Case: IP #9 in type 2N VWD sub-cohort

DiseaseAssertion: type 2N VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032370 - blood group A

CaseHPOFreeRext: VWF:Ag [IU/dL] = 93; VWF:Ac [IU/dL] = 107; FVIII:C [IU/dL] = 18

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.2446C > T p.Arg816Trp

HGVS:

ClinVarID: 295

CAID:

gnomAD: 0.00001983 (32 in 1613930) no homozygotes https://gnomad.broadinstitute.org/variant/12-6036488-G-A?dataset=gnomad_r4

MultipleGeneVariants:

Gene: VWF

Variant: c.2561G>A p.Arg854Gln

ClinVar: 296

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

Case: IP #8 in type 2N VWD sub-cohort

DiseaseAssertion: type 2N VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032370 - blood group A

CaseHPOFreeRext: VWF:Ag [IU/dL] = 61; VWF:Ac [IU/dL] = 59; FVIII:C [IU/dL] = 25

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.2446C > T p.Arg816Trp

HGVS:

ClinVarID: 295

CAID:

gnomAD: 0.00001983 (32 in 1613930) no homozygotes https://gnomad.broadinstitute.org/variant/12-6036488-G-A?dataset=gnomad_r4

MultipleGeneVariants:

Gene: VWF

Variant: c.2561G>A p.Arg854Gln

ClinVar: 296

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

Case: IP #7 in type 2N VWD sub-cohort

DiseaseAssertion: type 2N VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032440 - blood group B

CaseHPOFreeRext: VWF:Ag [IU/dL] = 166; VWF:Ac [IU/dL] = 144; FVIII:C [IU/dL] = 2

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.2446C>T p.Arg816Trp

HGVS:

ClinVarID: 295

CAID:

gnomAD: 0.00001983 (32 in 1613930) no homozygotes https://gnomad.broadinstitute.org/variant/12-6036488-G-A?dataset=gnomad_r4

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

DiseaseAssertion: type 2N VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: VWF:Ag [IU/dL] = 50; VWF:Ac [IU/dL] = 55; FVIII:C [IU/dL] = 15

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.2446C > T p.Arg816Trp

HGVS:

ClinVarID: 295

CAID:

gnomAD: 0.00001983 (32 in 1613930) no homozygotes https://gnomad.broadinstitute.org/variant/12-6036488-G-A?dataset=gnomad_r4

MultipleGeneVariants:

Gene: VWF

Variant: c.2561G>A p.Arg854Gln

ClinVar: 296

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

Case: P89, Chinese, female, 51yo

DiseaseAssertion: VWD2N

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type O blood, bleeding score = 7; VWF:Ag (%) = 125.8, VWF:RCo (%) = 119.6, FVIII:C (%) = 9.8, VWF:CB (%) = 127.8, VWFpp (%) = 109.8, VWF:RCo/VWF:Ag = 1.0, VWF:CB/VWF:Ag = 1.0, VWFpp/VWF:Ag = 0.9, FVIII:C/VWF:Ag = 0.1, VWF: FVIIIB (%) = 0.1

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.2446C>T (p.Arg816Trp)

HGVS: NM_000552.4(VWF):c.2446C>T (p.Arg816Trp)

ClinVarID: 295; https://www.ncbi.nlm.nih.gov/clinvar/variation/295/

CAID: NA

gnomAD: MAF = 0.0002541 (9/35418 alleles) in the Latino/Admixed American population; https://gnomad.broadinstitute.org/variant/12-6145654-G-A?dataset=gnomad_r2_1

Case: P5, Chinese, female, 65yo

DiseaseAssertion: VWD2N

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type O blood, bleeding score = 14; VWF:Ag (%) = 55.2, VWF:RCo (%) = 51.4, FVIII:C (%) = 1.3, VWF:CB (%) = 58.2, VWFpp (%) = 49.3, VWF:RCo/VWF:Ag = 0.9, VWF:CB/VWF:Ag = 1.1, VWFpp/VWF:Ag = 0.9, FVIII:C/VWF:Ag = 0.0, VWF: FVIIIB (%) = 0.1

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant 1: c.1911delC - unregistered variant

HGVS: NA

ClinVarID: NA

CAID: NA

gnomAD: NA

Variant 2: c.2446C>T (p.Arg816Trp)

HGVS: NM_000552.4(VWF):c.2446C>T (p.Arg816Trp)

ClinVarID: 295; https://www.ncbi.nlm.nih.gov/clinvar/variation/295/

CAID: NA

gnomAD: MAF = 0.0002541 (9/35418 alleles) in the Latino/Admixed American population; https://gnomad.broadinstitute.org/variant/12-6145654-G-A?dataset=gnomad_r2_1

Case: 38 year old Napalese woman

DiseaseAssertion: type 2N VWD

FamilyInfo: mother and elder brother had bleeding manifestations since childhood.

CasePresentingHPOs: HP:0005261, HP:0012233, HP:0000132, HP:0003645, HP:0003125

CaseHPOFreeRext: diagnosed as hemophilia A with factor VIII level of 3.6%. normal CBC; bleeding time, 2 min; PT, 14.9 sec (11-14 sec); aPTT, 51.2 sec (24-38 sec); and factor VIII, 4.9% (50-150%)

CaseNOTHPOFreeText: No abnormalities were found in the vWF antigen level (71.3%), ristocetin cofactor assay (130.4%), and multimer assay

GenotypingMethod: direct DNA sequencing of the VWF gene

Gene: VWF

Variant: c.2446C>T (p.Arg816Trp)

HGVS: NM_000552.5:c.2446C>T p.(Arg816Trp)

ClinVarID: 295

gnomAD: MAF of 0.0001667 (10/59984) in Admixed American population https://gnomad.broadinstitute.org/variant/12-6036488-G-A?dataset=gnomad_r4