:Ag (0.33 IU/mL), FVIII:C (0.21 IU/mL), and VWF:RiCoF (0.04 IU/mL), absent multimers

Genotype: p.Arg273Trp reported as c.1067C>T (MANE transcript is 817C>T)

CAID: CA228829

PMID: 28660968

Gene: VWF

HGNCID: 12726

PMID: 28874064

Gene: VWF

HGNCID: 12726

PMID: 28533135

Gene: VWF

HGNCID: 12726

Case: Patient 1, female, 6.3yo

DiseaseAssertion: VWD2A

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147, HP:0030129, HP:0030130, HP:0030132

(Reduced quantity of VWF, impaired ristocetin cofactor assay activity, Impaired von Willebrand factor collagen binding activity, Absence of large von Willebrand factor multimers)

CaseHPOFreeText: VWF:Ag = 22%, undetectable VWF:RCo and VWF:CB; Platelets (*109/L) = 194, Mean Platelet Volume (fL) = 11.6, FVIII:C (\%) = 23, VWF:CB (\%) <5, VWF:RCo (\%) = <5, aPTT (sec) = 47.6, PT (\%) = 94

CaseNOTHPOs: HP:0001873

(Thrombocytopenia)

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: sequencing of exon 28 of the VWF

PreviouslyPublished: NA

Gene: VWF

Variant: c.3816C>G (p.Cys1272Trp)

HGVS: NM_000552.3:c.3816C>G (p.Cys1272Trp)

ClinVarID: NA

CAID: CA383506988; http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA383506988

gnomAD: absent

PMID: 29997693

Gene: VWF

HGNCID: 12726