PMID: 28236847

Gene: VWF

HGNCID: 12726

Case: n.a.

DiseaseAssertion: VWD 2A/M

FamilyInfo:n.a.

ParentalGenotype(s):n.a.

CasePresentingHPOs:n.a.

CaseHPOFreeRext:n.a.

CaseNOTHPOs:n.a.

CaseNOTHPOFreeText:n.a.

CasePreviousTesting:n.a.

GenotypingMethod:n.a.

PreviouslyPublished: If applicable. n.a.

Gene:VWF

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

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

ClinVarID:100310

CAID:n.a.

gnomAD:n.a.

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

Disease Assertion: VWD1

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

Parental Genotype: Not listed

CasePresentingHPOs: N/A

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: Bleeding Score 5

Protein Expression: N/A

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

Gene: VWF

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

ClinVar: 100418 ClinVar1

CAID: CA228702 and CA923726359 CAID1 CAID2

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

gnomAD1

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

Disease Assertion: VWD 1

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

Parental Genotype: Not listed

CasePresentingHPOs: N/A

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: Bleeding Score 2

Protein Expression: N/A

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

Gene: VWF

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

ClinVar: 100436 ClinVar

CAID: CA383496267 and CA202650 CAID1 CAID2

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

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

Disease Assertion: VWD1

FamilyInfo: Patient is the only member of Family #0507

Parental Genotype: Not listed

CasePresentingHPOs: N/A

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

Protein Expression: N/A

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

Gene: VWF

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

ClinVar: 308 ClinVar

CAID: CA114160 CAID

gnomAD: N/A

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

Disease Assertion: VWD 1

FamilyInfo: Not listed

Parental Genotype: Not listed

CasePresentingHPOs: N/A

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

Protein Expression: N/A

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

Gene: VWF

Variant: Not determined

ClinVar: N/A

CAID: N/A

gnomAD: N/A

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

Disease Assertion: VWD 1

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

Parental Genotype: Not listed

CasePresentingHPOs: N/A

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

Protein Expression: N/A

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

Gene: VWF

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

ClinVar: N/A

CAID: CA6403542 and CA6402177 CAID1 CAID2

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

gnomAD1 gnomAD2

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

Disease Assertion: VWD 1

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

Parental Genotype: Not listed

CasePresentingHPOs: N/A

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

Protein Expression: N/A

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

Gene: VWF

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

ClinVar: 100418 and 100485 ClinVar1 ClinVar2

CAID: CA228702 and CA228816 CAID1 CAID2

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

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

Disease Assertion: VWD 1

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

Parental Genotype: not listed

CasePresentingHPOs:

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

CaseNotHPOs:

CaseNotHPOFreeText:

Protein Expression:

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

Gene: VWF

Variant: NM_000552.4:c.3223-7_3236dup (p.Pro1079_Tyr1080insLeuGlnValAspProGluPr)

ClinVar: N/A

CAID: CA1139532066

gnomAD: N/A

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

Disease Assertion: VWD 1

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

Parental Genotype: Not listed

CasePresentingHPOs: N/A

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: Bleeding Score 3

Protein Expression: N/A

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

Gene: VWF

Variant: NM_000552.4:c.324-2_326dup (p.Ser110GlufsTer13)

ClinVar: N/A

CAID: CA1139532196 CAID

gnomAD:N/A

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

Disease Assertion: VWD type 1

FamilyInfo: Not listed

Parental Genotype: Not listed

CasePresentingHPOs:

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

Protein Expression: N/A

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

Gene: VWF

Variant: NM_000552.4:c.7730-56C>T

ClinVar: N/A

CAID: CA232280547

CAID

gnomAD: N/A

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

Disease Assertion: VWD1

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

Parental Genotype: Not listed

CasePresentingHPOs: N/A

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

Protein Expression: N/A

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

Gene: VWF

Variant: NM_000552.4:c.2119T>C

ClinVar: N/A

CAID: CA383494546 CAID

gnomAD: N/A

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

Disease Assertion: VWD 1

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

Parental Genotype: Not listed

CasePresentingHPOs: N/A

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

Protein Expression:N/A

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

Gene: VWF

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

ClinVar: 100342 ClinVar

CAID: CA228565 CAID

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

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

DiseaseAssertion: VWD type 3

FamilyInfo: consanguinity, positive family history

ParentalGenotype: not reported

CasePresentingHPOs:

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

CaseNotHPOs:

CaseNotHPOFreeText:

CasePreviousTesting: not reported

GenotypingMethod: CSGE and Sanger sequencing of VWF gene only.

Gene: VWF

Variant: homozygous c.311_312delAG

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

ClinVarID: 1065296

CAID: CA690612114

gnomAD: not found

MultipleGeneVariants:

Case#: F3, I:1

DiseaseAssertion: Type 2 VWD

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

CasePreviousTesting: Not clearly described

Gene: VWF

Variant: p.[P1266L];[=]

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

CAID: CA114170

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

Case#: F2, II:1

DiseaseAssertion: Type 2 VWD

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

CasePreviousTesting: Not clearly described

Gene: VWF

Variant: p.[P1266L];[=]

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

CAID: CA114170

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

Case#: F12, II:1

DiseaseAssertion: Type 2 VWD

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

CasePreviousTesting: Not clearly described

Gene: VWF

Variant: p.[R1341Q];[=]

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

CAID: CA114129

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

Case#: F2, I:1

DiseaseAssertion: Type 2 VWD

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

CasePreviousTesting: Not clearly described

Gene: VWF

Variant: p.[P1266L];[=]

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

CAID: CA114170

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

Case#: F11, I:1

DiseaseAssertion: Type 2 VWD

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

CasePreviousTesting: Not clearly described

Gene: VWF

Variant: p.[R1306W];[=]

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

CAID: CA114123

gnomAD: absent from gnomad v4.1.0

PMID: 26206100

Gene: VWF

HGNCID: 12726

Case#: F1, II:1

DiseaseAssertion: Type 2 VWD

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

CasePreviousTesting: Not clearly described

Gene: VWF

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

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

CAID: CA228433, CA114170

Case#: F10, II:3

DiseaseAssertion: Type 2 VWD

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

CasePreviousTesting: Not clearly described

Gene: VWF

Variant: p.[R1306W];[=]

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

CAID: CA114123

gnomAD: absent from gnomad v4.1.0

Case: 4

DiseaseAssertion: type 2A VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

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

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

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

PreviouslyPublished:

Gene: VWF

Variant: c.1681_1684dup p.Leu562Argfs

HGVS:

ClinVarID: not found

CAID: absent

gnomAD: absent

MultipleGeneVariants:

Gene: VWF

Variant: c.5278G > A p.Val1760Ile

CAID: CA228708

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

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

DiseaseAssertion: unclassified (A/1) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032442 - blood group O

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

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

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

PreviouslyPublished:

Gene: VWF

Variant: c.6981T>G

HGVS:

ClinVarID: not found

CAID: CA383492037

gnomAD: absent

Case: IP #14

DiseaseAssertion: type 2A (IIE) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032370 - blood group A

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

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

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

PreviouslyPublished:

Gene: VWF

Variant: c.3362G>T p.Arg1121Met

HGVS:

ClinVarID: not found

CAID: CA383511879

gnomAD: absent

Case: P22, F/5

DiseaseAssertion: VWD2A

FamilyInfo: Positive family history, no details provided.

ParentalGenotype: NA

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

CasePreviousTesting: NA

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

Gene: VWF

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

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

ClinVar: 100395

CAID: CA228665

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

Case: P21, F/5

DiseaseAssertion: VWD2M

FamilyInfo: Positive family history, no details provided.

ParentalGenotype: NA

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

CasePreviousTesting: NA

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

Gene: VWF

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

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

ClinVar: 100331

CAID: CA228543

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

PMID: 31240882

Gene: VWF

HGNCID: 12726

Case: VWD type 2M patients

DiseaseAssertion: VWD 2M

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

ParentalGenotypes(s):

CasePresentingHPOs:

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

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

Gene: VWF

Variant:

HGVS:

ClinVar:

CAID:

gnomAD:

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

DiseaseAssertion: Clinical exome sequencing showed the recurrent VWA1 founder mutation

FamilyInfo: no family history of neurological or musculoskeletal conditions

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

CaseHPOFreeText: Gower's sign

Gene: VWA1

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

HGVS: NM_022834.5:c.62_71dup

ClinVar: 830327

gnomad: does not exist in database

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

PMID: 31423628

Gene: VWF

HGNC: 12726

Case: T032, F, 19

DiseaseAssertion: VWD type 3

FamilyInfo: n/a

CasePresentingHPOs: n/a

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

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

Gene: VWF

Variant:

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

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

Case: T121, M, 62

DiseaseAssertion: VWD type 3

FamilyInfo: n/a

CasePresentingHPOs: n/a

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

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

Gene: VWF

Variant:

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

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

Compound heterozygous

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

Case: T085, M, 17

DiseaseAssertion: VWD type 3

FamilyInfo: n/a

CasePresentingHPOs: n/a

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

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

Gene: VWF

Variant:

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

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

Compound heterozygous

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

PMID: 28696025

Gene: VWF

HGNCID: 12726

Case: 7, F, 4 years, Indian

DiseaseAssertion: VWD type 3

FamilyInfo: Consanguinity: yes, no family history of disease

ParentalGenotype: n/a

CasePresentingHPOs: n/a

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

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

Gene: VWF

Variant:

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

Case: 51, F, 22 years, Indian

DiseaseAssertion: VWD type 3

FamilyInfo: no family history of disease, Consanguinity: no

ParentalGenotype: n/a

CasePresentingHPOs: n/a

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

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

Gene: VWF

Variant:

c.3379+1G>A, Exon 25

Heterozygous

Case: 46, F, 5 years, Indian

DiseaseAssertion: VWD type 3

FamilyInfo: family history of disease, Consanguinity: no

ParentalGenotype: n/a

CasePresentingHPOs: n/a

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

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

Gene: VWF

Variant:

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

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

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

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

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

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

Heterozygous

Case: 67, M, 13 years, Indian

DiseaseAssertion: VWD type 3

FamilyInfo: family history of disease, Consanguinity: yes

ParentalGenotype: n/a

CasePresentingHPOs: n/a

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

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

Gene: VWF

Variant:

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

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

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

Homozygous

Case: 24, F, 0.8 years, Indian

DiseaseAssertion: VWD type 3

FamilyInfo: Consanguinity: yes, no family history of disease

ParentalGenotype: n/a

CasePresentingHPOs: n/a

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

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

Gene: VWF

Variant:

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

Case: 85, F, 6 years, Indian

DiseaseAssertion: VWD type 3

FamilyInfo: no family history of disease, Consanguinity: yes

ParentalGenotype: n/a

CasePresentingHPOs: n/a

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

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

Gene: VWF

Variant:

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

Heterozygous

Case: 32, M, 18 years, Indian

DiseaseAssertion: VWD type 3

FamilyInfo: no family history of disease, Consanguinity: no

ParentalGenotype: n/a

CasePresentingHPOs: n/a

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

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

Gene: VWF

Variant:

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

Case: 30, M, 1.1 years, Indian

DiseaseAssertion: VWD type 3

FamilyInfo: Consanguinity: yes, no family history of disease

ParentalGenotype: n/a

CasePresentingHPOs: n/a

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

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

Gene: VWF

Variant:

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

Case: 11, F, 13 years, Indian

DiseaseAssertion: VWD type 3

FamilyInfo: Consanguinity: no, no family history of disease

ParentalGenotype: n/a

CasePresentingHPOs: n/a

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

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

Gene: VWF

Variant:

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

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

DiseaseAssertion: VWD2A (IIE)

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

ParentalGenotype(s): NA

CasePresentingHPOs:

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

CaseNOTHPOs:

CaseNOTHPOFreeText: Blood group O+

CasePreviousTesting:

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

PreviouslyPublished: NA

Gene: VWF

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

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

ClinVarID:

CAID: CA6403368

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

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

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

ClinVarID: 422844

CAID: CA6403245

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

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

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

ClinVarID: 100206

CAID: CA201316

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

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

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

ClinVarID: 100224

CAID: CA228345

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

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

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

ClinVarID: 309

CAID: CA228410

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

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

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

ClinVarID: 256679

CAID: CA6402534

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

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

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

ClinVarID: 100443

CAID: CA228748

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

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

DiseaseAssertion: VWD2A (IIE)

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

ParentalGenotype(s): NA

CasePresentingHPOs:

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

CaseNOTHPOs:

CaseNOTHPOFreeText: Blood group O+

CasePreviousTesting:

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

PreviouslyPublished: NA

Gene: VWF

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

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

ClinVarID:

CAID: CA6403368

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

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

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

ClinVarID: 422844

CAID: CA6403245

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

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

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

ClinVarID: 100206

CAID: CA201316

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

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

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

ClinVarID: 100224

CAID: CA228345

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

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

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

ClinVarID: 993127

CAID: CA6403049

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

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

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

ClinVarID: 309

CAID: CA228410

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

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

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

ClinVarID: 256679

CAID: CA6402534

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

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

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

ClinVarID: 619937

CAID: CA6402355

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

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

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

ClinVarID: 100443

CAID: CA228748

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

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

DiseaseAssertion: VWD2A (IIE)

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

ParentalGenotype(s): NA

CasePresentingHPOs:

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

CaseNOTHPOs:

CaseNOTHPOFreeText: Blood group O+

CasePreviousTesting:

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

PreviouslyPublished: NA

Gene: VWF

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

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

ClinVarID:

CAID: CA6403368

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

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

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

ClinVarID: 422844

CAID: CA6403245

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

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

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

ClinVarID: 100206

CAID: CA201316

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

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

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

ClinVarID: 100224

CAID: CA228345

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

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

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

ClinVarID: 309

CAID: CA228410

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

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

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

ClinVarID: 256679

CAID: CA6402534

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

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

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

ClinVarID: 100443

CAID: CA228748

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

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

DiseaseAssertion: VWD2B

FamilyInfo: NA

ParentalGenotype(s): NA

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

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

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

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: Sequencing of exon 28 of VWF

PreviouslyPublished: NA

Gene: VWF

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

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

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

CAID: NA

gnomAD: absent

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

DiseaseAssertion: VWD2B

FamilyInfo: NA

ParentalGenotype(s): NA

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

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

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

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: Sequencing of exon 28 of VWF

PreviouslyPublished: NA

Gene: VWF

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

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

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

CAID: NA

gnomAD: absent

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

DiseaseAssertion: VWD2B

FamilyInfo: NA

ParentalGenotype(s): NA

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

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

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

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: Sequencing of exon 28 of VWF

PreviouslyPublished: NA

Gene: VWF

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

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

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

CAID: NA

gnomAD: absent

PMID: 33556167

Gene: VWF

HGNCID: 12726

Case: P86, Chinese, female, 20yo

DiseaseAssertion: VWD3

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

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

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

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

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

ClinVarID: NA

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

gnomAD: absent

Variant: Exons 6–16 del - unregistered variant

HGVS:

ClinVarID:

CAID:

gnomAD:

Proband: FB_II:3, male age unknown

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

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

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

CAID: CA228829

PMID: 28660968

Gene: VWF

HGNCID: 12726

Case: 1, F, 38, Italian

DiseaseAssertion: VWD type 3

FamilyInfo: Consanguinity: no

ParentalGenotype: n/a

CasePresentingHPOs: n/a

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

CaseNotHPOs: n/a

CaseNotHPOFreeText: Anti-VWF alloantibodies: no

CasePreviousTesting: n/a

Gene: VWF

Variant:

276delT (FS), Exon 4

2157delA (FS), Exon 16

Homozygous

Case: 40, M, 26, Indian

DiseaseAssertion: VWD type 3

FamilyInfo: Consanguinity: No

ParentalGenotype: n/a

CasePresentingHPOs: n/a

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

CaseNotHPOs: n/a

CaseNotHPOFreeText: Anti-VWF alloantibodies: no

CasePreviousTesting: n/a

Gene: VWF

Variant:

5053+1G→A (intronic), Exon 28

7294delGT (FS), Exon 43

Compound Heterozygous

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

Case: 16, F, 16, Iranian

DiseaseAssertion: VWD type 3

FamilyInfo: Consanguinity: Yes

ParentalGenotype: n/a

CasePresentingHPOs: n/a

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

CaseNotHPOs: n/a

CaseNotHPOFreeText: Anti-VWF alloantibodies: no

CasePreviousTesting: n/a

Gene: VWF

Variant:

1093C→T (Arg365X), Exon 9, Homozygous

Case: 34, M, 15, Indian

DiseaseAssertion: VWD type 3

FamilyInfo: Consanguinity: No

ParentalGenotype: n/a

CasePresentingHPOs: n/a

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

CaseNotHPOs: n/a

CaseNotHPOFreeText: Anti-VWF alloantibodies: no

CasePreviousTesting: n/a

Gene: VWF

Variant:

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

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

Case: Croatian adult patient

DiseaseAssertion: VWD1

FamilyInfo: Not specified

ParentalGenotype(s): Not specified

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

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

CaseNOTHPOs: Not specified

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

CasePreviousTesting: Not reported

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

PreviouslyPublished: None

Gene: VWF

Variant: c.6596G>A

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

ClinVarID: Not available

CAID: CA383490627

gnomAD: Not available

Case: Croatian adult patient

DiseaseAssertion: VWD3

FamilyInfo: Not specified

ParentalGenotype(s): Not specified

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

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

CaseNOTHPOs: Not specified

CaseNOTHPOFreeText: Not specified.

CasePreviousTesting: Not reported

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

PreviouslyPublished: None

Gene: VWF

Variant: c.571T>C

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

ClinVarID: Not available

CAID: CA383514932

gnomAD: Not available

PMID: 28874064

Gene: VWF

HGNCID: 12726

PMID: 28533135

Gene: VWF

HGNCID: 12726

Case: Patient 1, female, 6.3yo

DiseaseAssertion: VWD2A

FamilyInfo: NA

ParentalGenotype(s): NA

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

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

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

CaseNOTHPOs: HP:0001873

(Thrombocytopenia)

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: sequencing of exon 28 of the VWF

PreviouslyPublished: NA

Gene: VWF

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

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

ClinVarID: NA

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

gnomAD: absent

PMID: 29997693

Gene: VWF

HGNCID: 12726

Case: Patient III-1, Male, 43 years (as of Dec 2010 follow-up) DiseaseAssertion: VWD type 2A, phenotype IIC ("VWD2AIIC-Miami"). Bleeding score 9 (elevated; nv <4). FamilyInfo: Son of II-3; part of 4-member, 2-generation pedigree, dominant transmission. ParentalGenotype(s): Mother (II-3) heterozygous for the variant, affected. Father's genotype not tested/not reported. CasePresentingHPOs: HP:0000421 (Epistaxis), HP:0001934 (Persistent bleeding after trauma — bleeding from minor wounds), HP:0004846 (Prolonged bleeding after surgery — post-surgical bleeding, bleeding at tooth extraction), HP:0030130 (Impaired VWF collagen binding activity; VWF:CB/Ag ratio 0.14, nv ≥0.8), HP:0030129 (Impaired VWF:RCo; VWF:RCo/Ag ratio 0.18, nv ≥0.8), HP:0030132 (Absence of large VWF multimers) CaseHPOFreeText: VWF:Ag markedly ELEVATED at 2.72× normal (nv 0.5-1.6) — highest of the four patients. Absolute VWF:RCo 0.40 and VWF:CB 0.37 (both below the ≥0.5 absolute threshold, so reduced in both absolute and ratio terms, unlike II-3). VWF:GPIbα binding 0.55 absolute / 0.20 ratio. FVIII:C 0.99 (normal, nv ≥0.6) with reduced FVIII-binding ratio (F8Br 0.49, nv ≥0.6). VWF propeptide:Ag ratio (ppr) 0.32, markedly reduced (nv 0.8-2.2). PFA-100 closure times markedly prolonged (both >300 sec). Hematoma and oral cavity bleeding also reported. No menorrhagia (not applicable, male). CaseNOTHPOs: NA CaseNOTHPOFreeText: NA CasePreviousTesting: Same family-wide testing history as Patient II-3 (extensive prior negative Sanger sequencing, causative variant found only via MLPA); not genome-wide. GenotypingMethod: Same as Patient II-3 — MLPA plus confirmatory RT-PCR/sequencing. PreviouslyPublished: PMID 8324222 (Ledford et al. 1993) — same family as originally reported. Gene: VWF Variant: Heterozygous complex in-frame duplication of VWF exons 9-10 (same variant as Patient II-3). HGVS: NM_000552.3:c.998_1156dup (p.Glu333_Pro385dup) ClinVarID: NA CAID: NA gnomAD: NA

Case: Patient III-5, Female, 37 years (as of Dec 2010 follow-up) DiseaseAssertion: VWD type 2A, phenotype IIC ("VWD2AIIC-Miami"). Bleeding score not done (nd). FamilyInfo: Daughter of II-3; part of 4-member, 2-generation pedigree, dominant transmission. ParentalGenotype(s): Mother (II-3) heterozygous for the variant, affected. Father's genotype not tested/not reported. CasePresentingHPOs: HP:0030130 (Impaired VWF collagen binding activity; VWF:CB/Ag ratio 0.14, nv ≥0.8), HP:0030129 (Impaired VWF:RCo; VWF:RCo/Ag ratio 0.15, nv ≥0.8), HP:0030132 (Absence of large VWF multimers) CaseHPOFreeText: Specific bleeding symptoms not individually itemized in the text for this patient (her bleeding score was not done, and the itemized symptom list in the Results section explicitly covers only the three patients with bleeding scores recorded). Text states only that "all studied patients" including this one have "a significant bleeding tendency with typical mucocutaneous bleeding symptoms." VWF:Ag ELEVATED at 2.01× normal (nv 0.5-1.6). Absolute VWF:RCo 0.30 and VWF:CB 0.29 (both below the ≥0.5 absolute threshold). VWF:GPIbα binding 0.39 absolute / 0.19 ratio. FVIII:C 0.85 (normal, nv ≥0.6) with reduced FVIII-binding ratio (F8Br 0.44, nv ≥0.6). VWF propeptide:Ag ratio (ppr) 0.61, reduced (nv 0.8-2.2). PFA-100 closure times prolonged (Epinephrine >267 sec, ADP >278 sec). CaseNOTHPOs: NA CaseNOTHPOFreeText: NA CasePreviousTesting: Same family-wide testing history as Patient II-3; not genome-wide. GenotypingMethod: Same as Patient II-3 — MLPA plus confirmatory RT-PCR/sequencing. PreviouslyPublished: PMID 8324222 (Ledford et al. 1993) — same family as originally reported. Gene: VWF Variant: Heterozygous complex in-frame duplication of VWF exons 9-10 (same variant as Patient II-3). HGVS: NM_000552.3:c.998_1156dup (p.Glu333_Pro385dup) ClinVarID: NA CAID: NA gnomAD: NA

Case: Patient III-3, Female, 41 years (as of Dec 2010 follow-up) DiseaseAssertion: VWD type 2A, phenotype IIC ("VWD2AIIC-Miami"). Bleeding score 14 (elevated; nv <4). FamilyInfo: Daughter of II-3; part of 4-member, 2-generation pedigree, dominant transmission. ParentalGenotype(s): Mother (II-3) heterozygous for the variant, affected. Father's genotype not tested/not reported. CasePresentingHPOs: HP:0000421 (Epistaxis), HP:0000132 (Menorrhagia), HP:0001934 (Persistent bleeding after trauma — bleeding from minor wounds), HP:0004846 (Prolonged bleeding after surgery — bleeding at tooth extraction), HP:0030130 (Impaired VWF collagen binding activity; VWF:CB/Ag ratio 0.12, nv ≥0.8), HP:0030129 (Impaired VWF:RCo; VWF:RCo/Ag ratio 0.15, nv ≥0.8), HP:0030132 (Absence of large VWF multimers) CaseHPOFreeText: VWF:Ag ELEVATED at 1.78× normal (nv 0.5-1.6) — least elevated of the four, though still above range. Absolute VWF:RCo 0.27 and VWF:CB 0.22 (both below the ≥0.5 absolute threshold). VWF:GPIbα binding 0.35 absolute / 0.20 ratio. FVIII:C 0.75 (normal, nv ≥0.6) with reduced FVIII-binding ratio (F8Br 0.50, nv ≥0.6). VWF propeptide:Ag ratio (ppr) 0.57, reduced (nv 0.8-2.2). PFA-100 closure times markedly prolonged (Epinephrine >300 sec, ADP >284 sec). No explicit mention of post-surgery bleeding for this patient specifically (unlike II-3 and III-1). CaseNOTHPOs: NA CaseNOTHPOFreeText: NA CasePreviousTesting: Same family-wide testing history as Patient II-3; not genome-wide. GenotypingMethod: Same as Patient II-3 — MLPA plus confirmatory RT-PCR/sequencing. PreviouslyPublished: PMID 8324222 (Ledford et al. 1993) — same family as originally reported. Gene: VWF Variant: Heterozygous complex in-frame duplication of VWF exons 9-10 (same variant as Patient II-3. HGVS: NM_000552.3:c.998_1156dup (p.Glu333_Pro385dup) ClinVarID: NA CAID: NA gnomAD: NA

Case: Patient II-3, Female, 67 years (as of Dec 2010 follow-up) DiseaseAssertion: VWD type 2A, phenotype IIC ("VWD2AIIC-Miami") — a historically named variant of type 2A characterized by paradoxically elevated VWF:Ag with reduced function; dominantly inherited in this family (unlike classic/most VWD2AIIC, which is recessive). Bleeding score 21 (very high; nv <4). FamilyInfo: Mother of III-1, III-3, and III-5 (all three affected); 4-member, 2-generation pedigree, dominant transmission. ParentalGenotype(s): NA — her own parents not part of this study. CasePresentingHPOs: HP:0000421 (Epistaxis), HP:0000132 (Menorrhagia), HP:0001934 (Persistent bleeding after trauma — bleeding from minor wounds), HP:0004846 (Prolonged bleeding after surgery — post-surgical bleeding, bleeding at tooth extraction), HP:0030130 (Impaired VWF collagen binding activity; VWF:CB/Ag ratio 0.18, nv ≥0.8), HP:0030129 (Impaired VWF:RCo; VWF:RCo/Ag ratio 0.22, nv ≥0.8), HP:0030132 (Absence of large VWF multimers) CaseHPOFreeText: VWF:Ag markedly ELEVATED at 2.50× normal (nv 0.5-1.6). Absolute VWF:RCo 0.54 and VWF:CB 0.46 (both near/within the lower end of normal in absolute terms, nv ≥0.5, but severely reduced relative to the elevated antigen). VWF:GPIbα binding 0.74 absolute / 0.30 ratio. FVIII:C 1.08 (normal, nv ≥0.6) with reduced FVIII-binding ratio (F8Br 0.61, at threshold, nv ≥0.6). VWF propeptide:Ag ratio (ppr) 0.71, reduced (nv 0.8-2.2) — indicates decreased clearance of mature VWF relative to propeptide. PFA-100 closure times markedly prolonged (Epinephrine and ADP both >300 sec, nv ≤165/≤118). Hematoma (bruising) and oral cavity bleeding also reported. Post-partum bleeding ultimately requiring hysterectomy. Historical DDAVP test performed in this patient specifically showed findings consistent with delayed VWF clearance. Oral contraceptive/desmopressin use not specified. CaseNOTHPOs: NA CaseNOTHPOFreeText: NA CasePreviousTesting: Extensive prior negative testing — partial sequencing in the original 1993 study plus subsequent complete Sanger sequencing of all VWF coding exons by multiple independent groups over ~20 years found no candidate mutation. The causative variant was only found via MLPA (multiplex ligation-dependent probe amplification), which detects copy-number changes that exon sequencing alone misses. Not genome-wide; VWF-targeted. GenotypingMethod: MLPA identified signal gain at exons 9-10 in all 4 family members; confirmed by duplication-junction-specific RT-PCR (sense primer in exon 10, antisense in exon 9) and by RT-PCR/sequencing across exons 8-11. Full genomic characterization (PCR primer walking, RepeatMasker, MFold in silico DNA-folding analysis) defined a complex rearrangement: a 5,047 bp duplication (intron 8 through part of intron 10, including exons 9 and 10) plus two deletions (1,348 bp and 2,301 bp) within intron 10, apparently mediated by inverted Alu repeat elements (proposed mechanism: replication slippage for the duplication, a stable Alu3/Alu4 inverted-repeat DNA secondary structure for the deletion). PreviouslyPublished: PMID 8324222 (Ledford MR, Rabinowitz I, Sadler JE, Kent JW, Civantos F. "New variant of von Willebrand disease type II with markedly increased levels of von Willebrand factor antigen and dominant mode of inheritance: von Willebrand disease type IIC Miami." Blood. 1993;82:169-75) — this is the original report of this same family. Gene: VWF Variant: Heterozygous complex in-frame duplication of VWF exons 9-10 (net transcript-level effect), D1 domain (VWF propeptide region). Recombinant expression studies (not patient-specific, applies to the variant generally): "homozygous" mutant VWF secreted only as dimers (no higher-order multimers); co-expression with WT VWF reproduced the patients' plasma multimer pattern exactly; mutant retained in unusually large intracellular granules colocalizing with PDI in the ER; ADAMTS13 proteolysis was not resistant, but an aberrant extra proteolytic band appeared in both patient plasma and recombinant mutant; infusion of recombinant mutant VWF into VWF-/- mice showed significantly prolonged half-life vs. WT (mean residence time 3.15h vs 1.90h, p=0.015), supporting decreased clearance as the mechanism for the paradoxically elevated VWF:Ag. HGVS: NM_000552.3:c.998_1156dup (p.Glu333_Pro385dup) ClinVarID: NA CAID: NA gnomAD: NA

PMID: 27472426

Gene: VWF

HGNCID: 12726

Case: L881R/N1421K heterozygous proband

DiseaseAssertion: VWD1

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: FVIII:C = 30 IU/dL, VWF:RCo = 3 IU/dL, VWF:Ag = 27 IU/dL, VWF:CB = 22 IU/dL, VWF:RCo/VWF:Ag = 0.11

CaseNOTHPOs: HP:0030132

(Absence of large von Willebrand factor multimers)

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NA

PreviouslyPublished: PMID: 16985174

Gene: VWF

Variant 1: c.2642T>G (p.Leu881Arg)

HGVS: NM_000552.5:c.2642T>G

ClinVarID: NA

CAID: CA383520052; http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA383520052

gnomAD: absent

Variant 2: c.4263C>G (p.Asn1421Lys)

HGVS: NM_000552.4(VWF):c.4263C>G (p.Asn1421Lys)

ClinVarID: 100345; https://www.ncbi.nlm.nih.gov/clinvar/variation/100345/

gnomAD: absent

PMID: 27885890

Gene: VWF

HGNCID: 12726

PMID: 36034607

Gene: VWF

HGNCID: 12726

PMID: 17000885

Gene: VWF

HGNC: 12726

Disease: von Willebrand disease type 2M

MONDO: 0015630

InheritancePattern: Autosomal Dominant

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

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

Case: Proband (II-1), male, 56yo, Italian

DiseaseAssertion: VWD1 and Hemophilia A

FamilyInfo: Pedigree in Fig. 1 - Father had VWD1 and Mother had Hemophilia A - parents have normal or higher VWF levels, and normal FVIII/VWF:Ag ratios, as well as a normal bleeding score; 2 daughters carry F8 variant

ParentalGenotype(s): Paternal = NM_000552.4(VWF):c.4751A>G (p.Tyr1584Cys); Maternal = NM_000132.3(F8):c.2167G>A (p.Ala723Thr)

CasePresentingHPOs: HP:0012147, HP:0030129, HP:0030130, HP:0001892, HP:0000421, HP:0000978, HP:0004846, HP:0000225, HP:0005261, HP:0040242

(Reduced quantity of VWF, Impaired ristocetin cofactor assay activity, Impaired von Willebrand factor collagen binding activity, abnormal bleeding, epistaxis, Bruising susceptibility, Prolonged bleeding after surgery, bleeding gums, joint hemorrhage, muscle hemorrhage)

CaseHPOFreeText: blood group = 0, aPTT = 0.56sec, FVIII = 9.8 IU/dL, VWF:Ag = 43.2 IU/dL, VWF:CB = 35.6 IU/dL, VWF:Rco = 42.1 IU/dL, VWF:FVIIIB = 41.3 IU/dL, Platelet VWF:Ag = 58.2 IU/dL, bleeding score = 27

CaseNOTHPOs: HP:0011871

(Impaired RIPA)

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: PCR and direct sequencing of VWF and FVIII

PreviouslyPublished: NA

Gene: VWF

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

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

ClinVarID: 310; https://www.ncbi.nlm.nih.gov/clinvar/variation/310/

CAID: NA

gnomAD: MAF = 0.004024 (519/128972 alleles, 4 homozygotes) in European (non-Finnish) population

MultipleGeneVariants:

Gene: F8

Variant: c.2167G>A (p.Ala723Thr)

HGVS: NM_000132.3(F8):c.2167G>A (p.Ala723Thr)

ClinVarID: 10246; https://www.ncbi.nlm.nih.gov/clinvar/variation/10246/

CAid: NA

gnomAD: MAF = 0.00005257 (1/19022 alleles, 1 hemizygote) in South Asian population

PMID: 2557900

Gene: VWF

HGNC: 12726

Disease: von Willebrand disease type 2M

MONDO: 0015630

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: 23179108

Gene: VWF

HGNC: 12726

Disease: von Willebrand disease type 2B

MONDO: 0015629

InheritancePattern: Autosomal Dominant

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

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

Case: Female, Caucasian, 11 years at diagnosis

DiseaseAssertion: VWD1

FamilyInfo: Non-consanguineous family, parents carry no bleeding history but have risk factors (prolonged closure time and modestly decreased VWF:Ag level)

ParentalGenotype(s): Mother has c.7464C>T, Father carries no mutation.

CasePresentingHPOs: HP:0000421, HP:0000978, HP:0001934, HP:0030140, HP:0004846, HP:0006298

CaseHPOFreeText: Cumulative bleeding score of 17, Reduced VWF:Ag of 9IU/dL, VWF:GPIb of 6 I/dL, and factor VIII coagulant activity of 35 IU/dL, prolonged PFA closure time of >300 and reduced concentration of all multimers.

CaseNOTHPOs: None reported

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

CasePreviousTesting: NA

GenotypingMethod: Direct sequencing of genomic DNA exons 1 to 52, exon/intron boundaries, 5' and 3' UTR, promoter region, and whole intron 44 of VWF. RT-PCR followed by sequencing of cDNA to detect splicing defect due to c.7464C>T.

PreviouslyPublished: PMID:22871923

Gene: VWF

Variant: c.7464C>T

HGVS: NM_000552.5:c.7464C>T (p.Gly2488=)

ClinVarID: 619755

CAID: CA232284628

gnomAD: 0.000008799 MAF in European (non-Finnish) and 0.000008664 MAF in XX. https://gnomad.broadinstitute.org/variant/12-6080849-G-A

Case: 7, M, 34, Italian

DiseaseAssertion: VWD type 3

FamilyInfo: Consanguinity: no

ParentalGenotype: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: VWF:Ag (IU/dL): <1, FVIII:C (IU/dL): 3, Bleeding Score: 13

CaseNotHPOs: n/a

CaseNotHPOFreeText: Anti-VWF alloantibodies: no

CasePreviousTesting: n/a

Gene: VWF

Variant:

c.6551G>C (p.Cys2184Ser), Exon 37, D4 domain

Compound Heterozygous

Note: The second mutant allele is unknown

PMID: 30036281<br /> Gene: VWF<br /> Disease: von Willebrand disease<br /> MonDO: 0015631<br /> HGNCID:

PMID: 1409710

Gene: VWF

HGNC: 12726

Disease: von Willebrand disease type 2M

MONDO: 0015630

InheritancePattern: Autosomal Dominant

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

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

Case: p.R1374C, Male, Age 39, Caucasian

Disease Assertion: VWD2M

FamilyInfo: 25 family members tested, 1 with high bleeding score, some affected by VWD (number not defined)

Parental Genotype: Not listed

CasePresentingHPOs:

CaseHPOFreeText: VWF:RCo 12 IU/dL, VWF:GPIbM 18 U/dL, VWF:CB3 19 IU/dL, VWF:CB4 14 U/dL, VWF:RCo/VWF:Ag ratio 0.55

CaseNotHPOs: HP:0040240

(Increased Ratio of VWF Propeptide to VWF antigen)

CaseNotHPOFreeText:bleeding score 2, normal multimer distribution,VWF:Ag 22 IU/dL

Protein Expression:

CasePreviousTesting: VWF sequencing

Gene: VWF

Variant: NM_000552.4(VWF):c.4120C>T (p.Arg1374Cys)

ClinVar: 100329 ClinVarID

CAID: CA228539

CAID

gnomAD: MAF of 0.000008824 (1/113322 alleles) in the European (non-Finnish) population.

gnomAD

PMID: 29296853

Gene: VWF

HGNCID: 12726

Proband: Mazurier_II2

AgeAtReport: 20yo female

HPO: HP:0000421, HP:0002248, hematoma but did not specify spontaneous and/or frequent

Labs: 4 measurements taken for the same proband so values are a range: FVIII:C 4-10 IU/dL, VWF:Ag 30-53 IU/dL, FVIII:Ag 4-8 IU/dL, VWF:FVIIIB absent

Variant: C1060R - NM_000552.5:c.3178T>C (maternal)

Variant: Y357X - NM_000552.5:c.1071C>A (paternal)

CAID: CA114176

CAID: CA114174

Case: Patient C

DiseaseAssertion: VWD2N

FamilyInfo: Family 2

ParentalGenotype(s):

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

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

CaseNOTHPOs:

CaseNOTHPOFreeText: n/a

CasePreviousTesting: n/a

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

PreviouslyPublished: n/a

Gene: VWF

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

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

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

CAID: n/a

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

PMID: 42460955

Gene: MYBPC3

HGNC ID: 7551

PMID: 24134628

Gene: MYH7

HGNC: 7577

DiseaseAssertion: Hypertrophic Cardiomyopathy

VariantPreviousTesting: ACTC1, ACTN2, CSRP3, LAMP2, MYBPC3, MYH7, NEXN, PLN, TNNC1, TNNI3, TNNT2, TPM1, CAV3, GLA, MYL2, MYL3, MYOZ2, PRKAG2, and TTR were all tested via NGS.

VariantGenotypingMethod: Next-generation sequencing panels were used to sequence and read the genetic information of the 760 HCM probands for variants within exons and in +/- 10 nucleotides within the flanking introns of the genes provided above. These variants were then interpreted and filtered for pathogenicity.

VariantAddInfo: Seen in one HCM probands

Variant: NM_000257.4(MYH7):c.715G>A (p.Asp239Asn)

ClinVar: 43100 https://www.ncbi.nlm.nih.gov/clinvar/variation/43100/

gnomAD: 0.00002891, http://gnomad.broadinstitute.org/variant/14-23900811-C-T

DiseaseAssertion: Hypertrophic Cardiomyopathy

VariantPreviousTesting: ACTC1, ACTN2, CSRP3, LAMP2, MYBPC3, MYH7, NEXN, PLN, TNNC1, TNNI3, TNNT2, TPM1, CAV3, GLA, MYL2, MYL3, MYOZ2, PRKAG2, and TTR were all tested via NGS.

VariantGenotypingMethod: Next-generation sequencing panels were used to sequence and read the genetic information of the 760 HCM probands for variants within exons and in +/- 10 nucleotides within the flanking introns of the genes provided above. These variants were then interpreted and filtered for pathogenicity.

VariantAddInfo: Seen in three HCM probands

Variant: NM_000257.4(MYH7):c.2681A>G (p.Glu894Gly)

ClinVarID: 42922 https://www.ncbi.nlm.nih.gov/clinvar/variation/42922/

gnomAD: Not in gnomAD

DiseaseAssertion: None

VariantPreviousTesting: Some combination of ACTC1, ACTN2, CSRP3, LAMP2, MYBPC3, MYH7, NEXN, PLN, TNNC1, TNNI3, TNNT2, TPM1, ABCC9, CTF1, DES, EMD, LDB3, LMNA, MYH6, RBM20, SGCD, TAZ, TCAP, TTN, VCL, CAV3, GLA, MYL2, MYL3, MYOZ2, PRKAG2, TTR, DSC2, DSG2, DSP, JUP, PKP2, RYR2, TMEM43, CASQ2 and RYR2 were tested via NGS.

VariantGenotypingMethod: Next-generation sequencing panels were used to sequence and read the genetic information of probands for variants within exons and in +/- 10 nucleotides within the flanking introns of the genes provided above. These variants were then interpreted and filtered for pathogenicity.

Variant: NM_000257.4(MYH7):c.4399C>G (p.Leu1467Val)

ClinVar: 43015 https://www.ncbi.nlm.nih.gov/clinvar/variation/43015/

gnomAD: 0.001111, http://gnomad.broadinstitute.org/variant/14-23886482-G-C

DiseaseAssertion: Hypertrophic Cardiomyopathy

VariantPreviousTesting: ACTC1, ACTN2, CSRP3, LAMP2, MYBPC3, MYH7, NEXN, PLN, TNNC1, TNNI3, TNNT2, TPM1, CAV3, GLA, MYL2, MYL3, MYOZ2, PRKAG2, and TTR were all tested via NGS.

VariantGenotypingMethod: Next-generation sequencing panels were used to sequence and read the genetic information of the 760 HCM probands for variants within exons and in +/- 10 nucleotides within the flanking introns of the genes provided above. These variants were then interpreted and filtered for pathogenicity.

VariantAddInfo: Seen in two HCM probands

Variant: NM_000257.4(MYH7):c.1988G>A (p.Arg663His)

ClinVarID: 42875 https://www.ncbi.nlm.nih.gov/clinvar/variation/42875/

gnomAD: 0.00003097, http://gnomad.broadinstitute.org/variant/14-23896042-C-T

DiseaseAssertion: Hypertrophic Cardiomyopathy

VariantPreviousTesting: ACTC1, ACTN2, CSRP3, LAMP2, MYBPC3, MYH7, NEXN, PLN, TNNC1, TNNI3, TNNT2, TPM1, CAV3, GLA, MYL2, MYL3, MYOZ2, PRKAG2, and TTR were all tested via NGS.

VariantGenotypingMethod: Next-generation sequencing panels were used to sequence and read the genetic information of the 760 HCM probands for variants within exons and in +/- 10 nucleotides within the flanking introns of the genes provided above. These variants were then interpreted and filtered for pathogenicity.

VariantAddInfo: Seen in one proband

Variant: NM_000257.4(MYH7):c.1063G>A (p.Ala355Thr)

ClinVarID: 42820 https://www.ncbi.nlm.nih.gov/clinvar/variation/42820/

gnomAD: Not in gnomAD

Case#: index case, III.4, female, 52 yrs,

DiseaseAssertion: HCM

FamilyInfo: Yes, III.3, IV.3 and IV.4 also diagnosed

CasePresentingHPOs: Cafe-au-lait spot, freckling, neurofibromas, heart murmur, left ventricular hypertrophy (HP:0000957, HP:0001480, HP:0001067, HP:0030148, HP:0001712)

CaseHPOFreeText: 20 mm IVS, 56% EF, 50 mmHg LVOTO, NSVT (VA)

CaseNotHPOs: N/A

CaseNotHPOFreeText: No AV, no ICD

CasePreviousTesting: N/A

CaseGenotypingMethod: ECG, cardiac magnetic resonance, physical examination, NGS tech

Variant: NM_000257.4(MYH7):c.1357C>T (p.Arg453Cys)

ClinVar: 14089 https://www.ncbi.nlm.nih.gov/clinvar/variation/14089/

CAID: N/A

gnomAD: absent

MultipleGeneVariants:

(1) NF1 Variant:

Variant: NM_000267.3(NF1):c.6709C>T (p.Arg2237Ter)

ClinVar: 230389 https://www.ncbi.nlm.nih.gov/clinvar/variation/230389/

CAID: N/A

gnomAD: absent

PMID: 25189259

Gene MYH7

HGNC: 7577

https://www.ias.ac.in/article/fulltext/jgen/093/02/0557-0560

CaseHCM147: 31 yrs report, Vietnam, Asian

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: Family history of Sudden Cardiac Death and Hypertrophic Cardiomyopathy, Has a 9 year old daughter with the same variant but no symptoms

CasePresentingHPOs: HP:0100749, HP:0006698, HP:0031295 (Chest pain, Dilatation of the ventricular cavity, Left atrial enlargement)

HPOsFreeText: Maximal LV thickness 32 mm

CaseNotHPOs: HP:0005110, HP:0001297, HP:0004756 (Atrial fibrillation, Stroke, Ventricular tachycardia)

NotHPOsFreeText: N/A

CaseAddInfo: N/A

CasePreviousTesting: The gene panel included 10 sarcomeric genes (MYH7, MYBPC3, TNNT2, TNNI3, TPM1, MYL2, MYL3, ACTC1, TNNC1, MYH6), 9 genes encoding Z-disk components and Ca2+ homeostasis factors (LDB3, CSRP3, TCAP, VCL, ACTN2, MYOZ2, NEXN, JPH2, PLN), and 4 genes involved in HCM phenocopies (GLA, LAMP2, PRKAG2, TTR), All probands had left ventricular wall thickness >= 15 mm and no other diseases that can cause secondary hypertrophy

CaseGenotypingMethod: The coding region, flanking sequences, and untranslated regions of each gene were enriched by LC-PCR, amplified, and sequenced on the Illumina MiSeq or MiniSeq platform. Identified variants were then filtered for pathogenicity and confirmed by Sanger sequencing.

Variant: NM_000257.4(MYH7):c.2156G>A (p.Arg719Gln)

ClinVar: 14107 https://www.ncbi.nlm.nih.gov/clinvar/variation/14107/

gnomAD: Not in gnomAD

CaseIX: Brazil, Caucasian

DiseaseAssertion: Hypertrophic cardiomyopathy

FamilyInfo: Family history of HCM

CasePresentingHPOs: HP:0001712, HP:0001639 (Left ventricular hypertrophy, Hypertrophic cardiomyopathy)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: N/A

CasePreviousTesting: Only MYH7, MYBPC3, and TNNT2 were tested.

CaseGenotypingMethod: DNA was extracted from peripheral blood and the above genes were subject to PCR amplification and directly sequenced. The resulting sequences were compared with the reference and filtered for pathogenicity.

Variant: NM_000257.3:c.788T>C (p.Ile263Thr)

ClinVar: 43106 https://www.ncbi.nlm.nih.gov/clinvar/variation/43106/

gnomAD: European (Non-Finnish) 8.792e-6, Overall 3.977e-6 https://gnomad.broadinstitute.org/variant/14-23900635-A-G