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: P32, Chinese, male, 3yo

DiseaseAssertion: VWD1

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: patient coexisting with severe haemophilia A; type O blood, bleeding score = 3; VWF:Ag (%) = 51.3, VWF:RCo (%) = 50.7, FVIII:C (%) = 1.0, VWF:CB (%) = 50.3, VWFpp (%) = 49.2, VWF:RCo/VWF:Ag = 1.0, VWF:CB/VWF:Ag = 1.0, VWFpp/VWF:Ag = 1.0, FVIII:C/VWF:Ag = 0.0

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.646G>A (p.Glu216Lys)

HGVS: NM_000552.5(VWF):c.646G>A (p.Glu216Lys)

ClinVarID: 870925; https://www.ncbi.nlm.nih.gov/clinvar/variation/870925/

CAID: NA

gnomAD: 0.001353 (27/19952 alleles) in East Asian population; https://gnomad.broadinstitute.org/variant/12-6204637-C-T?dataset=gnomad_r2_1

MultipleGeneVariants

Gene: F8

Variant: p.Arg446Ter - Unregistered Variant

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: P10, Chinese, male, 5yo

DiseaseAssertion: VWD1

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type A blood, bleeding score = 2; VWF:Ag (%) = 4.2, VWF:RCo (%) = 3.8, FVIII:C (%) = 30.1, VWF:CB (%) = 3.5, VWFpp (%) = 4.1, VWF:RCo/VWF:Ag = 0.9, VWF:CB/VWF:Ag = 0.8, VWFpp/VWF:Ag = 1.0, FVIII:C/VWF:Ag = 7.4, RIPA (1.2 mg/ml, %) = 40.1

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant 1: c.7199delA (p.Asn2400Thrfs*4) - Unregistered Variant

HGVS: NA

ClinVarID: NA

CAID: NA

gnomAD: NA

Variant 2: c.8155+5G>C - Unregistered Variant

HGVS: NA

ClinVarID: NA

CAID: NA

gnomAD: NA

Case: P6, Chinese, male, 57yo

DiseaseAssertion: VWD2A

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type AB blood, bleeding score = 15; VWF:Ag (%) = 18.5, VWF:RCo (%) = 5.8, FVIII:C (%) = 39.0, VWF:CB (%) = 4.9, VWFpp (%) = 36.4, VWF:RCo/VWF:Ag = 0.3, VWF:CB/VWF:Ag = 0.3, VWFpp/VWF:Ag = 2.0, FVIII:C/VWF:Ag = 2.1

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.3920T>G (p.Leu1307Arg)

HGVS: NM_000552.5:c.3920T>G (p.Leu1307Arg)

ClinVarID: NA

CAID: CA383506205; http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA383506205

gnomAD: absent

Case: P72, Chinese, female, 25yo

DiseaseAssertion: VWD2B

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type A blood, bleeding score = 7; VWF:Ag (%) = 31.1, VWF:RCo (%) = 10.5, FVIII:C (%) = 44.8, VWF:CB (%) = 5.4, VWFpp (%) = 73, VWF:RCo/VWF:Ag = 0.3, VWF:CB/VWF:Ag = 0.2, VWFpp/VWF:Ag = 2.3, FVIII:C/VWF:Ag = 1.4, RIPA (0.5 mg/ml, %) = 8.7, PLT(×109/l) = 181

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.3939G>C (p.Trp1313Cys)

HGVS: NM_000552.4(VWF):c.3939G>C (p.Trp1313Cys)

ClinVarID: 287; https://www.ncbi.nlm.nih.gov/clinvar/variation/287/

CAID: NA

gnomAD: absent

Case: P77, Chinese, female, 10yo

DiseaseAssertion: VWD3

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type B blood, bleeding score = 7; VWF:Ag (%) = 3.0, VWF:RCo (%) = 2.7, FVIII:C (%) = 6.8, VWF:CB (%) = 2.1, VWFpp (%) = 3.2, VWF:RCo/VWF:Ag = 0.9, VWF:CB/VWF:Ag = 0.7, VWFpp/VWF:Ag = 1.1, FVIII:C/VWF:Ag = 2.3

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant 1: c.6771C>A (p.Cys2257Ter)

HGVS: NM_000552.5:c.6771C>A (p.Cys2257Ter)

ClinVarID: NA

CAID: CA383489897; http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA383489897

gnomAD: absent

Variant 2: c.8116-2delA - unregistered variant

HGVS: NA

ClinVarID: NA

CAID: NA

gnomAD: NA

Case: P34, Chinese, female, 34yo

DiseaseAssertion: VWD2B

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type O blood, bleeding score = 13; VWF:Ag (%) = 20.2, VWF:RCo (%) = 6.9, FVIII:C (%) = 32.9, VWF:CB (%) = 4.8, VWFpp (%) = 54.5, VWF:RCo/VWF:Ag = 0.3, VWF:CB/VWF:Ag = 0.2, VWFpp/VWF:Ag = 2.7, FVIII:C/VWF:Ag = 1.6, RIPA (0.5 mg/ml, %) = 65.1, PLT(×109/l) = 153

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

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

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

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

CAID: NA

gnomAD: absent

Case: P61, Chinese, female, 34yo

DiseaseAssertion: VWD1

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type O blood, bleeding score = 2; VWF:Ag (%) = 57.6, VWF:RCo (%) = 57.8, FVIII:C (%) = 76.2, VWF:CB (%) = 67.4, VWFpp (%) = 62.7, VWF:RCo/VWF:Ag = 1.0, VWF:CB/VWF:Ag = 1.2, VWFpp/VWF:Ag = 1.1, FVIII:C/VWF:Ag = 1.3

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.-128G>A

HGVS: NM_000552.3:c.-128G>A

ClinVarID: NA

CAID: CA603092904; http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA603092904

gnomAD: MAF = 0.001182 (1/846 alleles) in Latino/Admixed American population; https://gnomad.broadinstitute.org/variant/12-6233714-C-T

Case: P27, Chinese, female, 3yo

DiseaseAssertion: VWD2N

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type B blood, bleeding score = 6; VWF:Ag (%) = 9.5, VWF:RCo (%) = 8.9, FVIII:C (%) = 6.5, VWF:CB (%) = 6.9, VWFpp (%) = 10.8, VWF:RCo/VWF:Ag = 0.9, VWF:CB/VWF:Ag = 0.7, VWFpp/VWF:Ag = 1.1, FVIII:C/VWF:Ag = 0.7, VWF: FVIIIB (%) = 0.0

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant 1: c.2396G>A (p.Cys799Tyr)

HGVS: NM_000552.5:c.2396G>A (p.Cys799Tyr)

ClinVarID: NA

CAID: CA232300402; http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA232300402

gnomAD: absent

Variant 2: c.3197_3201del - unregistered variant

HGVS: NA

ClinVarID: NA

CAID: NA

gnomAD: NA

Case: P36, Chinese, male, 56yo

DiseaseAssertion: VWD3

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type A blood, bleeding score = 10; VWF:Ag (%) = 1.0, VWF:RCo (%) = 0.9, FVIII:C (%) = 4.1, VWF:CB (%) = 0.9, VWFpp (%) = 0.9, VWF:RCo/VWF:Ag = 0.9, VWF:CB/VWF:Ag = 0.9, VWFpp/VWF:Ag = 0.9, FVIII:C/VWF:Ag = 4.1

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.5870delA - unregistered variant

HGVS: NA

ClinVarID: NA

CAID: NA

gnomAD: NA

Case: P83, Chinese, male, 5yo

DiseaseAssertion: VWD1

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: patient coexisting with mild haemophilia A; type O blood, bleeding score = 3; VWF:Ag (%) = 44.5, VWF:RCo (%) = 36.7, FVIII:C (%) = 12.6, VWF:CB (%) = 49.2, VWFpp (%) = 35.2, VWF:RCo/VWF:Ag = 0.8, VWF:CB/VWF:Ag = 1.1, VWFpp/VWF:Ag = 0.8, FVIII:C/VWF:Ag = 0.3

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

Multiple Gene Variants

Gene: F8

Variant: c.943G>T (p.Ala315Ser)

HGVS: NM_000132.3:c.943G>T (p.Ala315Ser)

ClinVarID: NA

CAID: CA414917823; http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA414917823

gnomAD: absent

Case: P29, Chinese, male, 10yo

DiseaseAssertion: VWD2M

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type B blood, bleeding score = 5; VWF:Ag (%) = 13.9, VWF:RCo (%) = 5.9, FVIII:C (%) = 37.8, VWF:CB (%) = 17.4, VWFpp (%) = 31.3, VWF:RCo/VWF:Ag = 0.4, VWF:CB/VWF:Ag = 1.3, VWFpp/VWF:Ag = 2.3, FVIII:C/VWF:Ag = 2.7

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

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

HGVS: NM_000552.4(VWF):c.3943C>T (p.Arg1315Cys)

ClinVarID: 100310; https://www.ncbi.nlm.nih.gov/clinvar/variation/100310/

CAID: NA

gnomAD: absent

Case: P22, Chinese, male, 22yo

DiseaseAssertion: VWD3

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type O blood, bleeding score = 10; VWF:Ag (%) = 1.4, VWF:RCo (%) = 1.2, FVIII:C (%) = 5.1, VWF:CB (%) = 1.3, VWFpp (%) = 1.0, VWF:RCo/VWF:Ag = 0.9, VWF:CB/VWF:Ag = 0.9, VWFpp/VWF:Ag = 0.7, FVIII:C/VWF:Ag = 3.6

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.8116–2delA - Unregistered variant

HGVS: NA

ClinVarID: NA

CAID: NA

gnomAD: NA

Case: P42, Chinese, male, 10yo

DiseaseAssertion: VWD1

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type O blood, bleeding score = 1; VWF:Ag (%) = 41.9, VWF:RCo (%) = 33.9, FVIII:C (%) = 54.7, VWF:CB (%) = 46.8, VWFpp (%) = 34.6, VWF:RCo/VWF:Ag = 1.0, VWF:CB/VWF:Ag = 1.1, VWFpp/VWF:Ag = 0.8, FVIII:C/VWF:Ag = 1.3

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.-672C>T

HGVS: NA

ClinVarID: NA

CAID: NA

gnomAD: NA

PMID: 28536718

Gene: VWF

HGNCID: 12726

Case: P33, Chinese, female, 35yo

DiseaseAssertion: VWD3

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type A blood, bleeding score = 10; VWF:Ag (%) = 0.5, VWF:RCo (%) = <0.5, FVIII:C (%) = 5.0, 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 = 10.0

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.813C>G (p.Tyr271Ter)

HGVS: NM_000552.5:c.813C>G (p.Tyr271Ter)

ClinVarID: NA

CAID: CA383508522; http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA383508522

gnomAD: MAF = 0.0001088 (2/18380 alleles) in the East Asian popualtion; https://gnomad.broadinstitute.org/variant/12-6184562-G-C

PMID: 30111575

PMID: 28640903

Gene: VWF

HGNCID: 12726

Case: Patient 9 (Family B), male, 71yo

DiseaseAssertion: VWD2B

FamilyInfo: NA

ParentalGenotype(s): NA

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

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

CaseHPOFreeText: blood group O, Platelet count x103/μl = 56, PFA 100 sec = >300, SPA % = 22, MADR mg/mL = 0.3, VWF:Ag U/dL = 81.2, VWF:CB U/dL = 25.9, VWF:CB ratio = 0.32, VWF:RCo U/dL = 33.75, VWF:RCo ratio = 0.41, Platelet VWF U/dL = 146.2, FVIII U/dL = 52, BAT F/M = NA

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: Sequencing of exon 28 of VWF

PreviouslyPublished: NA

Gene: VWF

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

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

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

CAID: NA

gnomAD: absent

Case: Patient 3 (Family B), male, 55yo

DiseaseAssertion: VWD2B

FamilyInfo: NA

ParentalGenotype(s): NA

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

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

CaseHPOFreeText: blood group O, Platelet count x103/μl = 204, PFA 100 sec = >300, SPA % = 0, MADR mg/mL = 0.45, VWF:Ag U/dL = 23.4, VWF:CB U/dL = 21.1, VWF:CB ratio = 0.9, VWF:RCo U/dL = 17.2, VWF:RCo ratio = 0.74, Platelet VWF U/dL = 42.6, FVIII U/dL = 60.5, BAT F/M = 20

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: Sequencing of exon 28 of VWF

PreviouslyPublished: NA

Gene: VWF

Variant 1: c.3797C>T (p.Pro1266Leu)

HGVS: NM_000552.4(VWF):c.3797C>T (p.Pro1266Leu)

ClinVarID: 314; https://www.ncbi.nlm.nih.gov/clinvar/variation/314/

CAID: NA

gnomAD: MAF = 0.003667 (92/25086 alleles; 1 homozygote) in the European (Finnish) population; https://gnomad.broadinstitute.org/variant/12-6128787-G-A?dataset=gnomad_r2_1

Variant 2: c.7085G>T (p.Cys2362Phe)

HGVS: NM_000552.4(VWF):c.7085G>T (p.Cys2362Phe)

ClinVarID: 315; https://www.ncbi.nlm.nih.gov/clinvar/variation/315/

CAID: NA

gnomAD: absent

Case: Patient 4 (Family C), female, 76yo

DiseaseAssertion: VWD2B

FamilyInfo: NA

ParentalGenotype(s): NA

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

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

CaseHPOFreeText: blood group O, Platelet count x103/μl = 236, PFA 100 sec = >300, SPA % = 8.4, MADR mg/mL = 0.75, VWF:Ag U/dL = 35.4, VWF:CB U/dL = 37.3, VWF:CB ratio = 1.05, VWF:RCo U/dL = 25.4, VWF:RCo ratio = 0.72, Platelet VWF U/dL = 66.8, FVIII U/dL = 32.0, BAT F/M = 16

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: Sequencing of exon 28 of VWF

PreviouslyPublished: NA

Gene: VWF

Variant: c.4135C>T (p.Arg1379Cys)

HGVS: NM_000552.4(VWF):c.4135C>T (p.Arg1379Cys)

ClinVarID: 100333; https://www.ncbi.nlm.nih.gov/clinvar/variation/100333/

CAID: NA

gnomAD: MAF = 0.00003891 (5/128500 alleles) in the European (non-Finnish) population; https://gnomad.broadinstitute.org/variant/12-6128449-G-A?dataset=gnomad_r2_1

Case#: p.P1162L, Female, Age 52, African American

Disease Assertion: Normal Variant

Family Info: Two family members tested with normal clinical phenotype

Parental Genotype: Not listed

CasePresentingHPOs:

CaseHPOFreeText: VWF:RCo/VWF:Ag Ratio 0.50, VWF:GPIbM 98

CaseNotHPOs: HP:0040240

(Increased Ratio of VWF Propeptide to VWF antigen)

CaseNotHPOFreeText:bleeding score 2, VWF:Ag 144 IU/dL, VWF:RCo 72 IU/dL, normal multimer distribution

ProteinExpression:

CasePreviousTesting: VWF Sequencing

Gene:VWF

Variant: NM_000552.4(VWF):c.3485C>T (p.Pro1162Leu)

ClinVar: 256669 ClinVarID

CAID: CA6402756

CAID

gnomAD: MAF of 0.2207 (2023/9166 alleles) in the African American population.

gnomAD

Case#: p.I1453N, Male, Age 25, Caucasian

Disease Assertion: VWD2M

FamilyInfo: No affected family members enrolled in study

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: bleeding score 11, VWF:RCo/VWF:Ag ratio 0.55, VWF:Ag 20 IU/dL, VWF:RCo 11 IU/dL,

CaseNotHPOs:HP:0040240

(Increased Ratio of VWF Propeptide to VWF antigen)

CaseNotHPOFreeText: Normal multimer distribution

Protein Expression: N/A

CasePreviousTesting: VWF sequencing

Gene: VWF

Variant: NM_000552.4:c.4358T>A (p.Ile1453Asn)

ClinVar: N/A

CAID: CA383502477

CAID

gnomAD: N/A

Case#: p.D1283Y, Female, Age 85, Caucasian

Disease Assertion: VWD2M

FamilyInfo: Single affected family member with similar bleeding score

Parental Genotype: Not listed

CasePresentingHPOs:

CaseHPOFreeText: VWF:RCo/ VWF:Ag ratio 0.34, bleeding score 12, VWF:RCo 12 IU/dL, VWF:Ag 25 IU/dL

CaseNotHPOs: HP:0040240

(Increased Ratio of VWF Propeptide to VWF antigen)

CaseNotHPOFreeText: Normal multimer distribution

Protein Expression: N/A

CasePreviousTesting: VWF Sequencing

Gene: VWF

Variant: NM_000552.4:c.3847G>T (p.Asp1283Tyr)

ClinVar: N/A

CAID: CA383506819

CAID

gnomAD: N/A

PMID: 28544236

Gene VWF

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#: 06012, Age 10, Male, Blood Type O+ (Table S3)

Disease Assertion: VWD1

FamilyInfo: Patient is member of Family# 0609, which includes 3 individuals. All members of the family have the same variant.

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding score 10, VWF:Ag: 13, VWF:RCo:14, FVIII:C:40, VWF:CB:13

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.3363G>T (p.Arg1121Ser)

ClinVar: N/A

CAID: CA383511875 CAID

gnomAD: N/A

Case#: 02064, Age 32, Male, Blood type O- (Table S3)

Disease Assertion: VWD 1

FamilyInfo: Patient is a part of family # 0224. There are 3 other members of the family (02065, 02066, 02067). All members of the family have the same variant.

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding score 13, VWF:Ag: 4.7, VWF:RCo: 5, FVIII:C: 16, 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

CAID1

gnomAD: N/A

Case#: 27024, Age 56, Female, Blood Type A+ (Table S3)

Disease Assertion: VWD 1

FamilyInfo: The patient is the only member of Family#2713.

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: VWF:Ag:5.3, VWF:RCo:6, FVIII:C:38, VWF:CB:4.2

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.3467C>T (p.Thr1156Met) and c.-3151T>G

ClinVar: 100264 ClinVar

CAID: CA228414 CAID

gnomAD: N/A

Case#: 06024, Age 36, Female, Blood Type O+ (Table S3)

Disease Assertion: VWD1

FamilyInfo: The patient is the only member of Family#0617.

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding Score 1, VWF:Ag:35, VWF:RCo:25, FVIII:C:69, VWF:CB: 27

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.7300C>T (p.Arg2434Ter)

ClinVar: 100464 ClinVar

CAID: CA228781 CAID

gnomAD: MAF of 0.0001298 (2/15414 alleles) in the European (non-Finnish) population. gnomAD

Case#: 02058, Age 64, Female, Blood type A+ (Table S3)

Disease Assertion: VWD1

FamilyInfo: Patient is the only member of family #0221.

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding score 19, VWF:Ag: 7.3, VWF:RCo: 5.9, FVIII:C: 19, 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

Case#: 03035, Age 51, Male (Table S3)

Disease Assertion: VWD1

FamilyInfo: A part of family #03150 along with two other patients.

Parental Genotype: Not listed

CasePresentingHPOs: Not listed

CaseHPOFreeText: Bleeding Score 4, VWF:Ag: 34, VWF:RCo: 26, FVIII:C: 43, VWF:CB 33

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

Protein Expression:N/A

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

Gene: VWF

Variant: NM_000552.4:c.3467C>T (p.Thr1156Met) and NM_000552.3:c.-3151T>G

ClinVar: 100264 ClinVar

CAID: CA228414 CAID

gnomAD: N/A

Case#: 32002, Age 49, Female, Blood Type +

Disease Assertion: VWD 1

FamilyInfo: The patient is the only member of Family# 3202.

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: VWF:Ag: 34, VWF:RCo: 30, FVIII:C: 53, VWF:CB: 29

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.7408C>T (p.Gln2470Ter)

ClinVar: 100469 ClinVar

CAID: CA228790 CAID

gnomAD: MAF of 0.00002891 (1/34590 alleles) in the Latino population.

Case#: 06007, Age 54, Male, Blood Type O+ (Table S3)

Disease Assertion: VWD

FamilyInfo: Two total patients were documented from family# 0606.

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: VWF:Ag: 28, VWF:RCo: 26.1, FVIII:C: 56, VWF:CB: 23

CaseNotHPOs: N/A

CaseNotHPOFreeText: Bleeding Score 5

Protein Expression: N/A

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

Gene: VWF

Variant: NM_000552.4:c.1156+2T>C (intronic)

ClinVar: N/A

CAID: CA383504978 CAID

gnomAD: N/A

Case#: 36008, Age 34, Female, Blood Type O+ (Table S3)

Disease Assertion: VWD 1

FamilyInfo: The patient is the only member of Family#3606.

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding Score 8, VWF:Ag: 34, VWF:RCo:14, FVIII:C: 37, VWF:CB: 25

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

Protein Expression: N/A

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

Gene: VWF

Variant: NM_000552.4:c.2771G>A(p.Arg924Gln) and NM_000552.4:c.3390C>T (p.Cys1130=)

ClinVar: 627186 ClinVar

CAID: CA228368 and CA478101454 CAID1 CAID2

gnomAD: MAF of 0.01866 (2411/ 129182 alleles) in the European (non-Finnish) population (CA228368). gnomAD

Case#: 02052, Age 25, Male, Blood type A+ (Table S3)

Disease Assertion: VWD 1

FamilyInfo: Patient is the only family member of family # 0220

Parental Genotype: Not listed

CasePresentingHPOs:N/A

CaseHPOFreeText: Bleeding Score: 11, VWF:Ag: 15, VWF:RCO:12, FVIII:C:20, 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: NM_000552.4:c.1625C>G (p.Ala542Gly) and NM_000552.4:c.6187C>T (p.Pro2063Ser)

ClinVar: 381621 and 100436 ClinVar1

ClinVar2

CAID: CA6403319 and CA202650 CAID1

CAID2

gnomAD: MAF of 0.001355 (48/ 35418 alleles) in the Latino population (CA6403319). MAF of 0.04854 (1486/ 30616 alleles) in the South Asian Population (CA202650).

gnomAD1

gnomAD2

Case: T3-5, female, 19yo

DiseaseAssertion: VWD3

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeText: Blood type: O+, bleeding score = 12, VWF:Ag (IU/mL) = 0.01; VWF:RCo (IU/mL) = 0.08; FVIII:C (IU/mL) = 0.04

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: qRT-PCR

PreviouslyPublished:

Gene: VWF

Variant: c.1729+3A>C

HGVS: NM_000552.5(VWF):c.1729+3A>C

ClinVarID: 1065249; https://www.ncbi.nlm.nih.gov/clinvar/variation/1065249/?oq=c.1729+3A%3EC&m=NM_000552.5(VWF):c.1729%203A%3EC

CAID: n/a

gnomAD: absent

PMID: 28362648

Gene: VWF

HGNCID: 12726

Case: T3-2, female, 11yo

DiseaseAssertion: VWD3

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeText: Blood type: O+, bleeding score = 13, VWF:Ag (IU/mL) = 0.01; VWF:RCo (IU/mL) = 0.03; FVIII:C (IU/mL) = 0.01

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: qRT-PCR

PreviouslyPublished:

Gene: VWF

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

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

ClinVarID: n/a

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

gnomAD: absent

Case: 2B, male, 55yo

DiseaseAssertion: VWD2B

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeText: Blood type: O+, bleeding score = 17, VWF:Ag (IU/mL) = 0.40; VWF:RCo (IU/mL) = 0.13; FVIII:C (IU/mL) = 0.46

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: qRT-PCR

PreviouslyPublished:

Gene: VWF

Variant: c.3946G>A (p.Val1316Met)

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

ClinVarID: 290; https://www.ncbi.nlm.nih.gov/clinvar/variation/290/?new_evidence=false

CAID:

gnomAD: absent

Case: 2M, female, 25yo

DiseaseAssertion: VWD2M

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeText: Blood type: A+, bleeding score = 7, VWF:Ag (IU/mL) = 0.11; VWF:RCo (IU/mL) = 0.03; FVIII:C (IU/mL) = 0.39

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: qRT-PCR

PreviouslyPublished:

Gene: VWF

Variant: c.4145T>C (p.Leu1382Pro)

HGVS: NM_000552.5:c.4145T>C (p.Leu1382Pro)

ClinVarID: n/a

CAID: CA383504407; https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA383504407

gnomAD: absent

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: Patient 32, Family K (Table 1.), F/17, Afro-Caribbean

DiseaseAssertion: VWD2A (IIE)

FamilyInfo: Patient 18 (F/53, Afro-Carribean), Patient 29 (F/33, Afro-Caribbean), Patient 33 (F/49, Afro-Caribbean) also from Family K. (Table 1.)

ParentalGenotype(s): NA

CasePresentingHPOs:

CaseHPOFreeRext: BAT =4, FVIII:C (IU/dL) = 79, VWF:Ag (IU/dL) = 49, VWF:Act (IU/dL) = 37

CaseNOTHPOs:

CaseNOTHPOFreeText: Blood type 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.2365A > G, p.(Thr789Ala)

HGVS: NM_000552.5:c.2365A>G (p.Thr789Ala)

ClinVarID: 256659

CAID: CA6403090

gnomAD: MAF of 0.5793 (43409/74928 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6044368-T-C?dataset=gnomad_r4

Variant: c.2385T > C, p.(Tyr795 =)

HGVS: NM_000552.5:c.2385T>C (p.Tyr795=)

ClinVarID: 256660

CAID: CA6403087

gnomAD: MAF of 0.5788 (43385/74952 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6044348-A-G?dataset=gnomad_r4

Variant: c.2880G > A, p.(Arg960 =)

HGVS: NM_000552.5:c.2880G>A (p.Arg960=)

ClinVarID: 195657

CAID: CA201877

gnomAD: MAF of 0.3169 (23737/74896 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6029429-C-T?dataset=gnomad_r4

Variant: c.3505T > A, p.(Cys1169Ser)

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

ClinVarID:

CAID: CA383511219

gnomAD:

Case: Patient 39, Family S (Table 1.), F/76, Afro-Caribbean

DiseaseAssertion: VWD2A (IIA)

FamilyInfo: Patient 40 (F/38, Afro-Caribbean), Patient 41 (M/63, Afro-Caribbean) and Patient 52 (F/48, Afro Caribbean) also from Family S. (Table 1.)

ParentalGenotype(s): NA

CasePresentingHPOs:

CaseHPOFreeRext: BAT = 3, FVIII:C (IU/dL) = 74, VWF:Ag (IU/dL) = 35, 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: deletion of exons 9-10

HGVS: NM_000552.5:c.1030_1317del (p.Gly344_Arg439del)

ClinVarID:

CAID: CA3260663889

gnomAD:

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.4628C > G p.(Ser1543Cys)

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

ClinVarID: 4533008

CAID: CA383500651

gnomAD:

Case: Patient 9, Family F (Table 1.), F/76, Afro-Caribbean

DiseaseAssertion: VWD2A (IIE)

FamilyInfo: Patient 8 (M/86, Afro-Caribbean) and Patient 28 (F/55, Afro-Caribbean) also from Family F. (Table 1.)

ParentalGenotype(s): NA

CasePresentingHPOs:

CaseHPOFreeRext: BAT =11, FVIII:C (IU/dL) = 40, VWF:Ag (IU/dL) = 30, VWF:Act (IU/dL) = 28

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.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 45, Family V (Table 1.), M/51, Afro-Caribbean

DiseaseAssertion: VWD2M

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs:

CaseHPOFreeRext: BAT = 5, FVIII:C (IU/dL) = 45, VWF:Ag (IU/dL) = 96, VWF:Act (IU/dL) = 59

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.4196G > A, p.(Arg1399His)

HGVS: NM_000552.5:c.4196G>A (p.Arg1399His)

ClinVarID: 293

CAID: CA114133

gnomAD: MAF of 0.01540 (456/29604 alleles) in Ashkenazi Jewish population https://gnomad.broadinstitute.org/variant/chr12-6019222-C-T?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: P1413L heterozygous

DiseaseAssertion: VWD1

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: FVIII:C = 58 IU/dL, VWF:RCo = 39 IU/dL, VWF:Ag = 44 IU/dL, VWF:CB = 37 IU/dL, VWF:RCo/VWF:Ag = 0.89

CaseNOTHPOs: HP:0030132

(Absence of large von Willebrand factor multimers)

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NA

PreviouslyPublished: PMID: 16985174

Gene: VWF

Variant: c.4238C>T (p.Pro1413Leu)

HGVS: NM_000552.4(VWF):c.4238C>T (p.Pro1413Leu)

ClinVarID: 100342; https://www.ncbi.nlm.nih.gov/clinvar/variation/100342/

CAID:

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

PMID: 28218427

Gene: VWF

HGNCID: 12726

PMID: 19694940

Gene: VWF

HGNC: 12726

PMID: 28791655

Gene: VWF

HGNCID: 12726

PMID: 28447419

Gene: VWF

HGNCID: 12726

Case: 2M-2

DiseaseAssertion: VWD2M

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: AcuStar RCo/Ag = 0.01; AcuStar CB/Ag = 1.16; ELISA CB/Ag = 1.41

CaseHPOFreeText:

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: not described

PreviouslyPublished: 1409710

Gene: VWF

Variant: c.3970G>A (p.Gly1324Ser)

HGVS: NM_000552.5(VWF):c.3970G>A (p.Gly1324Ser)

ClinVarID: 300; https://www.ncbi.nlm.nih.gov/clinvar/variation/300/?new_evidence=false

CAID:

gnomAD: MAF = 0.00003267 in South Asian population; https://gnomad.broadinstitute.org/variant/12-6128614-C-T

Case: 2A-5

DiseaseAssertion: VWD2A

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: AcuStar RCo/Ag = 0.36; AcuStar CB/Ag = 0.15; ELISA CB/Ag = 0.24

CaseHPOFreeText:

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: not described

PreviouslyPublished: PMID: 1537829

Gene: VWF

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

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

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

CAID:

gnomAD: absent

Case: 2B-5

DiseaseAssertion: VWD2B

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: AcuStar RCo/Ag = 0.32; AcuStar CB/Ag = 0.19; ELISA CB/Ag = 0.38

CaseHPOFreeText:

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: not described

PreviouslyPublished: 1373334

Gene: VWF

Variant: c.4010C>T (p.Pro1337Leu)

HGVS: NM_000552.5(VWF):c.4010C>T (p.Pro1337Leu)

ClinVarID: 100314; https://www.ncbi.nlm.nih.gov/clinvar/variation/100314/?new_evidence=false

CAID:

gnomAD: MAF = 0.00005440 in East Asian population; https://gnomad.broadinstitute.org/variant/12-6128574-G-A

Case: 2B-8

DiseaseAssertion: VWD2B

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: AcuStar RCo/Ag = 0.99; AcuStar CB/Ag = 1.35; ELISA CB/Ag = 1.02

CaseHPOFreeText:

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: not described

PreviouslyPublished: 16985174

Gene: VWF

Variant: c.3797C>T (p.Pro1266Leu)

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

ClinVarID: 314; https://www.ncbi.nlm.nih.gov/clinvar/variation/314/?new_evidence=false

CAID:

gnomAD: MAF (European, Finnish) = 0.003667; 1 homozygote; https://gnomad.broadinstitute.org/variant/12-6128787-G-A

Case: 2A-7

DiseaseAssertion: VWD2A

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: AcuStar RCo/Ag = 0.27; AcuStar CB/Ag = 0.10; ELISA CB/Ag = 0.39

CaseHPOFreeText:

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: not described

PreviouslyPublished: PMID:1673047

Gene: VWF

Variant: c.4883T>C (p.Ile1628Thr)

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

ClinVarID: 284; https://www.ncbi.nlm.nih.gov/clinvar/variation/284/?new_evidence=false

CAID:

gnomAD: absent

Case: 2A-1

DiseaseAssertion: VWD2A

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: AcuStar RCo/Ag = 0.49; AcuStar CB/Ag = 0.29; ELISA CB/Ag = 0.33

CaseHPOFreeText:

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: not described

PreviouslyPublished: PMID: 8435341

Gene: VWF

Variant: c.4541T>G (p.Phe1514Cys)

HGVS: NM_000552.5(VWF):c.4541T>G (p.Phe1514Cys)

ClinVarID: 304; https://www.ncbi.nlm.nih.gov/clinvar/variation/304/?new_evidence=false

CAID:

gnomAD: absent

Case: 2B-2

DiseaseAssertion: VWD2B

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: AcuStar RCo/Ag = 0.62; AcuStar CB/Ag = 0.50; ELISA CB/Ag = 0.47

CaseHPOFreeText:

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: not described

PreviouslyPublished: 1373334

Gene: VWF

Variant: c.4010C>T (p.Pro1337Leu)

HGVS: NM_000552.5(VWF):c.4010C>T (p.Pro1337Leu)

ClinVarID: 100314; https://www.ncbi.nlm.nih.gov/clinvar/variation/100314/?new_evidence=false

CAID:

gnomAD: MAF = 0.00005440 in East Asian population; https://gnomad.broadinstitute.org/variant/12-6128574-G-A

PMID: 28060120

Gene: VWF

HGNCID: 12726

PMID: 8865541

Gene: VWF

HGNC: 12726

Disease: von Willebrand disease type 2B

MONDO: 0015629

InheritancePattern: Autosomal Dominant

Prevalence: Overall VWD prevalence is estimated to be as high as 1 in 100 in the general population, with 1 in 10,000 pursuing tertiary care referral ((PMID: 28847738).

Penetrance: Fully penetrant / nearly fully penetrant for most pathogenic type 2 variants

Case#: Male, 31<br /> DiseaseAssertion: VWD 2N<br /> FamilyInfo: A younger brother with mild HA, sister with normal VWF levels, no other famile members with bleeding disorders<br /> ParentalGenotype: <br /> CasePresentingHPOs: HP:0000421 (epistaxis), HP:0007420 (spontaneous hematoma)<br /> CaseHPOFreeText: Soft tissue bleeding, VWF:Ag 80%, VWF:RCo 60%, normal VWF multimer pattern<br /> CaseNotHPOs:<br /> CaseNotHPOFreeText: <br /> CasePreviousTesting: Genotyping using Next Gen screening, by Sanger sequence screening of all 26 exons of F8 gene, by a multiplex ligation-dependent probe affinity assay, and by a VWF:FVIII binding assay<br /> Gene: VWF<br /> Variant: c2390T>G in exon 18<br /> ClinVar:<br /> CAID: gnomAD:

Case: Index Patient (IP), Female, 26 years old; described as from a genetically isolated population (not further specified), consistent with elevated homozygosity rates in that population. DiseaseAssertion: Type 3 VWD, confirmed by VWF:Ag <4 IU/dL (virtual absence of VWF). FamilyInfo: NA — no relatives' bleeding history or genotype reported ParentalGenotype(s): NA (not tested/not reported) CasePresentingHPOs: HP:0000421 (Epistaxis — frequent nosebleeds), HP:0000132 (Menorrhagia — heavy, prolonged, led to iron-deficiency anemia), HP:0001934 (Persistent bleeding after trauma — bleeding following injury), HP:0012147 (Reduced quantity of VWF; VWF:Ag <4 IU/dL), HP:0030129 (Impaired VWF:RCo-type activity; VWF:GPIbM <4 IU/dL) CaseHPOFreeText: Easy bruising (no matching HPO code in the approved list); FVIII:C 2.0 IU/dL (nv 70–157); referred to Hemophilia Centre at age 1 for bleeding complications; declined recommended lifelong prophylaxis due to injection discomfort, later underwent prophylaxis with plasma-derived VWF/FVIII concentrates and on-demand treatment (tranexamic acid, oral contraceptives, replacement therapy). Supporting functional evidence from patient-derived endothelial colony-forming cells (ECFCs): virtual absence of VWF mRNA (RQ ~0.04–0.05 vs. 1.00 in healthy controls, across 4 primer/probe sets); VWF secretion into ECFC medium 6.2% ± 0.4% of healthy controls (p<0.0001); near-total absence of Weibel-Palade bodies on immunofluorescence (only 1–3 small WPBs seen in some cells vs. normal stick-shaped WPBs in controls); altered intracellular trafficking of angiopoietin-2 (WPB inflammatory cargo) in the absence of WPBs. CaseNOTHPOs: NA CaseNOTHPOFreeText: NA CasePreviousTesting: Routine testing (Sanger sequencing of coding exons, ~50 bp flanking intronic regions, promoter, 5'/3'-UTR, plus MLPA) was negative — patient was "mutation-negative" prior to this study. Not genome-wide; targeted to VWF only, but comprehensive: this study's NGS covered the entire 176 kb VWF locus (all 52 exons, full intronic regions, promoter) at 30x coverage, going well beyond standard exon+flanking-intron approaches specifically to find deep intronic variants. GenotypingMethod: Illumina NovaSeq 6000 NGS (2×150 bp reads) of the whole VWF genomic region; variant annotation via Ensembl VEP with SpliceAI, PolyPhen-2, SIFT; splice effect independently confirmed with Neural Network Splicing, ASSP, and MaxEnt/HSF prediction tools. Functional validation via patient-derived ECFCs: RT-qPCR of VWF mRNA (4 primer/probe sets), cDNA sequencing, VWF:Ag ELISA of ECFC secretion, immunofluorescence microscopy, and whole-transcriptome RNA-seq. PreviouslyPublished: NA — no indication this patient was reported elsewhere; paper explicitly frames this variant/mechanism as a first report. Gene: VWF Variant: Novel homozygous deep intronic variant, intron 8, creating a new donor splice site that outcompetes the native donor site, causing inclusion of a 118-bp pseudoexon, frameshift, premature stop codon, and nonsense-mediated decay of the transcript. HGVS: NM_000552.5:c.997+118T>G (confirmed via ClinGen Allele Registry Community Standard Title; not explicitly stated in the paper's main text, which only gives cDNA/genomic coordinates without a transcript version). Genomic: g.6073501A>C (GRCh38/hg38; note the T>G/A>C discrepancy reflects VWF being transcribed from the minus strand of chr12). ClinVarID: NA CAID: CA3275979827 gnomAD: NA

PMID: 28904675

Gene: VWF

HGNCID: 12726

PMID: 30046717

Gene: von Willebrand Factor (VWF)

PMID: 28512017

Gene: VWF

HGNCID: 12726

PMID: 2010538

Gene: VWF

HGNC: 12726

Disease: von Willebrand disease type 2B

MONDO: 0015629

InheritancePattern: Autosomal Dominant

Prevalence: Overall VWD prevalence is estimated to be as high as 1 in 100 in the general population, with 1 in 10,000 pursuing tertiary care referral ((PMID: 28847738).

Penetrance: Fully penetrant / nearly fully penetrant for most pathogenic type 2 variants

PMID 16322474

Notes Recombinant full length p.Ile1628Thr expressed in HEK293 and purified from growth media was NOT digested by recombinant ADAMTS13 in non-denaturing conditions (Table 1, Fig 5a). However, the the A1-A3 p.Ile1628Thr truncations were digested by ADAMTS13 in non-denaturing conditions while WT recombinant VWF truncations were not (Fig 6).

PMID: 29126301

Gene: VWF

HGNC: 12726 (type 1)

Note: This article is about platelet coagulation and how to test it.

PMID: 28151804

Gene: VWF

HGNCID: 12726

PMID: 27785858

Gene: VWF

HGNCID: 12726

PMID: 29115727

Gene: VWF

HGNC: 12726 (type 1)

Note: This article is about how the median ISTH-BAT questionnaire score for VWD type 1 was 7 (IQR; 2,11).

Case: Patient B, male, 11 years old at WIL-29 study entry; ethnicity not reported.

DiseaseAssertion: VWD3. The patient was initially suspected to have VWD2A based on the family history but was reclassified as VWD3 after next-generation sequencing.

FamilyInfo: Patient B and Patient A are brothers from a consanguineous family. Both parents were diagnosed with VWD. Figure 2 shows both parents as heterozygous and Patient A and Patient B as homozygous for the familial VWF variant. The pedigree also includes another brother affected with VWD whose genetic testing was underway and a sister whose VWD diagnosis and genetic testing were pending.

ParentalGenotype: Both parents were heterozygous for the familial VWF variant, as shown in Figure 2.

CasePresentingHPOs: HP:0000421, HP:0030129 (Epistaxis, Impaired ristocetin cofactor assay activity)

CaseHPOFreeText: Recurrent spontaneous epistaxis. Historical VWF:RCo 1%; historical VWF:Ag not measured. VWF:RCo 1 IU/dL at WIL-31 screening. At the month 0 pharmacokinetic visit, pre-injection FVIII 16 IU/dL and VWF:RCo <5 IU/dL; after 60 IU/kg wilate, maximum VWF:RCo 65 IU/dL and in vivo recovery 1.02 kg/dL. VWF inhibitors were confirmed present at WIL-31 study entry; no VWF inhibitor was detectable at the 12-month visit.

CaseNotHPOs: NA

CaseNotHPOFreeText: No anaphylactic reactions or severe treatment-related adverse events were reported.

CasePreviousTesting: Diagnosed with VWD shortly after birth and initially suspected to have VWD2A based on family history. Historical VWF activity testing, and subsequent pharmacokinetic and VWF inhibitor testing, were performed. Historical VWF antigen was not measured. No earlier molecular genetic testing was reported.

GenotypingMethod: Next-generation sequencing performed in Bonn, Germany. Additional technical details regarding the sequencing assay or panel were not provided.

Gene: VWF

Variant: c.4094T>C p.Leu1365Pro, homozygous

HGVS: NM_000552.5:c.4094T>C (p.Leu1365Pro)

ClinVar: 2438545

CAID: NA

gnomAD: Absent (not reported in gnomAD; 0/251040 control chromosomes)

Case: P5, male, 73yo

DiseaseAssertion: VWD2M

FamilyInfo: NA

ParentalGenotype(s): NA

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

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

CaseHPOFreeText: bleeding score = 8; VWF:Ag (%) = 46, VWF:RCo(%) = 8.5, VWF:RCo/VWF:Ag ratio = 0.18, VWF:CIIIB (%) = 19.5, VWF:CIIIB/VWF:Ag ratio = 0.4, VWF:CVIB (%) = 15, VWF:CVIB/VWF:Ag ratio = 0.33

CaseNOTHPOs: HP:0030132

(Absence of large von Willebrand factor multimers)

CaseNOTHPOFreeText: NA

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.4121G>A (p.Arg1374His)

HGVS: NM_000552.4(VWF):c.4121G>A (p.Arg1374His)

ClinVarID: 100330; https://www.ncbi.nlm.nih.gov/clinvar/variation/100330/

CAID:

gnomAD: absent

Case: P7, male, 9yo

DiseaseAssertion: VWD2M

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0030129, HP:0030130

(Impaired ristocetin cofactor assay activity, Impaired von Willebrand factor collagen binding activity)

CaseHPOFreeText: bleeding score = 7; VWF:Ag (%) = 56, VWF:RCo(%) = 32, VWF:RCo/VWF:Ag ratio = 0.58, VWF:CIIIB (%) = 37, VWF:CIIIB/VWF:Ag ratio = 0.67, VWF:CVIB (%) = 17.4, VWF:CVIB/VWF:Ag ratio = 0.31

CaseNOTHPOs: HP:0030132

(Absence of large von Willebrand factor multimers)

CaseNOTHPOFreeText: NA

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.4195C>T (p.Arg1399Cys)

HGVS: NM_000552.4(VWF):c.4195C>T (p.Arg1399Cys)

ClinVarID: 100337; https://www.ncbi.nlm.nih.gov/clinvar/variation/100337/

CAID:

gnomAD: MAF = 0.0001386 (1/7214 alleles) in the Other population; https://gnomad.broadinstitute.org/variant/12-6128389-G-A?dataset=gnomad_r2_1

PMID: 28693644

Gene: VWF

HGNCID: 12726

PMID: 1673047

Gene: VWF

HGNCID: 12726

Case: Patient IV-4, Female (mother of proband V-2) DiseaseAssertion: Type 2A VWD, based on history of abnormal bleeding, low plasma VWF:Ag and activity, and lack of plasma HMW VWF multimers. FamilyInfo: Mother of proband V-2; part of 5-affected-member pedigree (Fig. 1). ParentalGenotype(s): Not described (her own parents' genotype status not reported in extracted text — see Figure 1). CasePresentingHPOs: HP:0000421 (Epistaxis), HP:0000132 (Menorrhagia), HP:0012147 (Reduced quantity of VWF; VWF:Ag 21.7 U/dL), HP:0030129 (Impaired VWF:RCo; VWF:Rco 5.0 U/dL), HP:0030132 (Absence of large VWF multimers — plasma), HP:0011871 (Impaired RIPA; 3.0%), HP:0003645 (Prolonged partial thromboplastin time; APTT 46.1 sec) CaseHPOFreeText: Anemia (secondary to menorrhagia; no matching HPO code in the approved list); FVIII:C not tested (N/A); TT 18.1 sec and PT 14.1 sec both within normal range. CaseNOTHPOs: NA CaseNOTHPOFreeText: Platelet VWF multimer status NOT tested for this patient ("Platelet samples were not available from IV-4") — do not assume the "normal platelet multimers" finding reported for the other four affected members applies here. CasePreviousTesting: Targeted confirmation of the familial VWF variant (not described as independent full 52-exon screening for this individual specifically); not genome-wide. GenotypingMethod: Sanger sequencing/allele-specific analysis, same platform as proband (Applied Biosystems 310 DNA analyzer). PreviouslyPublished: NA Gene: VWF Variant: Same novel heterozygous in-frame 6-bp deletion, exon 28, ΔD1529V1530 (VWF A2 domain) HGVS: c.4585_4590del (p.Asp1529_Val1530del) ClinVarID: NA CAID: NA gnomAD: NA

Case: Patient IV-2 (daughter of III-3; first cousin of proband's mother IV-4) DiseaseAssertion: Type 2A VWD, based on low plasma VWF:Ag and activity and lack of plasma HMW VWF multimers. FamilyInfo: Daughter of III-3 (proband's granduncle); first cousin of IV-4 (proband's mother); part of 5-affected-member pedigree (Fig. 1). ParentalGenotype(s): Father (III-3) heterozygous for the variant, affected. Mother's genotype not reported. CasePresentingHPOs: HP:0012147 (Reduced quantity of VWF; VWF:Ag 30.4 U/dL), HP:0030129 (Impaired VWF:RCo; VWF:Rco 8.4 U/dL), HP:0030132 (Absence of large VWF multimers — plasma), HP:0003645 (Prolonged partial thromboplastin time; APTT 45.8 sec) CaseHPOFreeText: Described only generically as having "abnormal bleedings" / "similar clinical symptoms" — no itemized bleeding symptoms given specifically for this individual. FVIII:C 50.0 U/dL — at the exact lower limit of normal (nv 50-150), notably higher than the other affected members. RIPA not tested (N/A). TT 15.6 sec and PT 13.8 sec both within normal range. CaseNOTHPOs: NA CaseNOTHPOFreeText: Platelet-associated VWF multimers normal (HMW multimers present) per the group finding covering this patient. CasePreviousTesting: Targeted confirmation of the familial VWF variant; not genome-wide. GenotypingMethod: Sanger sequencing/allele-specific analysis, same platform as proband. PreviouslyPublished: NA Gene: VWF Variant: Same novel heterozygous in-frame 6-bp deletion, exon 28, ΔD1529V1530 (VWF A2 domain) HGVS: c.4585_4590del (p.Asp1529_Val1530del) ClinVarID: NA CAID: NA gnomAD: NA

PMID: 16985174

Gene: VWF

HGNC: 12726

Disease: von Willebrand disease type 2B

MONDO: 0015629

InheritancePattern: Autosomal Dominant

Prevalence: Overall VWD prevalence is estimated to be as high as 1 in 100 in the general population, with 1 in 10,000 pursuing tertiary care referral ((PMID: 28847738).

Penetrance: Fully penetrant / nearly fully penetrant for most pathogenic type 2 variants

PMID: 28792666

Gene: VWF

HGNCID: 12726