Case: P20, Chinese, female, 15yo

DiseaseAssertion: VWD3

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type A blood, bleeding score = 12; VWF:Ag (%) = 0.7, VWF:RCo (%) = 0.6, FVIII:C (%) = 3.9, VWF:CB (%) = 0.5, VWFpp (%) = 0.6, VWF:RCo/VWF:Ag = 0.9, VWF:CB/VWF:Ag = 0.7, VWFpp/VWF:Ag = 0.9, FVIII:C/VWF:Ag = 5.6

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.2217_2220dup - Unregistered Variant

HGVS: NA

ClinVarID: NA

CAID: NA

gnomAD: NA

Case: P88, Chinese, female, 4yo

DiseaseAssertion: VWD3

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type O blood, bleeding score = 11; VWF:Ag (%) = 0.5, VWF:RCo (%) = <0.5, FVIII:C (%) = 3.0, 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 = 6.0

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: 1 c.1591C>T (p.Gln531Ter)

HGVS: NM_000552.5:c.1591C>T (p.Gln531Ter)

ClinVarID: NA

CAID: CA383498290; http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA383498290

gnomAD: absent

Variant 2: c.6678dupC - Unregistered Variant

HGVS: NA

ClinVarID: NA

CAID: NA

gnomAD: NA

Case: P54, Chinese, female, 30yo

DiseaseAssertion: VWD2A

FamilyInfo: both parents had mild type 1 VWD, a second undetected variant may exist in patient

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type A blood, bleeding score = 4; VWF:Ag (%) = 27.0, VWF:RCo (%) = 1.8, FVIII:C (%) = 44.6, VWF:CB (%) = 1.1, VWFpp (%) = 11.2, VWF:RCo/VWF:Ag = 0.1, VWF:CB/VWF:Ag = 0.0, VWFpp/VWF:Ag = 0.4, FVIII:C/VWF:Ag = 1.7

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.875–5T>G - Unregistered Variant

HGVS: NA

ClinVarID: NA

CAID: NA

gnomAD: NA

Case: P43, Chinese, male, 7yo

DiseaseAssertion: VWD2N

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type B blood, bleeding score = 3; VWF:Ag (%) = 48.8, VWF:RCo (%) = 49.9, FVIII:C (%) = 6.4, VWF:CB (%) = 63.9, VWFpp (%) = 52.4, VWF:RCo/VWF:Ag = 0.9, VWF:CB/VWF:Ag = 1.3, VWFpp/VWF:Ag = 1.1, FVIII:C/VWF:Ag = 0.1, VWF: FVIIIB (%) = 0.0

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant 1: c.2372C>T (p.Thr791Met)

HGVS: NM_000552.4(VWF):c.2372C>T (p.Thr791Met)

ClinVarID: 294; https://www.ncbi.nlm.nih.gov/clinvar/variation/294/

CAID: NA

gnomAD: MAF = 0.00003984 (1/25100 alleles) in European (Finnish) population; https://gnomad.broadinstitute.org/variant/12-6153527-G-A?dataset=gnomad_r2_1

Variant 2: c.2574C>G (p.Cys858Trp)

HGVS: NM_000552.5:c.2574C>G (p.Cys858Trp)

ClinVarID: NA

CAID: CA232299278; http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA232299278

gnomAD: MAF = 0.0001002 (2/19954 alleles) in the East Asian population; https://gnomad.broadinstitute.org/variant/12-6143965-G-C

Case: P73, Chinese, female, 16yo

DiseaseAssertion: VWD1

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type O blood, bleeding score = 2; VWF:Ag (%) = 29.6, VWF:RCo (%) = 35.4, FVIII:C (%) = 63.1, VWF:CB (%) = 35.0, VWFpp (%) = 78.3, VWF:RCo/VWF:Ag = 1.2, VWF:CB/VWF:Ag = 1.2, VWFpp/VWF:Ag = 2.6, FVIII:C/VWF:Ag = 2.1

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.2279G>A (p.Arg760His)

HGVS: NM_000552.4(VWF):c.2279G>A (p.Arg760His)

ClinVarID: 31011; https://www.ncbi.nlm.nih.gov/clinvar/variation/31011/

CAID: NA

gnomAD: MAF = 0.00008009 (2/24972 alleles) in African/African-American population; https://gnomad.broadinstitute.org/variant/12-6155891-C-T?dataset=gnomad_r2_1

Case: P18, Chinese, male, 23yo

DiseaseAssertion: VWD2A

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type O blood, bleeding score = 7; VWF:Ag (%) = 25.0, VWF:RCo (%) = 5.2, FVIII:C (%) = 39.0, VWF:CB (%) = 6.7, VWFpp (%) = 49.6, VWF:RCo/VWF:Ag = 0.2, VWF:CB/VWF:Ag = 0.3, VWFpp/VWF:Ag = 2.0, FVIII:C/VWF:Ag = 1.6

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.4735G>A (p.Gly1579Arg)

HGVS: NM_000552.4(VWF):c.4735G>A (p.Gly1579Arg)

ClinVarID: 100385; https://www.ncbi.nlm.nih.gov/clinvar/variation/100385/

CAID: NA

gnomAD: absent

Case: P74, Chinese, female, 26yo

DiseaseAssertion: VWD1

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type A blood, bleeding score = 10; VWF:Ag (%) = 4.7, VWF:RCo (%) = 4.1, FVIII:C (%) = 31.0, VWF:CB (%) = 3.6, VWFpp (%) = 5.2, VWF:RCo/VWF:Ag = 0.9, VWF:CB/VWF:Ag = 0.8, VWFpp/VWF:Ag = 1.1, FVIII:C/VWF:Ag = 6.6, RIPA (1.2 mg/ml, %) = 93.4

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant 1: c.-1+3A>C

HGVS: NA

ClinVarID: NA

CAID: NA

gnomAD: NA

Variant 2: c.3322G>C (p.Ala1108Pro)

HGVS: NM_000552.3:c.3322G>C (p.Ala1108Pro)

ClinVarID: NA

CAID: CA383512138; http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA383512138

gnomAD: absent

Case: P23, Chinese, female 23

DiseaseAssertion: VWD3

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type O blood, bleeding score = 14; VWF:Ag (%) = 1.0, VWF:RCo (%) = 0.9, FVIII:C (%) = 4.7, VWF:CB (%) = 0.8, VWFpp (%) = 0.7, VWF:RCo/VWF:Ag = 0.9, VWF:CB/VWF:Ag = 0.8, VWFpp/VWF:Ag = 0.8, FVIII:C/VWF:Ag = 5.6

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.7361C>A (p.Thr2454Asn)

HGVS: NM_000552.5:c.7361C>A (p.Thr2454Asn)

ClinVarID: NA

CAID: CA6401695; http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA6401695

gnomAD: MAF = 0.0003263 (6/18390 alleles) in the East Asian population; https://gnomad.broadinstitute.org/variant/12-6085353-G-T

Case: P90, Chinese, female, 30yo

DiseaseAssertion: VWD2A

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type O blood, bleeding score = 12; VWF:Ag (%) = 10.1, VWF:RCo (%) = 3.3, FVIII:C (%) = 10.7, VWF:CB (%) = 2.6, VWFpp (%) = 151.7, VWF:RCo/VWF:Ag = 0.3, VWF:CB/VWF:Ag = 0.3, VWFpp/VWF:Ag = 15.0, FVIII:C/VWF:Ag = 1.1

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant 1: c.1730-2A>G

HGVS: NM_000552.4(VWF):c.1730-2A>G

ClinVarID: 100189; https://www.ncbi.nlm.nih.gov/clinvar/variation/100189/

CAID: NA

gnomAD: absent

Variant 2: c.6979T>A (p.Cys2327Ser)

HGVS: NM_000552.3:c.6979T>A (p.Cys2327Ser)

ClinVarID: NA

CAID: CA383492042; http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA383492042

gnomAD: absent

Case: P38, Chinese, female, 14yo

DiseaseAssertion: VWD3

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type O blood, bleeding score = 9; VWF:Ag (%) = 1.3, VWF:RCo (%) = 1.0, FVIII:C (%) = 4.5, VWF:CB (%) = 0.7, VWFpp (%) = 0.8, VWF:RCo/VWF:Ag = 0.8, VWF:CB/VWF:Ag = 0.5, VWFpp/VWF:Ag = 0.6, FVIII:C/VWF:Ag = 3.5

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant 1: c.2684A>G (p.Gln895Arg)

HGVS: NM_000552.5:c.2684A>G (p.Gln895Arg)

ClinVarID: NA

CAID: CA383519914; http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA383519914

gnomAD: NA

Variant 2: c.3043G>T (p.Glu1015Ter)

HGVS: NM_000552.5:c.3043G>T (p.Glu1015Ter)

ClinVarID: NA

CAID: CA383514739; http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA383514739

gnomAD: absent

Case: P87, Chinese, female, 27yo

DiseaseAssertion: VWD1

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type O blood, bleeding score = 3; VWF:Ag (%) = 55.9, VWF:RCo (%) = 55.8, FVIII:C (%) = 70.1, VWF:CB (%) = 61.3, VWFpp (%) = 88.0, VWF:RCo/VWF:Ag = 1.0, VWF:CB/VWF:Ag = 1.1, VWFpp/VWF:Ag = 1.6, FVIII:C/VWF:Ag = 1.3

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.6860G>A (p.Arg2287Gln)

HGVS: NM_000552.3:c.6860G>A (p.Arg2287Gln)

ClinVarID: NA

CAID: CA6401877; http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA6401877

gnomAD: MAF = 0.005415 (108/19946 alleles) in the East Asian population; https://gnomad.broadinstitute.org/variant/12-6094770-C-T

Case: P2, Chinese, female, 3yo

DiseaseAssertion: VWD1

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type O blood, bleeding score = 4; VWF:Ag (%) = 55.0, VWF:RCo (%) = 53.0, FVIII:C (%) = 59.0, VWF:CB (%) = 47.0, VWFpp (%) = 57.4, VWF:RCo/VWF:Ag = 1.0, VWF:CB/VWF:Ag = 0.9, VWFpp/VWF:Ag = 1.0, FVIII:C/VWF:Ag = 1.1

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.6104G>A (p.Gly2035Asp)

HGVS: NM_000552.3:c.6104G>A (p.Gly2035Asp)

ClinVarID: NA

CAID: CA6402069; http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA6402069

gnomAD: MAF = 0.005613 (112/19954 alleles; 2 homozygotes) in the East Asian population; https://gnomad.broadinstitute.org/variant/12-6103733-C-T

Case: P71, Chinese, female, 23yo

DiseaseAssertion: VWD1

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type O blood, bleeding score = 1; VWF:Ag (%) = 57.9, VWF:RCo (%) = 55.6, FVIII:C (%) = 71.3, VWF:CB (%) = 69.7, VWFpp (%) = 66.9, VWF:RCo/VWF:Ag = 1.0, VWF:CB/VWF:Ag = 1.2, VWFpp/VWF:Ag = 1.2, FVIII:C/VWF:Ag = 1.2

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.4850A>G (p.Lys1617Arg)

HGVS: NM_000552.3:c.4850A>G (p.Lys1617Arg)

ClinVarID: NA

CAID: CA6402448; http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA6402448

gnomAD: MAF = 0.0002507 (5/19942 alleles) in the East Asian population; https://gnomad.broadinstitute.org/variant/12-6127734-T-C

Case: P7, Chinese, female, 27yo

DiseaseAssertion: VWD1

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type O blood, bleeding score = 9; VWF:Ag (%) = 5.4, VWF:RCo (%) = 5.3, FVIII:C (%) = 28, VWF:CB (%) = 4.1, VWFpp (%) = 4.8, VWF:RCo/VWF:Ag = 1.0, VWF:CB/VWF:Ag = 0.8, VWFpp/VWF:Ag = 0.9, FVIII:C/VWF:Ag = 5.2, RIPA (1.2 mg/ml, %) = 73.3

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant 1: c.711C>G (p.Cys237Trp)

HGVS: NM_000552.3:c.711C>G (p.Cys237Trp)

ClinVarID: NA

CAID: CA383509260; http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA383509260

gnomAD: absent

Variant: c.1109+47T>A - Unregistered Variant

HGVS: NA

ClinVarID: NA

CAID: NA

gnomAD: NA

Case: Patient 16, Family G (Table 1.), F/58, Afro-Caribbean

DiseaseAssertion: VWD2A (IIE)

FamilyInfo: Patient 10 (M/22, Afro-Caribbean) and Patient 17 (F/79, Afro-Caribbean) also from Family G. (Table 1.)

ParentalGenotype(s): NA

CasePresentingHPOs:

CaseHPOFreeRext: BAT =23, FVIII:C (IU/dL) = 44, VWF:Ag (IU/dL) = 20, VWF:Act (IU/dL) = 14

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.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 2, Family A (Table 1.), F/15, Afro-Caribbean

DiseaseAssertion: VWD2B

FamilyInfo: Patient 1 (F/49, Afro-Caribbean) from same family G. (Table 1.)

ParentalGenotype(s): NA

CasePresentingHPOs:

CaseHPOFreeRext: BAT = 3, FVIII:C (IU/dL) = 50, VWF:Ag (IU/dL) = 57, VWF:Act (IU/dL) = 14

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.3946G > A p.(Val1316Met)

HGVS: NM_000552.5:c.3946G>A (p.Val1316Met)

ClinVarID: 290

CAID: CA114127

gnomAD:

Case: Patient 54, Family A1 (Table 1.), M/33, Afro-Caribbean

DiseaseAssertion: VWD1

FamilyInfo: Patient 55 (F/54, Afro-Caribbean), Patient 56 (M/64, Afro-Caribbean), Patient 57 (F/26, Afro-Caribbean), Patient 63 (F/59, Afro-Caribbean) also from Family A1. (Table 1.)

ParentalGenotype(s): NA

CasePresentingHPOs:

CaseHPOFreeRext: BAT = 1, FVIII:C (IU/dL) = 58.1, VWF:Ag (IU/dL) = 35, VWF:Act (IU/dL) = 38

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.7472G > A, p.(Cys2491Tyr)

HGVS: NM_000552.5:c.7472G>A (p.Cys2491Tyr)

ClinVarID:

CAID: CA383489765

gnomAD:

Case: Patient 19, Family L (Table 1.), M/76, Afro-Caribbean

DiseaseAssertion: VWD2A (IIE)

FamilyInfo:

ParentalGenotype(s): NA

CasePresentingHPOs:

CaseHPOFreeRext: BAT =4, FVIII:C (IU/dL) = NA, VWF:Ag (IU/dL) = 70, VWF:Act (IU/dL) = 28

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.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 13, Family I (Table 1.), F/65, Afro-Caribbean

DiseaseAssertion: VWD2A (IIE)

FamilyInfo: Patient 21 (F/97, Afro-Caribbean), Patient 22 (F/67, Afro-Caribbean), Patient 23 (F/86, Afro-Caribbean), Patient 24 (F/92, Afro-Caribbean), Patient 25 (F/62, Afro-Carribean) also from Family I. (Table 1.)

ParentalGenotype(s): NA

CasePresentingHPOs:

CaseHPOFreeRext: BAT =12, FVIII:C (IU/dL) = 18, VWF:Ag (IU/dL) = 18, VWF:Act (IU/dL) = 7

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.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 8, Family F (Table 1.), M/86, Afro-Caribbean

DiseaseAssertion: VWD2A (IIE)

FamilyInfo: Patient 9 (F/76, Afro-Caribbean) and Patient 28 (F/55, Afro-Caribbean) also from Family F. (Table 1.)

ParentalGenotype(s): NA

CasePresentingHPOs:

CaseHPOFreeRext: BAT = 5, FVIII:C (IU/dL) = 17, VWF:Ag (IU/dL) = 20, 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.3426T > C, p.(Cys1142 =)

HGVS: NM_000552.5:c.3426T>C (p.Cys1142=)

ClinVarID: 256668

CAID: CA6402757

gnomAD: MAF of 0.2077 (7935/38206 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6022852-A-G?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.3485C > T, p.(Pro1162Leu)

HGVS: NM_000552.5(VWF):c.3485C>T (p.Pro1162Leu)

ClinVarID: 256669

CAID: CA6402756

gnomAD: MAF of 0.2076 (7087/34136 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6022793-G-A?dataset=gnomad_r4

Variant: c.3486A > G, p.(Pro1162 =)

HGVS: NM_000552.5:c.3486A>G (p.Pro1162=)

ClinVarID: 256670

CAID: CA6402755

gnomAD: MAF of 0.2083 (7074/33968 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6022792-T-C?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 53, Family Z (Table 1.), F/92, Afro-Caribbean

DiseaseAssertion: VWD1

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs:

CaseHPOFreeRext: BAT = 0, FVIII:C (IU/dL) = 33, VWF:Ag (IU/dL) = 35, VWF:Act (IU/dL) = 30

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

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.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

Variant: c.6647del, (Cys2216Phefs*9)

HGVS: NM_000552.5:c.6647del (p.Cys2216Phefs*9)

ClinVarID:

CAID: CA2695216024

gnomAD:

Variant: c.6859C > T, p.(Arg2287Trp)

HGVS: NM_000552.5:c.6859C>T (p.Arg2287Trp)

ClinVarID: 100450

CAID: CA228760

gnomAD: MAF of 0.008928 (670/75044 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-5985605-G-A?dataset=gnomad_r4

Case: Patient 21, Family I (Table 1.), F/97, Afro-Caribbean

DiseaseAssertion: VWD2A (IIE)

FamilyInfo: Patient 13 (F/65, Afro-Caribbean), Patient 22 (F/67, Afro-Caribbean), Patient 23 (F/86, Afro-Caribbean), Patient 24 (F/92, Afro-Caribbean), Patient 25 (F/62, Afro-Carribean) also from Family I. (Table 1.)

ParentalGenotype(s): NA

CasePresentingHPOs:

CaseHPOFreeRext: BAT =0, FVIII:C (IU/dL) = 35, VWF:Ag (IU/dL) = 25, VWF:Act (IU/dL) = 8

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 14, Family J (Table 1.), M/36, Afro-Caribbean

DiseaseAssertion: VWD2A (IIE)

FamilyInfo: Patient 15 (F/64, Afro-Carribean) also from Family J. (Table 1.)

ParentalGenotype(s): NA

CasePresentingHPOs:

CaseHPOFreeRext: BAT =0, FVIII:C (IU/dL) = 25, VWF:Ag (IU/dL) = 25, VWF:Act (IU/dL) = 8

CaseNOTHPOs:

CaseNOTHPOFreeText:

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.3505T > A, p.(Cys1169Ser)

HGVS: NM_000552.5:c.3505T>A (p.Cys1169Ser)

ClinVarID:

CAID: CA383511219

gnomAD:

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 25, Family I (Table 1.), F/62, 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 24 (F/92, Afro-Carribean) also from Family I. (Table 1.)

ParentalGenotype(s): NA

CasePresentingHPOs:

CaseHPOFreeRext: BAT =6, FVIII:C (IU/dL) = 16, VWF:Ag (IU/dL) = 25, VWF:Act (IU/dL) = 14

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.4138A > G, p.(Ile1380Val)

HGVS: NM_000552.5:c.4138A>G (p.Ile1380Val)

ClinVarID: 310063

CAID: CA6402595

gnomAD: MAF of 0.1184 (8878/74958 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6019280-T-C?dataset=gnomad_r4

Variant: c.4304A > G, p.(Asn1435Ser)

HGVS: NM_000552.5:c.4304A>G (p.Asn1435Ser)

ClinVarID: 310062

CAID: CA6402552

gnomAD: MAF of 0.1124 (8427/74964 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6019114-T-C?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 12, Family H (Table 1.), F/99, Afro-Caribbean

DiseaseAssertion: VWD2A (IIE)

FamilyInfo: Patient 11 (M/71, Afro-Caribbean) also from Family H. (Table 1.)

ParentalGenotype(s): NA

CasePresentingHPOs:

CaseHPOFreeRext: BAT =8, FVIII:C (IU/dL) = 56, VWF:Ag (IU/dL) = 15, VWF:Act (IU/dL) = 24

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 3, Family B (Table 1.), M/30, Afro-Caribbean

DiseaseAssertion: VWD2A (IIE)

FamilyInfo: Patient 5 (F/47, Afro-Caribbean) from same family B (Table 1.).

ParentalGenotype(s): NA

CasePresentingHPOs:

CaseHPOFreeRext: BAT = 4, FVIII:C (IU/dL) = 14, VWF:Ag (IU/dL) = 10, VWF:Act (IU/dL) = 4.9

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.2739A > C, p.(Gly913 =)

HGVS: NM_000552.5:c.2739A>C p.(Gly913=)

ClinVarID: 1336650

CAID: CA6402959

gnomAD: MAF of 0.003374 (253/74996 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/12-6031525-T-G?dataset=gnomad_r4

Variant: c.2815G > A, p.(Gly939Arg)

HGVS: NM_000552.5:c.2815G>A (p.Gly939Arg)

ClinVarID: 2500546

CAID: CA6402950

gnomAD: MAF of 0.0009595 (72/75038 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/12-6031449-C-T?dataset=gnomad_r4

Variant: c.3101_3103delCCA (p.Thr1034del)

HGVS: NM_000552.5:c.3101_3103delCCA (p.Thr1034del)

ClinVarID: 802812

CAID: CA6402852

gnomAD: MAF of 0.01532 (1150/7504 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6025910-CTGG-C?dataset=gnomad_r4

Variant: c.4138A > G, p.(Ile1380Val)

HGVS: NM_000552.5:c.4138A>G (p.Ile1380Val)

ClinVarID: 310063

CAID: CA6402595

gnomAD: MAF of 0.1184 (8878/74958 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6019280-T-C?dataset=gnomad_r4

Variant: c.4304A > G p.(Asn1435Ser)

HGVS: NM_000552.5:c.4304A>G (p.Asn1435Ser)

ClinVarID: 310062

CAID: CA6402552

gnomAD: MAF of 0.1124 (8427/74964 alleles) in Africa/African American population https://gnomad.broadinstitute.org/variant/chr12-6019114-T-C?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 7, Family E (Table 1.), M/47, Afro-Caribbean

DiseaseAssertion: VWD2A (IIE)

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs:

CaseHPOFreeRext: BAT = 1, FVIII:C (IU/dL) = 15, VWF:Ag (IU/dL) = 15, VWF:Act (IU/dL) = 11

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 6, Family D (Table 1.), F/60, Afro-Caribbean

DiseaseAssertion: VWD2A (IIE)

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs:

CaseHPOFreeRext: BAT = 12, FVIII:C (IU/dL) = 13, VWF:Ag (IU/dL) = 10, VWF:Act (IU/dL) = 12

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.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.3426T > C, p.(Cys1142 =)

HGVS: NM_000552.5:c.3426T>C (p.Cys1142=)

ClinVarID: 256668

CAID: CA6402757

gnomAD: MAF of 0.2077 (7935/38206 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6022852-A-G?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.3485C > T, p.(Pro1162Leu)

HGVS: NM_000552.5:c.3485C>T (p.Pro1162Leu)

ClinVarID: 256669

CAID: CA6402756

gnomAD: MAF of 0.2076 (7087/34136 alleles) African/African American population https://gnomad.broadinstitute.org/variant/chr12-6022793-G-A?dataset=gnomad_r4

Variant: c.3486A > G, p.(Pro1162 =)

HGVS: NM_000552.5:c.3486A>G (p.Pro1162=)

ClinVarID: 256670

CAID: CA6402755

gnomAD: MAF of 0.2083 (7074/33968 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6022792-T-C?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 11, Family H (Table 1.), M/71, Afro-Caribbean

DiseaseAssertion: VWD2A (IIE)

FamilyInfo: Patient 12 (F/99, Afro-Caribbean) also from Family H. (Table 1.)

ParentalGenotype(s): NA

CasePresentingHPOs:

CaseHPOFreeRext: BAT =15, FVIII:C (IU/dL) = 30, VWF:Ag (IU/dL) = 15, VWF:Act (IU/dL) = 7

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 30, Family O (Table 1.), M/42, Afro-Caribbean

DiseaseAssertion: VWD2A (IIE)

FamilyInfo: Patient 31 (F/73, Afro-Caribbean) also from Family O. (Table 1.)

ParentalGenotype(s): NA

CasePresentingHPOs:

CaseHPOFreeRext: BAT = 4, FVIII:C (IU/dL) = 35, VWF:Ag (IU/dL) = 10, VWF:Act (IU/dL) = 29

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#: 35004, Age 16, Male, Blood Type A+ (Table S3)

Disease Assertion: VWD 1

FamilyInfo: The patient is one of 4 members of Family# 3501. All members have the same variants, and patient 35001 has an additional variant.

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding Score 6, VWF:Ag: 5.6, VWF:RCo: 7.9, FVIII:C: 19, VWF:CB: 7.8

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_000552.3:c.5198T>C (p.Leu1733Pro) and NM_000552.4: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#: 21011, Age 54, Male, Blood Type A+ (Table S3)

Disease Assertion: VWD 1

FamilyInfo: The patient is the only member of Family#2111.

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding Score 5, VWF:Ag: 12, VWF:RCo:20.3, FVIII:C 33, VWF:CB:16

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: NP_000543.2:p.Ser83Ter (c.246_247insT)

ClinVar: N/A

CAID: PA1139532036 CAID

gnomAD: N/A

Case#: 02068, Age 58, Female, Blood Type O+ (Table S3)

Disease Assertion: VWD 1

FamilyInfo: Patient is the only member of family #0225

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding Score 13,VWF:Ag: 11, VWF:RCo: 9.2, FVIII:C: 46, VWF:CB:14

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.6352C>T (p.Arg2118Trp) and NM_000552.4:c.8155+3G>C

ClinVar: 100490

ClinVar

CAID: CA6402006 and CA228825

CAID1

CAID2

gnomAD: MAF of 0.0001504 (3/19950 alleles) in the East Asian population (CA6402006).

gnomAD

Case#: 32004, Age 65, Female, Blood Type A-

Disease Assertion: VWD 1

FamilyInfo: The patient is the only member of Family#3204.

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding Score 19, VWF:Ag: 9.8, VWF:RCo:4, FVIII:C: 6.3, VWF:CB: 5

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.2821-123A>C (p.=)

ClinVar: N/A

CAID: CA1139532189 CAID

gnomAD: N/A

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

Case#: 23013, Age 46, Female, Blood Type O+ (Table S3)

Disease Assertion: VWD 1

FamilyInfo: The patient is the member of Family #2309.

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding Score 0, VWF:Ag: 33, VWF:RCo: 27.5, FVIII:C:56, VWF:CB:26

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.6911G>A (p.Cys2304Tyr)

ClinVar: 100451 ClinVar

CAID: CA228762 CAID

gnomAD: N/A

Case#: 36004, Age 69, Female, Blood Type O- (Table S3)

Disease Assertion: VWD 1

FamilyInfo: The patient is the only member of Family#3603.

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: VWF:Ag: 22, VWF:RCo:18.5, FVIII:C: 19, VWF:CB: 19

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.2546+55G>T (p.=)

ClinVar: N/A

CAID: N/A

gnomAD: N/A

Case#: 10003, Age 33, Male, Blood Type A+ (Table S3)

Disease Assertion: VWD1

FamilyInfo: The patient and one other patient are members of Family#1002. The second member has the same exonic variant and also has an intronic variant.

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding Score 1, VWF:Ag:7.4, VWF:RCo: 7.2, FVIII:C:11, VWF:CB: 6.3

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

PMID: 28971901

Gene: von Willebrand Disease (VWF)

Case#: 36001, Age 5, Male, Blood Type A+ (Table S3)

Disease Assertion: VWD 1

FamilyInfo: The patient is the only member of Family#3601.

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: VWF:Ag: 33, VWF:RCo: 26.4, FVIII:C: 88, VWF:CB: 58

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

Case#: 22006, Age 58, Male, Blood Type O+ (Table S3)

Disease Assertion: VWD 1

FamilyInfo: The patient is one of 2 patients in Family# 2206. Patient 22007's variant information was not described.

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding Score 7, VWF:Ag: 27, VWF:RCo: 20, FVIII:C: 12, VWF:CB:22

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.1001G>A (p.Gly334Glu) and NM_000552.4(VWF):c.2561G>A (p.Arg854Gln)

ClinVar: 626947 and 296 ClinVar1 ClinVar2

CAID: CA232322015 and CA114139 CAID1 CAID2

gnomAD: MAF of 0.000008824 (1/11326 alleles) in the European (non-Finnish) population (CA232322015). gnomAD1

MAF of 0.005692 (143/25122 alleles) in the European (Finnish) population (CA114139). gnomAD2

Case#: 13010, Age 37, Female, Blood Type O+ (Table S3)

Disease Assertion: VWD1

FamilyInfo: The patient is one of two members of Family#1308. Patient 13011 has one of the same exonic variant but has one different exonic variant (c.546G>A).

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding Score 18, VWF:Ag:16, VWF:RCo:15.1, FVIII:C:45, VWF:CB14

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.1472G>C(p.Arg491Pro) and NM_000552.4:c.546G>A (p.=)

ClinVar: 256684 ClinVar

CAID: CA383500718 and CA6403759 [CAID1] (http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA383500718)

CAID2

gnomAD: MAF of 0.002398 (85/35440 alleles) in the Latino population (CA6403759).

gnomAD

Case#: 30037, Age 69, Male, Blood Type O+ (Table S3)

Disease Assertion: VWD 1

FamilyInfo: The patient is the only member of Family# 3013

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: VWF:Ag: 20, VWF:RCo: 17, FVIII:C: 25, VWF:CB: 13

CaseNotHPOs: N/A

CaseNotHPOFreeText: Bleeding Score 1

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.5336G>T (p.Arg1779Leu)

ClinVar: N/A

CAID: CA383495656 CAID

gnomAD:MAF of 0.00002891 (1/ 34592 alleles) in the Latino population. gnomAD

Case#: 13012, Age 42, Male, Blood Type A+ (Table S3)

Disease Assertion: VWD 1

FamilyInfo: The patient is the only member of Family#1309.

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding score 7, VWF:Ag:14, VWF:RCo:9, FVIII:C: 20, VWF:CB:11

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) and

ClinVar: 308 ClinVar

CAID: CA114160 and CA6403769 CAID1 CAID2

gnomAD: MAF of 0.0005784 (20/34578 alleles) in the Latino population (CA6403769). gnomAD

Case#: 21023, Age 43, Female, Blood Type O+ (Table S3)

Disease Assertion: VWD 1

FamilyInfo: The patient is the only member of Family #2120.

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: VWF:Ag:7.6, VWF:RCo:6, FVIII:C: 11, VWF:CB:3.9

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.1110-26T>A (p.=) , NM_000552.4:c.2103C>T (p.Cys701=), and NM_000552.4:c.6248G>A (p.Gly2083Asp)

ClinVar: 310076 ClinVar1

CAID: CA6403542 , CA6403175, and CA383492072 CAID1 CAID2 CAID3

gnomAD: MAF of 0.008911 (222/ 24914 alleles) in the African population (CA6403542). MAF of 0.005928 (148/ 24968 alleles) in the African population (CA6403175). gnomAD1

Case#: 23012, Age 32, Female, Blood Type O+ (Table S3)

Disease Assertion: VWD 1

FamilyInfo: The patient is one of two members of Family# 2308. Patient 23011 has an additional exonic variant.

Parental Genotype: Not listed

CasePresentingHPOs:N/A

CaseHPOFreeText: Bleeding score 12, VWF:Ag:7, VWF:RCo:5.3, FVIII:C:6.5, VWF:CB:6

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#: 35003, Age 75, Female, Blood Type A- (Table S3)

Disease Assertion: VWD 1

FamilyInfo: The patient is one of two members in Family# 3502.

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: VWF:Ag: 6.6, VWF:RCo: 8.5, FVIII:C:13, VWF:CB: 11

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.3614G>A (p.Arg1205His)

ClinVar: 308 ClinVar

CAID: CA114160 CAID

gnomAD: N/A

Case#: 13001, Age 61, Female, Blood Type O+ (Table S3)

Disease Assertion: VWD 1

FamilyInfo: The patient was the only member of Family# 1301.

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding Score 27, VWF:Ag: 11, VWF:RCo: 9.7, FVIII:C: 36, VWF:CB: 12

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.7985A>G

ClinVar: N/A

CAID: CA383487641 CAID

gnomAD: N/A

Case#: 02042, Age 41, Male, Blood Type: O+ (Table S3)

Disease Assertion: VWD 1

FamilyInfo: Family#: 0215; 5 Members of the family were included in the study. 1 was diagnosed type 3 (patient 02039) and the other 4 were carriers for VW

Parental Genotype: Not listed

CasePresentingHPOs:

CaseHPOFreeText: VWF:Ag: 25, VWF:RCo: 21, FVIII:C:77, VWF:CB: 27

CaseNotHPOs:

CaseNotHPOFreeText: Bleeding score 1

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.1109G>A

ClinVar: N/A

CAID:CA6403559

CAID

gnomAD: MAF of 0.000008802 (1/113608 alleles) in the European (non-Finnish population). gnomAD

Case#: 02074, Age 37, Female, Blood Type A+ (Table S3)

Disease Assertion: VWD 1

FamilyInfo: Patient was the only member of family #0228.

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding Score 3, VWF:Ag: 24, VWF:RCo: 21, FVIII:C: 111, VWF:CB: 29

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(VWF):c.3426T>C (p.Cys1142=), NM_000552.4:c.6254G>T (p.Cys2085Phe), and NM_000552.4:c.3485_3486inv (p.Pro1162Leu)

ClinVar: 256668 and 619934 ClinVar ClinVar2

CAID: CA6402757, CA383492060, and CA658683073

CAID1

CAID2

gnomAD: MAF of 0.2228 (2240/10052 alleles) in the African population (CA6402757).

Case#: 27032, Age 49, Female, Blood Type O+

Disease Assertion: VWD 1

FamilyInfo: The patient is one of two members of Family#2716. The other member has the same variant, but is only a carrier.

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding Score 8, VWF:Ag:31, VWF:RCo: 22.7, FVIII:C: 72, VWF:CB: 38

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.2518G>T (p.Glu840Ter)

ClinVar: N/A

CAID:CA383520331 CAID

gnomAD: N/A

Case: Case 3, female

DiseaseAssertion: Platelet-type VWD (PT-VWD)

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0000978, HP:0000421, HP:0000132, HP:0004846, HP:0001873, HP:0030129, HP:0030132

(easy bruising, epistaxis, Menorrhagia, Prolonged bleeding after surgery, thrombocytopenia, Impaired ristocetin cofactor assay activity, Absence of large von Willebrand factor multimers)

CaseHPOFreeText: pregnancy complicated by progressive thrombocytopenia; Platelet (×109/L) = 135, Factor VIII (IU/mL) = 0.78, VWF:Ag (IU/mL) = 0.69, VWF:RCo (IU/mL) = 0.22, VWF:CB (IU/mL) = ND, RCo/Ag ratio = 0.32, CB/Ag ratio = ND, VWF: HMW Multimers = absent

CaseNOTHPOs: NA

CaseNOTHPOFreeText: NA

CasePreviousTesting: NA

GenotypingMethod: NA

PreviouslyPublished: NA

Gene: GP1BA

Variant: c.746G>T (p.Gly249Val)

HGVS: NM_000173.7(GP1BA):c.746G>T (p.Gly249Val)

ClinVarID: 4153; https://www.ncbi.nlm.nih.gov/clinvar/variation/4153/

CAID:

gnomAD: absent

Case: Case 1, male, 13yo at assessment, symptom onset at 45 days old

DiseaseAssertion: Platelet-type VWD (PT-VWD)

FamilyInfo: 1 symptomatic sister (menorrhagia, hemorrhagic follicular cyst); 1 asymptomatic sister; 3 brothers: twin died at 45days old due to leukemia, 1 symptomatic with daily epistaxis, 1 asymptomatic; father had bleeding symptoms; mom had severe bleeding with c-section requiring hysterectomy

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0001973, HP:0001892, HP:0000421, HP:0000979, HP:0001873, HP:0002090, HP:0000023, HP:0030132, HP:0011871

(Autoimmune thrombocytopenia, abnormal bleeding, epistaxis, purpura, thrombocytopenia, pneumonia, inguinal hernia, Absence of large von Willebrand factor multimers, impaired RIPA)

CaseHPOFreeText: bleeding treated with intravenous gamma-globulin (IVIg) and corticosteroids, laparoscopic splenectomy complicated by massive intraperitoneal bleeding, multiple bone marrow aspirations performed; born via c-section of twin pregnancy due to placenta previa; mepacrine uptake assay by flow cytometry was normal, Blood smear showed very large platelets with clear signs of activation and pseudopods; Platelet (×109/L) = 95, Factor VIII (IU/mL) = 1.00, VWF:Ag (IU/mL) = 1.29, VWF:RCo (IU/mL) = 0.28, VWF:CB (IU/mL) = 0.70, RCo/Ag ratio = 0.22, CB/Ag ratio = 0.54, VWF: HMW Multimers = partial loss

CaseNOTHPOs: NA

CaseNOTHPOFreeText: NA

CasePreviousTesting: NA

GenotypingMethod: NA

PreviouslyPublished: NA

Gene: GP1BA

Variant: c.763A>G (p.Met255Val)

HGVS: NM_000173.7(GP1BA):c.763A>G (p.Met255Val)

ClinVarID: 4155; https://www.ncbi.nlm.nih.gov/clinvar/variation/4155/

CAID:

gnomAD: absent

Case: Case 4, female, 5yo at onset, 20yo at report

DiseaseAssertion: Platelet-type VWD (PT-VWD)

FamilyInfo: Fhx of VWD; father diagnosed with type 2B VWD

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0000978, HP:0000421, HP:0000132, HP:0001873, HP:0004846

(easy bruising, epistaxis, menorrhagia, thrombocytopenia, Prolonged bleeding after surgery)

CaseHPOFreeText: pregnancy complicated by thrombocytopenia, Platelet aggregation studies were normal to ADP, epinephrine, collagen, and arachidonic; Platelet (×109/L) = 156, Factor VIII (IU/mL) = ND, VWF:Ag (IU/mL) = 0.57, VWF:RCo (IU/mL) = 0.86, VWF:CB (IU/mL) = ND, RCo/Ag ratio = 1.15, CB/Ag ratio = ND, VWF: HMW Multimers = normal

CaseNOTHPOs: NA

CaseNOTHPOFreeText: NA

CasePreviousTesting: no mutations in exon 28 of the VWF gene

GenotypingMethod: NA

PreviouslyPublished: NA

Gene: GP1BA

Variant: c.746G>T (p.Gly249Val)

HGVS: NM_000173.7(GP1BA):c.746G>T (p.Gly249Val)

ClinVarID: 4153; https://www.ncbi.nlm.nih.gov/clinvar/variation/4153/

CAID:

gnomAD: absent

Case#: Iannuzzi_1991_IV-1, M, age unknown, origin unknown

DiseaseAssertion: VWD type 2A

FamilyInfo: Affected mother, aunt, grandfather, and many other relatives. LOD score 3.61 reported (12 affected and genotype positive, 4 unaffected genotype positive. 4 affected also have HTT with vWD.

ParentalGenotype:

CasePresentingHPOs: As reported elsewhere (Hanna etal1984), the diagnosis of typeII AvWD was based on the following: bleedingtime, FVIII procoagulant activity, vFW:Ag, ristocetincofactoractivity, platelet aggregation studies, and vWF multimer analysis

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

CasePreviousTesting:

GenotypingMethod: PCR-RFLP of exon 28 of VWF

Gene: VWF

Variant:

HGVS: NM_000552.5(VWF):c.4883T>C (p.Ile1628Thr)

ClinVarID: 284

CAID:

gnomAD: not reported

MultipleGeneVariants:

Case: IP #8 (also in row 5 table 6)

DiseaseAssertion: type 2A (IIC) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032442 - blood group O

CaseHPOFreeRext: VWF:Ag [IU/dL] = 68; VWF:Ac [IU/dL] = 49; FVIII:C [IU/dL] = 76

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.1915C>T p.Arg639Cys

HGVS:

ClinVarID: not found

CAID: CA232310080

gnomAD: 0.00001592 (24 in 1508000) no homozygotes https://gnomad.broadinstitute.org/variant/12-6056887-G-A?dataset=gnomad_r4

Case: IP #31

DiseaseAssertion: type 2A VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: VWF:Ag [IU/dL] = 14; VWF:Ac [IU/dL] = 6; FVIII:C [IU/dL] = n/a

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.4151T>G p.Leu1384Arg

HGVS:

ClinVarID: not found

CAID: CA383504381

gnomAD: absent

Case: IP #6 (also in row 3 table 6)

DiseaseAssertion: type 2A (IIC) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032442 - blood group O

CaseHPOFreeRext: VWF:Ag [IU/dL] = 63; VWF:Ac [IU/dL] = 39; FVIII:C [IU/dL] = 88

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.1835T>G p.Val612Gly

HGVS:

ClinVarID: not found

CAID: CA383497104

gnomAD: 0.000001298 (2 in 1541314) no homozygotes https://gnomad.broadinstitute.org/variant/12-6056967-A-C?dataset=gnomad_r4

Case: IP #21 (also in row 9 table 6)

DiseaseAssertion: type 2A (IIE) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: VWF:Ag [IU/dL] = 27; VWF:Ac [IU/dL] = 22; FVIII:C [IU/dL] = 57

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.3469T>G p.Cys1157Gly

HGVS:

ClinVarID:

CAID: CA383511299

gnomAD: absent

Case: IP #53 (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] = 35; VWF:Ac [IU/dL] = 11; FVIII:C [IU/dL] = 62

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: IP #30

DiseaseAssertion: type 2A VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: VWF:Ag [IU/dL] = 15; VWF:Ac [IU/dL] = 6; FVIII:C [IU/dL] = 28

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.4151T>G p.Leu1384Arg

HGVS:

ClinVarID: not found

CAID: CA383504381

gnomAD: absent

Case: IP #16

DiseaseAssertion: type 2A (IIE) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: VWF:Ag [IU/dL] = 65; VWF:Ac [IU/dL] = 39; FVIII:C [IU/dL] = 78

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.3433C>T p.Arg1145Cys

HGVS:

ClinVarID: not found

CAID: CA383511379

gnomAD: absent

Case: 7 (also in row 2 splice variants table 6)

DiseaseAssertion: type 2A VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032442 - blood group O

CaseHPOFreeRext: VWF:Ag [IU/dL] = 27; VWF:Ac [IU/dL] = 16; FVIII:C [IU/dL] = 31

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.2546+1G > A

HGVS:

ClinVarID: not found

CAID: CA383520269

gnomAD: 0.000001239 (2 in 1614166) no homozygotes https://gnomad.broadinstitute.org/variant/12-6036387-C-T?dataset=gnomad_r4

MultipleGeneVariants:

Gene: VWF

Variant: c.5092G > T p.Gly1698Cys

CAID: CA383496674

gnomAD: 6.196e-7 (1 in 1613980) no homozygotes https://gnomad.broadinstitute.org/variant/chr12-6016832-C-A?dataset=gnomad_r4

Case#: F10, III:3

DiseaseAssertion: Type 2 VWD

CaseHPOFreeText: complete loss of high MWM, VWF:Ag = 25; VWF:RCo = 6; VWF:GPIbM = 17; 0.23; 0.67; 2.95

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#: F10, I:3

DiseaseAssertion: Type 2 VWD

CaseHPOFreeText: complete loss of high MWM, VWF:Ag = 50; VWF:RCo = 6; VWF:GPIbM = 29; 0.12; 0.58; 4.82

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#: F10, I:1

DiseaseAssertion: Type 2 VWD

CaseHPOFreeText: complete loss of high MWM, VWF:Ag = 82; VWF:RCo = 27; VWF:GPIbM = 97; 0.33; 1.19; 3.62

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#: F9, I:1

DiseaseAssertion: Type 2 VWD

CaseHPOFreeText: complete loss of high MWM, VWF:Ag = 23; VWF:RCo = 7; VWF:GPIbM = 21; 0.29; 0.93; 3.18

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#: F1, I:1

DiseaseAssertion: Type 2 VWD

CaseHPOFreeText: all mutimers present, VWF:Ag = 63; VWF:RCo = 56; VWF:GPIbM = 52; VWF:RCo/VWF:Ag = 0.88; VWF:GPIbM/VWF:Ag = 0.82; VWF:GPIbM/VWF:RCo = 0.93

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: Patient 18, M, Hungarian

DiseaseAssertion: VWD type 3

FamilyInfo: compatible with recessive inheritance

ParentalGenotype(s): n/a

CasePresentingHPOs: n/a

CaseHPOFreeRext: Bleeding score: 20, VWF:Ag (IU dL−1): < 1, VWF:CB (IU dL−1): < 1, FVIII:C (IU dL−1): 3, VWF:RCo below detection limit (<10 IU dL−1), not detectable VWF on multimer gels

CaseNOTHPOs: n/a

CaseNOTHPOFreeText: no inhibitor detected, did not become refractory to factor replacement therapy

CasePreviousTesting: n/a

Gene: VWF

Variant:

c.1992insC (p.Cys665LeufsX13), Exon 16

c.5557C>T (p.Arg1853X), Exon 32

Intron 40 VNTR 15/16

Note: multimer electrophoresis, Recombinant VWF antigen concentrations and Collagen binding activity (VWF:CB) measured by ELISA, direct sequencing of the 51 exons and the exon‐intron boundaries, Breakpoint analysis and breakpoint‐specific PCR

Case: Patient 14, M, Hungarian

DiseaseAssertion: VWD type 3

FamilyInfo: compatible with recessive inheritance

ParentalGenotype(s): n/a

CasePresentingHPOs: n/a

CaseHPOFreeRext: Bleeding score: 14, VWF:Ag (IU dL−1): 1, VWF:CB (IU dL−1): 1, FVIII:C (IU dL−1): 2, VWF:RCo below detection limit (<10 IU dL−1), not detectable VWF on multimer gels, anaphylactic reaction to the VWF concentrate, inhibitor and alloantibodies detected

CaseNOTHPOs: n/a

CaseNOTHPOFreeText: did not become refractory to factor replacement therapy

CasePreviousTesting: n/a

Gene: VWF

Variant:

c.3622delT (p.S1208QfsX7), Exon 27, Homozygous

Intron 40 VNTR 18/18

Note: multimer electrophoresis, Recombinant VWF antigen concentrations and Collagen binding activity (VWF:CB) measured by ELISA, direct sequencing of the 51 exons and the exon‐intron boundaries, Breakpoint analysis and breakpoint‐specific PCR

Case: Patient 20, M, Hungarian

DiseaseAssertion: VWD type 3

FamilyInfo: compatible with recessive inheritance

ParentalGenotype(s): n/a

CasePresentingHPOs: n/a

CaseHPOFreeRext: Bleeding score: 14, VWF:Ag (IU dL−1): < 1, VWF:CB (IU dL−1): < 1, FVIII:C (IU dL−1): 6, VWF:RCo below detection limit (<10 IU dL−1), not detectable VWF on multimer gels

CaseNOTHPOs: n/a

CaseNOTHPOFreeText: did not become refractory to factor replacement therapy

CasePreviousTesting: n/a

Gene: VWF

Variant:

c.103T>C (p.Cys35Arg), Exon 3

c.4975C>T (p.Arg1659X), Exon 28

Intron 40 VNTR 14/16

Note: multimer electrophoresis, Recombinant VWF antigen concentrations and Collagen binding activity (VWF:CB) measured by ELISA, direct sequencing of the 51 exons and the exon‐intron boundaries, Breakpoint analysis and breakpoint‐specific PCR

PMID: 27655998

Gene: VWF

HGNCID: 12726

PMID: 29296713

Gene: VWF

HGNCID: 12726

Case: 9, M, 2.5 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): 7, VWF:Ag (U/dl): 1.5, Bleeding Score: 9

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

Gene: VWF

Variant:

c.4975C>T (p.Arg1659*), Exon 28, Homozygous

Case: 3, F, 22 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): <1, Bleeding Score: 4

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

Gene: VWF

Variant:

c.970C>T (p.Arg324*), Exon 8, Homozygous

Case: 55, F, 9 years, Indian

DiseaseAssertion: VWD type 3

FamilyInfo: 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: 9

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

Gene: VWF

Variant:

c.2303G>A (p.Arg768Gln), Exon 18

Heterozygous

Case: 66, F, 5 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): 1.4, VWF:Ag (U/dl): 2.3, Bleeding Score: 6

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

Gene: VWF

Variant:

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

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

c.3951C>T (p.Ala1317Ala), Exon 28

c.4027A>G (p.Ile1343Val), Exon 28

Heterozygous

Case: 82, M, 2 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): 1.4, VWF:Ag (U/dl): <1, Bleeding Score: 6

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

Gene: VWF

Variant:

c.1830C>A (p.Tyr610*), Exon 15, Homozygous

Case: 72, F, 6 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): 2.5, VWF:Ag (U/dl): 4, Bleeding Score: 4

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

Gene: VWF

Variant:

c.2208G>T (p.Met736Ile), Exon 17

Heterozygous

Case: 6, F, 24 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: 22

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

Gene: VWF

Variant:

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

Case: 1, M, 10 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: 11

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

Gene: VWF

Variant:

c.100C>T (p.Arg34*), Exon 3, Homozygous

Case: 49, F, 1.1 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): 4, VWF:Ag (U/dl): 2.6, Bleeding Score: 3

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

Gene: VWF

Variant:

c.2443-1G>C, Exon 19

Homozygous

Case: 65, M, 10 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): 2.1, VWF:Ag (U/dl): 1.4, Bleeding Score: 5

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

Gene: VWF

Variant:

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

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

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

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

c.3951C>T (p.Ala1317Ala), Exon 28

Homozygous

Case: 25, M, 26 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): 2.5, VWF:Ag (U/dl): <1, Bleeding Score: 6

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

Gene: VWF

Variant:

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

Case: 47, F, 2 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): 2.3, Bleeding Score: 6

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

Gene: VWF

Variant:

c.478G>A (p.Gly160Arg), Exon 5

Homozygous

Case: 8, F, 2 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): 4.5, VWF:Ag (U/dl): <1, Bleeding Score: 11

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

Gene: VWF

Variant:

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

Case: 21, M, 22 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): 8, VWF:Ag (U/dl): 4.9, Bleeding Score: 9

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

Gene: VWF

Variant:

c.8145C>A (p.Cys2715*), Exon 50, Homozygous

Case: T065, M, 15

DiseaseAssertion: VWD type 3

FamilyInfo: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: Bleeding Score: 22 (Kruskal–Wallis followed by Mann–Whitney U post-hoc testing Post-hoc testing ), VWF:Ag (IU/ml): 0.01, VWF:RCo (IU/ml): 0.02, FVIII:C (IU/ml): 0.01

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

Gene: VWF

Variant:

c.3303C>A (p.Cys1101*), Exon 25, 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: T099, F, 3

DiseaseAssertion: VWD type 3

FamilyInfo: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: Bleeding Score: 18 (Kruskal–Wallis followed by Mann–Whitney U post-hoc testing Post-hoc testing ), VWF:Ag (IU/ml): 0.04, VWF:RCo (IU/ml): 0.02, FVIII:C (IU/ml): 0.06

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

Gene: VWF

Variant:

c.1750_1765delinsCG (p.Cys584_Ser589delinsArg), Exon 15, 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: T110, F, 41

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): 0.01, VWF:RCo (IU/ml): 0.01, FVIII:C (IU/ml): 0.02

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: T018, F, 12

DiseaseAssertion: VWD type 3

FamilyInfo: n/a

CasePresentingHPOs: HP:0000421

CaseHPOFreeText: Bleeding Score: 12 (Kruskal–Wallis followed by Mann–Whitney U post-hoc testing Post-hoc testing ), VWF:Ag (IU/ml): 0.04, VWF:RCo (IU/ml): 0.00, FVIII:C (IU/ml): 0.03, inhibitor positive

CaseNotHPOs: has not developed any anaphylactic reactions and/or become refractory to replacement therapy

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: T030, M, 66

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): 0.03, VWF:RCo (IU/ml): 0.01, FVIII:C (IU/ml): 0.09

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

Gene: VWF

Variant:

c.-2328T>G

c.2220G>A (p.Met740Ile)

c.3379 + 7A>C

c.3539-33G>A

c.3539-49C>T

c.4414dupC (p.His1472 fs)

c.5620 + 33-40delA

c.6554G>A (p.Arg2185Gln)

c.6902-5T>A

c.8418_8419insTCCC (p.Ser2807 fs)

Exon 28/52

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: T036, F, 41

DiseaseAssertion: VWD type 3

FamilyInfo: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: Bleeding Score: 25 (Kruskal–Wallis followed by Mann–Whitney U post-hoc testing Post-hoc testing ), VWF:Ag (IU/ml): 0.01, VWF:RCo (IU/ml): 0.01, FVIII:C (IU/ml) : 0.01

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

Gene: VWF

Variant:

c.5180_5181insTT (p.Leu1727 fs), Exon 30, 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: T141, F, 16

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): 0.04, VWF:RCo (IU/ml): 0.04, FVIII:C (IU/ml): 0.06

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

Gene: VWF

Variant:

c.817T>C (p.Arg273Trp), Exon 7, 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: T093, M, 8

DiseaseAssertion: VWD type 3

FamilyInfo: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: Bleeding Score: 10 (Kruskal–Wallis followed by Mann–Whitney U post-hoc testing Post-hoc testing ), VWF:Ag (IU/ml): 0.02, VWF:RCo (IU/ml): 0.02, FVIII:C (IU/ml): 0.04

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

Gene: VWF

Variant:

c.6709T>C (p.Cys2237Arg), Exon 38

c.220 + 20G>T

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: T118, F, 30

DiseaseAssertion: VWD type 3

FamilyInfo: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: Bleeding Score: 8 (Kruskal–Wallis followed by Mann–Whitney U post-hoc testing Post-hoc testing ), VWF:Ag (IU/ml): 0.02, VWF:RCo (IU/ml): 0.00, FVIII:C (IU/ml): 0.05

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: T086, M, 1

DiseaseAssertion: VWD type 3

FamilyInfo: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: Bleeding Score: 3 (Kruskal–Wallis followed by Mann–Whitney U post-hoc testing Post-hoc testing ), VWF:Ag (IU/ml): 0.01, VWF:RCo (IU/ml): 0.02, FVIII:C (IU/ml): 0.01

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

Gene: VWF

Variant:

c.1A>G (p.Met1Val), Exon 2

c.2377C>T (p.Gln793*), 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

Case: T050, F, 21

DiseaseAssertion: VWD type 3

FamilyInfo: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: Bleeding Score: 24 (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.876delC (p.Ser293 fs), Exon 8

c.1255C>T (p.Gln419*), Exon 11

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:Croatian adult patient

DiseaseAssertion: VWD1

ParentalGenotype(s): Not specified

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

CaseHPOFreeText: Normal VWF:Ag of 62.8%, VWF:GPIbM of 60.8%, FVIII:C of 71% and VWF:CBA of 41.9%. 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.1531A>C

HGVS: NM_000552.4:c.1531A>C (p.Lys511Gln)

ClinVarID: Not available

CAID: CA383500354

gnomAD: Not available

Case: Croatian adult patient

DiseaseAssertion: VWD2A

FamilyInfo: No variant detected in a family member with VWD2

ParentalGenotype(s): Not specified

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

CaseHPOFreeText: Reduced VWF:Ag of 17.2%, VWF:GPIbM of 10.9%, FVIII:C of 21% and VWF:CBA of 10.1%. Reduced levels of HMWM and IMWM in multimer distribution.

CaseNOTHPOs: Not specified

CaseNOTHPOFreeText: Not reported.

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.3829G>T

HGVS: NM_000552.4:c.3829G>T (p.Asp1277Tyr)

ClinVarID: Not available

CAID: CA383506920

gnomAD: Not available

PMID:35505650

Gene: VWF

HGNCID: 12726