Case: IP #1 in type U VWD sub-cohort

DiseaseAssertion: unclassified VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: VWF:Ag [IU/dL] = 17; VWF:Ac [IU/dL] = 13; FVIII:C [IU/dL] = 49

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.2435del p.Pro812Argfs*31

HGVS:

ClinVarID: 303

CAID:

gnomAD: 0.00007187 (116 in 1613916) no homozygotes https://gnomad.broadinstitute.org/variant/12-6044297-CG-C?dataset=gnomad_r4

MultipleGeneVariants:

Gene: VWF

Variant: c.3797C>T p.Pro1266Leu

ClinVarID: 314

gnomAD: 0.0006678 (1077 in 1612852) 2 homozyogotes https://gnomad.broadinstitute.org/variant/12-6019621-G-A?dataset=gnomad_r4

Case: IP #5 in type 2N VWD sub-cohort

DiseaseAssertion: type 2N VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: VWF:Ag [IU/dL] = 29; VWF:Ac [IU/dL] = 26; FVIII:C [IU/dL] = 10

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.2435del p.Pro812Argfs*31

HGVS:

ClinVarID: 303

CAID:

gnomAD: 0.00007187 (116 in 1613916) no homozygotes https://gnomad.broadinstitute.org/variant/12-6044297-CG-C?dataset=gnomad_r4

MultipleGeneVariants:

Gene: VWF

Variants: c.2561G>A p.Arg854Gln

ClinVarID: 296

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

Case: IP #6 in type 2N VWD sub-cohort

DiseaseAssertion: type 2N VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: VWF:Ag [IU/dL] = 74; VWF:Ac [IU/dL] = 80; FVIII:C [IU/dL] = 40

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.2435del p.Pro812Argfs*31

HGVS:

ClinVarID: 303

CAID:

gnomAD: 0.00007187 (116 of 1613916) no homozygotes https://gnomad.broadinstitute.org/variant/12-6044297-CG-C?dataset=gnomad_r4

MultipleGeneVariants:

Gene: VWF

Variant: c.2561G>A p.Arg854Gln

ClinVarID: 296

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

Case: Row 17 in Supplemental Table 1. Found in 2 patients in the same family.

DiseaseAssertion: type 1 VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: FVIII:C/VWF:Ag = 2.3 (1.7-3.2); VWFpp/VWF:Ag = 3.0 (2.9-3.2)

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Genetic analysis was performed at the laboratory of hematology of the Radboud University Medical Center in Nijmegen. Ion semiconductor sequencing (Ion-Torrent) was used to analyze the VWF gene from peripheral blood obtained in EDTA tubes or from saliva samples. The 52 exons of VWF gene were analyzed including ±20 bp exon-intron boundaries. If no VWF gene variant was detected, multiplex ligation-dependent probe amplification (MLPA) analysis was performed to find large deletions or duplications. Thus, MLPA was performed in 183 patients (46.9%). All variants were confirmed with Sanger sequencing.

PreviouslyPublished:

Gene: VWF

Variant: 2435delC P812R fs*31

HGVS: VWF:c.2435del p.Pro812Argfs*31

ClinVarID: 303

CAID:

gnomAD: 0.00007187 (116 in 1613916) no homozygotes https://gnomad.broadinstitute.org/variant/12-6044297-CG-C?dataset=gnomad_r4

Gene: VWF

HGNCID: 12726

Case: 4 month old female

DiseaseAssertion: VWD type 3

FamilyInfo: both parents were sequenced ParentalGenotype(s): mother is VWF:c.2435delC carrier, father was negative

CasePresentingHPOs: HP:0011889 CaseHPOFreeRext: bleeding from injection site following vaccination administration CaseNOTHPOs: CaseNOTHPOFreeText: normal PT/PTT at 4 months. prolonged PTT, normal PT and platelet count upon repeat. Factor VIII levels <1%, VWF activity <15%

GenotypingMethod: unknown

Gene: VWF

Variant: c.2435delC in VWF gene, deletion in exon 6 of VWF gene

HGVS: NM_000552.5:c.2435del

ClinVarID: 303

gnomAD: 0.00007187 (116/1613916) https://gnomad.broadinstitute.org/variant/12-6044297-CG-C?dataset=gnomad_r4

PMID: unknown

Gene: VWF

HGNCID: 12726

Case: 2 year old female

DiseaseAssertion: type 3 VWD

FamilyInfo: 27 year old parents with no history of abnormal bleeding, non-consanguineous. Older brother (4 years old) with symptoms, younger brother asymptomatic.

ParentalGenotype(s): Mother is heterozygous for c.2345del variant. Father is heterozygous for exon 6 deletion.

CasePresentingHPOs: HP:0001934, HP:0000978, HP:0000225, HP:0001058, HP:0001058, HP:0012147, HP:0030132

CaseHPOFreeRext: reduced VWF activity

CaseNOTHPOs: HP:0001873, HP:0008151

CaseNOTHPOFreeText: reduced factor VIII

CasePreviousTesting: n/a

GenotypingMethod: unknown

PreviouslyPublished: n/a

Gene: VWF

Variant: compound heterozygous c2345delC in exon 18 and deletion in exon 6

HGVS: NM_000552.5:c.2435del p. (Pro812ArgfsTer31)

ClinVarID: 303

CAID:

gnomAD: 0.00007187 (11/1613916 alleles) https://gnomad.broadinstitute.org/variant/12-6044297-CG-C?dataset=gnomad_r4