Case: P5 Female, Korean, 31 years at report

DiseaseAssertion: VWD2A

FamilyInfo: Positive family history, no details provided.

ParentalGenotype: NA

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

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

CaseHPOFreeText: bleeding score 9, FVII:C 3%, VWF:Rco 4 IU/dL, VWF:Ag 14 IU/Dl, VWF:Rco/VWF:Ag 0.3, RIPA 1 ohms

CaseNotHPOs: HP:0003645, HP:0001873

(Prolonged partial thromboplastin time, Thrombocytopenia)

CaseNotHPOFreeText: aPTT 36s, platelets 210x10^9/L

CasePreviousTesting: NA

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

Gene: VWF

Variant: c.2574C>G p.C858W

HGVS: NM_000552.4:c.2574C>G (p.Cys858Trp)

ClinVar: NA

CAID: CA232299278

gnomAD: MAF of 0.0001002 (2/19954 alleles) in the East Asian population

https://gnomad.broadinstitute.org/variant/12-6143965-G-C

Case: P18, F/39

DiseaseAssertion: VWD1

FamilyInfo: No family history

ParentalGenotype: NA

CaseHPOFreeText: The bleeding score was 9, aPTT was 40 seconds, FVIII:C was 15%, VWF:RCo was 6 IU/dL, and VWF:Ag was 8 IU/dL, with a VWF:RCo/VWF:Ag ratio of 0.8. The VWF multimer pattern was absent, RIPA was 2 ohms, and the platelet count was 273 × 10⁹/L.

CasePreviousTesting: NA

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

Gene: VWF

Variant: c.3943C>T, p.R1315C — heterozygous

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

ClinVar: 100310

CAID: CA228502

gnomAD: https://gnomad.broadinstitute.org/variant/chr12-6019475-G-A?dataset=gnomad_r4

Case: P17, F/30

DiseaseAssertion: VWD2A

FamilyInfo: No family history

ParentalGenotype: NA

CaseHPOFreeText: The bleeding score was 8, aPTT was 42 seconds, FVIII:C was 23%, VWF:RCo was 20 IU/dL, and VWF:Ag was 11 IU/dL, with a VWF:RCo/VWF:Ag ratio of 1.8. The VWF multimer pattern showed a loss of intermediate and high molecular weight multimers, RIPA was not tested, and the platelet count was 276 × 10⁹/L.

CasePreviousTesting: NA

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

Gene: VWF

Variant: c.3814T>C, p.C1272R — heterozygous

HGVS: NM_000552.5(VWF):c.3814T>C (p.Cys1272Arg)

ClinVar: 301

CAID: CA114149

gnomAD: absent from gnomad v4.1.0

Case: P15, M/45

DiseaseAssertion: VWD1

FamilyInfo: Positive family history, no details provided.

ParentalGenotype: NA

CaseHPOFreeText: The bleeding score was 11, aPTT was 59 seconds, FVIII:C was 3%, VWF:RCo was 11 IU/dL, and VWF:Ag was 6 IU/dL, with a VWF:RCo/VWF:Ag ratio of 1.8. The VWF multimer pattern was normal, RIPA was 2 ohms, and the platelet count was 378 × 10⁹/L.

CasePreviousTesting: NA

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

Gene: VWF

Variant: c.2574C>G, p.C858W — heterozygous

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

ClinVar:

CAID: CA232299278

gnomAD: https://gnomad.broadinstitute.org/variant/chr12-6034799-G-C?dataset=gnomad_r4

Case: P11, M/19

DiseaseAssertion: VWD1

FamilyInfo: No family history

ParentalGenotype: NA

CaseHPOFreeText: The bleeding score was 3, aPTT was 49 seconds, FVIII:C was 29%, VWF:RCo was 42 IU/dL, and VWF:Ag was 58 IU/dL, with a VWF:RCo/VWF:Ag ratio of 0.7. The VWF multimer pattern was normal, RIPA was not tested, and the platelet count was 234 × 10⁹/L.

CasePreviousTesting: NA

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

Gene: VWF

Variant: c.2289dupG, p.S764Efs*16 — heterozygous

HGVS: NM_000552.5(VWF):c.2289dup (p.Ser764GlufsTer16)

ClinVar:

CAID: CA2695215960

gnomAD: absent from gnomad v4.1.o

Case: P9, M/26

DiseaseAssertion: VWD1

FamilyInfo: No family history

ParentalGenotype: NA

CaseHPOFreeText: The bleeding score was 1, aPTT was 44 seconds, FVIII:C was 9%, VWF:RCo was 13 IU/dL, and VWF:Ag was 6 IU/dL, with a VWF:RCo/VWF:Ag ratio of 2.0. The VWF multimer pattern was normal, RIPA was 3 ohms, and the platelet count was 217 × 10⁹/L.

CasePreviousTesting: NA

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

Gene: VWF

Variant: c.3614G>A, p.R1205H — heterozygous

HGVS: NM_000552.5(VWF):c.3614G>A (p.Arg1205His)

ClinVar: 308

CAID: CA114160

gnomAD: https://gnomad.broadinstitute.org/variant/chr12-6021960-C-T?dataset=gnomad_r4

Case: P8, M/32

DiseaseAssertion: VWD1

FamilyInfo: Positive family history, no details provided.

ParentalGenotype: NA

CaseHPOFreeText: The bleeding score was 7, aPTT was 39 seconds, FVIII:C was 10%, VWF:RCo was 14 IU/dL, and VWF:Ag was 13 IU/dL, resulting in a VWF:RCo/VWF:Ag ratio of 1.1. The VWF multimer pattern showed a mild loss of high molecular weight multimers, RIPA was not tested, and the platelet count was 286 × 10⁹/L.

CasePreviousTesting: NA

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

Gene: VWF

Variant: c.2665T>C, p.C889R — heterozygous

HGVS: NM_000552.5(VWF):c.2665T>C (p.Cys889Arg)

ClinVar:

CAID: CA383519992

gnomAD: absent from gnomad v4.1.0

Case: P10, M/2

DiseaseAssertion: VWD1

FamilyInfo: No family history

ParentalGenotype: NA

CaseHPOFreeText: The bleeding score was 1, aPTT was 33 seconds, FVIII:C was 96%, VWF:RCo was 30 IU/dL, and VWF:Ag was 36 IU/dL, resulting in a VWF:RCo/VWF:Ag ratio of 0.8. The VWF multimer pattern was normal, RIPA was not tested, and the platelet count was 222 × 10⁹/L.

CasePreviousTesting: NA

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

Gene: VWF

Variant: c.3835G>A, p.V1279I — heterozygous

HGVS: NM_000552.5(VWF):c.3835G>A (p.Val1279Ile)

ClinVar: 100288

CAID: CA228459

gnomAD: https://gnomad.broadinstitute.org/variant/chr12-6019583-C-T?dataset=gnomad_r4

Case: Patient 3 (Family A), female, 38yo

DiseaseAssertion: VWD2B

FamilyInfo: NA

ParentalGenotype(s): NA

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

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

CaseHPOFreeText: blood group A, Platelet count x103/μl = 207, PFA 100 sec = >300, SPA % = 0, MADR mg/mL = 0.45, VWF:Ag U/dL = 67.9, VWF:CB U/dL = 3.6, VWF:CB ratio = 0.06, VWF:RCo U/dL = 33.1, VWF:RCo ratio = 0.48, Platelet VWF U/dL = 128, FVIII U/dL = 54.5, BAT F/M = 10

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 2 (Family A), female, 75yo

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 A, Platelet count x103/μl = 322, PFA 100 sec = NA, SPA % = 10, MADR mg/mL = 0.6, VWF:Ag U/dL = 133, VWF:CB U/dL = 144.2, VWF:CB ratio = 1.1, VWF:RCo U/dL = 106, VWF:RCo ratio = 0.79, Platelet VWF U/dL = 129.5, FVIII U/dL = 126, BAT F/M = 3

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: Sequencing of exon 28 of VWF

PreviouslyPublished: NA

Gene: VWF

Variant: c.4115T>G (p.Ile1372Ser)

HGVS: NM_000552.4(VWF):c.4115T>G (p.Ile1372Ser)

ClinVarID: 100327; https://www.ncbi.nlm.nih.gov/clinvar/variation/100327/

gnomAD: MAF = 0.00006175 (7/113356 alleles) in the European (non-Finnish) population; https://gnomad.broadinstitute.org/variant/12-6128469-A-C?dataset=gnomad_r2_1

Case: Patient 10 (Family C), female, 70yo

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 = 168, PFA 100 sec = >300, SPA % = 15, MADR mg/mL = 0.75, VWF:Ag U/dL = 44.6, VWF:CB U/dL = 10.3, VWF:CB ratio = 0.23, VWF:RCo U/dL = 21.4, VWF:RCo ratio = 0.47, Platelet VWF U/dL = 202.0, FVIII U/dL = 53.2, BAT F/M = 15

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 20 (Family G), male, 58yo

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 B, Platelet count x103/μl = 213, PFA 100 sec = >300, SPA % = 12.6, MADR mg/mL = 0.3, VWF:Ag U/dL = 48.4, VWF:CB U/dL = 4.6, VWF:CB ratio = 0.10, VWF:RCo U/dL = 13.5, VWF:RCo ratio = 0.28, Platelet VWF U/dL = 175, FVIII U/dL = 56.4, BAT F/M = 17

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: Sequencing of exon 28 of VWF

PreviouslyPublished: NA

Gene: VWF

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

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

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

CAID: NA

gnomAD: absent

Case: Patient 1 (Family A), female, 3yo

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 B, Platelet count x103/μl = 290, PFA 100 sec = >264, SPA % = NA, MADR mg/mL = NA, VWF:Ag U/dL = 41.0, VWF:CB U/dL = 4.4, VWF:CB ratio = 0.11, VWF:RCo U/dL = 13.2, VWF:RCo ratio = 0.33, Platelet VWF U/dL = 76.4, FVIII U/dL = 36.1, 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 14 (Family C), male, 39yo

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 = 210, PFA 100 sec = >300, SPA % = 0, MADR mg/mL = 0.6, VWF:Ag U/dL = 61.3, VWF:CB U/dL = 10.4, VWF:CB ratio = 0.17, VWF:RCo U/dL = 18.5, VWF:RCo ratio = 0.3, Platelet VWF U/dL = 119, FVIII U/dL = 40.0, BAT F/M = 6

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: Sequencing of exon 28 of VWF

PreviouslyPublished: NA

Gene: VWF

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

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

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

CAID: NA

gnomAD: absent

Case: Patient 2 (Family A), male, 78yo

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 = 119, PFA 100 sec = >300, SPA % = 7, MADR mg/mL = 0.75, VWF:Ag U/dL = 44.7, VWF:CB U/dL = 11.8, VWF:CB ratio = 0.27, VWF:RCo U/dL = 28.4, VWF:RCo ratio = 0.63, Platelet VWF U/dL = 115, FVIII U/dL = 48.2, BAT F/M = 1

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 18 (Family E), female, 1yo

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 = 28, PFA 100 sec = >300, SPA % = NA, MADR mg/mL = NA, VWF:Ag U/dL = 142.9, VWF:CB U/dL = 97.0, VWF:CB ratio = 0.68, VWF:RCo U/dL = 102.7, VWF:RCo ratio = 0.72, Platelet VWF U/dL = 135, FVIII U/dL = 98.1, BAT F/M = NA

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: Sequencing of exon 28 of VWF

PreviouslyPublished: NA

Gene: VWF

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

HGVS: NM_000552.4(VWF):c.3946G>A (p.Val1316Met)

ClinVarID: 290; https://www.ncbi.nlm.nih.gov/clinvar/variation/290/

CAID: NA

gnomAD: absent

Case: Patient 12 (Family C), female, 60yo

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 = 154, PFA 100 sec = >300, SPA % = NA, MADR mg/mL = 0.75, VWF:Ag U/dL = 44.6, VWF:CB U/dL = 8.1, VWF:CB ratio = 0.18, VWF:RCo U/dL = 23.0, VWF:RCo ratio = 0.51, Platelet VWF U/dL = 127, FVIII U/dL = 68.0, BAT F/M = 18

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 16 (Family D), male, 67yo

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 = 60, PFA 100 sec = >300, SPA % = 20, MADR mg/mL = 0.15, VWF:Ag U/dL = 34.3, VWF:CB U/dL = 10.5, VWF:CB ratio = 0.31, VWF:RCo U/dL = 14.0, VWF:RCo ratio = 0.41, Platelet VWF U/dL = 142.50, FVIII U/dL = 43.5, BAT F/M = 20

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: Sequencing of exon 28 of VWF

PreviouslyPublished: NA

Gene: VWF

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

HGVS: NM_000552.4(VWF):c.3946G>A (p.Val1316Met)

ClinVarID: 290; https://www.ncbi.nlm.nih.gov/clinvar/variation/290/

CAID: NA

gnomAD: absent

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: T143, F, 64

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): 0.04, VWF:RCo (IU/ml): 0.04, FVIII:C (IU/ml): 0.03

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

Gene: VWF

Variant:

c.8043_8044delAG (p.Arg2681 fs), Exon 49, 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: 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: T028, M, 34

DiseaseAssertion: VWD type 3

FamilyInfo: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: Bleeding Score: 16 (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): 0.03

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

Gene: VWF

Variant:

c.7730-1 G>T, Exon 46, Homozygous

c.7906A>T (p.Asn7906Tyr), Exon 48, Heterozygous

Note: ELISA-based assay for detecting alloantibodies, genomic analysis via sequecning 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: IP #33

DiseaseAssertion: type 2A (IIA) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032442 - blood group O

CaseHPOFreeRext: VWF:Ag [IU/dL] = 21; VWF:Ac [IU/dL] = 4; FVIII:C [IU/dL] = 27

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.4513G>A p.Gly1505Arg

HGVS:

ClinVarID: not found

CAID: CA383501612

gnomAD: absent

Case: IP #10 in type 2B VWD sub-cohort

DiseaseAssertion: type 2B VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032442 - blood group O

CaseHPOFreeRext: VWF:Ag [IU/dL] = 34; VWF:Ac [IU/dL] = n/a; FVIII:C [IU/dL] = 64

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

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

PreviouslyPublished:

Gene: VWF

Variant: c.3922C>A p.Arg1308Ser

HGVS:

ClinVarID: not found

CAID: CA383506203

gnomAD: absent

Case: IP #7 (also in row 4 table 6)

DiseaseAssertion: type 2A (IIC) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032370 - blood group A

CaseHPOFreeRext: VWF:Ag [IU/dL] = 28; VWF:Ac [IU/dL] = 14; FVIII:C [IU/dL] = 33

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.1855C>T p.Arg619Cys

HGVS:

ClinVarID: not found

CAID: CA232310118

gnomAD: 0.000005855 (9 in 1537178) no homozygotes https://gnomad.broadinstitute.org/variant/12-6056947-G-A?dataset=gnomad_r4

Case: IP #66 (also in row 25 table 6)

DiseaseAssertion: type 2A VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: VWF:Ag [IU/dL] = 56; VWF:Ac [IU/dL] = 39; FVIII:C [IU/dL] = 89

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.7060T>G p.Cys2354Gly

HGVS:

ClinVarID: not found

CAID: CA383491801

gnomAD: 6.196e-7 (1 in 1613900) no homozygotes https://gnomad.broadinstitute.org/variant/12-5983171-A-C?dataset=gnomad_r4

Case: IP #16 in type 2M VWD sub-cohort (also in row 27 table 6)

DiseaseAssertion: type 2M VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: VWF:Ag [IU/dL] = 44; VWF:Ac [IU/dL] = 31; FVIII:C [IU/dL] = 34; VWF:CB (IU/dL) = 39

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.7694G>A p.Cys2565Ser

HGVS:

ClinVarID: not found

CAID: CA383489277

gnomAD: absent

Case: IP #12 (also in row 6 table 6)

DiseaseAssertion: type 2A (IIE) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032370 - blood group A

CaseHPOFreeRext: VWF:Ag [IU/dL] = 265; VWF:Ac [IU/dL] = 44; FVIII:C [IU/dL] = 183

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.3296G>A p.Cys1099Tyr

HGVS:

ClinVarID: not found

CAID: CA383512195

gnomAD: absent

Case: IP #37 ((also in row 17 table 6)

DiseaseAssertion: type 2A (IIA) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032440 - blood group B

CaseHPOFreeRext: VWF:Ag [IU/dL] = 22; VWF:Ac [IU/dL] = 14; FVIII:C [IU/dL] = 27

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.4541T>C p.Phe1514Ser

HGVS:

ClinVarID: not found

CAID: CA383501434

gnomAD: absent

Case: IP #42 (also in row 20 table 6)

DiseaseAssertion: type 2A (IIA) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032370 - blood group A

CaseHPOFreeRext: VWF:Ag [IU/dL] = 45; VWF:Ac [IU/dL] = 14.0; FVIII:C [IU/dL] = 41

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.4730A>C p.Asn1577Thr

HGVS:

ClinVarID: not found

CAID: CA383499838

gnomAD: absent

Case: IP #54 (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] = 32; VWF:Ac [IU/dL] = 7; FVIII:C [IU/dL] = 53

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 #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 #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: IP #42 in type U VWD sub-cohort (also in row 26 table 6)

DiseaseAssertion: unclassified VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032442 - blood group O

CaseHPOFreeRext: VWF:Ag [IU/dL] = 9; VWF:Ac [IU/dL] = 16; FVIII:C [IU/dL] = 41

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.7645T>C p.Cys2549Arg

HGVS:

ClinVarID: not found

CAID: CA383489376

gnomAD: absent

Case: IP #2 in type 2M VWD sub-cohort (also in row 12 table 6)

DiseaseAssertion: type 2M VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032370 - blood group A

CaseHPOFreeRext: VWF:Ag [IU/dL] = 45; VWF:Ac [IU/dL] = 9; FVIII:C [IU/dL] = 70; VWF:CB (IU/dL) = 38

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.3847G>A p.Asp1283Asn

HGVS:

ClinVarID: not found

CAID: CA383506815

gnomAD: absent

Case#: 10013, Age 23, Female, Blood Type O+ (Table S3)

Disease Assertion: VWD1

FamilyInfo: The patient is the only member of Family#1011.

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding Score 3, VWF:Ag:7.2, VWF:RCo:5.6, FVIII:C:19, VWF:CB:6.5

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.5198T>C (p.Leu1733Pro)

ClinVar: N/A

CAID: CA383496267 CAID

gnomAD: N/A

Case#: 02047, Age 71, Male, Blood Type: O+ (Table S3)

Disease Assertion:VWD 1

FamilyInfo: Family# 0218; 3 Family members were included in the study. All 3 members had VWD type 1. All 3 have the same variant as patient 02047.

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding Score 9, VWF:Ag: 9.3, VWF:RCo:6.4, FVIII:C: 30, VWF:CB: 6.1

CaseNotHPOs:N/A

CaseNotHPOFreeText:N/A

Protein Expression: N/A

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

Gene: VWF

Variant: NM_000552.4:c.5471C>A (p.Pro1824His)

ClinVar: 100430 ClinVar

CAID:CA228725

CAID

gnomAD: N/A

Case#: 32010, Age 21, Male, Blood Type not determined (Table S3)

Disease Assertion: VWD 1

FamilyInfo: The patient is one of two members of Family#3210. The second member is a carrier of the variant c.3931C>T.

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding Score 12, VWF:Ag:7.2, VWF:RCo: 5.7, FVIII:C: 21, VWF:CB: 6.8

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_000552.4:c.3931C>T (p.Gln1311Ter) and NM_000552.4:c.55G>A (p.Gly19Arg)

ClinVar: 100307 and 100432 ClinVar1 ClinVar

CAID: CA228496 and CA228729 CAID1 CAID2

gnomAD: MAF of 0.0003921 (12/ 30604 alleles) in the South Asian population (CA228496). gnomAD

MAF of 0.0008819 (27/ 30616 alleles) in the South Asian population.

gnomAD

Case#: 06002, Age 39, Female,Blood Type O+ (Table S3)

Disease Assertion: VWD1

FamilyInfo: Two total members in Family #0602. Patient 06003 has the c.2685G>C variant and a seperate intronic variant.

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding score 8, VWF:Ag: 25, VWF:RCo: 19.1, FVIII:C:88, VWF:CB:24

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.2685G>C (p.Gln895His) and NM_000552.4:c.4751A>G (p.Tyr1584Cys)

ClinVar: 310

ClinVar

CAID: CA383519910 and CA114162

CAID1 CAID2

gnomAD: MAF of 0.004024 (519/128972 alleles) in the European (non-Finnish) population.

gnomAD

Case#: 06009, Age 60, Female, Blood Type O+ (Table S3)

Disease Assertion: VWD1

FamilyInfo: The patient is the only member of family#0607.

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding Score 2, VWF:Ag:23, VWF:RCo: 25, FVIII:C 83, VWF:CB: 23

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.2435del (p.Pro812fs)

ClinVar: 303 ClinVar

CAID: CA114153 CAID

gnomAD: MAF of 0.0003601(9/ 24994 alleles) in the European (Finnish) population.

gnomAD

Case#: 13006, Age 66, Male, Blood Type A-

Disease Assertion: VWD 1

FamilyInfo: The patient is the only member of Family# 1304.

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding Score 8, VWF:Ag:10, VWF:RCo: 6, FVIII:C:16, VWF:CB:6.1

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

Protein Expression: N/A

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

Gene: VWF

Variant: NM_000552.4:c.3614G>A (p.Arg1205His)

ClinVar: 308 ClinVar

CAID: CA114160 CAID

gnomAD: N/A

Case#: 13014, Age20, Male, Blood type O+ (TableS3)

Disease Assertion: VWD 1

FamilyInfo: The patient is the only member of Family#1311.

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding Score 6, VWF:Ag:24, VWF:RCo: 22.5, FVIII:C:40, VWF:CB: 20

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

Protein Expression: N/A

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

Gene: VWF

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

ClinVar: 310 ClinVar

CAID: CA114162 CAID

gnomAD: MAF of 0.004024 (519/ 128972 alleles) in the European (non-Finnish) population

Case#: 03044, Age 27, Female (Table S3)

Disease Assertion: VWD 1

FamilyInfo: Patient was the only member of family #03230

Parental Genotype: not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding Score 3, VWF:Ag: 22, VWF:RCo:18, FVIIIC:29, VWF:CB: 17

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

Protein Expression: N/A

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

Gene: VWF

Variant: c.6699_6702dup (p.Cys2235ArgfsTer8)

ClinVar:

CAID:

gnomAD:

Case#: 27012, Age 24, Female, Blood Type O+ (Table S3)

Disease Assertion: VWD 1

FamilyInfo: The patient is the only member of Family #2707.

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: VWF:Ag: 33, VWF:RCo: 29, FVIII:C: 91, VWF:CB: 32

CaseNotHPOs: N/A

CaseNotHPOFreeText: Bleeding score 0

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:

Case#: 37006, Age 45, Female, Blood Type B+ (Table S3)

Disease Assertion: VWD 1

FamilyInfo: The patient is the only member of Family#3706.

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: VWF:Ag:7.6, VWF:RCo:5, FVIII:C: 8.9, VWF:CB: 6.9

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.3426T>C (p.Cys1142=), NM_000552.4:c.3614G>A (p.Arg1205His), NM_000552.4:c.7771-49G>A , NM_000552.4:c.3485_3486delinsTG (pPro1162Leu)

ClinVar: 256668 , 308, 619934 ClinVar1 ClinVar2 ClinVar3

CAID: CA6402757, CA114160, CA1139532197, and CA658683073 CAID1 CAID2 CAID3 CAID4

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

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

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#: 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#: 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#: 18001, Age 50, Male, Blood Type B+ (Table S3)

Disease Assertion: VWD 1

FamilyInfo: The patient one of 3 members of Family#1801. All of the patients have the same variant.

Parental Genotype: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: VWF:Ag:10, VWF:RCo:6.1, FVIII:C:17, VWF:CB:8.2

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 NM_000552.4:c.6989T>G (p.Val2330Gly)

ClinVar: 308 ClinVar1

CAID: CA114160 and CA6401808 CAID1 CAID2

gnomAD: MAF of 0.000008823 (1/113342 alleles) in the European (non-Finnish population) (CA6401808) gnomAD

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: Moreno-Castano_2021_Case_1, female, age 21 at time of study

DiseaseAssertion: VWD2A

FamilyInfo: The phenotypes of the affected propositus, the two unaffected parents, and the unaffected sibling are documented in Table I and Figure 1, while the family relationsihps and genotypes are not shown but described.

ParentalGenotype(s): The parental genotypes are negative for the variant, indicating that the variant is likely de novo in the proband.

CasePresentingHPOs: HP:0030129 (Impaired ristocetin cofactor assay activity), HP:0011871 (Impaired ristocetin-induced platelet aggregation), HP:0040225 (Decrease in high molecular weight von Willebrand factor Multimers), HP:0000978 (Bruising susceptibility), HP:0000421 (Epistaxis)

CaseHPOFreeText: Low VWF:RCo/VWF:Ag ratio

CaseNOTHPOs: HP:0030976 (Abnormal factor VIII activity)

CaseNOTHPOFreeText: Normal / slightly higher VWF antigen level

CasePreviousTesting: Because of the detailed clinical phenotype, genotyping was limited to the VWF locus alone.

GenotypingMethod: Genotyping consisted of PCR amplification and Sanger sequencing of the 52 exons of the VWF gene, as well as linkage analysis using four STRs located within the VWF locus.

PreviouslyPublished: The case appears to have been first published in PMID: 28971901.

Gene: VWF

Variant: NM_000552.5(VWF):c.8318G>C (p.Cys2773Ser)

ClinVarID: 100503

gnomAD: This variant is absent from gnomAD v2.1.1 and v3.1.2.

Case#: F10, III:1

DiseaseAssertion: Type 2 VWD

CaseHPOFreeText: complete loss of high MWM, VWF:Ag = 39; VWF:RCo = 12; VWF:GPIbM = 26; 0.31; 0.67; 2.18

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#: F10, II:1

DiseaseAssertion: Type 2 VWD

CaseHPOFreeText: complete loss of high MWM, VWF:Ag = 30; VWF:RCo = 5; VWF:GPIbM = 17; 0.17; 0.57; 3.44

CasePreviousTesting: Not clearly described

Gene: VWF

Variant: p.[R1306W];[=]

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

CAID: CA114123

gnomAD: absent from gnomad v4.1.0

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#: F20, II:1

DiseaseAssertion: Type 2 VWD

CaseHPOFreeText: loss of high and intermediate MWMs, VWF:Ag = 45; VWF:RCo = 7; VWF:GPIbM = 43; 0.16; 0.95; 6.11

CasePreviousTesting: Not clearly described

Gene: VWF

Variant: p.[V1316M];[=]

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

CAID: CA114127

gnomAD: absent from gnomad v4.1.0

Case#: F8, I:1

DiseaseAssertion: Type 2 VWD

CaseHPOFreeText: partial loss of high molecular weight multimers, VWF:Ag = 37; VWF:RCo = 21; VWF:GPIbM = 34; 0.57; 0.92; 1.60

CasePreviousTesting: Not clearly described

Gene: VWF

Variant: p.[P1337L];[=]

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

CAID: CA228510

gnomAD: https://gnomad.broadinstitute.org/variant/12-6019408-G-A?dataset=gnomad_r4

Case: 14, F, 2 years, Indian

DiseaseAssertion: VWD type 3

FamilyInfo: family history of disease, Consanguinity: yes

ParentalGenotype: n/a

CasePresentingHPOs: n/a

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

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

Gene: VWF

Variant:

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

Heterozygous

Case: 85, F, 6 years, Indian

DiseaseAssertion: VWD type 3

FamilyInfo: no family history of disease, Consanguinity: yes

ParentalGenotype: n/a

CasePresentingHPOs: n/a

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

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

Gene: VWF

Variant:

c.2282-2A>G, Exon 18

Heterozygous

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: 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: 10, M, 42 years, Indian

DiseaseAssertion: VWD type 3

FamilyInfo: Consanguinity: no, family history of disease

ParentalGenotype: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: FVIII:C: (U/dl): <1, VWF:Ag (U/dl): <1, Bleeding Score: 34

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

Gene: VWF

Variant:

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

Case: 23, F, 10 years, Indian

DiseaseAssertion: VWD type 3

FamilyInfo: family history of disease, Consanguinity: yes

ParentalGenotype: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: FVIII:C: (U/dl): 3.1, VWF:Ag (U/dl): <1, Bleeding Score: 8

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

Gene: VWF

Variant:

c.954T>A (p.Asn318Lys), Exon 8

Heterozygous

Case: 23, F, 10 years, Indian

DiseaseAssertion: VWD type 3

FamilyInfo: Consanguinity: yes, family history of disease

ParentalGenotype: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: FVIII:C: (U/dl): 3.1, VWF:Ag (U/dl): <1, Bleeding Score: 8

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

Gene: VWF

Variant:

c.2430C>A (p.Cys810*), Exon 18, Heterozygous

PMID:32618441

Gene: VWF

HGNCID:12726

Case:6 days old female infant

DiseaseAssertion:Type 2B

FamilyInfo:Her family history included no family members with low platelet levels or with bleeding diathesis.

ParentalGenotype(s):Negative for mutation by Sanger sequencing

CasePresentingHPOs:HP:0001873

CaseHPOFreeRext:Petechiae on her body and subependymal hemorrhage and bilateral intraventricular hemorrhage on US

GenotypingMethod:NGS

Gene:VWF

Variant:De Novo p.Val1316Met

HGVS:NP_000543.3:p.Val1316Met

ClinVarID:290

CAID:CA114127

gnomAD:6.20e-7

Case: Patient 15, Family J (Table 1.), F/64, Afro-Caribbean

DiseaseAssertion: Indeterminate effect of the VWF defect due to ISTH BAT at 0

FamilyInfo: Patient 14 (M/36, Afro-Carribean) also from Family J. (Table 1.)

ParentalGenotype(s): NA

CasePresentingHPOs:

CaseHPOFreeRext: BAT =0, FVIII:C (IU/dL) = 110, VWF:Ag (IU/dL) = 102, VWF:Act (IU/dL) = 40

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:

Case: Patient 1, Family A (Table 1.), F/49, Afro-Caribbean

DiseaseAssertion: VWD2B

FamilyInfo: Patient 2 (F/15, Afro-Caribbean) from same family A (Table 1.)

ParentalGenotype(s): NA

CasePresentingHPOs:

CaseHPOFreeRext: BAT = 7, FVIII:C (IU/dL) = 28, VWF:Ag (IU/dL) = 35, VWF:Act (IU/dL) = 10

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.3946G > A p.(Val1316Met)

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

ClinVarID: 290

CAID: CA114127

gnomAD:

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:

PMID: 36468906

Gene: VWF

HGNCID: 12726

Case: 6 year old boy living in Croatia

DiseaseAssertion: type 1 VWD

FamilyInfo: family history of bleeding disorders

CasePresentingHPOs: HP:0000421, HP:0011889, HP:0000978, HP:0008151

CaseHPOFreeRext: VWF:GPIbM = 23.6% (decreased), VWF"Ag = 24.7% (decreased), VWF:GPIbM/VWF:Ag (ratio) = 0.96, FVIII = 54.0% (normal), VWF:CB = 24.2% (decreased)

GenotypingMethod: NGS, MLPA

Gene: VWF

Variant: heterozygous deletion of exons 1-6 within the VWF gene

Case#: A 29 years old male DCM patient

DiseaseAssertion:Familial dilated cardiomyopathy (FDCM), associated with the TNNT2 gene missense variant p.Arg144Trp (R144W)

FamilyInfo: Family members had revealed its presence in three other individuals with DCM. A history of sudden cardiac deaths (SCD) in the family. Two individuals in the family, who were diagnosed with DCM, had died due to severe congestive heart failure at the age of 45 and 25 years. However, a 66-year-old individual in the same family with DCM having mild symptoms.

ParentalTesting:NR

CasePresentingHPOs: HP:0001644, HP:4000141, HP:0012664, HP:0004308, HP:0012828, HP:0001653

CaseHPOFreeText: Dilated cardiomyopathy with left ventricular dilation, Age of onset, 25, left ventricular internal diastolic dimension of 72mm, reduced ejection fraction of 26%, has Ventricular arrhythmia, severe mitral regurgitation.

CaseNotHPOs:NR

CaseNotHPOFreeText: NR

CasePreviousTesting:NR

Genotyping Method: Used PCR with GenBank No. NM_000364, then followed by mutation subsequent screening analysis

FunctionalAnalysis:The R144W mutation was found to be within the tropomyosin-binding domain of cTnT and alters the charge of the residue, so it is expected to have a significant impact on the structure and function of the protein. The novel unique/private R144W mutation identified in our present study is associated with FDCM

Variant:NM_001276345.2:c.445C>T

ClinVar:43640

CAID:CA004505

gnomAD: gnomAD v2: 1:201333470 G / A https://gnomad.broadinstitute.org/variant/1-201333470-G-A?dataset=gnomad_r2_1 gnomAD v4: chr1-201364342-G-A https://gnomad.broadinstitute.org/variant/chr1-201364342-G-A?dataset=gnomad_r4

AdditionalInfo:25 bp deletion was found to be associated with both HCM and DCM in India and south Asia

Case2: Patient M2, Female, French Gypsy, age is not specified

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: See Figure 2 for pedigree

ParentalGenotype: Unaffected parents see pedigree Fig 2

CasePresentingHPOs: N/A

CaseHPOFreeText: France, GT is particularly frequent in the Gypsy population, mainly represented by the Manouche tribe. Their clinical phenotype is the same as for classic type I disease, with a moderate and occasional severe bleeding syndrome

CaseNotHPOs: N/A

CaseNotHPOsFreeText: N/A

ProteinExpression: Flow cytometry analysis has shown that these patients' surface expresses <5% of normal GPIIIa and GPIIb levels (we are not given an exact value for each proband)

PlateletAggregation: "Absent platelet aggregation" this is all the information we are given for platelet aggregation

CasePreviousTesting: N/A

Gene: ITGA2B

Variant: NM_000419.3:c.1544+1G>A

LegacyVariant: N/A

ClinVar: 2895

CAiD: CA10575473

gnomAD: N/A

Case10: Patient M10, Male, French Gypsy, age is not specified

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: See Figure 2 for pedigree

ParentalGenotype: Unaffected parents see pedigree Fig 2

CasePresentingHPOs: N/A

CaseHPOFreeText: France, GT is particularly frequent in the Gypsy population, mainly represented by the Manouche tribe. Their clinical phenotype is the same as for classic type I disease, with a moderate and occasional severe bleeding syndrome

CaseNotHPOs: N/A

CaseNotHPOsFreeText: N/A

ProteinExpression: Flow cytometry analysis has shown that these patients' surface expresses <5% of normal GPIIIa and GPIIb levels (we are not given an exact value for each proband)

PlateletAggregation: "Absent platelet aggregation" this is all the information we are given for platelet aggregation

CasePreviousTesting: N/A

Gene: ITGA2B

Variant: NM_000419.3:c.1544+1G>A

LegacyVariant: N/A

ClinVar: 2895

CAiD: CA10575473

gnomAD: N/A

Supplementary Table S1:

Case40: GT47, French, gender and age not specified

DiseaseAssertion: Glanzmann thrombasthenia type I

FamilyInfo: N/A

ParentalGenotype: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: All patients had a life-long history of mucocutaneous bleeding

CaseNotHPOs: N/A

CaseNotHPOsFreeText: N/A

ProteinExpression: All patients in this study met the clinical and platelet function requirements for GT-- this includes an absent or strongly reduced expression of alphaIIbBeta3 in platelets

PlateletAggregation: All patients in this study met the clinical and platelet function requirements for GT-- this includes absent or severely reduced platelet aggregation with at least three physiological agonists

CasePreviousTesting: Sanger sequencing was performed. Sanger sequencing ensured coverage of all exons and splice sties of the ITGA2B and ITGB3 genes and extended 300-500 bp into the introns as well as including the UTR. They sequenced 416 bp upstream of the ITGA2B promoter and 463 bp upstream of the ITGB3 promoter. In total they sequenced 51.2% of the ITGA2B gene and 19.4% of the larger ITGB3 gene

Gene: ITGA2B

Variant: NM_000419.3:c.832del (p.Asp278IlefsTer101)

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA915940374

gnomAD: N/A

Supplementary Table S1:

Case30: GT35a, USA, gender and age not specified

DiseaseAssertion: Glanzmann thrombasthenia type I

FamilyInfo: N/A

ParentalGenotype: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: All patients had a life-long history of mucocutaneous bleeding

CaseNotHPOs: N/A

CaseNotHPOsFreeText: N/A

ProteinExpression: All patients in this study met the clinical and platelet function requirements for GT-- this includes an absent or strongly reduced expression of alphaIIbBeta3 in platelets

PlateletAggregation: All patients in this study met the clinical and platelet function requirements for GT-- this includes absent or severely reduced platelet aggregation with at least three physiological agonists

CasePreviousTesting: Sanger sequencing was performed. Sanger sequencing ensured coverage of all exons and splice sties of the ITGA2B and ITGB3 genes and extended 300-500 bp into the introns as well as including the UTR. They sequenced 416 bp upstream of the ITGA2B promoter and 463 bp upstream of the ITGB3 promoter. In total they sequenced 51.2% of the ITGA2B gene and 19.4% of the larger ITGB3 gene

Gene: ITGA2B and ITGB3

Variant: ITGA2B: NM_000419.3:c.2264G>A (p.Arg755Gln) NM_000212.2:c.392G>C (p.Arg131Pro) and NM_000212.2:c.777+1G>A

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA8602771, CA8622954, CA8623036

gnomAD: MAF in the Latino population is 0.0001903 https://gnomad.broadinstitute.org/variant/17-42454380-C-T and MAF in the African population is 0.00006152 https://gnomad.broadinstitute.org/variant/17-45361839-G-C and MAF in the African population is 0.0006774 https://gnomad.broadinstitute.org/variant/17-45363789-G-A

Supplementary Table S1:

Case17: GT20, French, gender and age not specified

DiseaseAssertion: Glanzmann thrombasthenia type I

FamilyInfo: N/A

ParentalGenotype: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: All patients had a life-long history of mucocutaneous bleeding

CaseNotHPOs: N/A

CaseNotHPOsFreeText: N/A

ProteinExpression: All patients in this study met the clinical and platelet function requirements for GT-- this includes an absent or strongly reduced expression of alphaIIbBeta3 in platelets

PlateletAggregation: All patients in this study met the clinical and platelet function requirements for GT-- this includes absent or severely reduced platelet aggregation with at least three physiological agonists

CasePreviousTesting: Sanger sequencing was performed. Sanger sequencing ensured coverage of all exons and splice sties of the ITGA2B and ITGB3 genes and extended 300-500 bp into the introns as well as including the UTR. They sequenced 416 bp upstream of the ITGA2B promoter and 463 bp upstream of the ITGB3 promoter. In total they sequenced 51.2% of the ITGA2B gene and 19.4% of the larger ITGB3 gene

Gene: ITGA2B

Variant: M_000419.3:c.2800G>T (p.Val934Phe)

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA290946484

gnomAD: N/A

Case3: Female, 8 years old, Japanese

DiseaseAssertion: Thrombocytopenia

FamilyInfo: Information on mother and grandfather available in Table 1(minimal information on other family members)

ParentalGenotype: Mother: ITGB3 (p.Asp621_Glu660del heterozygous) See Table 1

CasePresentingHPOs: HP:0000978 (Bruising)

CaseHPOFreeText: Subaponeurotic hematoma

CaseNotHPOs: N/A

CaseNotHPOsFreeText: N/A

ProteinExpression: Surface expression levels of αIIbβ3 in platelets of patient were decreased to around 65% of normal subjects with increase of CD42b (See Table 1)

PlateletAggregation: N/A

CasePreviousTesting: Sequence analysis of DNA revealed the patient's mutation. RT-PCR was also performed. The entire coding sequence of exons and exon-intron boundaries of ITGA2B and ITGB3 and the whole coding regions of ITGA2B and ITGB3 cDNA obtained from platelets were sequenced.

Gene: ITGB3

Variant: NM_000212.2:c.2134+1G>A (p.Asp621_Glu660del)

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA400033344

gnomAD: N/A

Case34: (GT-44) Female, age or ethnicity not specified

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: Proband GT43-GT44 are related

ParentalGenotype: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding severity: Information not available (See Supplementary Table 3)

CaseNotHPOs: N/A

CaseNotHPOsFreeText: N/A

ProteinExpression: Flow cytometry performed and CD41 and CD61 were observed (See Supplementary Table 3)

PlateletAggregation: Minimal information (See Supplementary Table 3)

CasePreviousTesting: DNA was extracted from peripheral blood samples from patients and family members, and Sanger sequencing and PCR was performed. Samples were processed for targeted sequencing using the available SHGp heme panel of 393 genes.

Gene: ITGA2B

Variant: NM_000419.3:c.1620G>C (p.Gln540His) and NM_000419.3:c.1616T>G (p.Leu539Arg)

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA399802407 and CA399802416

gnomAD: N/A

Case54: (GT-73) Gender, age, or ethnicity not specified

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: N/A

ParentalGenotype: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding severity: Information not given (See Supplementary Table 3)

CaseNotHPOs: N/A

CaseNotHPOsFreeText: N/A

ProteinExpression: Flow cytometry performed and CD41 and CD61 were observed (See Supplementary Table 3)

PlateletAggregation: Minimal information (See Supplementary Table 3)

CasePreviousTesting: DNA was extracted from peripheral blood samples from patients and family members, and Sanger sequencing and PCR was performed. Samples were processed for targeted sequencing using the available SHGp heme panel of 393 genes.

Gene: ITGB3

Variant: NM_000212.2:c.985A>G (p.Asn329Asp)

LegacyVariant: N/A

ClinVar: 323865

CAiD: CA8623107

gnomAD: MAF in Other population 0.0005534 http://gnomad.broadinstitute.org/variant/17-45367092-A-G

Case12: (GT-14) Female, carrier, age or ethnicity not specified

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: Probands GT11 -GT13 are related to GT-14 see Table 1

ParentalGenotype: Parents may be included in Table 1; however, not specified so no information

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding severity: Not available (See Supplementary Table 3)

CaseNotHPOs: N/A

CaseNotHPOsFreeText: N/A

ProteinExpression: Flow cytometry performed and CD41 and CD61 were observed (See Supplementary Table 3)

PlateletAggregation: Minimal information (See Supplementary Table 3)

CasePreviousTesting: DNA was extracted from peripheral blood samples from patients and family members, and Sanger sequencing and PCR was performed. Samples were processed for targeted sequencing using the available SHGp heme panel of 393 genes.

Gene: ITGB3

Variant: NM_000212.2:c.727G>C (p.Asp243His)

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA400023600

gnomAD: N/A

Case47: (GT-58) Female, age or ethnicity not specified

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: N/A

ParentalGenotype: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding severity: Severe (See Supplementary Table 3)

CaseNotHPOs: N/A

CaseNotHPOsFreeText: N/A

ProteinExpression: Flow cytometry performed and CD41 and CD61 were observed (See Supplementary Table 3)

PlateletAggregation: Minimal information (See Supplementary Table 3)

CasePreviousTesting: DNA was extracted from peripheral blood samples from patients and family members, and Sanger sequencing and PCR was performed. Samples were processed for targeted sequencing using the available SHGp heme panel of 393 genes.

Gene: ITGB3

Variant: NM_000212.2:c.1543del (p.Ser513fs)

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA500651429

gnomAD: N/A

Case35: (GT-45) Male, age or ethnicity not specified

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: Proband GT45-GT48 are related

ParentalGenotype: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding severity: Information not available (See Supplementary Table 3)

CaseNotHPOs: N/A

CaseNotHPOsFreeText: N/A

ProteinExpression: Flow cytometry performed and CD41 and CD61 were observed (See Supplementary Table 3)

PlateletAggregation: Minimal information (See Supplementary Table 3)

CasePreviousTesting: DNA was extracted from peripheral blood samples from patients and family members, and Sanger sequencing and PCR was performed. Samples were processed for targeted sequencing using the available SHGp heme panel of 393 genes.

Gene: ITGA2B

Variant: NM_000419.3:c.1879-2A>G

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA290949031

gnomAD: N/A

Case50: (GT-62) Female, age or ethnicity not specified

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: N/A

ParentalGenotype: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding severity: Severe (See Supplementary Table 3)

CaseNotHPOs: N/A

CaseNotHPOsFreeText: N/A

ProteinExpression: Flow cytometry performed and CD41 and CD61 were observed (See Supplementary Table 3)

PlateletAggregation: Minimal information (See Supplementary Table 3)

CasePreviousTesting: DNA was extracted from peripheral blood samples from patients and family members, and Sanger sequencing and PCR was performed. Samples were processed for targeted sequencing using the available SHGp heme panel of 393 genes.

Gene: ITGA2B and ITGB3

Variant: NM_000419.3:c.985G>T (p.Val329Phe) and NM_000212.2:c.1265G>A (p.Ser422Asn)

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA399804719 (p.Val329Phe) and CA291225740 (p.Ser422Asn)

gnomAD: N/A

Case18: (GT-20) Female, age or ethnicity not specified

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: Probands GT15-GT19 are related to GT-20 see Table 1

ParentalGenotype: Parents may be included in Table 1; however, not specified so no information

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding severity: Information not available on bleeding phenotype/severity (See Supplementary Table 3)

CaseNotHPOs: N/A

CaseNotHPOsFreeText: N/A

ProteinExpression: Flow cytometry performed and CD41 and CD61 were observed (See Supplementary Table 3)

PlateletAggregation: Minimal information (See Supplementary Table 3)

CasePreviousTesting: DNA was extracted from peripheral blood samples from patients and family members, and Sanger sequencing and PCR was performed. Samples were processed for targeted sequencing using the available SHGp heme panel of 393 genes.

Gene: ITGB3

Variant: NM_000212.2:c.727G>C (p.Asp243His)

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA400023600

gnomAD: N/A

Case17: (GT-19) Male, carrier status, age or ethnicity not specified

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: Probands GT15-GT20 are related to GT-19 see Table 1

ParentalGenotype: Parents may be included in Table 1; however, not specified so no information

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding severity: Information not available on bleeding phenotype/severity (See Supplementary Table 3)

CaseNotHPOs: N/A

CaseNotHPOsFreeText: N/A

ProteinExpression: Flow cytometry performed and CD41 and CD61 were observed (See Supplementary Table 3)

PlateletAggregation: Minimal information (See Supplementary Table 3)

CasePreviousTesting: DNA was extracted from peripheral blood samples from patients and family members, and Sanger sequencing and PCR was performed. Samples were processed for targeted sequencing using the available SHGp heme panel of 393 genes.

Gene: ITGB3

Variant: NM_000212.2:c.727G>C (p.Asp243His)

LegacyVariant: N/A

ClinVar: N/A