PMID: 30046717

Gene: von Willebrand Factor (VWF)

PMID: 31793247

Gene: VMF

HGNCID: HGNC:12726

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: P6, F/7

DiseaseAssertion: VWD1

FamilyInfo: No family history

ParentalGenotype: NA

CaseHPOFreeText: The bleeding score was 5, aPTT was 29 seconds, FVIII:C was 71%, VWF:RCo was 19 IU/dL, and VWF:Ag was 19 IU/dL, with a VWF:RCo/VWF:Ag ratio of 1.0. The VWF multimer pattern was normal, RIPA was not tested, and the platelet count was 475 × 10⁹/L.

CasePreviousTesting: NA

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

Gene: VWF

Variant: no mutation detected

HGVS:

ClinVar:

CAID:

gnomAD:

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: 3, F, 21, Italian

DiseaseAssertion: VWD type 3

FamilyInfo: Consanguinity: no

ParentalGenotype: n/a

CasePresentingHPOs: n/a

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

CaseNotHPOs: n/a

CaseNotHPOFreeText: Anti-VWF alloantibodies: no

CasePreviousTesting: n/a

Gene: VWF

Variant:

666G→A (Trp222X), Exon 7

823T→A (Cys275Ser), Exon 7

Compound Heterozygous

Case: 2, F, 58, Italian

DiseaseAssertion: VWD type 3

FamilyInfo: Consanguinity: no

ParentalGenotype: n/a

CasePresentingHPOs: n/a

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

CaseNotHPOs: n/a

CaseNotHPOFreeText: Anti-VWF alloantibodies: no

CasePreviousTesting: n/a

Gene: VWF

Variant:

421G→T (Asp141Tyr), Exon 5

2016del4 (FS), Exon 16

Compound Heterozygous

Case: 8, F, 7, Italian

DiseaseAssertion: VWD type 3

FamilyInfo: Consanguinity: no

ParentalGenotype: n/a

CasePresentingHPOs: n/a

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

CaseNotHPOs: n/a

CaseNotHPOFreeText: Anti-VWF alloantibodies: no

CasePreviousTesting: n/a

Gene: VWF

Variant:

4013C→G (Ser1338X), Exon 28

6385G→T (Glu2129X), Exon 37

Compound Heterozygous

Case: 4 , M, 55, Italian

DiseaseAssertion: VWD type 3

FamilyInfo: Consanguinity: no

ParentalGenotype: n/a

CasePresentingHPOs: n/a

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

CaseNotHPOs: n/a

CaseNotHPOFreeText: Anti-VWF alloantibodies: no

CasePreviousTesting: n/a

Gene: VWF

Variant:

1093C→T (Arg365X), Exon 9

1830C→A (Tyr610X), Exon 15

Compound Heterozygous

Case: 30, F, 32, Indian

DiseaseAssertion: VWD type 3

FamilyInfo: Consanguinity: No

ParentalGenotype: n/a

CasePresentingHPOs: n/a

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

CaseNotHPOs: n/a

CaseNotHPOFreeText: Anti-VWF alloantibodies: no

CasePreviousTesting: n/a

Gene: VWF

Variant:

6977-1G→C (intronic), Exon 41, Homozygous

Note: The article assumes 6977-1G→C would be a frameshift mutation. It is possible that the homozygous zygosity was detected from a PCR artifact (e.g. presence of a large gene deletion or point mutation that prevents amplification); different sets of primers were used, providing conformation and excluding the possibility for a PCR artifact due to point mutation. No potential splice site mutation was confirmed at the mRNA level; “Splice Site Prediction program” found all mutations likely to disrupt normal splicing. No possible splice site mutation could be identified on 100 chromosomes from a group of 50 normal subjects with same genetic background as patients, excluding the possibility that these mutations represent common polymorphisms

Case: 18, M, 21, Iranian

DiseaseAssertion: VWD type 3

FamilyInfo: Consanguinity: Yes

ParentalGenotype: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: VWF:Ag (U/dl): 2, Bleeding symptoms: Severe

CaseNotHPOs: n/a

CaseNotHPOFreeText: Anti-VWF alloantibodies: no

CasePreviousTesting: n/a

Gene: VWF

Variant:

1930G→T (Glu644X), Exon 15, Homozygous

Case: 37, F, 29, Indian

DiseaseAssertion: VWD type 3

FamilyInfo: Consanguinity: No

ParentalGenotype: n/a

CasePresentingHPOs: n/a

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

CaseNotHPOs: n/a

CaseNotHPOFreeText: Anti-VWF alloantibodies: no

CasePreviousTesting: n/a

Gene: VWF

Variant:

1896G→A (Trp642X), Exon 15

3212G→T (Cys1071Phe), Exon 24

Compound Heterozygous

Case: 2B-8

DiseaseAssertion: VWD2B

FamilyInfo:

ParentalGenotype(s):

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

CaseHPOFreeText:

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: not described

PreviouslyPublished: 16985174

Gene: VWF

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

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

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

CAID:

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

Case: 2A-7

DiseaseAssertion: VWD2A

FamilyInfo:

ParentalGenotype(s):

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

CaseHPOFreeText:

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: not described

PreviouslyPublished: PMID:1673047

Gene: VWF

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

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

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

CAID:

gnomAD: absent

Case: 2A-1

DiseaseAssertion: VWD2A

FamilyInfo:

ParentalGenotype(s):

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

CaseHPOFreeText:

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: not described

PreviouslyPublished: PMID: 8435341

Gene: VWF

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

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

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

CAID:

gnomAD: absent

Case: 18, M, 8 years, Indian

DiseaseAssertion: VWD type 3

FamilyInfo: Consanguinity: yes, no family history of disease

ParentalGenotype: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: FVIII:C: (U/dl): 8, VWF:Ag (U/dl): 4.6, Bleeding Score: 8

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

Gene: VWF

Variant:

c.7300C>T (p.Arg2434*), Exon 47, Homozygous

Note: Look over exon

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: 62, F, 5 years, Indian

DiseaseAssertion: VWD type 3

FamilyInfo: Consanguinity: yes, no family history of disease

ParentalGenotype: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: FVIII:C: (U/dl): 3.5, VWF:Ag (U/dl): 2.6, Bleeding Score: 15

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

Gene: VWF

Variant:

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

Case: 29, F, 0.8 years, Indian

DiseaseAssertion: VWD type 3

FamilyInfo: Consanguinity: yes, family history of disease

ParentalGenotype: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: FVIII:C: (U/dl): 1.6, VWF:Ag (U/dl): 1.8, Bleeding Score: 3

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

Gene: VWF

Variant:

c.7558C>T (p.Gln2520* ), Exon 45, Homozygous

Case: 15, M, 29 years, Indian

DiseaseAssertion: VWD type 3

FamilyInfo: Consanguinity: no, family history of disease

ParentalGenotype: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: FVIII:C: (U/dl): 1.8, VWF:Ag (U/dl): <1, Bleeding Score: 16

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

Gene: VWF

Variant:

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

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

Case: 12, F, 16 years, Indian

DiseaseAssertion: VWD type 3

FamilyInfo: Consanguinity: no, family history of disease

ParentalGenotype: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: FVIII:C: (U/dl): 6, VWF:Ag (U/dl): <1, Bleeding Score: 16

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

Gene: VWF

Variant:

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

Case: 20, M, 10 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: 8

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

Gene: VWF

Variant:

c.7603C>T (p.Arg2535*), Exon 45, Homozygous

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

Disease Assertion: VWD 1

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

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding score 13, VWF:Ag: 4.7, VWF:RCo: 5, FVIII:C: 16, VWF:CB:6

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

Protein Expression: N/A

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

Gene:VWF

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

ClinVar: 308

ClinVar

CAID: CA114160

CAID1

gnomAD: N/A

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

Disease Assertion: VWD 1

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

Parental Genotype: Not listed

CasePresentingHPOs: N/A

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: Bleeding Score 3

Protein Expression: N/A

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

Gene: VWF

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

ClinVar: 100264 ClinVar

CAID: CA228414 CAID

gnomAD: N/A

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

Disease Assertion: VWD1

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

Parental Genotype: Not listed

CasePresentingHPOs: N/A

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

Protein Expression:N/A

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

Gene: VWF

Variant: NM_000552.4:c.7300C>T (p.Arg2434Ter)

ClinVar: 100464 ClinVar

CAID: CA228781 CAID

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

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

Disease Assertion: VWD1

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

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding score 19, VWF:Ag: 7.3, VWF:RCo: 5.9, FVIII:C: 19, VWF:CB: 6.3

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

Protein Expression: N/A

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

Gene: VWF

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

ClinVar: 308 ClinVar

CAID: CA114160 CAID

gnomAD: N/A

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

Disease Assertion: VWD1

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

Parental Genotype: Not listed

CasePresentingHPOs: Not listed

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

Protein Expression:N/A

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

Gene: VWF

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

ClinVar: 100264 ClinVar

CAID: CA228414 CAID

gnomAD: N/A

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

Disease Assertion: VWD 1

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

Parental Genotype: Not listed

CasePresentingHPOs: N/A

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: Bleeding Score 3

Protein Expression: N/A

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

Gene: VWF

Variant: NM_000552.4:c.7408C>T (p.Gln2470Ter)

ClinVar: 100469 ClinVar

CAID: CA228790 CAID

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

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

Disease Assertion: VWD

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

Parental Genotype: Not listed

CasePresentingHPOs: N/A

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: Bleeding Score 5

Protein Expression: N/A

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

Gene: VWF

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

ClinVar: N/A

CAID: CA383504978 CAID

gnomAD: N/A

Case#: 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: n.a.

DiseaseAssertion: VWD 2A

FamilyInfo: n.a.

ParentalGenotype(s):n.a.

CasePresentingHPOs:n.a.

CaseHPOFreeRext:n.a.

CaseNOTHPOs:n.a.

CaseNOTHPOFreeText:n.a.

CasePreviousTesting:n.a.

GenotypingMethod:n.a.

PreviouslyPublished: If applicable.n.a.

Gene:VWF

Variant:NM_000552.5(VWF):c.3437A>G (p.Tyr1146Cys)

HGVS:NM_000552.5:c.3437A>G

ClinVarID:31009

CAID:n.a.

gnomAD:n.a.

PMID: 35328514 Gene: VWF HGNCID: HGNC:12726

Case: P10, Chinese, male, 5yo

DiseaseAssertion: VWD1

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

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

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

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

HGVS: NA

ClinVarID: NA

CAID: NA

gnomAD: NA

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

HGVS: NA

ClinVarID: NA

CAID: NA

gnomAD: NA

Case: P6, Chinese, male, 57yo

DiseaseAssertion: VWD2A

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

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

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

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

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

ClinVarID: NA

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

gnomAD: absent

Case: P72, Chinese, female, 25yo

DiseaseAssertion: VWD2B

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

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

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

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

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

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

CAID: NA

gnomAD: absent

Case: P77, Chinese, female, 10yo

DiseaseAssertion: VWD3

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

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

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

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

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

ClinVarID: NA

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

gnomAD: absent

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

HGVS: NA

ClinVarID: NA

CAID: NA

gnomAD: NA

Case: P34, Chinese, female, 34yo

DiseaseAssertion: VWD2B

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

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

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

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

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

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

CAID: NA

gnomAD: absent

Case: P61, Chinese, female, 34yo

DiseaseAssertion: VWD1

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

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

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.-128G>A

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

ClinVarID: NA

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

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

Case: P27, Chinese, female, 3yo

DiseaseAssertion: VWD2N

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

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

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

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

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

ClinVarID: NA

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

gnomAD: absent

Variant 2: c.3197_3201del - unregistered variant

HGVS: NA

ClinVarID: NA

CAID: NA

gnomAD: NA

Case: P36, Chinese, male, 56yo

DiseaseAssertion: VWD3

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

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

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.5870delA - unregistered variant

HGVS: NA

ClinVarID: NA

CAID: NA

gnomAD: NA

Case: P83, Chinese, male, 5yo

DiseaseAssertion: VWD1

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

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

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

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

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

ClinVarID: NA

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

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

Multiple Gene Variants

Gene: F8

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

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

ClinVarID: NA

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

gnomAD: absent

Case: P29, Chinese, male, 10yo

DiseaseAssertion: VWD2M

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

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

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

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

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

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

CAID: NA

gnomAD: absent

Case: P22, Chinese, male, 22yo

DiseaseAssertion: VWD3

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

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

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.8116–2delA - Unregistered variant

HGVS: NA

ClinVarID: NA

CAID: NA

gnomAD: NA

Case: P42, Chinese, male, 10yo

DiseaseAssertion: VWD1

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

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

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.-672C>T

HGVS: NA

ClinVarID: NA

CAID: NA

gnomAD: NA

PMID: 28536718

Gene: VWF

HGNCID: 12726

Case: P33, Chinese, female, 35yo

DiseaseAssertion: VWD3

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

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

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

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

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

ClinVarID: NA

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

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

PMID: 28512017

Gene: VWF

HGNCID: 12726

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

PMID: 2010538

Gene: VWF

HGNC: 12726

Disease: von Willebrand disease type 2B

MONDO: 0015629

InheritancePattern: Autosomal Dominant

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

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

PMID 16322474

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

PMID: 35532874

Gene: VWF

HGNCID: 12726

PMID: 23311757 Gene: von Willebrand factor HGNCID: 12726

Case: T090, M, 2

DiseaseAssertion: VWD type 3

FamilyInfo: inherited heterozygous gene conversion from the father

CasePresentingHPOs: n/a

CaseHPOFreeText: Bleeding Score: 8 (Kruskal–Wallis followed by Mann–Whitney U post-hoc testing Post-hoc testing ), VWF:Ag (IU/ml): 0.01, VWF:RCo (IU/ml): 0.04, FVIII:C (IU/ml): 0.01

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

Gene: VWF

Variant:

c.1117C>T (p.Arg373*)

Gene Conversion (

c.3931C>T (p.Gln1311*)

c.4027A>G (p.Ile1343Val)

c.4079T>C (p.Val1360Ala)

c.4105T>A (p.Phe1369Ile)

)

Exon 10/28

Compound heterozygous

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

Case: T078, F, 5

DiseaseAssertion: VWD type 3

FamilyInfo: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: Bleeding Score: 9 (Kruskal–Wallis followed by Mann–Whitney U post-hoc testing Post-hoc testing ), VWF:Ag (IU/ml): 0.01, VWF:RCo (IU/ml): 0.03, FVIII:C (IU/ml): 0.01

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

Gene: VWF

Variant:

c.5455 + 2 T>C, Exon 31, Homozygous

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

Case: 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

PMID: 29126301

Gene: VWF

HGNC: 12726 (type 1)

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

Case: 8 (also in row 21 table 6)

DiseaseAssertion: type 2A/2N VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032370 - blood group A

CaseHPOFreeRext: VWF:Ag [IU/dL] = 16; VWF:Ac [IU/dL] = 8; FVIII:C [IU/dL] = 12

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.2561G>A p.Arg854Gln

HGVS:

ClinVarID: 296

CAID:

gnomAD: 0.004956 (8000 in 1614214) 26 homozygotes https://gnomad.broadinstitute.org/variant/12-6034812-C-T?dataset=gnomad_r4

MultipleGeneVariants:

Gene: VWF

Variant: c.4811T>A p.Val1604Asp

CAID: CA383499144

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: 2B, male, 55yo

DiseaseAssertion: VWD2B

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

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

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: qRT-PCR

PreviouslyPublished:

Gene: VWF

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

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

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

CAID:

gnomAD: absent

Case: 2M, female, 25yo

DiseaseAssertion: VWD2M

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

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

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: qRT-PCR

PreviouslyPublished:

Gene: VWF

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

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

ClinVarID: n/a

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

gnomAD: absent

Case: 2, M, 40, Italian

DiseaseAssertion: VWD type 3

FamilyInfo: Consanguinity: yes

ParentalGenotype: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: VWF:Ag (IU/dL): <1, FVIII:C (IU/dL): 6, Bleeding Score: 21

CaseNotHPOs: n/a

CaseNotHPOFreeText: Anti-VWF alloantibodies: no

CasePreviousTesting: n/a

Gene: VWF

Variant:

c.8155+1G>T (p.Gly2706_Cys2719delfsX25), Intron 50, Homozygous

Note: patient also has heterozygous insertion of five intronic nucleotides (GTAAG) between exons 45 and 46; c.8155+1G>T resulted in altering the normal mRNA splicing process

Case: 4, M, 5, Italian

DiseaseAssertion: VWD type 3

FamilyInfo: Consanguinity: not reported

ParentalGenotype: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: VWF:Ag (IU/dL): <1, FVIII:C (IU/dL): 17, Bleeding Score: 6

CaseNotHPOs: n/a

CaseNotHPOFreeText: Anti-VWF alloantibodies: no

CasePreviousTesting: n/a

Gene: VWF

Variant:

c.2269delCT (p.Leu757ValfsX22), Exon 17, Homozygous

Note: paretns investigated for the probands defects and confirmed to carry the expected mutation at the heterozygous state

Case: 6, M, 28, Italian

DiseaseAssertion: VWD type 3

FamilyInfo: Consanguinity: no

ParentalGenotype: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: VWF:Ag (IU/dL): <1, FVIII:C (IU/dL): 9, Bleeding Score: 15

CaseNotHPOs: n/a

CaseNotHPOFreeText: Anti-VWF alloantibodies: no

CasePreviousTesting: n/a

Gene: VWF

Variant:

c.2157delA (p.Asp20ThrfsX21), Exon 16

c.7729+7C>T (p.Glu2577GlyfsX21), Intron 45

Compound Heterozygous

Note: patient also has homozygous deletion of 40 bp (NP_000543.2, where 1 is adenine in ATG initiation codon) due to the skipping of exon 50; c.7729+7C>T resulted in altering the normal mRNA splicing process

Case: 3, F, 5, Italian

DiseaseAssertion: VWD type 3

FamilyInfo: Consanguinity: yes

ParentalGenotype: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: VWF:Ag (IU/dL): <1, FVIII:C (IU/dL): 4, Bleeding Score: 9

CaseNotHPOs: n/a

CaseNotHPOFreeText: Anti-VWF alloantibodies: no

CasePreviousTesting: n/a

Gene: VWF

Variant:

c.658–2A>G (p.Gly220_Ser292delfsX27), Intron 6, Homozygous

Note: patient also has homozygous deletion of 217 bp (NP_000543.2, where 1 is adenine in ATG initiation codon) due to the skipping of exon 7; c.658–2A>G resulted in altering the normal mRNA splicing process

PMID:35020809 Gene:VWF HGNC ID:12726

PMID: 28151804

Gene: VWF

HGNCID: 12726

PMID: 18728373

Gene: VWF

HGNCID: 12726

Case-Individual:

Case: 50-year old male of consanguinous parents

DiseaseAssertion: severe Type 1 Von Willebrand Disease, previously misclassified as Type 3

Family Info: Proband's parents and offspring had the same mutation, but at the heterozygous level; all asymptomatic

Parental Genotype: N/A

CasePresentingHPOs: HP:0000421, HP:0030140, HP:0006298, HP:0005261

Epistaxis, oral cavity bleeding, severe hemorrhagic complications after tooth extractions (HP is called Prolonged bleeding after dental extraction), hemarthrosis (joint bleeding)

CaseHPOFreeRext: Lifelong history of severe bleeding, frequent hematomas, bleeding from minor wounds (possibly HP:0030138, excessive bleeding from superficial cuts), impaired hemostatic picture, extremely high ISTH bleeding score (proband's was 30 whereas males usually range from 0-3)

CaseNOTHPOs: N/A

CaseNOTHPOFreeText: N/A

CasePreviousTesting: N/A

GenotypingMethod: Sequencing reactions were performed in an ABI3130 XL Genetic Analyzer; digital droplet polymerase chain reaction (ddPCR) assays were performed (in multiplex); in vitro expression also performed, then electrophoresis system used to run Western blot

Gene: VWD

HGVS: NM_000552.5:c.2269_2270del

Variant: Gene null homozygous c.2269_2270del mutation

ClinVarID: 100207

CAID: CA228313

gnomAD: MAF of 0.000002542 (3 of 1180022 alleles) in the European non-Finnish population

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

DiseaseAssertion: VWD2A (IIE)

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

ParentalGenotype(s): NA

CasePresentingHPOs:

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

CaseNOTHPOs:

CaseNOTHPOFreeText: Blood type O+

CasePreviousTesting:

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

PreviouslyPublished: NA

Gene: VWF

Variant: c.2365A > G, p.(Thr789Ala)

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

ClinVarID: 256659

CAID: CA6403090

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

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

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

ClinVarID: 256660

CAID: CA6403087

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

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

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

ClinVarID: 195657

CAID: CA201877

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

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

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

ClinVarID:

CAID: CA383511219

gnomAD:

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

DiseaseAssertion: VWD2A (IIA)

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

ParentalGenotype(s): NA

CasePresentingHPOs:

CaseHPOFreeRext: BAT = 3, FVIII:C (IU/dL) = 74, VWF:Ag (IU/dL) = 35, VWF:Act (IU/dL) = 12

CaseNOTHPOs:

CaseNOTHPOFreeText: Blood group O+

CasePreviousTesting:

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

PreviouslyPublished: NA

Gene: VWF

Variant: deletion of exons 9-10

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

ClinVarID:

CAID: CA3260663889

gnomAD:

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

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

ClinVarID: 310063

CAID: CA6402595

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

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

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

ClinVarID: 310062

CAID: CA6402552

gnomAD: MAF of 0.1124 (8427/74964 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6019114-T-C?dataset=gnomad_r4

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

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

ClinVarID: 256679

CAID: CA6402534

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

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

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

ClinVarID: 4533008

CAID: CA383500651

gnomAD:

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

DiseaseAssertion: VWD2A (IIE)

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

ParentalGenotype(s): NA

CasePresentingHPOs:

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

CaseNOTHPOs:

CaseNOTHPOFreeText: Blood group B-

CasePreviousTesting:

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

PreviouslyPublished: NA

Gene: VWF

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

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

ClinVarID:

CAID: CA6403368

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

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

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

ClinVarID: 422844

CAID: CA6403245

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

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

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

ClinVarID: 100206

CAID: CA201316

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

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

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

ClinVarID: 100224

CAID: CA228345

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

Variant: c.3426T > C, p.(Cys1142 =)

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

ClinVarID: 256668

CAID: CA6402757

gnomAD: MAF of 0.2077 (7935/38206 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6022852-A-G?dataset=gnomad_r4

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

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

ClinVarID: 309

CAID: CA228410

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

Variant: c.3485C > T, p.(Pro1162Leu)

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

ClinVarID: 256669

CAID: CA6402756

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

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

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

ClinVarID: 256670

CAID: CA6402755

gnomAD: MAF of 0.2083 (7074/33968 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6022792-T-C?dataset=gnomad_r4

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

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

ClinVarID: 256679

CAID: CA6402534

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

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

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

ClinVarID: 100443

CAID: CA228748

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

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

DiseaseAssertion: VWD2M

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs:

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

CaseNOTHPOs:

CaseNOTHPOFreeText: Blood group O+

CasePreviousTesting:

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

PreviouslyPublished: NA

Gene: VWF

Variant: c.4196G > A, p.(Arg1399His)

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

ClinVarID: 293

CAID: CA114133

gnomAD: MAF of 0.01540 (456/29604 alleles) in Ashkenazi Jewish population https://gnomad.broadinstitute.org/variant/chr12-6019222-C-T?dataset=gnomad_r4

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

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

ClinVarID: 256679

CAID: CA6402534

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

Case#: Elayaperumal_2018_V-260 , M, 3y.o. (onset), origin in India

DiseaseAssertion: VWD type 3

FamilyInfo: consanguinity reported. No family history of bleeding

ParentalGenotype: not reported

CasePresentingHPOs:

CaseHPOFreeText: bleeding score of 9, VWF:Ag of 0, FVIII:C of 7.4%

CaseNotHPOs:

CaseNotHPOFreeText:

CasePreviousTesting: not reported

GenotypingMethod: CSGE and Sanger sequencing of VWF gene only.

Gene: VWF

Variant: homozygous c.665G>A (p.Trp222*)

HGVS: NM_000552.3:c.665G>A

ClinVarID: not found

CAID: CA383509511

gnomAD: not found

MultipleGeneVariants: n/a

Case#: Elayaperumal_2018_V-312 , M, 2.5 y.o. (onset), origin in India

DiseaseAssertion: VWD type 3

FamilyInfo: Consanguinity: Yes, Family history: No

ParentalGenotype: not reported

CasePresentingHPOs:

CaseHPOFreeText: Bleeding score: 7, VWF:Ag 0, FVIII:C 3.6%

CaseNotHPOs:

CaseNotHPOFreeText:

CasePreviousTesting: not reported

GenotypingMethod: CSGE and Sanger sequencing of VWF gene only.

Gene: VWF

Variant: homozygous c.3560delT

HGVS: NM_000552.3:c.3560delT (p.Leu1187Cysfs*28)

ClinVarID: not present

CAID: CA2580612141

gnomAD: not present

MultipleGeneVariants:

Case#: Elayaperumal_2018_V-316, F, 1.5 y.o. (onset), origin in India

DiseaseAssertion: VWD type 3

FamilyInfo: Consanguinity: Yes, Family history: Yes

ParentalGenotype: not reported

CasePresentingHPOs:

CaseHPOFreeText: Bleeding score: 0, VWF:Ag 0, FVIII:C 3.4%

CaseNotHPOs:

CaseNotHPOFreeText:

CasePreviousTesting: not reported

GenotypingMethod: CSGE and Sanger sequencing of VWF gene only.

Gene: VWF

Variant: homozygous c.2749 2752dupCCCT (p.Val919Leufs*18)

HGVS: NM_000552.3:c.2749 2752dupCCCT

ClinVarID: not present

CAID: CA2695215955

gnomAD: not present

MultipleGeneVariants:

PMID: 27785858

Gene: VWF

HGNCID: 12726

Case#: Elayaperumal_2018_V-115, female, 1 year old (onset), origin in India

DiseaseAssertion: VWD type 3

FamilyInfo: consanguinity

ParentalGenotype: not reported. family history of bleeding.

CasePresentingHPOs:

CaseHPOFreeText: bleeding score of 13. VWF:Ag of 0. FVIII:C of 1.9%

CaseNotHPOs:

CaseNotHPOFreeText:

CasePreviousTesting: not reported

GenotypingMethod: CSGE and Sanger sequencing of VWF only.

Gene: VWF

Variant: homozygous c.6321G>A (p.Trp2107*)

HGVS: NM_000552.3:c.6321G>A (p.Trp2107*)

ClinVarID: not found

CAID: CA383491677

gnomAD: not found

MultipleGeneVariants: not reported

PMID: 29115727

Gene: VWF

HGNC: 12726 (type 1)

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

Case: Patient 10, M, Hungarian

DiseaseAssertion: VWD type 3

FamilyInfo: compatible with recessive inheritance

ParentalGenotype(s): n/a

CasePresentingHPOs: n/a

CaseHPOFreeRext: Bleeding score: 18, VWF:Ag (IU dL−1): < 1, VWF:CB (IU dL−1): < 1, FVIII:C (IU dL−1): 3, VWF:RCo below detection limit (<10 IU dL−1), not detectable VWF on multimer gels

CaseNOTHPOs: n/a

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

CasePreviousTesting: n/a

Gene: VWF

Variant:

c.2269_2270delCT (p.L757VfsX22), Exon 17

c.2435delC (p.P812RfsX31), Exon 18

Intron 40 VNTR: 17/18

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

Case: Patient 17, F, Hungarian

DiseaseAssertion: VWD type 3

FamilyInfo: compatible with recessive inheritance

ParentalGenotype(s): n/a

CasePresentingHPOs: n/a

CaseHPOFreeRext: Bleeding score: 18, VWF:Ag (IU dL−1): < 1, VWF:CB (IU dL−1): < 1, FVIII:C (IU dL−1): 4, VWF:RCo below detection limit (<10 IU dL−1), not detectable VWF on multimer gels, bleeding episode severity increased after the menarche

CaseNOTHPOs: n/a

CaseNOTHPOFreeText: no inhibitor detecteddid not become refractory to factor replacement therapy

CasePreviousTesting: n/a

Gene: VWF

Variant:

c.7333delG (p.Glu2445ArgfsX16), Exon 43

c.7703C>A (p.Ser2568X), Exon 45

Intron 40 VNTR 17/18

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

Case: Patient 12, F, Hungarian

DiseaseAssertion: VWD type 3

FamilyInfo: compatible with recessive inheritance

ParentalGenotype(s): n/a

CasePresentingHPOs: n/a

CaseHPOFreeRext: Bleeding score: 32, VWF:Ag (IU dL−1): 1, VWF:CB (IU dL−1): 1, FVIII:C (IU dL−1): 7, VWF:RCo below detection limit (<10 IU dL−1), not detectable VWF on multimer gels, bleeding episode severity increased after the menarche

CaseNOTHPOs: n/a

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

CasePreviousTesting: n/a

Gene: VWF

Variant:

c.2124_2125delCT (p.Cys709LeufsX3), Exon 16, Homozygous

Intron 40 VNTR: 18/18

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

Case: Patient 8, M, Hungarian

DiseaseAssertion: VWD type 3

FamilyInfo: compatible with recessive inheritance

ParentalGenotype(s): n/a

CasePresentingHPOs: n/a

CaseHPOFreeRext: Bleeding score: 19, VWF:Ag (IU dL−1): 1, VWF:CB (IU dL−1): 1, FVIII:C (IU dL−1): 2, VWF:RCo below detection limit (<10 IU dL−1), not detectable VWF on multimer gels

CaseNOTHPOs: n/a

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

CasePreviousTesting: n/a

Gene: VWF

Variant:

c.2435delC (p.Pro812ArgfsX31), Exon 18, Homozygous

Intron 40 VNTR: 19/19

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

Case: Patient 15, F, Hungarian

DiseaseAssertion: VWD type 3

FamilyInfo: compatible with recessive inheritance

ParentalGenotype(s): n/a

CasePresentingHPOs: n/a

CaseHPOFreeRext: VWF:Ag (IU dL−1): 1, VWF:CB (IU dL−1): 1, FVIII:C (IU dL−1): 3, VWF:RCo below detection limit (<10 IU dL−1), not detectable VWF on multimer gels, bleeding episode severity increased after the menarche

CaseNOTHPOs: n/a

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

CasePreviousTesting: n/a

Gene: VWF

Variant:

c.3379+1G>A (Splice), Exon 25, Homozygous

(p.Arg924Gln), Exon 21, Homozygous

Intron 40 VNTR 18/18

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

Case#: 3, female, 19yo

DiseaseAssertion: VWD1

FamilyInfo: brother diagnosed with VWD

ParentalGenotype: N/A

CasePresentingHPOs: HP:0000978; HP:0000132, HP:0004846, HP:0012147, HP:0030129 (Bruising susceptibility, Menorrhagia, Reduced quantity of VWF, Impaired ristocetin cofactor assay activity)

CaseHPOFreeText: Type O blood, VWF:Ag (0·55–2 iu/ml) pre = 0·14, VWF:RCo (0·55–2 iu/ml) pre = 0·15, FVIII:C (0·55–2 iu/ml) pre = 0·1, FVIII:C/VWF:Ag ratio = 0·71, VWF:FVIII binding (>20%) = n/a, VWF:FVIII binding/VWF:Ag (>0·7) = n/a, spinal surgery with VWF concentrate and adequate haemostasis

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

ProteinExpression: N/A

CasePreviousTesting: RFLP; confirmatory sequencing

Gene: VWF

Variant 1: NM_000552.4(VWF):c.2561G>A (p.Arg854Gln)

ClinVar: 296; https://www.ncbi.nlm.nih.gov/clinvar/variation/296/

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

Variant 2: N/A - stated to be a compound heterozygote for a 2N VWD and a presumed null mutation

Case#: 4, male, 23yo

DiseaseAssertion: VWD1

FamilyInfo: N/A

ParentalGenotype: N/A

CasePresentingHPOs: HP:0004846, HP:0012147, HP:0030129 (Reduced quantity of VWF, Impaired ristocetin cofactor assay activity)

CaseHPOFreeText: Haemarthrosis in teens, Delayed bleeding after tonsillectomy (DDAVP given prior to procedure), VWF:Ag (0·55–2 iu/ml) pre = 0·35, VWF:RCo (0·55–2 iu/ml) pre = 0·32, FVIII:C (0·55–2 iu/ml) pre = 0·12, FVIII:C/VWF:Ag ratio = 0·34, VWF:FVIII binding (>20%) = n/a, VWF:FVIII binding/VWF:Ag (>0·7) = n/a, Surgery to repair a syringomyelia defect with VWF concentrate and no bleeding complications

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

ProteinExpression: N/A

CasePreviousTesting: RFLP; confirmatory sequencing

Gene: VWF

Variant 1: NM_000552.4(VWF):c.2561G>A (p.Arg854Gln)

ClinVar: 296; https://www.ncbi.nlm.nih.gov/clinvar/variation/296/

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

Variant 2: N/A - stated to be a compound heterozygote for a 2N VWD and a presumed null mutation

PMID: 28693644

Gene: VWF

HGNCID: 12726

PMID: 28544236

Gene VWF

Case: Croatian adult patient

DiseaseAssertion: VWD3

FamilyInfo: No variant detected in a family member with VWD3.

ParentalGenotype(s): Not specified

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

CaseHPOFreeText: Reduced VWF:Ag of <4.0%, VWF:GPIbM of 8.3%, FVIII:C of 5% and VWF:CBA below 1%.

CaseNOTHPOs: Not specified

CaseNOTHPOFreeText: Not specified.

CasePreviousTesting: Not reported

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

PreviouslyPublished: None

Gene: VWF

Variant: c.6151A>T

HGVS: NM_000552.4:c.6151A>T (c.6151A>T)

ClinVarID: Not available

CAID: CA383492290

gnomAD: Not available

Case: Croatian adult patient

DiseaseAssertion: VWD1

FamilyInfo: Not specified

ParentalGenotype(s): Not specified

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

CaseHPOFreeText: Reduced VWF:GPIbM of 41.3%. Normal VWF:Ag of 67.8%, FVIII:C of 72% and VWF:CBA of 50.5%. Normal multimer distribution.

CaseNOTHPOs: Not specified

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

CasePreviousTesting: Not reported

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

PreviouslyPublished: PMID: 34351388

Gene: VWF

Variant: c.2269_2270delCT

HGVS: NM_000552.4:c.2269_2270delCT (p.Leu757ValfsTer22)

ClinVarID: 100207

CAID: CA228313

**gnomAD: ** 0.000008794 in European (non-Finnish), 0.0003115 in XX and 0.0001629 in XY

https://gnomad.broadinstitute.org/variant/12-6155899-CAG-C?dataset=gnomad_r2_1

Case#: 1A

DiseaseAssertion:

FamilyInfo: Family 1. Her 2 offspring, 1B (son) and 1C (daughter), reported minor bleeding symptoms that had not required treatment. 1B was found to be heterozygous for Trp1745Cys only and 1C was heterozygous for Arg760His only, confirming that these mutations are in trans in 1A.

CaseHPOFreeText4: was an elderly woman with lifelong bleeding episodes, including epistaxis, ecchymosis, menorrhagia, and prolonged bleeding after dental extractions, requiring multiple medical interventions. The coexistence of both mutations appears to produce a more significant bleeding disorder as the bleeding score in 1A (8) was higher than that in either of her children (4 and 2). The position of Trp1745 in the A3 domain is shown in Figure 2. Both persons with this mutation (1A and 1B) had markedly reduced ratios of VWF collagen-binding activity to VWF antigen (CB:Ag) with type III collagen (0.1 and 0.3, respectively) and type I collagen (0.2 and 0.3, respectively). The ratio of VWF:RCo to VWF:Ag (RCo:Ag) was near unity in both persons, and VWF multimer analysis (Figure 1B) and RIPA were normal. Closure times in the PFA-100 were mildly prolonged with the ADP cartridge (1A = 173 seconds, 1B = 189 seconds, NR < 112 seconds). With the epinephrine cartridge, the closure time was prolonged in 1A only (1A = 271 seconds, 1B = 90 seconds, NR < 179 seconds).

CasePreviousTesting: Fifty-one primer sets were used to amplify the essential regions of VWF (52 exons, flanking intronic regions, 5′ promoter region, and the 3′ untranslated region).

Gene: VWF

Variant: 1A demonstrated compound heterozygosity for 2 mutations in the VWF gene. The first is a novel mutation in exon 30:c.5235 G → T resulting in Trp1745Cys and the second is c.2279 G → A resulting in Arg760His.

HGVS: NM_000552.5(VWF):c.5235G>T (p.Trp1745Cys), NM_000552.5(VWF):c.2279G>A (p.Arg760His)

ClinVar: 100421, 31011

CAID: CA228706, CA228316

gnomAD: 8.474e-7 in the european non finnish pop, 0.00002669 in the African American population

Case: 55-year-old Italian, male

DiseaseAssertion: VWD, Type 2B

FamilyInfo: Patient did not report any family history of bleeding and his daughter did not show any menorrhagia and hemorrhagic disorder. Genotyping for daughter was negative for variants of interest. Paternity of daughter established. Testing performed on both daughter and wife.

ParentalGenotype(s): No genotyping available on parents, as they were deceased.

CasePresentingHPOs: HP:0000421, HP:0004846, HP:0012147, HP:0030129, HP:0030130, . HP:0030132, HP:0011871, HP:0003645

CaseHPOFreeRext: aPTT,s=45.4, Fibrinogen,mg/dL=349, VFG:Ag, IU/dL=23.4, VWF:RCo, IU/dL=8.5, VWF:CBA, IU/dL=7.2, FVIII:C, IU/dL=28.2, VWFpp, %=63.4, VWF:RCo/VWF:Ag =0.36, VWF:CBA/VWF:Ag=0.31, VWFpp/VWF:Ag=2.7, FVIII/VWF:Ag=1.2,FVIII/VWF:binding, %=127.8, ADAMTS-13 act, U/dL=110.1, Platelets, ×109/L=121-166, Hb, g/dL=8.1-15.1, Blood group= A-Rh +Rh phenotype: ccDEe Kell/Cellano phenotype: kk

CaseNOTHPOs: none

CaseNOTHPOFreeText: none

CasePreviousTesting: none

GenotypingMethod: Molecular genetic analysis of the VWF gene was performed using 3100-Avant Genetic Analyzer. Sanger-sequencing procedures were carried out to validate the identified genetic variants.

PreviouslyPublished:

1) PMID: 27007659

2) PMID: 20492463

Gene: VWF

Variant:

1) c.2771G>A p.R924Q, exon 21, D′D3 domain,cis heterozygous

2) c.6532G>T p.A2178S, exon 37, cis heterozygous

HGVS:

1) NC_000012.12:g.6031493C>T, NC_000012.11:g.6140659C>T, NG_009072.2:g.98178G>A, NM_000552.5:c.2771G>A, NM_000552.4:c.2771G>A, NM_000552.3:c.2771G>A, XM_047429501.1:c.2771G>A, NP_000543.3:p.Arg924Gln, XP_047285457.1:p.Arg924Gln

2) NC_000012.12:g.5993928C>A, NC_000012.12:g.5993928C>T, NC_000012.11:g.6103094C>A, NC_000012.11:g.6103094C>T, NG_009072.2:g.135743G>T, NG_009072.2:g.135743G>A, NM_000552.5:c.6532G>T, NM_000552.5:c.6532G>A, NM_000552.4:c.6532G>T, NM_000552.4:c.6532G>A, NM_000552.3:c.6532G>T, NM_000552.3:c.6532G>A, XM_047429501.1:c.6532G>T, XM_047429501.1:c.6532G>A, NP_000543.3:p.Ala2178Ser, NP_000543.3:p.Ala2178Thr, XP_047285457.1:p.Ala2178Ser, XP_047285457.1:p.Ala2178Thr

ClinVarID:

1) 100240

2) 619942

CAID:

1) CA228368

2) CA6401974

gnomAD:

1) European (non-Finnish) 0.02225 https://gnomad.broadinstitute.org/variant/12-6031493-C-T?dataset=gnomad_r4

2) European (non-Finnish) 0.02318 https://gnomad.broadinstitute.org/variant/12-5993928-C-A?dataset=gnomad_r4

PMID: 1673047

Gene: VWF

HGNCID: 12726

Gene:VWF

HGNCID:12726

Case:13 yo female

DiseaseAssertion: Type 2N

FamilyInfo:Fig. 1, family 2, patient 7

ParentalGenotype(s):Unknown, obligate carriers

CasePresentingHPOs:HP:0000421, HP:0004846, HP:0012147 HP:0030132, HP:0030130

CaseHPOFreeRext:Oral cavity and joint bleeding, VWF:Ag 0.07 U/mL, VWF:Ac 0 U/mL, VWF:CB 0.05 U/mL, FVIII 0.04 U/mL, No VWF Multimers

GenotypingMethod: NGS

Gene:VWF

Variant:c.2311A>G

HGVS:NM_000552.5(VWF):c.2311A>G

ClinVarID:1065273

CAID:CA383522481

Gene:VWF

HGNCID:12726

Case:27 yo male

DiseaseAssertion: Type 2N

FamilyInfo:Fig. 1, family 1, patient 2

ParentalGenotype(s):Unknown, obligate carriers

CasePresentingHPOs:HP:0000421, HP:0012147 HP:0030132, HP:0030130

CaseHPOFreeRext:Skin, oral cavity, and joint bleeding, Bleeding after tooth extractions and small wounds, VWF: Ag 0.07 U/mL, VWF:Act 0.05 U/mL, VWF:CB <0.05 U/mL, FVIII:C 0.01 U/mL, Less VWF Multimers

GenotypingMethod: NGS

Gene:VWF

Variant:c.2311A>G

HGVS:NM_000552.5(VWF):c.2311A>G

ClinVarID:1065273

CAID:CA383522481

Gene:VWF

HGNCID:12726

Case:17 yo male

DiseaseAssertion: Type 2N

FamilyInfo:Fig. 1, family 1, patient 3

ParentalGenotype(s):Unknown, obligate carriers

CasePresentingHPOs:HP:0000421, HP:0012147 HP:0030132, HP:0030130

CaseHPOFreeRext:Oral cavity, skin, and muscle bleeding, Bleeding after tooth extractions, VWF: Ag 0.09 U/mL, VWF:Act 0.05 U/mL, VWF:CB 0.04 U/mL, FVIII:C 0.01 U/mL, No VWF Multimers

GenotypingMethod: NGS

Gene:VWF

Variant:c.2311A>G

HGVS:NM_000552.5(VWF):c.2311A>G

ClinVarID:1065273

CAID:CA383522481