Case#: 1, female, 44yo

DiseaseAssertion: VWD1

FamilyInfo: N/A

ParentalGenotype: N/A

CasePresentingHPOs: HP:0007420, HP:0000132, HP:0004846, HP:0012147, HP:0030129, HP:0030130 (spontaneous hematomas, Menorrhagia, Reduced quantity of VWF, Impaired ristocetin cofactor assay activity, Impaired von Willebrand factor collagen binding activity)

CaseHPOFreeText: Type O blood, VWF:Ag (0·55–2 iu/ml) pre = 0·47, VWF:RCo (0·55–2 iu/ml) pre = 0·5, FVIII:C (0·55–2 iu/ml) pre = 0·16, FVIII:C/VWF:Ag ratio = 0·32, VWF:FVIII binding (>20%) = 7%, VWF:FVIII binding/VWF:Ag (>0·7) = 0·15, patient died after motor vehicle accident

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#: 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

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 #24 in type 2N VWD sub-cohort (also in row 5 splice variants table 6)

DiseaseAssertion: type 2N/1 VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032441 - blood group AB

CaseHPOFreeRext: VWF:Ag [IU/dL] = 42; VWF:Ac [IU/dL] = 34; FVIII:C [IU/dL] = 16

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.6798+2T>A

ClinVarID: 1803122

gnomAD: absent