1,452 Matching Annotations
  1. Last 7 days
    1. 203

      Case#: 203 6.1yrs male, age at initial diagnosis 4.9 yrs DiseaseAssertion: MPS IH-S FamilyInfo:Nil CasePresentingHPOs: CaseHPOFreeText: CaseNotHPOs: CaseNotHPOFreeText: CaseEnzymeAssay: IDUA activity: low leukocyte IDUA enzyme activity CaseUrineGAGs: CaseERT: 1.7 yrs on ERT, then study drug, valanafusp alpha, also called AGT-181 for 12 months

      CaseBMT: No PreviouslyPublished Don't know Variant1:p.R621X Variant1ClinVarID: 11917 Variant1CAID: Variant2:IVS9-12_4delCAGGCCCCG . However the sequence at this location corresponds to "cccgccccg" Variant2ClinVarID: Variant2CAID:

    2. 211

      Case#: 211 2.5 yrs male, age at initial diagnosis 2.4 yrs DiseaseAssertion: MPS IH FamilyInfo:Nil CasePresentingHPOs: CaseHPOFreeText: CaseNotHPOs: CaseNotHPOFreeText: CaseEnzymeAssay: IDUA activity: low leukocyte IDUA enzyme activity CaseUrineGAGs: CaseERT: Nil, study drug, valanafusp alpha, also called AGT-181 for 12 months

      CaseBMT: No PreviouslyPublished Don't know Variant1:p.G208D Variant1ClinVarID: 554590 Variant1CAID: Variant2:p.G208D Variant2ClinVarID: 554590 Variant2CAID:

    1. Case#: Patient D2, Druze religious group, located in lower Galilee.

      DiseaseAssertion: MPS1-H

      FamilyInfo: N/A

      CasePresentingHPOs: N/A

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CaseEnzymeAssay: N/A

      CaseUrineGAGs: N/A

      CaseERT: N/A

      CaseBMT: N/A

      Variant1: c.928C>T (p.Q310X)

      Variant1ClinVarID: 11915

      Variant1CAID: N/A

      Variant2: N/A

      Variant2ClinVarID: N/A

      Variant2CAID: N/A

      AdditionalVariants: N/A

      ParentalGenotype: N/A

      PreviouslyPublished N/A

    2. Case#: Patient D4, Druze religious group, located in lower Galilee.

      DiseaseAssertion: N/A

      FamilyInfo: May have relation with Patient D5 due to being located in the same village. Parents were found to be heterozygous for the mutation.

      CasePresentingHPOs: N/A

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CaseEnzymeAssay: N/A

      CaseUrineGAGs: N/A

      CaseERT: N/A

      CaseBMT: N/A

      Variant1: c.1096A>C (p.T366P)

      Variant1ClinVarID: 11916

      Variant1CAID: CA:256117

      Variant2: N/A

      Variant2ClinVarID: N/A

      Variant2CAID: N/A

      AdditionalVariants: N/A

      ParentalGenotype: N/A

      PreviouslyPublished N/A

    3. Case#: Patient D5, Druze religious group, located in lower Galilee.

      DiseaseAssertion: N/A

      FamilyInfo: May have relation with Patient D5 due to being located in the same village. Parents were found to be heterozygous for the mutation.

      CasePresentingHPOs: N/A

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CaseEnzymeAssay: N/A

      CaseUrineGAGs: N/A

      CaseERT: N/A

      CaseBMT: N/A

      Variant1: c.1096A>C (p.T366P)

      Variant1ClinVarID: 11916

      Variant1CAID: CA:256117

      Variant2: N/A

      Variant2ClinVarID: N/A

      Variant2CAID: N/A

      AdditionalVariants: N/A

      ParentalGenotype: N/A

      PreviouslyPublished N/A

    4. Case#: Patient M2, Muslim religious group, located in lower Galilee.

      DiseaseAssertion: MPS1-H

      FamilyInfo: Parents of M2 were found to be heterozygous for this mutation.

      CasePresentingHPOs: N/A

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CaseEnzymeAssay: N/A

      CaseUrineGAGs: N/A

      CaseERT: N/A

      CaseBMT: N/A

      Variant1: c.1096A>C (p.T366P)

      Variant1ClinVarID: 11916

      Variant1CAID: CA:256117

      Variant2: N/A

      Variant2ClinVarID: N/A

      Variant2CAID: N/A

      AdditionalVariants: N/A

      ParentalGenotype: N/A

      PreviouslyPublished N/A

    1. In family B

      Case#: Patient 2 of family B: Female DiseaseAssertion:MPS1 FamilyInfo:Consanguinity Yes CasePresentingHPOs: NA CaseHPOFreeText: CaseNotHPOs: CaseNotHPOFreeText: CaseEnzymeAssay: enzyme values lower than the cut-off values CaseUrineGAGs: NA CaseERT: NA CaseBMT:Nil Variant1:c.1469T>C ,Leu490Pro Variant1ClinVar ID: 11919 Variant1CAID: Variant2:c.1469T>C ,Leu490Pro Variant2ClinVarID:11919 Variant2CAID: AdditionalVariants:Nil ParentalGenotype:NA PreviouslyPublishedNA

    1. three siblings

      Case#: Eldest child, female, age at diagnosis and onset are unknown, age at treatment is 6, age at report is 11 DiseaseAssertion: MPS1 FamilyInfo: All 3 cases are siblings CasePresentingHPOs: HP:0000280, HP:0008800, HP:0010501, HP:0006467, HP:0001659, HP:0001653, HP:0001634 (Coarse facial features, Limited hip movement, Limited shoulder movement, Limitation of knee mobility, Aortic regurgitation, Mitral regurgitation, Mitral valve prolapse) CaseHPOFreeText: Corneal clouding CaseNotHPOs: N/A CaseNotHPOFreeText: N/A CaseEnzymeAssay: N/A CaseUrineGAGs: N/A CaseERT: Yes CaseBMT: Don't know Variant1: p.Leu490Pro Variant1ClinVarID: 11919 Variant1CAID: Variant2: p.Leu490Pro Variant2ClinVarID: 11919 Variant2CAID: AdditionalVariants: N/A ParentalGenotype: N/A PreviouslyPublished N/A

    2. three siblings

      Case#: Youngest child, Female, age at diagnosis and onset are unknown, age at treatment is 4 months, age at report is 5 years, 4 months DiseaseAssertion: MPS1 FamilyInfo: All 3 cases are siblings CasePresentingHPOs: N/A CaseHPOFreeText: Mild corneal clouding, this study is to examine the efficacy of enzyme replacement therapy at different stages of teh disease, and it is assumed this patient is not yet old enough to have develped symptoms CaseNotHPOs: N/A CaseNotHPOFreeText: N/A CaseEnzymeAssay: N/A CaseUrineGAGs: N/A CaseERT: Yes CaseBMT: Don't know Variant1: p.Leu490Pro Variant1ClinVarID: 11919 Variant1CAID: Variant2: p.Leu490Pro Variant2ClinVarID: 11919 Variant2CAID: AdditionalVariants: N/A ParentalGenotype: N/A PreviouslyPublished N/A

    3. three siblings

      Case#: Middle child, Male, age at diagnosis and onset are unknown, age at treatment is 2.5 years, age at report is 7.5 years DiseaseAssertion: MPS1 FamilyInfo: All 3 cases are siblings CasePresentingHPOs: HP:0001634, HP:0001653 (mitral valve prolapse, mitral regurgitation) CaseHPOFreeText: Mild corneal clouding CaseNotHPOs: N/A CaseNotHPOFreeText: N/A CaseEnzymeAssay: N/A CaseUrineGAGs: N/A CaseERT: Yes CaseBMT: Don't know Variant1: p.Leu490Pro Variant1ClinVarID: 11919 Variant1CAID: Variant2: p.Leu490Pro Variant2ClinVarID: 11919 Variant2CAID: AdditionalVariants: N/A ParentalGenotype: N/A PreviouslyPublished N/A

    1. 6–8 U (2A/1) c.3437A > G p.Tyr1146Cys 26 D3-TIL3 htz Missense A/na/na 17/17/17 17/35/26 22/35/71

      Case: IP #8 in type U VWD sub-cohort

      DiseaseAssertion: unclassified (2A/1) VWD

      FamilyInfo:

      ParentalGenotype(s):

      CasePresentingHPOs:

      CaseHPOFreeRext: VWF:Ag [IU/dL] = 17; VWF:Ac [IU/dL] = 26; FVIII:C [IU/dL] = 71

      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.3437A>G p.Tyr1146Cys

      HGVS:

      ClinVarID: 31009

      CAID:

      gnomAD: 0.000001840 (1 in 543518) no homozygotes https://gnomad.broadinstitute.org/variant/12-6022841-T-C?dataset=gnomad_r4

    2. 59-62Type2A(IIA)c.4883T>C p.Ile1628Thr 28 A2 htz Missense na/A/O/na28.7/38/17/555/7/5/932/37CSA/20CSA/87

      Case: IP #62

      DiseaseAssertion: type 2A (IIA) VWD

      FamilyInfo:

      ParentalGenotype(s):

      CasePresentingHPOs:

      CaseHPOFreeRext: VWF:Ag [IU/dL] = 55; VWF:Ac [IU/dL] = 9; FVIII:C [IU/dL] = 87

      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.4883T>C p.Ile1628Thr

      HGVS:

      ClinVarID: 284

      CAID:

      gnomAD: 0.000001859 (3 in 1613848) no homozygotes https://gnomad.broadinstitute.org/variant/12-6018535-A-G?dataset=gnomad_r4

    3. 13–21 U (2A/2M/1C) c.3943C > T p.Arg1315Cys C 28 A1 htz Missense A/O/A/na/AB/A/O/A/A12/20/20/40/12/17/13/10 /147/13 RCo /15/10/6/14/8/6/426 CSA /39/28 OSCA /na

      Case: IP #16 in type U VWD sub-cohort

      DiseaseAssertion: unclassified (2A/2M/1C) VWD

      FamilyInfo:

      ParentalGenotype(s):

      CasePresentingHPOs:

      CaseHPOFreeRext: VWF:Ag [IU/dL] = 40; VWF:Ac [IU/dL] = 10; FVIII:C [IU/dL] = n/a

      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.3943C>T p.Arg1315Cys

      HGVS:

      ClinVarID: 100310

      CAID:

      gnomAD: 6.196e-7 (1 in 1613892) no homozygotes https://gnomad.broadinstitute.org/variant/12-6019475-G-A?dataset=gnomad_r4

    4. 9 c.3917G > T p.Arg1306Leu 28 A1 htz Missense A 85 56 30

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

      DiseaseAssertion: type 2B VWD

      FamilyInfo:

      ParentalGenotype(s):

      CasePresentingHPOs: HP:0032370 - blood group A

      CaseHPOFreeRext: VWF:Ag [IU/dL] = 85; VWF:Ac [IU/dL] = 56; FVIII:C [IU/dL] = 30

      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.3917G>T p.Arg1306Leu

      HGVS:

      ClinVarID: 100301

      CAID:

      gnomAD: 6.196e-7 (1 in 1613956) no homozygotes https://gnomad.broadinstitute.org/variant/12-6019501-C-A?dataset=gnomad_r4

    5. 23 c.4022G > A p.Arg1341Gln 28 A1 htz Missense A/O 42/32 17/15 51 CSA /55

      Case: IP #23 in type 2B VWD sub-cohort

      DiseaseAssertion: type 2B VWD

      FamilyInfo:

      ParentalGenotype(s):

      CasePresentingHPOs: HP:0032442 - blood group O

      CaseHPOFreeRext: VWF:Ag [IU/dL] = 32; VWF:Ac [IU/dL] = 15; FVIII:C [IU/dL] = 55

      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.4022G>A p.Arg1341Gln

      HGVS:

      ClinVarID: 291

      CAID:

      gnomAD: 0.000001239 (2 in 1613944) no homozygotes https://gnomad.broadinstitute.org/variant/12-6019396-C-T?dataset=gnomad_r4

    6. 1 c.3845T > C p.Leu1282Pro 28 A1 htz Missense na 30 na na na

      Case: IP #1 in type 2M VWD sub-cohort

      DiseaseAssertion: type 2M VWD

      FamilyInfo:

      ParentalGenotype(s):

      CasePresentingHPOs:

      CaseHPOFreeRext: VWF:Ag [IU/dL] = 30; VWF:Ac [IU/dL] = n/a; FVIII:C [IU/dL] = n/a; VWF:CB (IU/dL) = n/a

      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.3845T>C p.Leu1282Pro

      HGVS:

      ClinVarID: 100329

      CAID:

      gnomAD: absent

    7. 15 c.3923G > C p.Arg1308Pro 28 A1 htz Missense B 26 5 25.0

      Case: IP #15 in type 2B VWD sub-cohort

      DiseaseAssertion: type 2B VWD

      FamilyInfo:

      ParentalGenotype(s):

      CasePresentingHPOs: HP:0032440 - blood group B

      CaseHPOFreeRext: VWF:Ag [IU/dL] = 26; VWF:Ac [IU/dL] = 5; FVIII:C [IU/dL] = 25.0

      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.3923G>A p.Arg1308Pro

      HGVS:

      ClinVarID: 100303

      CAID:

      gnomAD: absent

    8. 14–21 Heterozygous2Nc.2561G > A p.Arg854Gln 20 D’-E’ htz Missense O/O/na/na /A/A/O/B55/67/93/46/151/45/49 /2230 Rco / 78 GPIbR /48/64/121/42/41/2656 OSCA /88/76/na

      Case: IP #17 in type 2N VWD sub-cohort

      DiseaseAssertion: type 2N VWD

      FamilyInfo:

      ParentalGenotype(s):

      CasePresentingHPOs:

      CaseHPOFreeRext: VWF:Ag [IU/dL] = 46; VWF:Ac [IU/dL] = 64; FVIII:C [IU/dL] = n/a

      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

    9. 16–21 c.3946G > A p.Val1316Met C 28 A1 htz Missense B/O/A/na/A/na63/62/25/58/48/3610/22 RCo /6/22/11/982 CSA /37/26/54

      Case: IP #19 in type 2B VWD sub-cohort

      DiseaseAssertion: type 2B VWD

      FamilyInfo:

      ParentalGenotype(s):

      CasePresentingHPOs:

      CaseHPOFreeRext: VWF:Ag [IU/dL] = 58; VWF:Ac [IU/dL] = 22; FVIII:C [IU/dL] = 54

      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.3946G>A p.Val1316Met

      HGVS:

      ClinVarID: 290

      CAID:

      gnomAD: absent

    10. 8–10 2N c.2446C > Tc.2561G > Ap.Arg816Trpp.Arg854Gln1920D’-TIL’D’-E’htzhtzMissenseMissenseA/A/na 61/93/50 59/107/55 25 CSA /18

      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

    11. 43-49Type2A(IIA)c.4789C>T p.Arg1597Trp 28 A2 htz Missense A/na/A/O/B/na/O22/30/26/64/24/16/5613/11RCo/9/16/6/6/1529

      Case: IP #43

      DiseaseAssertion: type 2A (IIA) VWD

      FamilyInfo:

      ParentalGenotype(s):

      CasePresentingHPOs: HP:0032370 - blood group A

      CaseHPOFreeRext: VWF:Ag [IU/dL] = 22; VWF:Ac [IU/dL] = 13; FVIII:C [IU/dL] = 29

      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.4789C>T p.Arg1597Trp

      HGVS:

      ClinVarID: 285

      CAID:

      gnomAD: 6.196e-7 (1 in 1614028) no homozygotes https://gnomad.broadinstitute.org/variant/12-6018629-G-A?dataset=gnomad_r4

    12. 43-49Type2A(IIA)c.4789C>T p.Arg1597Trp 28 A2 htz Missense A/na/A/O/B/na/O22/30/26/64/24/16/5613/11RCo/9/16/6/6/1529/47/30CSA/66

      Case: IP #46

      DiseaseAssertion: type 2A (IIA) VWD

      FamilyInfo:

      ParentalGenotype(s):

      CasePresentingHPOs: HP:0032442 - blood group O

      CaseHPOFreeRext: VWF:Ag [IU/dL] = 64; VWF:Ac [IU/dL] = 16; FVIII:C [IU/dL] = 66

      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.4789C>T p.Arg1597Trp

      HGVS:

      ClinVarID: 285

      CAID:

      gnomAD: 6.196e-7 (1 in 1614028) no homozygotes https://gnomad.broadinstitute.org/variant/12-6018629-G-A?dataset=gnomad_r4

    13. 6–8 U (2A/1) c.3437A > G p.Tyr1146Cys 26 D3-TIL3 htz Missense A/na/na 17/17/17 17/35/26 22/35

      Case: IP #7 in type U VWD sub-cohort

      DiseaseAssertion: unclassified (2A/1) VWD

      FamilyInfo:

      ParentalGenotype(s):

      CasePresentingHPOs:

      CaseHPOFreeRext: VWF:Ag [IU/dL] = 17; VWF:Ac [IU/dL] = 35; FVIII:C [IU/dL] = 35

      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.3437A>G p.Tyr1146Cys

      HGVS:

      ClinVarID: 31009

      CAID:

      gnomAD: 0.000001840 (1 in 543518) no homozygotes https://gnomad.broadinstitute.org/variant/12-6022841-T-C?dataset=gnomad_r4

    14. 21 U (2A/2M/1C) c.3943C > T p.Arg1315Cys C 28 A1 htz Missense A/O/A/na/AB/A/O/A/A12/20/20/40/12/17/13/10 /147/13 RCo /15/10/6/14/8/6/426 CSA /39/28 OSCA /na /26 CSA /26 CSA /22 CSA /12 CSA /31

      Case: IP #21 in type U VWD sub-cohort

      DiseaseAssertion: unclassified (2A/2M/1C) VWD

      FamilyInfo:

      ParentalGenotype(s):

      CasePresentingHPOs: HP:0032370 - blood group A

      CaseHPOFreeRext: VWF:Ag [IU/dL] = 14; VWF:Ac [IU/dL] = 4; FVIII:C [IU/dL] = 31

      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.3943C>T p.Arg1315Cys

      HGVS:

      ClinVarID: 100310

      CAID:

      gnomAD: 6.196e-7 (1 in 1613892) no homozygotes https://gnomad.broadinstitute.org/variant/12-6019475-G-A?dataset=gnomad_r4

    15. 11–13 2N c.2561G > A p.Arg854Gln 20 D’-E’ hmz Missense O/O/na 74/59/55 79/59/45 18/16

      Case: IP #12 in type 2N VWD sub-cohort

      DiseaseAssertion: type 2N VWD

      FamilyInfo:

      ParentalGenotype(s):

      CasePresentingHPOs: HP:0032442 - blood group O

      CaseHPOFreeRext: VWF:Ag [IU/dL] = 59; VWF:Ac [IU/dL] = 59; 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

    16. 59-62Type2A(IIA)c.4883T>C p.Ile1628Thr 28 A2 htz Missense na/A/O/na28.7/38/17/555/7/5/932/37CSA/20

      Case: IP #61

      DiseaseAssertion: type 2A (IIA) VWD

      FamilyInfo:

      ParentalGenotype(s):

      CasePresentingHPOs: HP:0032442 - blood group O

      CaseHPOFreeRext: VWF:Ag [IU/dL] = 17; VWF:Ac [IU/dL] = 5; FVIII:C [IU/dL] = 20

      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.4883T>C p.Ile1628Thr

      HGVS:

      ClinVarID: 284

      CAID:

      gnomAD: 0.000001859 (3 in 1613848) no homozygotes https://gnomad.broadinstitute.org/variant/12-6018535-A-G?dataset=gnomad_r4

    17. 13–21 U (2A/2M/1C) c.3943C > T p.Arg1315Cys C 28 A1 htz Missense A/O/A/na/AB/A/O/A/A12/20/20/40/12/17/13/10 /147/13 RCo /15/10/6/14/8/6/426 CSA /39/28

      Case: IP #15 in type U VWD sub-cohort

      DiseaseAssertion: unclassified (2A/2M/1C) VWD

      FamilyInfo:

      ParentalGenotype(s):

      CasePresentingHPOs: HP:0032370 - blood group A

      CaseHPOFreeRext: VWF:Ag [IU/dL] = 20; VWF:Ac [IU/dL] = 15; FVIII:C [IU/dL] = 28

      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.3943C>T p.Arg1315Cys

      HGVS:

      ClinVarID: 100310

      CAID:

      gnomAD: 6.196e-7 (1 in 1613892) no homozygotes https://gnomad.broadinstitute.org/variant/12-6019475-G-A?dataset=gnomad_r4

    18. 2–8 c.3916C > T p.Arg1306Trp C 28 A1 htz Missense A/na/O/B/O/O/A21/37/48/44/22/22/2713 RCo /na/33/25

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

      DiseaseAssertion: type 2B VWD

      FamilyInfo:

      ParentalGenotype(s):

      CasePresentingHPOs: HP:0032440 - blood group B

      CaseHPOFreeRext: VWF:Ag [IU/dL] = 44; VWF:Ac [IU/dL] = 25; FVIII:C [IU/dL] = 135

      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.3916C>T p.Arg1306Trp

      HGVS:

      ClinVarID: 288

      CAID:

      gnomAD: absent

    19. 22, 23 c.4022G > A p.Arg1341Gln 28 A1 htz Missense A/O 42/32 17/15 51

      Case: IP #22 in type 2B VWD sub-cohort

      DiseaseAssertion: type 2B VWD

      FamilyInfo:

      ParentalGenotype(s):

      CasePresentingHPOs: HP:0032370 - blood group A

      CaseHPOFreeRext: VWF:Ag [IU/dL] = 42; VWF:Ac [IU/dL] = 17; FVIII:C [IU/dL] = 51

      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.4022G>A p.Arg1341Gln

      HGVS:

      ClinVarID: 291

      CAID:

      gnomAD: 0.000001239 (2 in 1613944) no homozygotes https://gnomad.broadinstitute.org/variant/12-6019396-C-T?dataset=gnomad_r4

    20. 14–21 Heterozygous2Nc.2561G > A p.Arg854Gln 20 D’-E’ htz Missense O/O/na/na /A/A/O/B55/67/93/46/151/45/49 /2230 Rco / 78 GPIbR /48/64/121/42/41/2656 OSCA /88/76

      Case: IP #16 in type 2N VWD sub-cohort

      DiseaseAssertion: type 2N VWD

      FamilyInfo:

      ParentalGenotype(s):

      CasePresentingHPOs:

      CaseHPOFreeRext: VWF:Ag [IU/dL] = 93; VWF:Ac [IU/dL] = 48; FVIII:C [IU/dL] = 76

      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

    21. 16–21 c.3946G > A p.Val1316Met C 28 A1 htz Missense B/O/A/na/A/na63/62/25/58/48/3610/22 RCo /6/22/11/982 CSA /37/26

      Case: IP #18 in type 2B VWD sub-cohort

      DiseaseAssertion: type 2B VWD

      FamilyInfo:

      ParentalGenotype(s):

      CasePresentingHPOs: HP:0032370 - blood group A

      CaseHPOFreeRext: VWF:Ag [IU/dL] = 25; VWF:Ac [IU/dL] = 6; FVIII:C [IU/dL] = 26

      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.3946G>A p.Val1316Met

      HGVS:

      ClinVarID: 290

      CAID:

      gnomAD: absent

    22. 2–8 c.3916C > T p.Arg1306Trp C 28 A1 htz Missense A/na/O/B/O/O/A21/37/48/44/22/22/2713 RCo /na/33/25/5/6/837

      Case: IP #2 in type 2B VWD sub-cohort

      DiseaseAssertion: type 2B VWD

      FamilyInfo:

      ParentalGenotype(s):

      CasePresentingHPOs: HP:0032370 - blood group A

      CaseHPOFreeRext: VWF:Ag [IU/dL] = 21; VWF:Ac [IU/dL] = 13; FVIII:C [IU/dL] = 37

      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.3916C>T p.Arg1306Trp

      HGVS:

      ClinVarID: 288

      CAID:

      gnomAD: absent

    23. 14–21 Heterozygous2Nc.2561G > A p.Arg854Gln 20 D’-E’ htz Missense O/O/na/na /A/A/O/B55/67/93/46/151/45/49 /2230 Rco / 78 GPIbR /48/64/121/42/41/2656 OSCA /88/76/na/53 CSA /11 CSA /23 CSA /53

      Case: IP #21 in type 2N VWD sub-cohort

      DiseaseAssertion: type 2N VWD

      FamilyInfo:

      ParentalGenotype(s):

      CasePresentingHPOs: HP:0032440 - blood group B

      CaseHPOFreeRext: VWF:Ag [IU/dL] = 22; VWF:Ac [IU/dL] = 26; FVIII:C [IU/dL] = 53

      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

    24. 13–21 U (2A/2M/1C) c.3943C > T p.Arg1315Cys C 28 A1 htz Missense A/O/A/na/AB/A/O/A/A12/20/20/40/12/17/13/10 /147/13 RCo /15/10/6/14/8/6/426 CSA /39/28 OSCA /na /26 CSA /26 CSA /22 CSA /12

      Case: IP #20 in type U VWD sub-cohort

      DiseaseAssertion: unclassified (2A/2M/1C) VWD

      FamilyInfo:

      ParentalGenotype(s):

      CasePresentingHPOs: HP:0032370 - blood group A

      CaseHPOFreeRext: VWF:Ag [IU/dL] = 10; VWF:Ac [IU/dL] = 6; 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.3943C>T p.Arg1315Cys

      HGVS:

      ClinVarID: 100310

      CAID:

      gnomAD: 6.196e-7 (1 in 1613892) no homozygotes https://gnomad.broadinstitute.org/variant/12-6019475-G-A?dataset=gnomad_r4

    25. 6–8 U (2A/1) c.3437A > G p.Tyr1146Cys 26 D3-TIL3 htz Missense A/na/na 17/17/17 17/35/26 22

      Case: IP #6 in type U VWD sub-cohort

      DiseaseAssertion: unclassified (2A/1) VWD

      FamilyInfo:

      ParentalGenotype(s):

      CasePresentingHPOs: HP:0032370 - blood group A

      CaseHPOFreeRext: VWF:Ag [IU/dL] = 17; VWF:Ac [IU/dL] = 17; FVIII:C [IU/dL] = 22

      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.3437A>G p.Tyr1146Cys

      HGVS:

      ClinVarID: 31009

      CAID:

      gnomAD: 0.000001840 (1 in 543518) no homozygotes https://gnomad.broadinstitute.org/variant/12-6022841-T-C?dataset=gnomad_r4

    26. 8–10 2N c.2446C > Tc.2561G > Ap.Arg816Trpp.Arg854Gln1920D’-TIL’D’-E’htzhtzMissenseMissenseA/A/na 61/93/50 59/107/55 25

      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

    27. 36 Type2A(IIA)c.4541T>G p.Phe1514Cys 28 A2 htz Missense O 40 16 51

      Case: IP #36

      DiseaseAssertion: type 2A (IIA) VWD

      FamilyInfo:

      ParentalGenotype(s):

      CasePresentingHPOs: HP:0032442 - blood group O

      CaseHPOFreeRext: VWF:Ag [IU/dL] = 40; VWF:Ac [IU/dL] = 16; FVIII:C [IU/dL] = 51

      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.4541T>G p.Phe1514Cys

      HGVS:

      ClinVarID: 304

      CAID:

      gnomAD: absent

    28. 18-20Type2A (IIE)c.3437A>G p.Tyr1146Cys 26 D3-TIL-3htz Missense na/A/A19.3/12/299/5/18 30

      Case: IP #18

      DiseaseAssertion: type 2A (IIE) VWD

      FamilyInfo:

      ParentalGenotype(s):

      CasePresentingHPOs:

      CaseHPOFreeRext: VWF:Ag [IU/dL] = 19.3; VWF:Ac [IU/dL] = 9; FVIII:C [IU/dL] = 30

      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.3437A>G p.Tyr1146Cys

      HGVS:

      ClinVarID: 31009

      CAID:

      gnomAD: 0.000001840 (1 in 543518) no homozygotes https://gnomad.broadinstitute.org/variant/12-6022841-T-C?dataset=gnomad_r4

    29. 11–13 2N c.2561G > A p.Arg854Gln 20 D’-E’ hmz Missense O/O/na 74/59/55 79/59/45 18

      Case: IP #11 in type 2N VWD sub-cohort

      DiseaseAssertion: type 2N VWD

      FamilyInfo:

      ParentalGenotype(s):

      CasePresentingHPOs: HP:0032442 - blood group O

      CaseHPOFreeRext: VWF:Ag [IU/dL] = 74; VWF:Ac [IU/dL] = 79; 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.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

    30. 1 U c.2435delc.3797C > Tp.Pro812Argfs31p.Pro1266Leu C1828D’TIL’D3-E3htzhtzSmall Del.Missensena 17 13 GPIbR 49

      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

    31. 43-49Type2A(IIA)c.4789C>T p.Arg1597Trp 28 A2 htz Missense A/na/A/O/B/na/O22/30/26/64/24/16/5613/11RCo/9/16/6/6/1529/47/30CSA/66CSA/32CSA/20CSA/47

      Case: IP #49

      DiseaseAssertion: type 2A (IIA) VWD

      FamilyInfo:

      ParentalGenotype(s):

      CasePresentingHPOs: HP:0032442 - blood group O

      CaseHPOFreeRext: VWF:Ag [IU/dL] = 56; VWF:Ac [IU/dL] = 15; FVIII:C [IU/dL] = 47

      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.4789C>T p.Arg1597Trp

      HGVS:

      ClinVarID: 285

      CAID:

      gnomAD: 6.196e-7 (1 in 1614028) no homozygotes https://gnomad.broadinstitute.org/variant/12-6018629-G-A?dataset=gnomad_r4

    32. 13–21 U (2A/2M/1C) c.3943C > T p.Arg1315Cys C 28 A1 htz Missense A/O/A/na/AB/A/O/A/A12/20/20/40/12/17/13/10 /147/13 RCo /15/10/6/14/8/6/426 CSA /39

      Case: IP #14 in type U VWD sub-cohort

      DiseaseAssertion: unclassified (2A/2M/1C) VWD

      FamilyInfo:

      ParentalGenotype(s):

      CasePresentingHPOs: HP:0032442 - blood group O

      CaseHPOFreeRext: VWF:Ag [IU/dL] = 20; VWF:Ac [IU/dL] = 13; FVIII:C [IU/dL] = 39

      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.3943C>T p.Arg1315Cys

      HGVS:

      ClinVarID: 100310

      CAID:

      gnomAD: 6.196e-7 (1 in 1613892) no homozygotes https://gnomad.broadinstitute.org/variant/12-6019475-G-A?dataset=gnomad_r4

    33. 43-49Type2A(IIA)c.4789C>T p.Arg1597Trp 28 A2 htz Missense A/na/A/O/B/na/O22/30/26/64/24/16/5613/11RCo/9/16/6/6/1529/47/30

      Case: IP #45

      DiseaseAssertion: type 2A (IIA) VWD

      FamilyInfo:

      ParentalGenotype(s):

      CasePresentingHPOs: HP:0032370 - blood group A

      CaseHPOFreeRext: VWF:Ag [IU/dL] = 26; VWF:Ac [IU/dL] = 9; FVIII:C [IU/dL] = 30

      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.4789C>T p.Arg1597Trp

      HGVS:

      ClinVarID: 285

      CAID:

      gnomAD: 6.196e-7 (1 in 1614028) no homozygotes https://gnomad.broadinstitute.org/variant/12-6018629-G-A?dataset=gnomad_r4

    34. 13–21 U (2A/2M/1C) c.3943C > T p.Arg1315Cys C 28 A1 htz Missense A/O/A/na/AB/A/O/A/A12/20/20/40/12/17/13/10 /147/13 RCo /15/10/6/14/8/6/426 CSA /39/28 OSCA /na /26

      Case: IP #17 in type U VWD sub-cohort

      DiseaseAssertion: unclassified (2A/2M/1C) VWD

      FamilyInfo:

      ParentalGenotype(s):

      CasePresentingHPOs: HP:0032441 - blood group AB

      CaseHPOFreeRext: VWF:Ag [IU/dL] = 12; VWF:Ac [IU/dL] = 6; FVIII:C [IU/dL] = 26

      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.3943C>T p.Arg1315Cys

      HGVS:

      ClinVarID: 100310

      CAID:

      gnomAD: 6.196e-7 (1 in 1613892) no homozygotes https://gnomad.broadinstitute.org/variant/12-6019475-G-A?dataset=gnomad_r4

    35. 13–21 U (2A/2M/1C) c.3943C > T p.Arg1315Cys C 28 A1 htz Missense A/O/A/na/AB/A/O/A/A12/20/20/40/12/17/13/10 /147/13 RCo /15/10/6/14/8/6/426 CSA /39/28 OSCA /na /26 CSA /26 CSA /22

      Case: IP #19 in type U VWD sub-cohort

      DiseaseAssertion: unclassified (2A/2M/1C) VWD

      FamilyInfo:

      ParentalGenotype(s):

      CasePresentingHPOs: HP:0032442 - blood group O

      CaseHPOFreeRext: VWF:Ag [IU/dL] = 13; VWF:Ac [IU/dL] = 8; FVIII:C [IU/dL] = 22

      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.3943C>T p.Arg1315Cys

      HGVS:

      ClinVarID: 100310

      CAID:

      gnomAD: 6.196e-7 (1 in 1613892) no homozygotes https://gnomad.broadinstitute.org/variant/12-6019475-G-A?dataset=gnomad_r4

    36. 18-20Type2A (IIE)c.3437A>G p.Tyr1146Cys 26 D3-TIL-3htz Missense na/A/A19.3/12/299/5/18 30/24CSA/na

      Case: IP #20

      DiseaseAssertion: type 2A (IIE) VWD

      FamilyInfo:

      ParentalGenotype(s):

      CasePresentingHPOs: HP:0032370 - blood group A

      CaseHPOFreeRext: VWF:Ag [IU/dL] = 29; VWF:Ac [IU/dL] = 18; FVIII:C [IU/dL] = n/a

      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.3437A>G

      HGVS:

      ClinVarID: 31009

      CAID:

      gnomAD: 0.000001840 (1 in 543518) no homozygotes https://gnomad.broadinstitute.org/variant/12-6022841-T-C?dataset=gnomad_r4

    37. 14–21 Heterozygous2Nc.2561G > A p.Arg854Gln 20 D’-E’ htz Missense O/O/na/na /A/A/O/B55/67/93/46/151/45/49 /2230 Rco / 78 GPIbR /48/64/121/42/41/2656 OSCA /88/76/na/53

      Case: IP #18 in type 2N VWD sub-cohort

      DiseaseAssertion: type 2N VWD

      FamilyInfo:

      ParentalGenotype(s):

      CasePresentingHPOs: HP:0032370 - blood group A

      CaseHPOFreeRext: VWF:Ag [IU/dL] = 151; VWF:Ac [IU/dL] = 121; FVIII:C [IU/dL] = 53

      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

    38. 12–14 c.3922C > T p.Arg1308Cys C 28 A1 htz Missense na /AB/A 42/30/14 15 RCo /6/10 48/41 CSA /26

      Case: IP #14 in type 2B VWD sub-cohort

      DiseaseAssertion: type 2B VWD

      FamilyInfo:

      ParentalGenotype(s):

      CasePresentingHPOs: HP:0032370 - blood group A

      CaseHPOFreeRext: VWF:Ag [IU/dL] = 14; VWF:Ac [IU/dL] = 10; FVIII:C [IU/dL] = 26

      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.3922C>T p.Arg1308Cys

      HGVS:

      ClinVarID: 289

      CAID:

      gnomAD: absent

    39. 5, 6 2N/1 c.2435delc.2561G > Ap.Pro812Argfs31p.Arg854Gln1820D’-TIL’D’-E’htzhtzSmall Del.Missensena/na 29/74 26/80 10

      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

    40. 9 U c.3437A > Gc.3539–10T > G Np.Tyr1146Cys-2625D3-TIL-3D3-TIL-3htzhtzMissenseSplice SiteO 12 10 21

      Case: IP #9 in type U VWD sub-cohort

      DiseaseAssertion: unclassified VWD

      FamilyInfo:

      ParentalGenotype(s):

      CasePresentingHPOs: HP:0032442 - blood group O

      CaseHPOFreeRext: VWF:Ag [IU/dL] = 12; VWF:Ac [IU/dL] = 10; 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.3437A>G p.Tyr1146Cys

      HGVS:

      ClinVarID: 31009

      CAID:

      gnomAD: 0.000001840 (1 in 543518) no homozygotes https://gnomad.broadinstitute.org/variant/12-6022841-T-C?dataset=gnomad_r4

      MultipleGeneVariants:

      Gene: VWF

      Variant: c.3539–10T>G

      ClinVarID: not found

      **gnomAD: absent

    41. 14–21 Heterozygous2Nc.2561G > A p.Arg854Gln 20 D’-E’ htz Missense O/O/na/na /A/A/O/B55/67/93/46/151/45/49 /2230 Rco / 78 GPIbR /48/64/121/42/41/2656 OSCA /88

      Case: IP #15 in type 2N VWD sub-cohort

      DiseaseAssertion: type 2N VWD

      FamilyInfo:

      ParentalGenotype(s):

      CasePresentingHPOs: HP:0032442 - blood group O

      CaseHPOFreeRext: VWF:Ag [IU/dL] = 67; VWF:Ac [IU/dL] = 78; FVIII:C [IU/dL] = 88

      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

    42. 59-62Type2A(IIA)c.4883T>C p.Ile1628Thr 28 A2 htz Missense na/A/O/na28.7/38/17/555/7/5/932/37

      Case: IP #60

      DiseaseAssertion: type 2A (IIA) VWD

      FamilyInfo:

      ParentalGenotype(s):

      CasePresentingHPOs: HP:0032370 - blood group A

      CaseHPOFreeRext: VWF:Ag [IU/dL] = 38; VWF:Ac [IU/dL] = 7; FVIII:C [IU/dL] = 37

      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.4883T>C p.Ile1628Thr

      HGVS:

      ClinVarID: 284

      CAID:

      gnomAD: 0.000001859 (3 in 1613848) no homozygotes https://gnomad.broadinstitute.org/variant/12-6018535-A-G?dataset=gnomad_r4

    43. 23 2N/1 c.2561G > Ac.4751A > Gp.Arg854Glnp.Tyr1584Cys2028D’-E’A2htzhtzMissenseMissenseA 40 54 GPIbR 50

      Case: IP #23 in type 2N VWD sub-cohort

      DiseaseAssertion: type 2N/1 VWD

      FamilyInfo:

      ParentalGenotype(s):

      CasePresentingHPOs: HP:0032370 - blood group A

      CaseHPOFreeRext: VWF:Ag [IU/dL] = 40; VWF:Ac [IU/dL] = 54; FVIII:C [IU/dL] = 50

      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.4751A>G p.Tyr1584Cys

      ClinVarID: 310

      gnomAD: 0.003442 (5555 in 1613678) 15 homozygotes https://gnomad.broadinstitute.org/variant/12-6018667-T-C?dataset=gnomad_r4

    44. 14–21 Heterozygous2Nc.2561G > A p.Arg854Gln 20 D’-E’ htz Missense O/O/na/na /A/A/O/B55/67/93/46/151/45/49 /2230 Rco / 78 GPIbR /48/64/121/42/41/2656 OSCA /88/76/na/53 CSA /11 CSA /23

      Case: IP #20 in type 2N VWD sub-cohort

      DiseaseAssertion: type 2N VWD

      FamilyInfo:

      ParentalGenotype(s):

      CasePresentingHPOs: HP:0032442 - blood group O

      CaseHPOFreeRext: VWF:Ag [IU/dL] = 49; VWF:Ac [IU/dL] = 41; FVIII:C [IU/dL] = 23

      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

    45. 16–21 c.3946G > A p.Val1316Met C 28 A1 htz Missense B/O/A/na/A/na63/62/25/58/48/3610/22 RCo /6/22/11/982 CSA /37

      Case: IP #17 in type 2B VWD sub-cohort

      DiseaseAssertion: type 2B VWD

      FamilyInfo:

      ParentalGenotype(s):

      CasePresentingHPOs: HP:0032442 - blood group O

      CaseHPOFreeRext: VWF:Ag [IU/dL] = 62; VWF:Ac [IU/dL] = 22; FVIII:C [IU/dL] = 37

      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.3946G>A p.Val1316Met

      HGVS:

      ClinVarID: 290

      CAID:

      gnomAD: absent

    46. 3 c.4001G > A p.Arg1334Gln 28 A1 htz Missense 41na44 na na na

      Case: IP #3 in type 2M VWD sub-cohort

      DiseaseAssertion: type 2M VWD

      FamilyInfo:

      ParentalGenotype(s):

      CasePresentingHPOs:

      CaseHPOFreeRext: VWF:Ag [IU/dL] = 41na44; VWF:Ac [IU/dL] = n/a; FVIII:C [IU/dL] = n/a; VWF:CB (IU/dL) = n/a

      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.4001G>A p.Arg1334Gln

      HGVS:

      ClinVarID: 2572701

      CAID:

      gnomAD: 0.000006196 (10 in 1613834) no homozygotes https://gnomad.broadinstitute.org/variant/12-6019417-C-T?dataset=gnomad_r4

    47. 25 2N/HemophiliaAc.2561G > A p.Arg854Gln 20 D’-E’ htz Missense A 121 111 RCo 1

      Case: IP #25 in type 2N VWD sub-cohort

      DiseaseAssertion: type 2N VWD and hemophilia A

      FamilyInfo:

      ParentalGenotype(s):

      CasePresentingHPOs: HP:0032370 - blood group A

      CaseHPOFreeRext: VWF:Ag [IU/dL] = 121; VWF:Ac [IU/dL] = 111; FVIII:C [IU/dL] = 1

      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

    48. 13–21 U (2A/2M/1C) c.3943C > T p.Arg1315Cys C 28 A1 htz Missense A/O/A/na/AB/A/O/A/A12/20/20/40/12/17/13/10 /147/13 RCo /15/10/6/14/8/6/426

      Case: IP #13 in type U VWD sub-cohort

      DiseaseAssertion: unclassified (2A/2M/1C) VWD

      FamilyInfo:

      ParentalGenotype(s):

      CasePresentingHPOs: HP:0032370 - blood group A

      CaseHPOFreeRext: VWF:Ag [IU/dL] = 12; VWF:Ac [IU/dL] = 7; FVIII:C [IU/dL] = 26

      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.3943C>T p.Arg1315Cys

      HGVS:

      ClinVarID: 100310

      CAID:

      gnomAD: 6.196e-7 (1 in 1613892) no homozygotes https://gnomad.broadinstitute.org/variant/12-6019475-G-A?dataset=gnomad_r4

    49. 14–21 Heterozygous2Nc.2561G > A p.Arg854Gln 20 D’-E’ htz Missense O/O/na/na /A/A/O/B55/67/93/46/151/45/49 /2230 Rco / 78 GPIbR /48/64/121/42/41/2656

      Case: IP #14 in type 2N VWD sub-cohort

      DiseaseAssertion: type 2N VWD

      FamilyInfo:

      ParentalGenotype(s):

      CasePresentingHPOs: HP:0032442 - blood group O

      CaseHPOFreeRext: VWF:Ag [IU/dL] = 55; VWF:Ac [IU/dL] = 30; FVIII:C [IU/dL] = 56

      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

    50. 2–8 c.3916C > T p.Arg1306Trp C 28 A1 htz Missense A/na/O/B/O/O/A21/37/48/44/22/22/2713 RCo /na/33/25/5/6/837/na/46/135 CSA /27 CSA /20 CSA /33

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

      DiseaseAssertion: type 2B VWD

      FamilyInfo:

      ParentalGenotype(s):

      CasePresentingHPOs: HP:0032370 - blood group A

      CaseHPOFreeRext: VWF:Ag [IU/dL] = 27; VWF:Ac [IU/dL] = 8; FVIII:C [IU/dL] = 33

      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.3916C>T p.Arg1306Trp

      HGVS:

      ClinVarID: 288

      CAID:

      gnomAD: absent

    51. 13–21 U (2A/2M/1C) c.3943C > T p.Arg1315Cys C 28 A1 htz Missense A/O/A/na/AB/A/O/A/A12/20/20/40/12/17/13/10 /147/13 RCo /15/10/6/14/8/6/426 CSA /39/28 OSCA /na /26 CSA /26

      Case: IP #18 in type U VWD sub-cohort

      DiseaseAssertion: unclassified (2A/2M/1C) VWD

      FamilyInfo:

      ParentalGenotype(s):

      CasePresentingHPOs: HP:0032370 - blood group A

      CaseHPOFreeRext: VWF:Ag [IU/dL] = 17; VWF:Ac [IU/dL] = 14; FVIII:C [IU/dL] = 26

      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.3943C>T p.Arg1315Cys

      HGVS:

      ClinVarID: 100310

      CAID:

      gnomAD: 6.196e-7 (1 in 1613892) no homozygotes https://gnomad.broadinstitute.org/variant/12-6019475-G-A?dataset=gnomad_r4

    52. 2–8 c.3916C > T p.Arg1306Trp C 28 A1 htz Missense A/na/O/B/O/O/A21/37/48/44/22/22/2713 RCo /na/33/25/5/6/837/na/46

      Case: IP #4 in type 2B VWD sub-cohort

      DiseaseAssertion: type 2B VWD

      FamilyInfo:

      ParentalGenotype(s):

      CasePresentingHPOs: HP:0032442 - blood group O

      CaseHPOFreeRext: VWF:Ag [IU/dL] = 48; VWF:Ac [IU/dL] = 33; FVIII:C [IU/dL] = 46

      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.3916C>T p.Arg1306Trp

      HGVS:

      ClinVarID: 288

      CAID:

      gnomAD: absent

    53. 43-49Type2A(IIA)c.4789C>T p.Arg1597Trp 28 A2 htz Missense A/na/A/O/B/na/O22/30/26/64/24/16/5613/11RCo/9/16/6/6/1529/47/30CSA/66CSA/32CSA/20

      Case: IP #48

      DiseaseAssertion: type 2A (IIA) VWD

      FamilyInfo:

      ParentalGenotype(s):

      CasePresentingHPOs:

      CaseHPOFreeRext: VWF:Ag [IU/dL] = 16; VWF:Ac [IU/dL] = 6; FVIII:C [IU/dL] = 20

      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.4789C>T p.Arg1597Trp

      HGVS:

      ClinVarID: 285

      CAID:

      gnomAD: 6.196e-7 (1 in 1614028) no homozygotes https://gnomad.broadinstitute.org/variant/12-6018629-G-A?dataset=gnomad_r4

    54. 43-49Type2A(IIA)c.4789C>T p.Arg1597Trp 28 A2 htz Missense A/na/A/O/B/na/O22/30/26/64/24/16/5613/11RCo/9/16/6/6/1529/47

      Case: IP #44

      DiseaseAssertion: type 2A (IIA) VWD

      FamilyInfo:

      ParentalGenotype(s):

      CasePresentingHPOs:

      CaseHPOFreeRext: VWF:Ag [IU/dL] = 30; VWF:Ac [IU/dL] = 11; FVIII:C [IU/dL] = 47

      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.4789C>T p.Arg1597Trp

      HGVS:

      ClinVarID: 285

      CAID:

      gnomAD: 6.196e-7 (1 in 1614028) no homozygotes https://gnomad.broadinstitute.org/variant/12-6018629-G-A?dataset=gnomad_r4

    55. 59-62Type2A(IIA)c.4883T>C p.Ile1628Thr 28 A2 htz Missense na/A/O/na28.7/38/17/555/7/5/932

      Case: IP #59

      DiseaseAssertion: type 2A (IIA) VWD

      FamilyInfo:

      ParentalGenotype(s):

      CasePresentingHPOs:

      CaseHPOFreeRext: VWF:Ag [IU/dL] = 28.7; VWF:Ac [IU/dL] = 5; FVIII:C [IU/dL] = 32

      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.4883T>C p.Ile1628Thr

      HGVS:

      ClinVarID: 284

      CAID:

      gnomAD: 0.000001859 (3 in 1613848) no homozygotes https://gnomad.broadinstitute.org/variant/12-6018535-A-G?dataset=gnomad_r4

    56. 21 c.3946G > A p.Val1316Met C 28 A1 htz Missense B/O/A/na/A/na63/62/25/58/48/3610/22 RCo /6/22/11/982 CSA /37/26/54/46 CSA /36

      Case: IP #21 in type 2B VWD sub-cohort

      DiseaseAssertion: type 2B VWD

      FamilyInfo:

      ParentalGenotype(s):

      CasePresentingHPOs:

      CaseHPOFreeRext: VWF:Ag [IU/dL] = 36; VWF:Ac [IU/dL] = 9; FVIII:C [IU/dL] = 36

      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.3946G>A p.Val1316Met

      HGVS:

      ClinVarID: 290

      CAID:

      gnomAD: absent

    57. 14–21 Heterozygous2Nc.2561G > A p.Arg854Gln 20 D’-E’ htz Missense O/O/na/na /A/A/O/B55/67/93/46/151/45/49 /2230 Rco / 78 GPIbR /48/64/121/42/41/2656 OSCA /88/76/na/53 CSA /11

      Case: IP #19 in type 2N VWD sub-cohort

      DiseaseAssertion: type 2N VWD

      FamilyInfo:

      ParentalGenotype(s):

      CasePresentingHPOs: HP:0032370 - blood group A

      CaseHPOFreeRext: VWF:Ag [IU/dL] = 45; VWF:Ac [IU/dL] = 42; FVIII:C [IU/dL] = 11

      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

    58. 12–14 c.3922C > T p.Arg1308Cys C 28 A1 htz Missense na /AB/A 42/30/14 15 RCo /6/10 48/41

      Case: IP #13 in type 2B VWD sub-cohort

      DiseaseAssertion: type 2B VWD

      FamilyInfo:

      ParentalGenotype(s):

      CasePresentingHPOs: HP:0032441 - blood group AB

      CaseHPOFreeRext: VWF:Ag [IU/dL] = 30; VWF:Ac [IU/dL] = 6; 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.3922C>T p.Arg1308Cys

      HGVS:

      ClinVarID: 289

      CAID:

      gnomAD: absent

    59. 16–21 c.3946G > A p.Val1316Met C 28 A1 htz Missense B/O/A/na/A/na63/62/25/58/48/3610/22 RCo /6/22/11/982

      Case: IP #16 in type 2B VWD sub-cohort

      DiseaseAssertion: type 2B VWD

      FamilyInfo:

      ParentalGenotype(s):

      CasePresentingHPOs: HP:0032440 - blood group B

      CaseHPOFreeRext: VWF:Ag [IU/dL] = 63; VWF:Ac [IU/dL] = 10; FVIII:C [IU/dL] = 82

      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.3946G>A p.Val1316Met

      HGVS:

      ClinVarID: 290

      CAID:

      gnomAD: absent

    60. 18-20Type2A (IIE)c.3437A>G p.Tyr1146Cys 26 D3-TIL-3htz Missense na/A/A19.3/12/299/5/18 30/24

      Case: IP #19

      DiseaseAssertion: type 2A (IIE) VWD

      FamilyInfo:

      ParentalGenotype(s):

      CasePresentingHPOs: HP:0032370 - blood group A

      CaseHPOFreeRext: VWF:Ag [IU/dL] = 12; VWF:Ac [IU/dL] = 5; FVIII:C [IU/dL] = 24

      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.3437A>G

      HGVS:

      ClinVarID: 31009

      CAID:

      gnomAD: 0.000001840 (1 in 543518) no homozygotes https://gnomad.broadinstitute.org/variant/12-6022841-T-C?dataset=gnomad_r4

    61. 1 c.2561G > Ac.3916C > Tp.Arg854Glnp.Arg1306Trp C2028D’-E’A1htz MissenseMissenseA 17 4 26

      Case: IP #1 in type 2B VWD sub-cohort

      DiseaseAssertion: type 2B VWD

      FamilyInfo:

      ParentalGenotype(s):

      CasePresentingHPOs: HP:0032370 - blood group A

      CaseHPOFreeRext: VWF:Ag [IU/dL] = 17; VWF:Ac [IU/dL] = 4; FVIII:C [IU/dL] = 26

      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.3916C>T p.Arg1306Trp

      ClinVarID: 288

      gnomAD: absent

    62. 2–8 c.3916C > T p.Arg1306Trp C 28 A1 htz Missense A/na/O/B/O/O/A21/37/48/44/22/22/2713 RCo /na/33/25/5/6/837/na/46/135 CSA /27 CSA /20

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

      DiseaseAssertion: type 2B VWD

      FamilyInfo:

      ParentalGenotype(s):

      CasePresentingHPOs: HP:0032442 - blood group O

      CaseHPOFreeRext: VWF:Ag [IU/dL] = 22; VWF:Ac [IU/dL] = 6; FVIII:C [IU/dL] = 20

      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.3916C>T p.Arg1306Trp

      HGVS:

      ClinVarID: 288

      CAID:

      gnomAD: absent

    63. 16–21 c.3946G > A p.Val1316Met C 28 A1 htz Missense B/O/A/na/A/na63/62/25/58/48/3610/22 RCo /6/22/11/982 CSA /37/26/54/46

      Case: IP #20 in type 2B VWD sub-cohort

      DiseaseAssertion: type 2B VWD

      FamilyInfo:

      ParentalGenotype(s):

      CasePresentingHPOs: HP:0032370 - blood group A

      CaseHPOFreeRext: VWF:Ag [IU/dL] = 48; VWF:Ac [IU/dL] = 11; FVIII:C [IU/dL] = 46

      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.3946G>A p.Val1316Met

      HGVS:

      ClinVarID: 290

      CAID:

      gnomAD: absent

    64. 7 2N c.2446C > T p.Arg816Trp 19 D’TIL’ hmz Missense B 166 144 2

      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

    65. 12–14 c.3922C > T p.Arg1308Cys C 28 A1 htz Missense na /AB/A 42/30/14 15 RCo /6/10 48

      Case: IP #12 in type 2B VWD sub-cohort

      DiseaseAssertion: type 2B VWD

      FamilyInfo:

      ParentalGenotype(s):

      CasePresentingHPOs:

      CaseHPOFreeRext: VWF:Ag [IU/dL] = 42; VWF:Ac [IU/dL] = 15; FVIII:C [IU/dL] = 48

      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.3922C>T p.Arg1308Cys

      HGVS:

      ClinVarID: 289

      CAID:

      gnomAD: absent

    66. 5, 6 2N/1 c.2435delc.2561G > Ap.Pro812Argfs31p.Arg854Gln1820D’-TIL’D’-E’htzhtzSmall Del.Missensena/na 29/74 26/80 10 CSA /40

      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

    67. 2–8 c.3916C > T p.Arg1306Trp C 28 A1 htz Missense A/na/O/B/O/O/A21/37/48/44/22/22/2713 RCo /na

      Case: IP #3 in type 2B VWD sub-cohort

      DiseaseAssertion: type 2B VWD

      FamilyInfo:

      ParentalGenotype(s):

      CasePresentingHPOs:

      CaseHPOFreeRext: VWF:Ag [IU/dL] = 37; VWF:Ac [IU/dL] = n/a; FVIII:C [IU/dL] = n/a

      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.3916C>T p.Arg1306Trp

      HGVS:

      ClinVarID: 288

      CAID:

      gnomAD: absent

    68. 11–13 2N c.2561G > A p.Arg854Gln 20 D’-E’ hmz Missense O/O/na 74/59/55 79/59/45 18/16/16

      Case: IP #13 in type 2N VWD sub-cohort

      DiseaseAssertion: type 2N VWD

      FamilyInfo:

      ParentalGenotype(s):

      CasePresentingHPOs:

      CaseHPOFreeRext: VWF:Ag [IU/dL] = 55; VWF:Ac [IU/dL] = 45; 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

    69. 2–8 c.3916C > T p.Arg1306Trp C 28 A1 htz Missense A/na/O/B/O/O/A21/37/48/44/22/22/2713 RCo /na/33/25/5/6/837/na/46/135 CSA /27

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

      DiseaseAssertion: type 2B VWD

      FamilyInfo:

      ParentalGenotype(s):

      CasePresentingHPOs: HP:0032442 - blood group O

      CaseHPOFreeRext: VWF:Ag [IU/dL] = 22; VWF:Ac [IU/dL] = 5; FVIII:C [IU/dL] = 27

      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.3916C>T p.Arg1306Trp

      HGVS:

      ClinVarID: 288

      CAID:

      gnomAD: absent

    70. 43-49Type2A(IIA)c.4789C>T p.Arg1597Trp 28 A2 htz Missense A/na/A/O/B/na/O22/30/26/64/24/16/5613/11RCo/9/16/6/6/1529/47/30CSA/66CSA/32

      Case: IP #47

      DiseaseAssertion: type 2A (IIA) VWD

      FamilyInfo:

      ParentalGenotype(s):

      CasePresentingHPOs: HP:0032440 - blood group B

      CaseHPOFreeRext: VWF:Ag [IU/dL] = 24; VWF:Ac [IU/dL] = 6; FVIII:C [IU/dL] = 32

      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.4789C>T p.Arg1597Trp

      HGVS:

      ClinVarID: 285

      CAID:

      gnomAD: 6.196e-7 (1 in 1614028) no homozygotes https://gnomad.broadinstitute.org/variant/12-6018629-G-A?dataset=gnomad_r4

    71. 8–10 2N c.2446C > Tc.2561G > Ap.Arg816Trpp.Arg854Gln1920D’-TIL’D’-E’htzhtzMissenseMissenseA/A/na 61/93/50 59/107/55 25 CSA /18 CSA /15

      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

    72. 50 Type2A(IIA)c.4790G>A p.Arg1597Gln 28 A2 htz Missense na na 11 na

      Case: IP #50

      DiseaseAssertion: type 2A (IIA) VWD

      FamilyInfo:

      ParentalGenotype(s):

      CasePresentingHPOs:

      CaseHPOFreeRext: VWF:Ag [IU/dL] = n/a; VWF:Ac [IU/dL] = 11; FVIII:C [IU/dL] = n/a

      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.4790G>A p.Arg1597Gln

      HGVS:

      ClinVarID: 100391

      CAID:

      gnomAD: absent

    1. Case UZ075: 2 year old female (row 76 supplemental table)

      DiseaseAssertion: type 1 VWD

      FamilyInfo:

      ParentalGenotype(s):

      CasePresentingHPOs:

      CaseHPOFreeRext: vWF:Ag (%) = 27; vWF:GPIbR (%) = 25.5; Act/Ag ratio = 0.94; FVIII:C (%) = 94.6; Platelets (x10^9/L) = 317

      CaseNOTHPOs:

      CaseNOTHPOFreeText:

      CasePreviousTesting: The Thrombosis-Hemostasis gene panel test used whole exome sequencing and included 99 diagnostic-grade genes (table 1 in PMID:36696193)

      GenotypingMethod: WES using the coagulation subpanel of the UZ Leuven Thrombosis-Haemostasis gene panel test. WES was performed on the sequencing platform NovaSeq 6000 (Illumina), and Alissa Interpret software v5.2-5.4 (Agilent) was used for variant interpretation. Assessment of copy number variation was validated within the bioinformatics pipeline. The American College of Medical Genetics and Genomics and the Association of Molecular Pathology guidelines were used to classify variants as pathogenic (P), likely pathogenic (LP), a variant of uncertain significance (VUS), or (likely) benign (LB, B) variants

      PreviouslyPublished:

      Gene: VWF

      Variant: c.6551G>A p.Cys2184Tyr

      HGVS:

      ClinVarID: 1677275

      CAID:

      gnomAD: 0.000001239 (2 in 1613988) no homozygotes https://gnomad.broadinstitute.org/variant/12-5993909-C-T?dataset=gnomad_r4

      MultipleGeneVariants:

      Gene: F5:Leiden

      Variant: c.1601G>A p.Arg534Gln

      ClinVarID: 642

      gonmAD: 0.02143 (34574 in 1613166) 450 homozygotes https://gnomad.broadinstitute.org/variant/1-169549811-C-T?dataset=gnomad_r4

    2. 1 M Type 2 NOS VWD Type 1 VWD c.4342C>T p.Gln1448∗ LP

      Case 4: 1 y.o. male, study ID UZ079 in supplemental table. Also listed in Table 2 line 6

      DiseaseAssertion: type 2 NOS VWD presequencing; type 1 VWD postsequencing

      FamilyInfo:

      ParentalGenotype(s):

      CasePresentingHPOs: HP:0032370

      CaseHPOFreeRext: vWF:Ag (%) = 18; vWF:GPIbR (%) = 12.6; Act/Ag ratio = 0.70; FVIII:C (%) = 87.9; Platelets (x10^9/L) = 358

      CaseNOTHPOs:

      CaseNOTHPOFreeText:

      CasePreviousTesting: The Thrombosis-Hemostasis gene panel test used whole exome sequencing and included 99 diagnostic-grade genes (table 1 in PMID:36696193)

      GenotypingMethod: WES using the coagulation subpanel of the UZ Leuven Thrombosis-Haemostasis gene panel test. WES was performed on the sequencing platform NovaSeq 6000 (Illumina), and Alissa Interpret software v5.2-5.4 (Agilent) was used for variant interpretation. Assessment of copy number variation was validated within the bioinformatics pipeline. The American College of Medical Genetics and Genomics and the Association of Molecular Pathology guidelines were used to classify variants as pathogenic (P), likely pathogenic (LP), a variant of uncertain significance (VUS), or (likely) benign (LB, B) variants

      PreviouslyPublished: Gene: VWF

      Variant: c.4342C>T p.Gln1448*

      HGVS:

      ClinVarID: 2572655

      CAID:

      gnomAD: absent

    3. 32 F Type 2B VWD Type 2B Malmo/New York VWD c.3797C>T p.Pro1266Leu P

      Case 3: 32 y.o. female, study ID UZ002 in supplemental table

      DiseaseAssertion: type 2B VWD presequencing, type 2B Malmo/New York VWD postsequencing

      FamilyInfo:

      ParentalGenotype(s):

      CasePresentingHPOs:

      CaseHPOFreeRext: vWF:Ag (%) = 51; vWF:GPIbR (%) = 30; Act/Ag ratio = 0.59; FVIII:C (%) = 48; Platelets (x10^9/L) = 264

      CaseNOTHPOs:

      CaseNOTHPOFreeText:

      CasePreviousTesting: The Thrombosis-Hemostasis gene panel test used whole exome sequencing and included 99 diagnostic-grade genes (table 1 in PMID:36696193)

      GenotypingMethod:WES using the coagulation subpanel of the UZ Leuven Thrombosis-Haemostasis gene panel test. WES was performed on the sequencing platform NovaSeq 6000 (Illumina), and Alissa Interpret software v5.2-5.4 (Agilent) was used for variant interpretation. Assessment of copy number variation was validated within the bioinformatics pipeline. The American College of Medical Genetics and Genomics and the Association of Molecular Pathology guidelines were used to classify variants as pathogenic (P), likely pathogenic (LP), a variant of uncertain significance (VUS), or (likely) benign (LB, B) variants

      PreviouslyPublished:

      Gene: VWF

      Variant: c.3797C>T p.Pro1266Leu

      HGVS:

      ClinVarID: 314

      CAID:

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

    4. 33 F Type 1 VWD Type 2M VWD c.3863T>G p.Leu1288Arg LP

      Case 2: 33 y.o. female, study ID UZ104 in supplemental table

      DiseaseAssertion: type 1 VWD presequencing, type 2M VWD postsequencing

      FamilyInfo:

      ParentalGenotype(s):

      CasePresentingHPOs:

      CaseHPOFreeRext: vWF:Ag (%) = 14; vWF:GPIbR (%) = 10; Act/Ag ratio = 1.00; FVIII:C (%) = 8; Platelets (x10^9/L) = 239

      CaseNOTHPOs:

      CaseNOTHPOFreeText:

      CasePreviousTesting: The Thrombosis-Hemostasis gene panel test used whole exome sequencing and included 99 diagnostic-grade genes (table 1 in PMID:36696193)

      GenotypingMethod: WES using the coagulation subpanel of the UZ Leuven Thrombosis-Haemostasis gene panel test. WES was performed on the sequencing platform NovaSeq 6000 (Illumina), and Alissa Interpret software v5.2-5.4 (Agilent) was used for variant interpretation. Assessment of copy number variation was validated within the bioinformatics pipeline. The American College of Medical Genetics and Genomics and the Association of Molecular Pathology guidelines were used to classify variants as pathogenic (P), likely pathogenic (LP), a variant of uncertain significance (VUS), or (likely) benign (LB, B) variants

      PreviouslyPublished:

      Gene: VWF

      Variant: c.3863T>G p.Leu1288Arg

      HGVS:

      ClinVarID: 100294

      CAID:

      gnomAD: absent

    5. 4 M Type 2 NOS VWD Type 2M VWD c.3863T>G p.Leu1288Arg LP

      Case 6: 4 y.o. male, study ID UZ024 in supplemental table

      DiseaseAssertion: type 2 NOS VWD presequencing; type 2M VWD postsequencing

      FamilyInfo:

      ParentalGenotype(s):

      CasePresentingHPOs: HP:0032370

      CaseHPOFreeRext: vWF:Ag (%) = 12.2; vWF:GPIbR (%) = 6.3; Act/Ag ratio = 0.52; FVIII:C (%) = 37.1; Platelets (x10^9/L) = 570

      CaseNOTHPOs:

      CaseNOTHPOFreeText:

      CasePreviousTesting: The Thrombosis-Hemostasis gene panel test used whole exome sequencing and included 99 diagnostic-grade genes (table 1 in PMID:36696193)

      GenotypingMethod: WES using the coagulation subpanel of the UZ Leuven Thrombosis-Haemostasis gene panel test. WES was performed on the sequencing platform NovaSeq 6000 (Illumina), and Alissa Interpret software v5.2-5.4 (Agilent) was used for variant interpretation. Assessment of copy number variation was validated within the bioinformatics pipeline. The American College of Medical Genetics and Genomics and the Association of Molecular Pathology guidelines were used to classify variants as pathogenic (P), likely pathogenic (LP), a variant of uncertain significance (VUS), or (likely) benign (LB, B) variants

      PreviouslyPublished:

      Gene: VWF

      Variant: c.3863T>G p.Leu1288Arg

      HGVS:

      ClinVarID: 100294

      CAID:

      gnomAD: absent

    6. Case UZ036: 13 year old female

      DiseaseAssertion: type 1 VWD

      FamilyInfo:

      ParentalGenotype(s):

      CasePresentingHPOs: HP:0032370

      CaseHPOFreeRext: vWF:Ag (%) = 6.5; vWF:GPIbR (%) = 4.6; Act/Ag ratio = 0.71; FVIII:C (%) = 28.6; Platelets (x10^9/L) = 258

      CaseNOTHPOs:

      CaseNOTHPOFreeText:

      CasePreviousTesting: The Thrombosis-Hemostasis gene panel test used whole exome sequencing and included 99 diagnostic-grade genes (table 1 in PMID:36696193)

      GenotypingMethod: WES using the coagulation subpanel of the UZ Leuven Thrombosis-Haemostasis gene panel test. WES was performed on the sequencing platform NovaSeq 6000 (Illumina), and Alissa Interpret software v5.2-5.4 (Agilent) was used for variant interpretation. Assessment of copy number variation was validated within the bioinformatics pipeline. The American College of Medical Genetics and Genomics and the Association of Molecular Pathology guidelines were used to classify variants as pathogenic (P), likely pathogenic (LP), a variant of uncertain significance (VUS), or (likely) benign (LB, B) variants

      PreviouslyPublished:

      Gene: VWF

      Variant: c.8008G>A p.Gly2670Ser

      HGVS:

      ClinVarID: 1703812

      CAID:

      gnomAD: 0.000005576 (9 in 1614024) no homozygotes https://gnomad.broadinstitute.org/variant/12-5952498-C-T?dataset=gnomad_r4

      MultpleGeneVariants:

      Gene: FGG

      Variant: c.503C>T p.Thr168Met

      ClinVarID: 1703849

      gnomAD: 0.00003719 (60 in 1613552) no homozygotes https://gnomad.broadinstitute.org/variant/4-154610096-G-A?dataset=gnomad_r4

    7. 3 M Low VWF Low VWF c.7287+12T>G Splicing defect NA 0.03 0.00027 VUS

      Case 20: 3 year old male, study ID UZ067 in supplemental table

      DiseaseAssertion: low VWF

      FamilyInfo:

      ParentalGenotype(s):

      CasePresentingHPOs: HP:0032442

      CaseHPOFreeRext: vWF:Ag (%) = 49; vWF:GPIbR (%) = 50.5; Act/Ag ratio = 1.03; FVIII:C (%) = 90.3; Platelets (x10^9/L) = 336

      CaseNOTHPOs:

      CaseNOTHPOFreeText:

      CasePreviousTesting: The Thrombosis-Hemostasis gene panel test used whole exome sequencing and included 99 diagnostic-grade genes (table 1 in PMID:36696193)

      GenotypingMethod:WES using the coagulation subpanel of the UZ Leuven Thrombosis-Haemostasis gene panel test. WES was performed on the sequencing platform NovaSeq 6000 (Illumina), and Alissa Interpret software v5.2-5.4 (Agilent) was used for variant interpretation. Assessment of copy number variation was validated within the bioinformatics pipeline. The American College of Medical Genetics and Genomics and the Association of Molecular Pathology guidelines were used to classify variants as pathogenic (P), likely pathogenic (LP), a variant of uncertain significance (VUS), or (likely) benign (LB, B) variants

      PreviouslyPublished:

      Gene: VWF

      Variant: c.7287+12T>G p.?

      HGVS:

      ClinVarID: 2572109

      CAID:

      gnomAD: 0.000002479 (4 in 1613878) no homozygotes https://gnomad.broadinstitute.org/variant/12-5981774-A-C?dataset=gnomad_r4

    8. 2 F Type 2 NOS VWD Type 2B VWD + HA c.3946G>T p.Val1316Leu VUS

      Case 5: 2 y.o. female, study ID UZ068 in supplemental table

      DiseaseAssertion: type 2 NOS VWD presequencing, type 2B VWD + hemophilia A postsequencing

      FamilyInfo:

      ParentalGenotype(s):

      CasePresentingHPOs: HP:0032442

      CaseHPOFreeRext: vWF:Ag (%) = 43.3; vWF:GPIbR (%) = 25.2; Act/Ag ratio = 0.58; FVIII:C (%) = 21.6; Platelets (x10^9/L) = 384

      CaseNOTHPOs:

      CaseNOTHPOFreeText:

      CasePreviousTesting: The Thrombosis-Hemostasis gene panel test used whole exome sequencing and included 99 diagnostic-grade genes (table 1 in PMID:36696193)

      GenotypingMethod: WES using the coagulation subpanel of the UZ Leuven Thrombosis-Haemostasis gene panel test. WES was performed on the sequencing platform NovaSeq 6000 (Illumina), and Alissa Interpret software v5.2-5.4 (Agilent) was used for variant interpretation. Assessment of copy number variation was validated within the bioinformatics pipeline. The American College of Medical Genetics and Genomics and the Association of Molecular Pathology guidelines were used to classify variants as pathogenic (P), likely pathogenic (LP), a variant of uncertain significance (VUS), or (likely) benign (LB, B) variants

      PreviouslyPublished:

      Gene: VWF

      Variant: c.3946G>T p.Val1316Leu

      HGVS:

      ClinVarID: 1703818

      CAID:

      gnomAD: 0.000001239 (2/1613946) 0 homozygotes https://gnomad.broadinstitute.org/variant/12-6019472-C-G?dataset=gnomad_r4

      MultipleGeneVariants: variant: F8:c.5883G>A; p.Trp1961*; ClinVar ID: 1703846

    9. 2 M Low VWF Low VWF c.5746C>G p.Arg1916Gly 0.21 0.00 0.00048 VUS

      Case 19: 2 year old male, study ID UZ070 in supplmental table

      DiseaseAssertion: low VWF

      FamilyInfo:

      ParentalGenotype(s):

      CasePresentingHPOs: HP:0032442

      CaseHPOFreeRext: vWF:Ag (%) = 45; vWF:GPIbR (%) = 39.4; Act/Ag ratio = 0.88; FVIII:C (%) = 74.4; Platelets (x10^9/L) = 232

      CaseNOTHPOs:

      CaseNOTHPOFreeText:

      CasePreviousTesting: The Thrombosis-Hemostasis gene panel test used whole exome sequencing and included 99 diagnostic-grade genes (table 1 in PMID:36696193)

      GenotypingMethod:WES using the coagulation subpanel of the UZ Leuven Thrombosis-Haemostasis gene panel test. WES was performed on the sequencing platform NovaSeq 6000 (Illumina), and Alissa Interpret software v5.2-5.4 (Agilent) was used for variant interpretation. Assessment of copy number variation was validated within the bioinformatics pipeline. The American College of Medical Genetics and Genomics and the Association of Molecular Pathology guidelines were used to classify variants as pathogenic (P), likely pathogenic (LP), a variant of uncertain significance (VUS), or (likely) benign (LB, B) variants

      PreviouslyPublished:

      Gene: VWF

      Variant: c.5746C>G p.Arg1916Gly

      HGVS:

      ClinVarID: 2572097

      CAID:

      gnomAD: 0.000004337 (7 in 1613868) no homozygotes https://gnomad.broadinstitute.org/variant/12-6011713-G-C?dataset=gnomad_r4

      MultipleSequenceVariants:

      Gene: SERPINC1

      Variant: c.89T>A p.Val30Glu

      ClinVarID: 18012

      gnomAD: 0.002625 (4237 in 1614198) 14 homozygotes https://gnomad.broadinstitute.org/variant/1-173914872-A-T?dataset=gnomad_r4

    10. Case UZ096: 38 year old female (row97 in supplemental table)

      DiseaseAssertion: type 1 VWD

      FamilyInfo:

      ParentalGenotype(s):

      CasePresentingHPOs: HP:0032442

      CaseHPOFreeRext: vWF:Ag (%) = 22.8; vWF:GPIbR (%) = 22; Act/Ag ratio = 0.96; FVIII:C (%) = 53.2; Platelets (x10^9/L) = 149

      CaseNOTHPOs:

      CaseNOTHPOFreeText:

      CasePreviousTesting: The Thrombosis-Hemostasis gene panel test used whole exome sequencing and included 99 diagnostic-grade genes (table 1 in PMID:36696193)

      GenotypingMethod: WES using the coagulation subpanel of the UZ Leuven Thrombosis-Haemostasis gene panel test. WES was performed on the sequencing platform NovaSeq 6000 (Illumina), and Alissa Interpret software v5.2-5.4 (Agilent) was used for variant interpretation. Assessment of copy number variation was validated within the bioinformatics pipeline. The American College of Medical Genetics and Genomics and the Association of Molecular Pathology guidelines were used to classify variants as pathogenic (P), likely pathogenic (LP), a variant of uncertain significance (VUS), or (likely) benign (LB, B) variants

      PreviouslyPublished:

      Gene: VWF

      Variant: c.7636A>T p.Asn2546Tyr

      HGVS:

      ClinVarID: 100480

      CAID:

      gnomAD: 0.000003717 (6 in 1614024) no homozygotes https://gnomad.broadinstitute.org/variant/12-5969304-T-A?daset=gnomad_r4at

    11. 28 M Type 2 NOS VWD Type 2M VWD c.3943C>T p.Arg1315Cys P

      Case 10: 28 y.o. male, study ID UZ095 in Supplemental table

      DiseaseAssertion: Type 2 NOS VWD presequencing, type 2M VWD postsequencing

      FamilyInfo:

      ParentalGenotype(s):

      CasePresentingHPOs: HP:0032441

      CaseHPOFreeRext: vWF:Ag (%) = 11.8; vWF:GPIbR (%) = 5; Act/Ag ratio = 0.42; FVIII:C (%) = 18.8; Platelets (x10^9/L) = 180

      CaseNOTHPOs:

      CaseNOTHPOFreeText:

      CasePreviousTesting: The Thrombosis-Hemostasis gene panel test used whole exome sequencing and included 99 diagnostic-grade genes (table 1 in PMID:36696193)

      GenotypingMethod: WES using the coagulation subpanel of the UZ Leuven Thrombosis-Haemostasis gene panel test. WES was performed on the sequencing platform NovaSeq 6000 (Illumina), and Alissa Interpret software v5.2-5.4 (Agilent) was used for variant interpretation. Assessment of copy number variation was validated within the bioinformatics pipeline. The American College of Medical Genetics and Genomics and the Association of Molecular Pathology guidelines were used to classify variants as pathogenic (P), likely pathogenic (LP), a variant of uncertain significance (VUS), or (likely) benign (LB, B) variants

      PreviouslyPublished:

      Gene: VWF

      Variant: c.3943C>T p.Arg1315Cys

      HGVS:

      ClinVarID: 100310

      CAID:

      gnomAD: 6.196e-7 (1/1613892) 0 homozygotes https://gnomad.broadinstitute.org/variant/12-6019475-G-A?dataset=gnomad_r4

    12. Case UZ056: 8 year old male (row 57 in supplementary table)

      DiseaseAssertion: type 1/2M VWD

      FamilyInfo:

      ParentalGenotype(s):

      CasePresentingHPOs: HP:0032442

      CaseHPOFreeRext: vWF:Ag (%) = 10.8; vWF:GPIbR (%) = 9.6; Act/Ag ratio = 0.89; FVIII:C (%) = 30.2; Platelets (x10^9/L) = 196

      CaseNOTHPOs:

      CaseNOTHPOFreeText:

      CasePreviousTesting: The Thrombosis-Hemostasis gene panel test used whole exome sequencing and included 99 diagnostic-grade genes (table 1 in PMID:36696193).

      GenotypingMethod: WES using the coagulation subpanel of the UZ Leuven Thrombosis-Haemostasis gene panel test. WES was performed on the sequencing platform NovaSeq 6000 (Illumina), and Alissa Interpret software v5.2-5.4 (Agilent) was used for variant interpretation. Assessment of copy number variation was validated within the bioinformatics pipeline. The American College of Medical Genetics and Genomics and the Association of Molecular Pathology guidelines were used to classify variants as pathogenic (P), likely pathogenic (LP), a variant of uncertain significance (VUS), or (likely) benign (LB, B) variants

      PreviouslyPublished:

      Gene: VWF

      Variant: c.5198T>C p.Leu1733Pro

      HGVS:

      ClinVarID: 1703810

      CAID:

      gnomAD: absent

    13. Case UZ050: 3 year old male (row 51 supplemental table)

      DiseaseAssertion: type 1 VWD

      FamilyInfo:

      ParentalGenotype(s):

      CasePresentingHPOs: HP:0032370

      CaseHPOFreeRext: vWF:Ag (%) = 29.6; vWF:GPIbR (%) = 26; Act/Ag ratio = 0.88; FVIII:C (%) = 78

      CaseNOTHPOs:

      CaseNOTHPOFreeText:

      CasePreviousTesting: The Thrombosis-Hemostasis gene panel test used whole exome sequencing and included 99 diagnostic-grade genes (table 1 in PMID:36696193)

      GenotypingMethod: WES using the coagulation subpanel of the UZ Leuven Thrombosis-Haemostasis gene panel test. WES was performed on the sequencing platform NovaSeq 6000 (Illumina), and Alissa Interpret software v5.2-5.4 (Agilent) was used for variant interpretation. Assessment of copy number variation was validated within the bioinformatics pipeline. The American College of Medical Genetics and Genomics and the Association of Molecular Pathology guidelines were used to classify variants as pathogenic (P), likely pathogenic (LP), a variant of uncertain significance (VUS), or (likely) benign (LB, B) variants

      PreviouslyPublished:

      Gene: VWF

      Variant: c.6551G>A p.Cys2184Tyr

      HGVS:

      ClinVarID: 1677275

      CAID:

      gnomAD: 0.000001239 (2 in1613988) no homozygotes https://gnomad.broadinstitute.org/variant/12-5993909-C-T?dataset=gnomad_r4

    14. Case UZ098: 41 year old female (row 99 in supplemental table)

      DiseaseAssertion: type 1 VWD

      FamilyInfo:

      ParentalGenotype(s):

      CasePresentingHPOs: HP:0032370

      CaseHPOFreeRext: vWF:Ag (%) = 30.1; vWF:GPIbR (%) = 25.8; Act/Ag ratio = 0.86; FVIII:C (%) = 61.5; Platelets (x10^9/L) = 377

      CaseNOTHPOs:

      CaseNOTHPOFreeText:

      CasePreviousTesting: The Thrombosis-Hemostasis gene panel test used whole exome sequencing and included 99 diagnostic-grade genes (table 1 in PMID:36696193)

      GenotypingMethod: WES using the coagulation subpanel of the UZ Leuven Thrombosis-Haemostasis gene panel test. WES was performed on the sequencing platform NovaSeq 6000 (Illumina), and Alissa Interpret software v5.2-5.4 (Agilent) was used for variant interpretation. Assessment of copy number variation was validated within the bioinformatics pipeline. The American College of Medical Genetics and Genomics and the Association of Molecular Pathology guidelines were used to classify variants as pathogenic (P), likely pathogenic (LP), a variant of uncertain significance (VUS), or (likely) benign (LB, B) variants

      PreviouslyPublished:

      Gene: VWF

      Variant: c.4751A>G p.Tyr1584Cys

      HGVS:

      ClinVarID: 310

      CAID:

      gnomAD: 0.003442 (5555 in 1613678) 15 homozygotes https://gnomad.broadinstitute.org/variant/12-6018667-T-C?dataset=gnomad_r4

    15. Case UZ063: 10 year old male (row 64 supplemental table)

      DiseaseAssertion: type 2M VWD

      FamilyInfo:

      ParentalGenotype(s):

      CasePresentingHPOs: HP:0032442, HP:0040225

      CaseHPOFreeRext: vWF:Ag (%) = 20.2; vWF:GPIbR (%) = 8.5; Act/Ag ratio = 0.42; FVIII:C (%) = 28; Platelets (x10^9/L) = 242

      CaseNOTHPOs:

      CaseNOTHPOFreeText:

      CasePreviousTesting: The Thrombosis-Hemostasis gene panel test used whole exome sequencing and included 99 diagnostic-grade genes (table 1 in PMID:36696193)

      GenotypingMethod: WES using the coagulation subpanel of the UZ Leuven Thrombosis-Haemostasis gene panel test. WES was performed on the sequencing platform NovaSeq 6000 (Illumina), and Alissa Interpret software v5.2-5.4 (Agilent) was used for variant interpretation. Assessment of copy number variation was validated within the bioinformatics pipeline. The American College of Medical Genetics and Genomics and the Association of Molecular Pathology guidelines were used to classify variants as pathogenic (P), likely pathogenic (LP), a variant of uncertain significance (VUS), or (likely) benign (LB, B) variants

      PreviouslyPublished:

      Gene: VWF

      Variant: c.3863T>G p.Leu1288Arg

      HGVS:

      ClinVarID: 100294

      CAID:

      gnomAD: absent

    16. 47 F AVWS AVWS + type 1 VWD variant c.4751A>G p.Tyr1584Cys LP

      Case 17: 47 year old female, study ID UZ099 in supplemental table

      DiseaseAssertion: acquired VWD presequencing, acquired VWD + type 1 VWD variant postsequencing

      FamilyInfo:

      ParentalGenotype(s):

      CasePresentingHPOs: HP:0032370

      CaseHPOFreeRext: vWF:Ag (%) = 2.6; vWF:GPIbR (%) = 2.2; Act/Ag ratio = 0.85; FVIII:C (%) = 7; Platelets (x10^9/L) = 325

      CaseNOTHPOs:

      CaseNOTHPOFreeText:

      CasePreviousTesting: The Thrombosis-Hemostasis gene panel test used whole exome sequencing and included 99 diagnostic-grade genes (table 1 in PMID:36696193)

      GenotypingMethod: WES using the coagulation subpanel of the UZ Leuven Thrombosis-Haemostasis gene panel test. WES was performed on the sequencing platform NovaSeq 6000 (Illumina), and Alissa Interpret software v5.2-5.4 (Agilent) was used for variant interpretation. Assessment of copy number variation was validated within the bioinformatics pipeline. The American College of Medical Genetics and Genomics and the Association of Molecular Pathology guidelines were used to classify variants as pathogenic (P), likely pathogenic (LP), a variant of uncertain significance (VUS), or (likely) benign (LB, B) variants

      PreviouslyPublished:

      Gene: VWF

      Variant: c.4751A>G p.Tyr1584Cys

      HGVS:

      ClinVarID: 310

      CAID:

      gnomAD: 0.003442 (5555 in 1613678) 15 homozygotes https://gnomad.broadinstitute.org/variant/12-6018667-T-C?dataset=gnomad_r4

      MultipleGeneVariants:

      FGG variant

      Variant: c.323C>G p.Ala108Gly

      ClinVarID: 547969

      gnomAD: 0.003031 (4885 in 1611606) 12 homozygotes https://gnomad.broadinstitute.org/variant/4-154611883-G-C?dataset=gnomad_r4

    17. 0 M Low VWF Low VWF c.4342C>T p.Gln1448∗ NA NA 0 LP

      Case 18: 0 year old male, study ID UZ078 in supplmental table

      DiseaseAssertion: low VWF

      FamilyInfo:

      ParentalGenotype(s):

      CasePresentingHPOs: HP:0032370

      CaseHPOFreeRext: vWF:Ag (%) = 51.6; vWF:GPIbR (%) = 45.7; Act/Ag ratio = 0.89; FVIII:C (%) = 86.7; Platelets (x10^9/L) = 487

      CaseNOTHPOs:

      CaseNOTHPOFreeText:

      CasePreviousTesting: The Thrombosis-Hemostasis gene panel test used whole exome sequencing and included 99 diagnostic-grade genes (table 1 in PMID:36696193)

      GenotypingMethod: WES using the coagulation subpanel of the UZ Leuven Thrombosis-Haemostasis gene panel test. WES was performed on the sequencing platform NovaSeq 6000 (Illumina), and Alissa Interpret software v5.2-5.4 (Agilent) was used for variant interpretation. Assessment of copy number variation was validated within the bioinformatics pipeline. The American College of Medical Genetics and Genomics and the Association of Molecular Pathology guidelines were used to classify variants as pathogenic (P), likely pathogenic (LP), a variant of uncertain significance (VUS), or (likely) benign (LB, B) variants

      PreviouslyPublished:

      Gene: VWF

      Variant: c.4342C>T p.Gln1448*

      HGVS:

      ClinVarID: 2572655

      CAID:

      gnomAD: absent

    1. Case: Row 2 in Supplemental Table 1. Represents 1 patient that has two variants in VWF.

      DiseaseAssertion: type 3 VWD

      FamilyInfo:

      ParentalGenotype(s):

      CasePresentingHPOs:

      CaseHPOFreeRext: FVIII:C/VWF:Ag = 3.0 (1.7-4.0); VWFpp/VWF:Ag = 1.9 (1.5-2.9)

      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: Del exon 4-5

      HGVS: c.221-977_532+7059del

      ClinVarID: 156329

      CAID:

      gnomAD: absent

      MultipleVariants:

      Gene: VWF

      Variant: L2306R fs*4

    2. Case: Row 21 in Supplemental Table 1. Variant is found in 14 patients in 13 families

      DiseaseAssertion: 10 have type 1 VWD, 2 have VWD type 2A, 2 have VWD type 2M

      FamilyInfo:

      ParentalGenotype(s):

      CasePresentingHPOs:

      CaseHPOFreeRext: FVIII:C/VWF:Ag = 1.2 (1.1-1.4); VWFpp/VWF:Ag = 2.0 (1.2-2.9)

      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: 2771G>A R924Q

      HGVS: VWF:c.2561G>A p.Arg854Gln

      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: Type 1: two also had C2304Y and one had T1156M. 2M: one also had R1374H. 2A: one also had G1609R

    3. Case: Row 2 in Supplemental Table 1. Represents 13 patients in 13 families.

      DiseaseAssertion: 13 type 1 VWD

      FamilyInfo:

      ParentalGenotype(s):

      CasePresentingHPOs:

      CaseHPOFreeRext: FVIII:C/VWF:Ag = 3.0 (1.7-4.0); VWFpp/VWF:Ag = 1.9 (1.5-2.9)

      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: Del exon 4-5

      HGVS: c.221-977_532+7059del

      ClinVarID: 156329

      CAID:

      gnomAD: absent

    4. Case: Row 8 in Supplemental Table 1.

      DiseaseAssertion: type 3 VWD

      FamilyInfo:

      ParentalGenotype(s):

      CasePresentingHPOs:

      CaseHPOFreeRext: FVIII:C/VWF:Ag = 10.0; VWFpp/VWF:Ag = 1.0

      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: 1543_1544insGGACAGCT V515G fs*65

      HGVS: c.1543_1544insGGACAGCT (p.Val515Glyfs*65)

      ClinVarID: 1695359

      CAID:

      gnomAD: absent

    5. Case: Row 16 in Supplemental Table 1.

      DiseaseAssertion: type 2N VWD

      FamilyInfo:

      ParentalGenotype(s):

      CasePresentingHPOs:

      CaseHPOFreeRext: FVIII:C/VWF:Ag = 0.2; VWFpp/VWF:Ag = 2.0

      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: 2372C>T T791M

      HGVS: VWF:c.2372C>T p.Thr791Met

      ClinVarID: 294

      CAID:

      gnomAD: 0.00001797 (29 in 1614030) no homozygotes https://gnomad.broadinstitute.org/variant/12-6044361-G-A?dataset=gnomad_r4

      MultipleGeneVariants:

      Gene: VWF

      Variant: P812R fs*31

    6. Case: Row 20 in Supplemental Table 1. Variant is found in 14 patients in 14 families

      DiseaseAssertion: 7 have type 1 VWD, 7 have VWD type 2N

      FamilyInfo:

      ParentalGenotype(s):

      CasePresentingHPOs:

      CaseHPOFreeRext: FVIII:C/VWF:Ag = 1.2 (0.4-1.9); VWFpp/VWF:Ag = 2.7 (1.6-3.8)

      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: 2561G>A R854Q

      HGVS: VWF:c.2561G>A p.Arg854Gln

      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: Type 2N; Three also had R2535, one N2546Y, one 6257-1G>A (novel), and one H1419M fs22 (novel). Type 1: one also had S1090_C1099del (novel) and one had del exon 33-34

    7. 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

    1. CasePT-104: United States

      CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)

      HPOsFreeText: N/A

      CaseNotHPOs: HP:0001650, HP:0001658 (Aortic valve stenosis, Myocardial infarction)

      NotHPOsFreeText: N/A

      CaseAddInfo:


      CaseGenotypingMethod: DNA was collected from the participants using blood samples. 18 genes suspected on contributing to HCM were targeted and sequenced. The variants were then located and filtered for pathogenicity.


      Variant: NM_000257.3:c.4399C>G (p.Leu1467Val)

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

      gnomAD: South Asian 1.111e-3, Overall 1.352e-4 https://gnomad.broadinstitute.org/variant/14-23886482-G-C

    1. 1

      Case1: Male, 0.5 yr onset, 2.5 yr diagnosis, 10.04 yr report

      CasePresentingHPOs: HP:0001371 (Contractures)

      HPOsFreeText: Wheelchair used, FVC z-score sitting -0.25 (97% pred), FVC z-score supine -1.12 (87% pred), 65% MRC Scale, 530 CK U/l, 9.1 GAA activity (nmol/h/mg)^h from cultured fibroblasts

      NotHPOsFreeText: No respiratory support

    2. 7

      Case7: Male, 1 yr onset, 2 yr diagnosis, 13.7 yr report

      CasePresentingHPOs: HP:0002650 (Scoliosis)

      HPOsFreeText: Respiratory support at night, FVC z-score sitting -4.08 (54% pred), FVC z-score supine -5.4 (39% pred), 87% MRC Scale, 548 CK U/l, 17.9 GAA activity (nmol/h/mg)^h from cultured fibroblasts

      NotHPOsFreeText: No wheelchair used

    1. Patient 5

      Case5: Female, Caucasian, United States, 2 months onset and diagnosis, 0.4 years report

      CasePresentingHPOs: HP:0011968, HP:0011469, HP:0012378, HP:0004347, HP:0010453 (Feeding difficulties, Nasal regurgitation, Fatigue, Weakness of muscles of respiration, Pelvic bone asymmetry)

      HPOsFreeText: Difficulty in lying supine while eating, sleeping and self-limited gasping episodes was observed, PT evaluation showed mild consistent asymmetry with increased lateral head tilt to the right, Tendency towards flexion/abduction/external rotation positioning of lower extremities was noted, Slight lateral thigh grooves reflected early IT band tightness with decreased posterior weight shift and propping on forearms in prone, AIMS score was at 10th percentile for chronological age and 25th to 50th percentile for corrected age, ALT 27 U/L (Normal 5–40 U/L), AST 36 U/L (Normal 15–41 U/L), ALP 352 U/L (Normal 24–170 U/L), Urinary Glc4 4.1 mmol/mol creatinine (Normal ≤8.3 mmol/mol creatinine)

      CaseNotHPOs: HP:0002033, HP:0002015, HP:0004323, HP:0003808 (Poor suck, Poor swallowing, Abnormality of body weight, Abnormal muscle tone)

      NotHPOsFreeText: CK levels, ECG, and ECHO have consistently been within normal limits, Had normal passive ranges of motion and appropriate weight bearing through lower extremities in supported standing

    2. Patient 4

      Case4: Female, Caucasian, United States, 1 month onset, 6 months diagnosis, 1.1 years report

      CasePresentingHPOs: HP:0003236, HP:0012378, HP:0006589, HP:0003725 (Increased serum CK, Fatigue, Flaring of lower rib cage, Firm muscles)

      HPOsFreeText: HyperCKemia present in the first month (505 IU/L; Normal 30–279 IU/L) but normalized spontaneously at 4 months (188 IU/L), PT assessment revealed subtle motor signs including preferred position of ring sitting with hips in flexion/abduction/external rotation and bilateral IT band tightness, Imbalanced trunk flexion, Decreased use of abdominals and excessive use of spinal extension, Asymmetry was noted in reaching objects in prone and weight shifting with lateral flexion and shortening on the left at the neck and trunk, AIMS score was at the 25th percentile and GMFM was 22.14%, Urinary Glc4 4.8 mmol/mol creatinine (Normal ≤8.3 mmol/mol creatinine)

      CaseNotHPOs: HP:0003690 (Limb muscle weakness)

      NotHPOsFreeText: She had no head lag when pulled to sit and the ability to transfer objects and bring them to midline

    3. Patient 1

      Case1: Male, Caucasian, United States, Birth onset

      CasePresentingHPOs: HP:0008872, HP:0002100, HP:0001508, HP:0008947, HP:0001655, HP:0003236, HP:0200136, HP:0001290, HP:0002835, HP:0002194 (Feeding difficulties in infancy, Recurrent aspiration pneumonia, Poor weight gain, Infantile muscular hypotonia, Patent foramen ovale, Increased serum CK, Oropharyngeal dysphagia, Low muscle tone, Aspiration, Delayed gross motor development)

      HPOsFreeText: HyperCKemia was present since the early neonatal period (378 IU/L, day 8 of life; N: 60–305 IU/L), ERT at a dose of 20 mg/kg every 2 weeks was initiated at age 1 month, CK levels were normalized on ERT by age 4 months (80 IU/L), Flexion/abduction/ external rotation positioning of lower extremities, iliotibial (IT) band tightness, lack of independent sitting, AIMS score between 10th and 25th percentile, GMFM at 23.16%, At age 23 months, he had achieved significant motor milestones; started sitting with support at 10 months and without support at 12 months, pulled to stand at 12 months, walked at 15 months and could feed himself with an immature pincer grasp. Swallow study was normal, ALT 26 U/L (Normal 5–40 U/L), AST 45 U/L (Normal 15–41 U/L), ALP 211 U/L (Normal 24–170 U/L), Urinary Glc4 3.7 mmol/mol creatinine (Normal ≤8.3 mmol/mol creatinine)

      CaseNotHPOs: HP:0011675, HP:0002910 (ECG abnormality, Elevated hepatic transaminases)

      NotHPOsFreetext:

      CaseAddInfo: Older brother of Patient 2, Late-Onset Pompe Disease

    4. Patient 2

      Case2: Male, Caucasian, United States, Birth onset

      CasePresentingHPOs: HP:0001290, HP:0200136, HP:0002033, HP:0003236, HP:0001655, HP:0002058, HP:0002194, HP:0002421, HP:0000467, HP:0002015 (Generalized hypotonia, Oral-pharyngeal dysphagia, Poor suck, Increased serum CK, Patent foramen ovale, Myopathic face, Delayed gross motor development, Poor head control, Neck muscle weakness, Dysphagia)

      HPOsFreeText: hyperCKemia at 435 IU/L on day of life 4, Patent foramen ovale detected at birth by ECHO but resolved spontaneously, PT evaluation at age 2 months revealed flexion/abduction/external rotation positioning of lower extremities with tightness bilaterally in hip flexors, hamstrings, and IT bands, Had a tendency to remain on toes when held in supported standing with additional support required for weight bearing through lower extremities, Had difficulty lifting his head in prone, with asymmetric head lift to 45 degrees, and an inability to maintain head in midline when supine, AIMS score at age 2 months was between 10–25th percentile, ALT 41 U/L (Normal 5–40 U/L), AST 33 U/L (Normal 15–41 U/L), ALP 239 U/L (Normal 24–170 U/L), Urinary Glc4 4.5 mmol/mol creatinine (Normal ≤8.3 mmol/mol creatinine)

      CaseNotHPOs: HP:0011016 (Abnormality of urine glucose concentration)

      NotHPOsFreeText:

      CaseAddInfo: Younger brother of Patient 1, Late-Onset Pompe Disease

    5. Patient 7

      Case7: Female, Caucasian, United States, 6 months diagnosis, 8 months report

      CasePresentingHPOs: HP:0001643, HP:0006699, HP:0006682, HP:0003722, HP:0008969 (Patent ductus arteriosus, Premature atrial contractions, Premature ventricular contractions, Neck flexor weakness, Leg muscle stiffness)

      HPOsFreeText: At 6 months head lag during pull to sit was noted, Had predominant overall flexion position of lower extremities with a tendency towards hip flexion/abduction/external rotation, with lateral thigh grooves suggestive of bilateral IT band tightness, AIMS score was between 10th and 25th percentile for chronological age and 50th percentile for her corrected age adjusted for prematurity while GMFM score was 16.55%, ALT 37 U/L (Normal 5–40 U/L), AST 53 U/L (Normal 15–41 U/L), ALP 174 U/L (Normal 24–170 U/L)

      CaseNotHPOs: HP:0003236, HP:0001712, HP:0001290 (Increased serum CK, Left ventricular hypertrophy, Decreased muscle tone)

      NotHPOsFreeText: Other evaluations including pulmonary, speech, and swallow were normal

    6. Patient 6

      Case6: Male, Caucasian, United States, 1 month onset, 6 months diagnosis, 8 months report

      CasePresentingHPOs: HP:0003236, HP:0001655, HP:0003701, HP:0006589, HP:0003093, (Increased serum CK, Patent foramen ovale, Proximal muscle weakness, Flaring of lower rib cage, Limited hip extension,

      HPOsFreeText: HyperCKemia was noticed in the first month (438 U/L; Normal 60–305) but normalized spontaneously by age 6 months, flexion/abduction/external rotation positioning of lower extremities and with bilateral IT band tightness was revealed at the same time, also had decreased active use of abdominal oblique muscles with a lack of active trunk rotation, Decreased active use of lower abdominal muscles with inability to achieve a posterior pelvic tilt in supine, AIMS score was at 1st percentile for age and GMFM was at 12.3%, ALT 30 U/L (Normal 5–40 U/L), AST 90 U/L (Normal 15–41 U/L), ALP 249 U/L (Normal 24–170 U/L), Urinary Glc4 2.6 mmol/mol creatinine (Normal ≤8.3 mmol/mol creatinine)

      CaseNotHPOs: HP:0001712, HP:0001290 (Left ventricular hypertrophy, Decreased muscle tone)

      NotHPOsFreeText: Other evaluations including cardiac, pulmonary, speech, and swallow were normal

    1. one confirmed LOPD patient

      Case1: Female, 55 years report, 25 years onset, Brazil, African

      CasePresentingHPOs: HP:0003325, HP:0003236, HP:0003148, HP:0100284, HP:0011807, HP:0003326, HP:0008994, HP:0002527, HP:0003551, HP:0002015, HP:0000822, HP:0000819, HP:0003119, HP:0003707, HP:0003391, HP:0003327, HP:0001315, HP:0002515, HP:0010546 (Limb-girlde muscle weakness, Increased serum CK, Elevated serum acid phosphatase, EMG: myotonic discharges, Type 1 muscle fiber atrophy, Myalgia, Proximal muscle weakness in lower limbs, Falls, Difficulty climbing stairs, Dysphagia, Hypertension, Diabetes mellitus, Dyslipidemia, Calf muscle pseudohypertrophy, Gowers sign, Axial muscle weakness, Reduced deep tendon reflexes, Waddling gait, Muscle fibrillation)

      HPOsFreeText: Serum CK 1467 U/L (normal: ≤ 200U/L), NaG/AaGIA ratio 40.4, %INH 87.2, GAA activity 4.2% from dried blood spot, Falls occurring mainly when walking for long distances, Normal Mini-Mental State Examination score (27/30), Mild symmetrical weakness in proximal muscles in the lower limbs (Medical Research Council grade 4), Needle electromyography revealed motor unit potentials with low amplitude and short duration in the iliopsoas muscle associated with fibrillation and short myotonic discharge potentials in lumbar paraspinal muscles

      CaseNotHPOs: HP:0001270 (Motor delay)

      NotHPOsFreeText: Muscle biopsy with the absence of vacuolar myopathy

      CaseAddInfo: Late-Onset Pompe Disease, One sister diagnosed with LOPD based on low GAA activity and shared genetic variants but no other known relatives with the condition

    1. 3

      Case3: Male, 19 years report, Italy

      CasePresentingHPOs: HP:0003551 (Difficulty climbing stairs)

      HPOsFreeText: Height is 1.78 m, Weight is 60 kg, BMI is 18.9 kg/cm2, 7 years on ERT, Forced Vital Capacity at 107%

      CaseNotHPOs: HP:0002098 (Respiratory distress)

      NotHPOsFreeText: Nocturnal non-invasive ventilation

      CaseAddInfo: Late Onset Pompe Disease

    2. 1

      Case1: Female, 46 years report, Italy

      CasePresentingHPOs: HP:0003551 (Difficulty climbing stairs)

      HPOsFreeText: Height is 1.64 m, Weight is 50 kg, BMI is 18.6 kg/cm2, 2 years on ERT, Forced Vital Capacity at 108%

      CaseNotHPOs: HP:0002098 (Respiratory distress)

      NotHPOsFreeText: Nocturnal non-invasive ventilation

      CaseAddInfo: Late Onset Pompe Disease

    1. II

      CaseII: Adult onset, 71 years diagnosis

      CasePresentingHPOs: HP:0003701, HP:0003326, HP:0003236, HP:0003198 (Proximal muscle weakness, Myalgia, Increased serum CK, Myopathy)

      HPOsFreeText: Plasma CK 5–10× Normal, GAA activity from dried blood spot: 0%, 6-Minute Walking Test: 40 min, Forced Vital Capacity Seated: 850 (22%)

      CaseNotHPOs: HP:0002795 (Abnormal respiration)

      CaseAddInfo: Late-Onset Pompe Disease

    2. 1

      CaseV,1: Adolescent onset, 42 years diagnosis

      CasePresentingHPOs: HP:0003701, HP:0003236, HP:0003388, HP:0003326 (Proximal muscle weakness, Increased serum CK, Easy fatigability, Myalgia)

      HPOsFreeText: Plasma CK 5-10× Normal, Vacuoles in histology, 6-Minute Walking Test: 135 min, Forced Vital Capacity Seated: 950 (20%), GAA activity from dried blood spot: 0.20%

      CaseNotHPOs: HP:0002795 (Abnormal respiration)

      CaseAddInfo: Late-Onset Pompe Disease

    3. 3

      CaseV,3: Child onset, 45 years diagnosis

      CasePresentingHPOs: HP:0003701, HP:0003236 (Proximal muscle weakness, Increased serum CK)

      HPOsFreeText: Plasma CK 2.5-5× Normal, GAA activity from dried blood spot: 0.08%, 6-Minute Walking Test: 566 min

      CaseNotHPOs: HP:0002795 (Abnormal respiration)

      CaseAddInfo: Late-Onset Pompe Disease

    4. III

      CaseIII: Adult onset, 63 years diagnosis

      CasePresentingHPOs: HP:0003701, HP:0003388, HP:0003236, HP:0003198, HP:0002460, HP:0002015 (Proximal muscle weakness, Easy fatigability, Increased serum CK, Myopathy, Distal muscle weakness, Dysphagia)

      HPOsFreeText: Plasma CK 2.5–5× Normal, GAA activity from muscle: 11.7%

      CaseNotHPOs: HP:0002795 (Abnormal respiration)

      CaseAddInfo: Late-Onset Pompe Disease

    5. I

      CaseI: Early adult onset, 49 years diagnosis

      CasePresentingHPOs: HP:0003701, HP:0003388, HP:0003236, HP:0003198 (Proximal muscle weakness, Easy fatigability, Increased serum CK, Myopathy)

      HPOsFreeText: Plasma CK 5–10× Normal, GAA activity from lymphocytes: 14.2%

      CaseNotHPOs: HP:0002795 (Abnormal respiration)

      CaseAddInfo: Late-Onset Pompe Disease

    6. 2

      CaseV,2: Adult onset, 33 years diagnosis

      CasePresentingHPOs: HP:0003701, HP:0003236, HP:0003388 (Proximal muscle weakness, Increased serum CK, Easy fatigability)

      HPOsFreeText: Plasma CK 5-10× Normal, 6-Minute Walking Test: 566 min, Forced Vital Capacity Seated: 3000 (90%), GAA activity from dried blood spot: 0.20%

      CaseNotHPOs: HP:0002795 (Abnormal respiration)

      CaseAddInfo: Late-Onset Pompe Disease

    1. 9

      Case9: Male, 40 years onset, 45 years diagnosis, 74 years report, France

      CasePresentingHPOs: HP:0002540, HP:0002878, HP:0004887 (Inability to walk, Respiratory failure, Respiratory failure requiring assisted ventilation)

      HPOsFreeText: Lost ambulation at 50 years, Started invasive ventilation at 67 years, Started ERT given every other week at a dose of 20 mg/kg at 70 years for 43 months, Peak Anti-rhGAA antibodies at 1:409,600, Time off ventilation stayed constant at 0 min, Total Motor Function Measure from 29 to 26, 6MWT stayed constant at 0 meters

      CaseNotHPOs: HP:0030148 (Heart murmur)

      NotHPOsFreeText: No adverse reaction to ERT was recorded

      CaseAddInfo: Late Onset Pompe Disease

    2. 12

      Case12: Male, 35 years onset, 50 years diagnosis, 61 years report, France

      CasePresentingHPOs: HP:0002540, HP:0002878, HP:0004887 (Inability to walk, Respiratory failure, Respiratory failure requiring assisted ventilation)

      HPOsFreeText: Lost ambulation at 48 years, Started invasive ventilation at 35 years, Started ERT given every other week at a dose of 20 mg/kg at 56 years for 49 months, Peak Anti-rhGAA antibodies at 1:1600, FVC at 0 (L / % expected), MIP at 22 (cm H2O), MEP at 28 (cm H2O), Time off ventilation stayed constant at 0 min, 6MWT stayed constant at 0 meters

      CaseNotHPOs: HP:0030148 (Heart murmur)

      NotHPOsFreeText: No adverse reaction to ERT was recorded

      CaseAddInfo: Late Onset Pompe Disease

    3. 3

      Case3: Male, 28 years onset, 30 years diagnosis, 69 years report, France

      CasePresentingHPOs: HP:0002540, HP:0002878, HP:0004887, HP:0002093 (Inability to walk, Respiratory failure, Respiratory failure requiring assisted ventilation, Respiratory insufficency)

      HPOsFreeText: Lost ambulation at 58 years, Started invasive ventilation at 28 years, Started ERT given every other week at a dose of 20 mg/kg at 68 years for 11 months, Peak Anti-rhGAA antibodies at 1:1600, FVC at 0.45/13 (L / % expected), MIP at 17 (cm H2O), MEP at 29 (cm H2O), Time off ventilation stayed constant at 0, Total Motor Function Measure from 31 to 27

      CaseNotHPOs: HP:0030148 (Heart murmur)

      NotHPOsFreeText: No adverse reaction to ERT was recorded

      CaseAddInfo: Late Onset Pompe Disease, Patient died before publication

    1. 62-year-old man

      Case1: Male, 62 years report

      CasePresentingHPOs: HP:0002091, HP:0002878, HP:0003701, HP:0040047, HP:0002098, HP:0100786, HP:0006510, HP:0005978, HP:0000822, HP:0003124, HP:0001677, HP:0003236, HP:0004324, HP:0002329, HP:0030207, HP:0002098, HP:0040047, HP:0100750, HP:0002097, HP:0007269, HP:0040046 (Restrictive lung disease, Respiratory failure, Proximal muscle weakness, Abnormality of the right hemidiaphragm, Shortness of breath, Hypersomnia, Chronic obstructive pulmonary disease, Diabetes mellitus Type II, Hypertension, Hypercholesterolemia, Coronary artery disease, Elevated serum creatine kinase, Increased body weight, Drowsiness, Paradoxical respiration, Respiratory distress, Abnormality of the right hemidiaphragm, Atelectasis, Emphysema, Spinal muscular atrophy, Abnormality of the left hemidiaphragm)

      HPOsFreeText: Hypercapnic respiratory failure, Chronic phrenic neuropathy bilaterally, Long history of apparently idiopathic right hemidiaphragm paralysis, Underwent muscle biopsy and electromyography, both of which showed nonspecific myopathic features associated with mild denervation, On presentation, the patient's vital signs were a temperature of 36.5 °C (97.7 °F); heart rate, 94 beats/minute; blood pressure, 104/70 mm Hg; respiratory rate, 22 breaths/minute; oxygen saturation, 90% when receiving 2 L of supplemental oxygen per minute; and body mass index, 29.9 kg/m2, Decreased air entry bilaterally, Laboratory values were: Hemoglobin, 120 g/L; platelets, 279 × 109/L; white blood cells, 7.7 × 109/L; sodium, 140 mmol/L; potassium, 5.1 mmol/L; bicarbonate, 40 mmol/L; serum urea nitrogen, 3.6 mmol/L; creatinine, 70.7 μmol/L; and calcium, 2.48 mmol/L, Fatty atrophy of rotator cuff musculature, Tests for resting room-air arterial blood gases showed a pH of 7.29; PCO2, 89.4 mm Hg; PO2, 67.6 mm Hg; and serum bicarbonate, 43 mmol/L, Right diaphragm paralysis, Electromyography showed complete absence of phrenic compound muscle action potentials bilaterally. No activation of motor unit potentials was seen within the diaphragm, either with respiration or with volitional effort. Ultrasonography showed that the left hemidiaphragm was hyperechoic, 0.14 cm thick at functional residual capacity (FRC), with a thickening ratio of 1.1 (the thickening ratio is thickness at total lung capacity/thickness at FRC). The right hemidiaphragm was hyperechoic, 0.15 cm thick at FRC, with thickening ratio of 0.9. (Normal thickness is >0.15 cm, normal thickening ratio is >1.2.) The aldolase concentration was slightly increased at 9 U/L (reference level, <7.7 U/L). To complete the evaluation for rarer causes of diaphragmatic dysfunction, neurology services requested testing for inherited neuropathies. Three weeks later, the patient's serum GAA level was 1.0 nmol/mL/hour (reference level, >7.4 nmol/mL/hour)

      CaseNotHPOs: HP:0003549 (Abnormality of connective tissue)

      NotHPOsFreeText: The following tests were within reference range: creatine kinase, thyroid function tests, erythrocyte sedimentation rate, serum and protein electrophoresis, antinuclear antibody profile, and anti-Jo antibodies

      CaseAddInfo: Ex-Smoker with 40–80 pack-years of smoking, Medications at presentation to facility included aspirin, clopidogrel, simvastatin, diltiazem, sitagliptin, metformin, budesonide and formoterol inhaler, tiotropium bromide inhaler, and albuterol inhaler

    1. 1

      Case1: Female, 12 years report, 3 years onset, 12 years diagnosis

      CasePresentingHPOs: HP:0003325, HP:0002093, HP:0002650 (Limb-girdle muscle weakness, Respiratory insufficiency, Scoliosis)

      HPOsFreeText: 730 CK (U/L), Normal Heart, 0 GAA activity (µmol/L/h), Showed respiratory involvement and required nocturnal non-invasive ventilation, An ambulant patient with 284 m six minute walk distance at the time of diagnosis

      CaseNotHPOs: HP:0003457, HP:0001627 (EMG abnormality, Abnormality of the heart)

      NotHPOsFreeText: Muscle weakness confined to limb-girdle muscles

    1. 4

      Case4: 0.5 years diagnosis, Germany

      CasePresentingHPOs: HP:0031185, HP:0001635, HP:0001252, HP:0001324, HP:0003236, HP:0001639 (Increased NT-proBNP level, Cardiac failure, Muscular hypotonia, Muscle weakness, Increased serum CK, Hypertrophic cardiomyopathy)

      HPOsFreeText: 3924 BNP (pg/ml), 7.68 IVS (d) z score, 6.42 IVS (s) z score, Heart Failure at NYHA Class 3

      NotHPOsFreeText: No left-ventricular outflow tract obstruction

      CaseAddInfo: Infantile-Onset Pompe Disease

    1. 1117

      Case1117: Male, 35 years onset, Welsh/English, Caucasian

      CasePresentingHPOs: HP:0003560, HP:0005110 (Muscular dystrophy, Atrial fibrillation)

      HPOsFreeText: 1,000 –2000's CK level, Immunohistochemistry: dystrophin, sarcoglycans, merosin

      CaseNotHPOs: HP:0009051, HP:0002540 (Increased muscle glycogen content, Non-ambulatory)

    1. Patient Number 3

      Case3: Male, 35 years report, 5 years onset, Algeria, African

      CasePresentingHPOs: HP:0003323, HP:0003749, HP:0002355, HP:0007340, HP:0008956, HP:0003484, HP:0003236, HP:0003198 (Progressive muscle weakness, Pelvic girdle muscle weakness, Difficulty walking, Lower limb muscle weakness, Proximal lower limb amyotrophy, Upper limb muscle weakness, Increased serum CK, Myopathy)

      HPOsFreeText: At grade 3 of Vignos and Walton scales, CK rate was 5 times the normal value and AST and ALT were normal, EMG was compatible with a myopathic disorder, GAA activity measured in leukocytes was significantly decreased

      CaseNotHPOs: HP:0003115, HP:0003116, HP:0001270, HP:0001290, HP:0002240, HP:0001640, HP:0005952, HP:0002540 (Abnormal ECG, Abnormal echocardiography, Motor delay, Generalized hypotonia, Hepatomegaly, Cardiomegaly, Decreased pulmonary function, Non-ambulatory)

    1. 15

      Patient15: Male, 21 years report, 2 years onset

      CasePresentingHPOs: N/A

      HPOsFreeText: GAA activity 4.7% from a dried blood spot

      CaseNotHPOs: HP:0002098, HP:0001324, HP:0001640, HP:0002240 (Respiratory distress, Muscle weakness, Cardiomegaly, Hepatomegaly)

      NotHPOsFreeText: No wheelchair needed, Respiratory Assistance not needed

      CaseAddInfo: LOPD

    1. The affected patient

      Case1: Male, French-Canadian, 18 years onset, 54 years diagnosis and report

      CasePresentingHPOs: HP:0008994, HP:0000822, HP:0003119, HP:0004398, HP:0007185, HP:0009109, HP:0002094, HP:0012764, HP:0002098 (Proximal muscle weakness in lower limbs, High blood pressure, dyslipidemia, Peptic ulcer, Loss of consciousness, Denervation of the diaphragm, Dyspnea, Orthopnea, Shortness of breath)

      HPOsFreeText: Dependent on continuous positive airway pressure or bilevel positive airway pressure when he is lying flat or sleeping because of previous intubation and tracheostomy, GAA activity measured from dried blood spot was 0.87 pmol/h/punch (Normal 4.96 - 27.3)

      CaseAddInfo: Late Onset Pompe Disease, The patient’s mother had six miscarriages and died at age 75 of lung cancer and his father died of cardiac problems in his early sixties, It appears that no other family members, including his parents and two siblings, were affected, patient had a previous appendectomy, He has no allergies, stopped smoking in 2002, and denied any alcohol or drug use

    1. In order toprovide final proof that SLC6A8 deficiency is caused by a de-fect of the creatine transporter, we transfected the wild-typeSLC6A8 open reading frame (ORF) into primary fibroblastsof a SLC6A8-deficient patient, and tested the creatine uptakecapacity

      RescuePatientCell: Primary fibroblasts from a SLC6A8-deficient patient.

      GeneAlteration: c.1540C>T (p.Arg514X) (previously described by Salomons et al, 2001, Am J Hum Genet, 68: 1497-1500)

      RescuePhenotype: Ability to transport creatine into the cell.

      RescueMethod: The wild type SLC6A8 open reading frame was cloned into an expression vector with EGFP. This construct was stably transfected into primary fibroblasts from patient with creatine transporter deficiency due to a nonsense variant, c.1540C>T (p.Arg514X) in SLC6A8 (previously described in PMD 11326334). Expression of the SLC6A8 fusion protein or EGFP protein (empty vector) was confirmed by the presence of green fluorescence. Expression was also confirmed by RT-PCR. Transfected cells were incubated for 24 hours with 25 umol/L creatine, 500 umol/L creatine, or 500 umol/L creatine plus 500 umol/L guanidinoproprionate (creatine transporter inhibitor). Intracellular creatine level was measured by GC-MS.

      RescueEvidence: When the wild type SLC6A8 open reading frame was expressed in primary fibroblasts from patient with creatine tarnsporter deficiency, due to a nonsense variant, c.1540C>T (p.Arg514X) in SLC6A8 (previously described in PMID 11326334), creatine uptake was restored to a level comparable with controls.

      RescueVariants: ClinVarID: 11696

    1. brother

      CaseExome-2:II-2: Male, Japan, Asian

      CaseExome-2:II-2PresentingHPOs: HP:0001873, HP:0040185, HP:0000421 (Thrombocytopenia, Macrothrombocytopenia, Epistaxis)

      HPOsFreeText: Platelet Count at 124 (x (10^9)/l), Platelet Size at 2.9 ± 0.9 (μm), No bleeding tendency

      CaseNotHPOs:

      NotHPOsFreeText:

      CaseAddInfo: Brother of proband, II-1

    2. proband

      CaseSanger-3:II-2: Female, Japan, Asian

      CasePresentingHPOs: HP:0001873, HP:0040185, HP:0000421 (Thrombocytopenia, Macrothrombocytopenia, Epistaxis)

      HPOsFreeText: Platelet Count at 80 (x (10^9)/l), Platelet Size at 3.0 ± 0.9 (μm), 59% (2.5 μm) aggregation ADP

      CaseNotHPOs:

      NotHPOsFreeText:

      CaseAddInfo: Proband of Family Sanger-3

    3. proband

      CaseExome-2:II-1: Male, Japan, Asian

      CaseExome-2:II-1PresentingHPOs: HP:0001873, HP:0040185 (Thrombocytopenia, Macrothrombocytopenia)

      HPOsFreeText: Platelet Count at 54 (x (10^9)/l), Platelet Size at 3.1 ± 1.1 (μm), No bleeding tendency, 4.5 min bleeding time, 34% (2 μm) aggregation ADP

      CaseNotHPOs:

      NotHPOsFreeText:

      CaseAddInfo: Proband for Family Exome-2

    4. father

      CaseSanger-1:I-1: Male, Japan, Asian

      CasePresentingHPOs: HP:0001873, HP:0040185 (Thrombocytopenia, Macrothrombocytopenia)

      HPOsFreeText: Platelet Count at 131 (x (10^9)/l), Platelet Size at 4.2 ± 1.3 (μm), No bleeding tendency, 1 min bleeding time, 49% (2 μm) aggregation ADP

      CaseNotHPOs:

      NotHPOsFreeText:

      CaseAddInfo: Father of proband, II-1

    5. proband

      CaseSanger-1:II-1: Female, Japan, Asian

      CasePresentingHPOs: HP:0001873, HP:0040185 (Thrombocytopenia, Macrothrombocytopenia)

      HPOsFreeText: Platelet Count at 120 (x (10^9)/l), Platelet Size at 3.9 ± 1.6 (μm), No bleeding tendency, 66% (2 μm) aggregation ADP

      CaseNotHPOs:

      NotHPOsFreeText:

      CaseAddInfo: Proband for Family Sanger-1

    6. proband

      CaseSanger-2:III-2: Female, Japan, Asian

      CasePresentingHPOs: HP:0001873, HP:0040185 (Thrombocytopenia, Macrothrombocytopenia)

      HPOsFreeText: Platelet Count at 77 (x (10^9)/l), Platelet Size at 3.7 ± 1.5 (μm), No bleeding tendency, 2 min bleeding time

      CaseNotHPOs:

      NotHPOsFreeText:

      CaseAddInfo: Proband of Family Sanger-2, Had a sister, mother, and grandfather who had the disorder but were not genetically tested to confirm the presence or absence of her variant

    1. 926T > C and 236G > A in the other case

      Case: Haagerup II:5

      CasePresentingHPOs:

      CasePresentingHPOsFreeText: not specified

      CaseNOTHPOs:

      CaseNOTHPOSFreeText: not specified

      CasePreviousTesting: same as group

      CaseGenotypingMethod: same as group

      Variants: c926T>C and c236G>A

      ClinVarID: or CAID: ClinVarID: 8426; ClinVarID: 8424

      gnomAD: 2/129174 European (non-Finnish) alleles at a frequency of 0.00001548 with no homozygotes; not present in gnomAD

      AddCaseInfo:

      PreviouslyPublished: no

      VariantEvidence: predicted but variant was proven to segregate with disease; no detectable protease activity when analyzed by western blotting (PMID: 10074491)

    1. GroupID/ KindredID: VHL 48

      Case: Sex unknown, Age unknown, German

      DiseaseAssertion: assumed VHL

      FamilyInfo: One patient with the given mutation is stated to belong to VHL family 48

      CasePresentingHPOs: HP:0010797 (hemangioblastoma)

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: c.464-1G>A

      CaseProblemVariantFreeText: N/A

      LegacyVariant: c.677-1G>A

      ClinVarID: 43603 https://www.ncbi.nlm.nih.gov/clinvar/variation/43603/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: splice_site_variant

      CivicName: Splice Site (c.464-1G>A)

      MultipleGeneVariants: N/A

    1. 28F/32ASUnilateral PCCVHLIVS 2c.341-2 A>GSplice Site ChangeSplice site changeDisease causingNANANRNR

      150 index patients with pheochromocytoma/paraganglioma were evaluated. Phenotypic data were collected and germline mutations in five susceptibility genes (RET, VHL, SDHB, SDHD and SDHC) were tested. Out of 30 patients with familial presentation, 13 were clinically diagnosed as VHL syndrome. A 32 year old Asian Indian female presented with unilateral pheochromocytoma. Using PCR and Sanger sequencing through peripheral blood, genetic testing confirmed a non-familial splice mutation at c.341-2 A>G of the VHL gene. Family history is unknown.

    1. PMID: 7977367

      KindredID: 15

      DiseaseAssertion: VHL

      GroupSize: Unknown

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: N/A

      GroupAgeRange: N/A

      GroupInfo: This is a family belonging to prefigure No. 15. They are described as ‘VHL-affected’.

      GroupPresentingHPOs: HP:0005584 (renal cell carcinoma)

      GroupHPOFreeText: RCC-affected; other manifestations are possible but not clear.

      GroupNotHPOs: N/A

      GroupNotHPOFreeText: N/A

      GroupPreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.Y98H (c.292T>C)

      LegacyVariant: p.Y169H (c.505T>C)

      CaseProblemVariantFreeText: N/A

      ClinVarID: 2223 https://www.ncbi.nlm.nih.gov/clinvar/variation/2223/

      CAID: N/A

      gnomAD: 0.00001343, https://gnomad.broadinstitute.org/variant/3-10183823-T-C?dataset=gnomad_r2_1

      VariantEvidence: N/A

      MutationType: missense_variant; transition

      CivicName: Y98H (c.292T>C)

      MultipleGeneVariants: N/A

    1. Arg167Trp (712C-T)

      PatientID: (proband)

      KindredID: 4

      Case: M, Age unknown, Chinese

      DiseaseAssertion: pheochromocytoma 
FamilyInfo: There is a history of non-syndromic familial pheochromocytoma in this patient’s family history as well as a confirmed presence of this same germline mutation in their family. It is not perfectly clear which pedigree belongs to this family.

      CasePresentingHPOs: HP:0002666 (pheochromocytoma)

      CaseHPOFreeText: non-syndromic pheochromocytoma

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: No clinical manifestations of hereditary syndromes, including MEN2A, MEN2B, VHL, and NF1 were found

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.R167W (c.499C>T)

      LegacyVariant: p.R167W (c.712C>T)

      CaseProblemVariantFreeText: N/A

      ClinVarID: 2218, https://www.ncbi.nlm.nih.gov/clinvar/variation/2218/

      CAID: N/A

      gnomAD: 0.000007954, https://gnomad.broadinstitute.org/variant/3-10191506-C-T?dataset=gnomad_r2_1

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: R167W (c.499C>T)

      MultipleGeneVariants: N/A

    1. Genotype-phenotype correlations of 573 VHL patients were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). This missense mutation (c.496G>T), affecting surface residue of pVHL protein core, was found in 2 VHL type 2A families with 5 affected individuals altogether. Two of 5 patients had retinal angioma, 2 had cerebellar hemangioblastoma, and 4 had pheochromocytoma. This mutation was reported in the paper with an incorrect cDNA written as c.498A>G, however correct translation should be deduced to c.496G>T, as the Latif et al. 1993 (AFO10238) sequence given was as c.709G>T with p.V166F.

    2. Genotype-phenotype correlations of 573 VHL patients were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). This missense mutation (c.538A>G), affecting residue within the pVHL protein core, was found in a VHL patient with renal cell carcinoma diagnosed at 27Y. ACMG codes as follows: Supporting evidence of pathogenicity because Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease (PP2).

    1. c.262T > C p.Trp88Arg

      540 patients from 187 unrelated Chinese VHL families at the Peking University First Hospital were all screened for VHL clinical features and germline mutations. Of these, clinical characteristics were observed in 258 patients from 80 unrelated Chinese families. These were reported in this study, grouped by the 21 mutations found. PCR and MLPA on peripheral blood detected the VHL mutations. Of these, 21 patients from two families were found to harbour the VHL germline mutation c.262T>C (p.Trp88Arg). From family 1, a total of 17 family members including the proband were identified. Three of these did not present VHL clinical features. The 32 year old proband (patient 15) presented with pancreatic neuroendocrine tumor or pancreatic cyst and renal cell carcinoma. Her maternal grandfather presented with renal cell carcinoma at age 65. Her maternal great-uncle (patient 3), great-aunt (patient 4), mother (patient 6) and 6 first cousins once removed (patients 7, 8, 9, 10, 13, 14) each presented with cerebellar hemangioblastomas at ages 62, 37, 35, 41, 40, 35, 29 37 and 37 respectively. One of these cousins (9) also presented with renal cell carcinoma at age 42. Two other 1st cousins once removed (patients 11 and 12) presented with renal cell carcinoma at ages 35 and 40, as did her sister at the age of 27. From family 2, the proband presented with no clinical features, however, her mother (2) presented with pancreatic cancer at age 45. Both her maternal uncle (patient 3) and grandmother (patient 1) presented with cerebellar hemangioblastomas at ages 50 and 48 respectively. This same uncle also had pheochromocytoma, also identified at the age of 50. ACMG evidence codes: 'PP1' since we have cosegregation with the disease in multiple affected family members (both families 1 and 2), 'PP4' since the patient presents phenotypes highly specific for a disease with a single genetic etiology.

    1. Germline mutations were identified in 300/469 (63%) of the families tested; 137 distinct intragenic germline mutations were detected.

      Germline mutational data on VHL was gathered from various countries to assess variation in germline mutations that produce disease within different populations. Families were grouped according to three possible outcomes of disease: renal cell carcinoma without pheochromocytoma, renal cell carcinoma with pheochromocytoma, or pheochromocytoma alone. SSCP and denaturing gradient gel electrophoresis identified mutations in 300/469 (63%) of families affected with VHL. This germline familial VHL mutation (F136S (c.407T>C)) was taken from the Neuro Olcologie database in Paris, and the Cambridge, Department of Pathology database. It had an unknown number of members belonging to Family ID 53F, reported in Table 3, as being found in VHL families without pheochromocytoma, and with renal cell carcinoma. Additionally, it was reported in table 5, specified as families without detailed clinical information, under family ID 27CA. It was reported in the paper as c.620T>C due to a difference in transcript reference.

    1. nt 699 C to G, Cys to Trp

      Fourty-four of 389 patients with VHL (between 1988-1999) screened positive for PNETs either by pathologic analysis of tissue specimens or by characteristic radiographic appearance on CT and MRI. VHL gene germline mutations were determined by quantitative Southern blotting to detect deletions of the gene and gene rearrangements as well as complete gene sequencing. Patient 29 (29-year-old male) was found to harbour the c. 486C>G mutation in the VHL gene (stated as 699 C to G in the paper which used the Latif sequence as reference) and presented with two pathologic pancreatic neuroendocrine tumors. ACMG evidence codes: 'PP4' since the patient presents phenotypes highly specific for a disease with a single genetic etiology.

    1. GroupID: 3127

      DiseaseAssertion: assumed VHL

      GroupSize: 47

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: German

      GroupAgeRange: N/A

      GroupInfo: Familial VHL stated; 47 family members recorded with this mutation.

      GroupPresentingHPOs: HP:0010797; HP:0009711; HP:0002666 (hemangioblastoma, retinal capillary hemangioma, pheochromocytoma)

      GroupHPOFreeText:  22 members had an angioma (hemangioma), 27 had pheochromocytomas, and only 4 member had CNS hemangioblastoma

      GroupNotHPOs: HP:0005584 (renal cell carcinoma)

      GroupNotHPOFreeText: N/A

      GroupPreviousTesting: N/A

      PreviouslyPublished: 8956040 (family confirmed in Zbar 1996 as Type 2 3127NCI); 10458336

      SupplementalData: N/A

      Variant: p.Y98H (c.292T>C)

      CaseProblemVariantFreeText: N/A

      LegacyVariant: p.Y98H (c.505T>C)

      ClinVarID: 2223 https://www.ncbi.nlm.nih.gov/clinvar/variation/2223/

      CAID: N/A

      gnomAD: 0.00001343 https://gnomad.broadinstitute.org/variant/3-10183823-T-C

      VariantEvidence: N/A

      MutationType: missense_variant; transition

      CivicName: Y98H (c.292T>C)

      MultipleGeneVariants: N/A

    1. VHL (Exon:1)/ p.(Tyr98Ser)

      A retrospective study of metastatic (n = 10) or unresectable (n=5) PPGL patients who received Lu-DOTATATE therapy (registered at KEM Hospital, Mumbai, India) between January 2010 and December 2019 were examined. Two VHL mutations were found through genotyping based on the protocol from PMID: 27539324. One male aged 27Y when therapy started, had pheochromocytoma, pancreatic neuroendocrine tumor and sympathetic paraganglioma, which were considered progressive, along with liver metastasis. He had a Y98S (c.293A>C) VHL mutation. No family information was given.