missense mutation
Case#: Family HB90
DiseaseAssertion: Severe Hemophilia B
FamilyInfo: None
ParentalTesting: N/A
CasePresentingHPOs: HP:0011858
CaseHPOsFreeText: reduced factor IX activity (FIX:C:4 (post therapy values but clinically severe by criteria of Eyster et al. (1980)
CaseNotHPOs: N/A
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.127C>T (p.Arg43Trp)
ClinVar: 811505
CAID: CA414435537
gnomAD: Absent/Not Reported
AdditionalCaseInfo: Previously reported by Giannelli et al. (1990)
14.
Case#: 14
DiseaseAssertion: Hemophilia B, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0011858
CaseHPOFreeText: FIX:C = 10%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: All relevant sequences of F9 were PCR amplified and analyzed by DNA sequencing
Gene: F9
Variant: NM_000133.3:c.835G>A
LegacyVariant:
ClinVar: No
CAID: CA277507
gnomAD:
20.
Case#: 20
DiseaseAssertion: Hemophilia B, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0011858
CaseHPOFreeText: FIX:C = 6%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: All relevant sequences of F9 were PCR amplified and analyzed by DNA sequencing
Gene: F9
Variant: NM_000133.3:c.1136G>A
LegacyVariant:
ClinVar: No
CAID: CA255394
gnomAD:
7.
Case#: 7
DiseaseAssertion: Hemophilia B, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0011858
CaseHPOFreeText: FIX:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: All relevant sequences of F9 were PCR amplified and analyzed by DNA sequencing
Gene: F9
Variant: NM_000133.3:c.344A>G
LegacyVariant:
ClinVar: No
CAID: CA414437636
gnomAD:
28.
Case#: 28
DiseaseAssertion: Hemophilia B, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0011858
CaseHPOFreeText: FIX:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: All relevant sequences of F9 were PCR amplified and analyzed by DNA sequencing
Gene: F9
Variant: NM_000133.3:c.1274T>C
LegacyVariant:
ClinVar: No
CAID: CA414447009
gnomAD:
mutations
Case#: B21 (assumed male, Indian origin)
DiseaseAssertion: Severe Hemophilia B
FamilyInfo: None
ParentalTesting: N/A
CasePresentingHPOs: reduced factor IX activity (FIX:C: 1.3%)
CaseHPOsFreeText: HP:0011858
CaseNotHPOs: N/A
CasePreviousTesting: None
Gene: F9
Variant: NM_000133.4:c.127C>T (p.Arg43Trp)
ClinVar: 811505
CAID: CA414435537
gnomAD: Absent/Not Reported
38
Case#: 38, male, 10 years old, Chinese
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 13%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.530A>G
LegacyVariant:
ClinVar: No
CAID: CA414919515
gnomAD:
59
Case#: 59, male, 13 years old, Chinese
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 1.1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.1913G>A
LegacyVariant:
ClinVar: No
CAID: CA414909831
gnomAD:
57
Case#: 57, male, 9 years old, Chinese
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 2%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.1909A>G
LegacyVariant:
ClinVar: No
CAID: CA414909856
gnomAD:
35
Case#: 35, male, 19 years old, Chinese
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.385G>C
LegacyVariant:
ClinVar: No
CAID: CA414919872
gnomAD:
28
Case#: 28, male, 55 years old, Chinese
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.301G>C
LegacyVariant:
ClinVar: No
CAID: CA414920057
gnomAD:
51
Case#: 51, male, 8 years old, Chinese
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 22%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.1758G>A
LegacyVariant:
ClinVar: No
CAID: CA414911269
gnomAD:
67
Case#: 67, male, 30 years old, Chinese
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 8.5%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.2167G>A
LegacyVariant:
ClinVar: 10246
CAID: CA255138
gnomAD:
78
Case#: 78, male, 44 years old, Chinese
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 21%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.5558C>T
LegacyVariant:
ClinVar: 10284
CAID: CA255174
gnomAD:
86
Case#: 86, male, 63 years old, Chinese
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 26%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.6380A>G
LegacyVariant:
ClinVar: No
CAID: CA414899587
gnomAD:
82
Case#: 82, male, 38 years old, Chinese
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.5720G>A
LegacyVariant:
ClinVar: No
CAID: CA414907651
gnomAD:
55
Case#: 55, male, 36 years old, Chinese
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 17%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.1834C>T
LegacyVariant:
ClinVar: 10236
CAID: CA255129
gnomAD:
110
Case#: 110, male, 9 years old, Chinese
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.7021G>C
LegacyVariant:
ClinVar: No
CAID: CA414896760
gnomAD:
50
Case#: 50, male, 50 years old, Chinese
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 16.3%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.1745G>A
LegacyVariant:
ClinVar: No
CAID: CA414911614
gnomAD:
95
Case#: 95, male, 76 years old, Chinese
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 17%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.6506G>A
LegacyVariant:
ClinVar: 10315
CAID: CA255208
gnomAD:
33
Case#: 33, male, 25 years old, Chinese
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: NA
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 3.8%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.382T>C
LegacyVariant:
ClinVar: 811825
CAID: CA414919878
gnomAD:
103
Case#: 103, male, 10 years old, Chinese
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.6635C>T
LegacyVariant:
ClinVar: No
CAID: CA414905841
gnomAD:
72
Case#: 72, male, 31 years old, Chinese
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 4.6%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.5399G>A
LegacyVariant:
ClinVar: 10274
CAID: CA255162
gnomAD:
44
Case#: 44, male, 9 years old, Chinese
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 1.7%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.1171C>T
LegacyVariant:
ClinVar: 10125
CAID: CA255026
gnomAD:
mutations
Case#: Saad_Probands 86-92 (assumed male; from UK)
DiseaseAssertion: Saad_Probands 86-87: no disease assertion made ; Saad_Probands 88, 90, 91: Moderate Hemophilia B ; Saad_Probands 89, 92: Severe Hemophilia B
FamilyInfo: None
ParentalTesting: N/A
CasePresentingHPOs: HP:0011858
CaseHPOsFreeText: reduced factor IX activity (Proband_88 FIX:C:1 ; FIX:Ag:48, Proband_ 89 FIX:C: <1, Proband_90: FIX:C: 1 ; FIX:Ag:45, Proband_91: FIX:C: 2, Proband_92: FIX:C:<1)
CaseNotHPOs: None
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.128G>A (p.Arg43Gln)
ClinVar: 810864
CAID: CA414435539
gnomAD: Absent/Not Reported
060–2008
Case#: 060-2008
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.1618C>A
LegacyVariant:
ClinVar: No
CAID: CA414911950
gnomAD:
020–2015
Case#: 020-2015
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: 5% < FVIII:C < 40%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.5612T>G
LegacyVariant:
ClinVar: No
CAID: CA414908197
gnomAD:
004–2025
Case#: 004-2025
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: 5% < FVIII:C < 40%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.328A>G
LegacyVariant:
ClinVar: No
CAID: CA255057
gnomAD:
001–2049
Case#: 001-2049
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.901C>T
LegacyVariant:
ClinVar: No
CAID: CA414917990
gnomAD:
003–2012
Case#: 003-2012
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: 5% < FVIII:C < 40%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.992T>C
LegacyVariant:
ClinVar: No
CAID: CA414917621
gnomAD:
020–2052
Case#: 020-2052
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: 5% < FVIII:C < 40%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.923C>T
LegacyVariant:
ClinVar: No
CAID: CA255082
gnomAD:
003–2007
Case#: 003-2007
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: 1% < FVIII:C < 5%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.1475A>G
LegacyVariant:
ClinVar: No
CAID: CA337334224
gnomAD:
087–2003
Case#: 087-2003
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.5122C>T
LegacyVariant:
ClinVar: No
CAID: CA120919
gnomAD:
020–2045
Case#: 020-2045
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: 5% < FVIII:C < 40%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.458A>T
LegacyVariant:
ClinVar: No
CAID: CA414919676
gnomAD:
038–1003
Case#: 038-1003
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.331G>A
LegacyVariant:
ClinVar: No
CAID: CA414919991
gnomAD:
084–2006
Case#: 084-2006
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: 5% < FVIII:C < 40%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.1910A>G
LegacyVariant:
ClinVar: No
CAID: CA414909849
gnomAD:
001–2045
Case#: 001-2045
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.1462G>A
LegacyVariant:
ClinVar: No
CAID: CA414912862
gnomAD:
035–2017
Case#: 035-2017
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: 5% < FVIII:C < 40%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.1834C>T
LegacyVariant:
ClinVar: No
CAID: CA255129
gnomAD:
c.835G>A
Case#: 47
DiseaseAssertion: Hemophilia B
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FIX:C 18/26% (Mild Phenotype)
CasePreviousTesting: Screened for IVS-22 and IVS-1, sample was blinded for NGS and the sequencing component was validated by comparing results with Sanger Sequencing
Gene: F9
Variant: NM_000133.3(F9):c.835G>A (p.Ala279Thr)
ClinVar: 216926 https://www.ncbi.nlm.nih.gov/clinvar/variation/216926/
CAID: CA277507
gnomAD: Not reported
c.541G>A
Case#: 4
DiseaseAssertion: Hemophilia A
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FVIII:C 3/5/3% (Moderate Phenotype), No inhibitors present
CasePreviousTesting: Screened for IVS-22 and IVS-1, sample was blinded for NGS and the sequencing component was validated by comparing results with Sanger Sequencing
Gene: F8
Variant: NM_000132.3(F8):c.541G>A (p.Val181Met)
ClinVar: 10177 https://www.ncbi.nlm.nih.gov/clinvar/variation/10177/
CAID: CA255066
gnomAD: Not reported
B79 – B82
Case#: B79 - B82
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C Chr = 7, FVIII:AG = 15, inverse assay discrepancy present (OSA<CSA)
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: Coding region and intron/exon bound-aries of the F8 gene were amplified from all patient samples and directly sequenced using primers
Gene: F8
Variant: NM_000132.4:c.6413C>A
LegacyVariant:
ClinVar: No
CAID: CA255204
gnomAD:
B28. B29
Case#: B28, B29
DiseaseAssertion: NA
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C Chr = 78, FVIII:AG = 94, inverse assay discrepancy present (OSA<CSA)
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: Coding region and intron/exon bound-aries of the F8 gene were amplified from all patient samples and directly sequenced using primers
Gene: F8
Variant: NM_000132.4:c.2089G>C
LegacyVariant:
ClinVar: No
CAID: CA414909014
gnomAD:
A4
Case#: A4
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 6, FVIII:AG = 15, assay discrepancy present (OSA>CSA)
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: Coding region and intron/exon bound-aries of the F8 gene were amplified from all patient samples and directly sequenced using primers
Gene: F8
Variant: NM_000132.4:c.896A>T
LegacyVariant:
ClinVar: No
CAID: CA255078
gnomAD:
3-year-old boy
Case1: 3-year-old boy
DiseaseAssertion: Severe Hemophilia B
FamilyInfo: The pathogenic mutation of F9 gene in this family was identified, Mother and Grandmother are HB carriers, Father tested negative. Pedigree shown in Figure 1.
ParentalTesting: Sequences at the mutation locus in F9 genes were analyzed by Sanger sequencing.
CasePresentingHPOs: NA
CaseHPOFreeText: Hemorrhagic spots on his skin at birth, Gingival bleeding, APTT 66.5 s, FIX:C < 1%, FVIII:C 116.8%
CasePreviousTesting: PCR amplification for coding and flanking sequences of F9 gene, PCR amplification products sequenced by Songon Biotech Co. Ltd.
Gene: F9
Variant: NM_000133.3:c.1232G>C (p.Ser411Thr)
ClinVar: NA
CAID: CA414446686
gnomAD: NA
12
Case#: 12
DiseaseAssertion: NA
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: Na
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: All exons, UTRs, exon-intron junction regions, and the promotor of F9 were amplified by PCR and analyzed by direct DNA sequencing
Gene: F9
Variant: NM_000133.3:c.434G>A
LegacyVariant:
ClinVar: No
CAID: CA414438950
gnomAD:
22
Case#: 22
DiseaseAssertion: Hemophilia B, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FIX:C = 19.5%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: All exons, UTRs, exon-intron junction regions, and the promotor of F9 were amplified by PCR and analyzed by direct DNA sequencing
Gene: F9
Variant: NM_000133.3:c.571C>T
LegacyVariant:
ClinVar: No
CAID: CA255340
gnomAD:
UQU-HB3
Case#: UQU-HB3, Male, 1-months-old, Saudi Arabia
DiseaseAssertion: Hemophilia B
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: Severe, PTT 50.9, Disabled left ankle
CasePreviousTesting: Screened for all factor IX exons by capillary sequencing
Gene: F9
Variant: NM_001313913.1:c.580G>A (p.Asp194Asn)
ClinVar: NA
CAID: CA414441211
gnomAD: Not reported
UQU-HB9
Case#: UQU-HB9, Male, 1-months-old, Saudi Arabia
DiseaseAssertion: Hemophilia B
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: Moderate, PTT 51.4, Unable to flex knees fully
CasePreviousTesting: Screened for all factor IX exons by capillary sequencing
Gene: F9
Variant: NM_001313913.1:c.580G>A
ClinVar: NA
CAID: CA414441211
gnomAD: Not reported
UQU-HB11
Case#: UQU-HB11, Male, 1-months-old, Saudi Arabia
DiseaseAssertion: Hemophilia B
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0001892 (Abnormal bleeding)
CaseHPOFreeText: Severe, Unable to flex elbows fully, PTT 148.3
CasePreviousTesting: Screened for all factor IX exons by capillary sequencing
Gene: F9
Variant: NM_000133.4(F9):c.855G>C (p.Glu285Asp)
ClinVar: 828138 https://www.ncbi.nlm.nih.gov/clinvar/variation/828138/
CAID: CA414444506
gnomAD: Not reported
c.109G>A (p.Ala37Thr)
Case#: Odnoczko_Case (male, 74 y/o, in Poland)
DiseaseAssertion: Severe Hemophilia B (only in patients who receive vitamin K antagnoists (VKAs). The authors believe that during VKA therapy, the FIX activity is much lower than that of other vitamin K-dependent clotting factors for cases with this variant.
FamilyInfo: Family history of bleeding diathesis was negative
ParentalTesting:
CasePresentingHPOs: HP:0012233, HP:0031364, HP:0001892
CaseHPOsFreeText: left thigh & buttock hematoma, ecchymosis on extremeties with no mucosal bleeding, bleeding diathesis
CasePreviousTesting: local labaratory blood tests revealed anemia (hemoglobin concentration 8 g/dl; ref. range 14–18 g/dl), prolongation of prothrombin time (PT) with International Normalized Ratio (INR) within the therapeutic range (between 2.0 and 3.0). The proband's activated partial thromboplastin time (APTT) was significantly (>2-folds) prolonged and FIX activity markedly decreased
Gene: F9
Variant: NM_000133.4:c.109G>A (p.Ala37Thr)
ClinVar: 804089
CAID: CA10529736
gnomAD: Allele Frequency in population where variant was found in the highest (South Asian population): 0.0001128
mutation
Case#: Mutation found in 4 patients, and in 4 families
DiseaseAssertion: Severe in 2 cases, moderate in the other 2 cases
FamilyInfo: N/A
ParentalTesting: None
CasePresentingHPOs: HP:0011858, HP:0003645, HP:0001892
CaseHPOsFreeText: reduced factor IX activity, activated partial thromboplastin time (APTT), normal FVIII clotting activity and bleeding tendency
CaseNotHPOs: None
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.127C>T (p.Arg43Trp)
ClinVar: 811505
CAID: CA414435537
gnomAD: Absent/Not Reported
Case#: Patient HB401 (Hispanic; Male)
DiseaseAssertion: Moderate Hemophilia B
FamilyInfo: None
ParentalTesting: N/A
CasePresentingHPOs: HP:0011858
CaseHPOsFreeText: FIX Coagulant Activity: 1%
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.50T>A (p.Ile17Asn)
LegacyVariant: c.79T>A (p.Ile-30Asn)
ClinVar: Absent
CAID: CA414434315
gnomAD: Absent/Not Reported
identify the causative mutation
Case#: Belvini_Proband_14 (male, Italian)
DiseaseAssertion: Severe Hemophilia B
FamilyInfo: N/A
ParentalTesting: N/A
CasePresentingHPOs: HP:0011858
CaseHPOsFreeText: reduced factor IX activity
CaseNotHPOs: N/A
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.127C>T (p.Arg43Trp)
LegacyVariant:
ClinVar: 811505
CAID: CA414435537
gnomAD: Absent/Not Reported
Case#: Patient 63 (Spanish origin; assumed male)
DiseaseAssertion: Severe Hemophilia B
FamilyInfo: Not available
ParentalTesting: Not available
CasePresentingHPOs: HP:0011858
CaseHPOsFreeText: FIX:C = 3 (reduced factor IX activity)
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.128G>A (p.Arg43Gln)
ClinVar: 810864
CAID: CA414435539
gnomAD: Absent/Not Reported
Case#: Patient 66 (Spanish origin; assumed male)
DiseaseAssertion: Mild Hemophilia B
FamilyInfo: Not available
ParentalTesting: Not available
CasePresentingHPOs: HP:0011858
CaseHPOsFreeText: Factor IX: C = 30% (reduced factor IX activity)
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4(F9):c.19A>T (p.Ile7Phe)
LegacyVariant: c.48A>T (p.Ile-40Phe)
ClinVar: 367997
CAID: CA10529708
gnomAD: Filtering AF: 0.0007752 (no homozygotes)
Case#: Patient 72 (Spanish origin; assumed male)
DiseaseAssertion: Severe Hemophilia B
FamilyInfo: Not available
ParentalTesting: Not available
CasePresentingHPOs: HP:0011858
CaseHPOsFreeText: FIX:C = <1 (reduced factor IX activity)
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.127C>T (p.Arg43Trp)
ClinVar: 811505
CAID: CA414435537
gnomAD: Absent/Not Reported
For p.Ser577Tyr mutation (patient P4)
Case#: P4 (female)
DiseaseAssertion: Carrier
FamilyInfo: N/A
ParentalTesting: N/A
CasePresentingHPOs: HP:0003125, HP:0001928
CaseHPOFreeText: Low FVIII levels (FVIII:Ag showed a moderate reduction (29.8% ± 1.7, p < 0.01) compared to the WT; FVIII:C undetectable), abnormal blood coagulation
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: Molecular Analysis included a southern blot assay, PCR, dHPLC and a multiplex ligation-dependent probe amplification analysis. Plasmid mutagenesis, plasmid transfection and in silico analysis were also performed.
Gene: F8
Variant: NM_000132.4:c.1730C>A
CAID: CA414911649
gnomAD: Absent/Not Reported
C.6427A>G
Case#: 28
DiseaseAssertion: Hemophilia A
FamilyInfo: Sporadic
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: Mild
CasePreviousTesting: All 26 exons and exon-intron boundaries of the F8 gene were amplified using primers and PCR, analyzed by direct forward and reverse sequencing using a DNA sequencing kit
Gene: F8
Variant: NM_000132.3:c.6427A>G (p.Met2124Val)
ClinVar: NA
CAID: CA414899297
gnomAD: Not reported
c.1910A>T
Case#: 23
DiseaseAssertion: Hemophilia A
FamilyInfo: Sporadic
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: Moderate
CasePreviousTesting: All 26 exons and exon-intron boundaries of the F8 gene were amplified using primers and PCR, analyzed by direct forward and reverse sequencing using a DNA sequencing kit
Gene: F8
Variant: NM_000132.3:c.1910A>T (p.Asn618Ile)
ClinVar: NA
CAID: CA414909847
gnomAD: Not reported
c.1180G>T
Case#: 18, Spanish
DiseaseAssertion: Hemophilia A
FamilyInfo: Positive
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: Mild
CasePreviousTesting: All 26 exons and exon-intron boundaries of the F8 gene were amplified using primers and PCR, analyzed by direct forward and reverse sequencing using a DNA sequencing kit
Gene: F8
Variant: NM_000132.3:c.1180G>T (p.Ala375Ser)
ClinVar: NA
CAID: CA414916327
gnomAD: Not reported
Arg-4Leu
Case#: 37HBT150 (Turkish; assumed male)
DiseaseAssertion: Moderate Hemophilia B
FamilyInfo: N/A
ParentalTesting: Not provided
CasePresentingHPOs: HP:0011858
CaseHPOsFreeText: Reduced factor IX activity (FIX:C: 1.3)
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.128G>T (p.Arg43Leu)
LegacyVariant: c.6365 G>T (p.Arg-4Leu)
ClinVar: 993549
CAID: CA414435545
gnomAD: Absent/Not Reported
mutation
Case#: HB-125 (assumed male, India)
DiseaseAssertion: Severe Hemophilia B
FamilyInfo: N/A
ParentalTesting: None
CasePresentingHPOs: HP:0011858
CaseHPOsFreeText: reduced factor IX activity (FIX:C <1%)
CaseNotHPOs: None
CasePreviousTesting: None
Gene: F9
Variant: NM_000133.4:c.128G>A (p.Arg43Gln)
ClinVar: 810864
CAID: CA414435539
gnomAD: Absent/Not Reported
mutation
Case#: Heit_Proband_HB535 (assumed male, AmerIndian from Peru)
DiseaseAssertion: Severe Hemophilia B
FamilyInfo: N/A
ParentalTesting: N/A
CasePresentingHPOs: HP:0011858
CaseHPOsFreeText: reduced factor IX activity (FIX:C: <1%)
CaseNotHPOs: N/A
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.127C>T (p.Arg43Trp)
LegacyVariant: c.6364C>T (Arg-4Trp)
ClinVar: 811505
CAID: CA414435537
gnomAD: Absent/Not Reported
c.110C > T p (Ala37Val).
Case#: Mülling_Proband_1 (55 y/o, male)
DiseaseAssertion: Severe Hemophilia B
FamilyInfo: N/A
ParentalTesting: N/A
CasePresentingHPOs: HP:0011858, HP:0100584, HP:0002094
CaseHPOsFreeText: Reduced factor IX activity (FIX activity: 3%), infective endocarditis, dyspnea
CaseNotHPOs: N/A
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.110C>T (p.Ala37Val)
ClinVar: Absent
CAID: CA414435437
gnomAD: 0.00002186 in European (non-Finnish) population (highest frequency of variant found in this population)
AdditionalCaseInfo: Patient developed severe bleeding under therapy with phenprocoumon, aPTT was prolonged, while factor IX activity was significantly reduced. Acquired hemophilia was excluded, due to missing detection of inhibitors
mutations
Case#: Ghanem_Paris 2 (assumed male, from Paris) & Ghanem_ Caen 2 (assumed male, from Caen)
DiseaseAssertion: Severe Hemophilia B
FamilyInfo: N/A
ParentalTesting: None
CasePresentingHPOs: HP:0011858
CaseHPOsFreeText: reduced factor IX activity (Paris 2: FIX:C: <1, FIX:Ag: 28, Caen 2: FIX:C: <1
CaseNotHPOs: None
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.127C>T (p.Arg43Trp)
ClinVar: 811505
CAID: CA414435537
gnomAD: Highest AF (South Asian population): 0.0004904
Variant
Case#: Calgary 15
DiseaseAssertion: Hemophilia B (severity not provided)
FamilyInfo: None
ParentalTesting: N/A
CasePresentingHPOs: HP:0011858
CaseHPOsFreeText: reduced factor IX activity (does not specify severity for probands) "patients from these kindreds have various disease severity, with plasma factor IX activity from < 0.01 U/mL to 0.30 U/mL." "FIX antigen was not available from patients from 6 kindreds, reduced in seven, normal in six, and not available from six."
CaseNotHPOs: None
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.128G>A (p.Arg43Gln)
LegacyVariant: c.6365 G>A (p.Arg-4Gln)
ClinVar: 810864
CAID: CA414435539
gnomAD: Absent/Not Reported
I17N
Case#: N/A
DiseaseAssertion: Severe Hemophilia B
FamilyInfo: None
ParentalTesting: None
CasePresentingHPOs: HP:0001929
CaseHPOsFreeText: reduced factor IX activity
CaseNotHPOs: N/A
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.50T>A (p.Ile17Asn)
ClinVar: Absent
CAID: CA414434315
gnomAD: Absent/Not Reported
S14
Case#: S14, Iranian
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125, HP:0005261
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The F8 gene was directly sequenced for all 26 exons using the Sanger sequencing method. PCR was performed and subsequently analyzed
Gene: F8
Variant: NM_000132.3:c.575T>C
LegacyVariant:
ClinVar: No
CAID: CA414919417
gnomAD:
Case: P87, Chinese, female, 27yo
DiseaseAssertion: VWD1
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0012147
(Reduced quantity of VWF)
CaseHPOFreeText: type O blood, bleeding score = 3; VWF:Ag (%) = 55.9, VWF:RCo (%) = 55.8, FVIII:C (%) = 70.1, VWF:CB (%) = 61.3, VWFpp (%) = 88.0, VWF:RCo/VWF:Ag = 1.0, VWF:CB/VWF:Ag = 1.1, VWFpp/VWF:Ag = 1.6, FVIII:C/VWF:Ag = 1.3
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: NA
GenotypingMethod: NGS
PreviouslyPublished: NA
Gene: VWF
Variant: c.6860G>A (p.Arg2287Gln)
HGVS: NM_000552.3:c.6860G>A (p.Arg2287Gln)
ClinVarID: NA
CAID: CA6401877; http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA6401877
gnomAD: MAF = 0.005415 (108/19946 alleles) in the East Asian population; https://gnomad.broadinstitute.org/variant/12-6094770-C-T
Case: P2, Chinese, female, 3yo
DiseaseAssertion: VWD1
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0012147
(Reduced quantity of VWF)
CaseHPOFreeText: type O blood, bleeding score = 4; VWF:Ag (%) = 55.0, VWF:RCo (%) = 53.0, FVIII:C (%) = 59.0, VWF:CB (%) = 47.0, VWFpp (%) = 57.4, VWF:RCo/VWF:Ag = 1.0, VWF:CB/VWF:Ag = 0.9, VWFpp/VWF:Ag = 1.0, FVIII:C/VWF:Ag = 1.1
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: NA
GenotypingMethod: NGS
PreviouslyPublished: NA
Gene: VWF
Variant: c.6104G>A (p.Gly2035Asp)
HGVS: NM_000552.3:c.6104G>A (p.Gly2035Asp)
ClinVarID: NA
CAID: CA6402069; http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA6402069
gnomAD: MAF = 0.005613 (112/19954 alleles; 2 homozygotes) in the East Asian population; https://gnomad.broadinstitute.org/variant/12-6103733-C-T
Case: P32, Chinese, male, 3yo
DiseaseAssertion: VWD1
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0012147
(Reduced quantity of VWF)
CaseHPOFreeText: patient coexisting with severe haemophilia A; type O blood, bleeding score = 3; VWF:Ag (%) = 51.3, VWF:RCo (%) = 50.7, FVIII:C (%) = 1.0, VWF:CB (%) = 50.3, VWFpp (%) = 49.2, VWF:RCo/VWF:Ag = 1.0, VWF:CB/VWF:Ag = 1.0, VWFpp/VWF:Ag = 1.0, FVIII:C/VWF:Ag = 0.0
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: NA
GenotypingMethod: NGS
PreviouslyPublished: NA
Gene: VWF
Variant: c.646G>A (p.Glu216Lys)
HGVS: NM_000552.5(VWF):c.646G>A (p.Glu216Lys)
ClinVarID: 870925; https://www.ncbi.nlm.nih.gov/clinvar/variation/870925/
CAID: NA
gnomAD: 0.001353 (27/19952 alleles) in East Asian population; https://gnomad.broadinstitute.org/variant/12-6204637-C-T?dataset=gnomad_r2_1
MultipleGeneVariants
Gene: F8
Variant: p.Arg446Ter - Unregistered Variant
Case: P71, Chinese, female, 23yo
DiseaseAssertion: VWD1
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0012147
(Reduced quantity of VWF)
CaseHPOFreeText: type O blood, bleeding score = 1; VWF:Ag (%) = 57.9, VWF:RCo (%) = 55.6, FVIII:C (%) = 71.3, VWF:CB (%) = 69.7, VWFpp (%) = 66.9, VWF:RCo/VWF:Ag = 1.0, VWF:CB/VWF:Ag = 1.2, VWFpp/VWF:Ag = 1.2, FVIII:C/VWF:Ag = 1.2
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: NA
GenotypingMethod: NGS
PreviouslyPublished: NA
Gene: VWF
Variant: c.4850A>G (p.Lys1617Arg)
HGVS: NM_000552.3:c.4850A>G (p.Lys1617Arg)
ClinVarID: NA
CAID: CA6402448; http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA6402448
gnomAD: MAF = 0.0002507 (5/19942 alleles) in the East Asian population; https://gnomad.broadinstitute.org/variant/12-6127734-T-C
Case: P7, Chinese, female, 27yo
DiseaseAssertion: VWD1
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0012147
(Reduced quantity of VWF)
CaseHPOFreeText: type O blood, bleeding score = 9; VWF:Ag (%) = 5.4, VWF:RCo (%) = 5.3, FVIII:C (%) = 28, VWF:CB (%) = 4.1, VWFpp (%) = 4.8, VWF:RCo/VWF:Ag = 1.0, VWF:CB/VWF:Ag = 0.8, VWFpp/VWF:Ag = 0.9, FVIII:C/VWF:Ag = 5.2, RIPA (1.2 mg/ml, %) = 73.3
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: NA
GenotypingMethod: NGS
PreviouslyPublished: NA
Gene: VWF
Variant 1: c.711C>G (p.Cys237Trp)
HGVS: NM_000552.3:c.711C>G (p.Cys237Trp)
ClinVarID: NA
CAID: CA383509260; http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA383509260
gnomAD: absent
Variant: c.1109+47T>A - Unregistered Variant
HGVS: NA
ClinVarID: NA
CAID: NA
gnomAD: NA
Case: P6, Chinese, male, 57yo
DiseaseAssertion: VWD2A
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0012147
(Reduced quantity of VWF)
CaseHPOFreeText: type AB blood, bleeding score = 15; VWF:Ag (%) = 18.5, VWF:RCo (%) = 5.8, FVIII:C (%) = 39.0, VWF:CB (%) = 4.9, VWFpp (%) = 36.4, VWF:RCo/VWF:Ag = 0.3, VWF:CB/VWF:Ag = 0.3, VWFpp/VWF:Ag = 2.0, FVIII:C/VWF:Ag = 2.1
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: NA
GenotypingMethod: NGS
PreviouslyPublished: NA
Gene: VWF
Variant: c.3920T>G (p.Leu1307Arg)
HGVS: NM_000552.5:c.3920T>G (p.Leu1307Arg)
ClinVarID: NA
CAID: CA383506205; http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA383506205
gnomAD: absent
Case: P72, Chinese, female, 25yo
DiseaseAssertion: VWD2B
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0012147
(Reduced quantity of VWF)
CaseHPOFreeText: type A blood, bleeding score = 7; VWF:Ag (%) = 31.1, VWF:RCo (%) = 10.5, FVIII:C (%) = 44.8, VWF:CB (%) = 5.4, VWFpp (%) = 73, VWF:RCo/VWF:Ag = 0.3, VWF:CB/VWF:Ag = 0.2, VWFpp/VWF:Ag = 2.3, FVIII:C/VWF:Ag = 1.4, RIPA (0.5 mg/ml, %) = 8.7, PLT(×109/l) = 181
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: NA
GenotypingMethod: NGS
PreviouslyPublished: NA
Gene: VWF
Variant: c.3939G>C (p.Trp1313Cys)
HGVS: NM_000552.4(VWF):c.3939G>C (p.Trp1313Cys)
ClinVarID: 287; https://www.ncbi.nlm.nih.gov/clinvar/variation/287/
CAID: NA
gnomAD: absent
Case: P34, Chinese, female, 34yo
DiseaseAssertion: VWD2B
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0012147
(Reduced quantity of VWF)
CaseHPOFreeText: type O blood, bleeding score = 13; VWF:Ag (%) = 20.2, VWF:RCo (%) = 6.9, FVIII:C (%) = 32.9, VWF:CB (%) = 4.8, VWFpp (%) = 54.5, VWF:RCo/VWF:Ag = 0.3, VWF:CB/VWF:Ag = 0.2, VWFpp/VWF:Ag = 2.7, FVIII:C/VWF:Ag = 1.6, RIPA (0.5 mg/ml, %) = 65.1, PLT(×109/l) = 153
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: NA
GenotypingMethod: NGS
PreviouslyPublished: NA
Gene: VWF
Variant: c.3916C>T (p.Arg1306Trp)
HGVS: NM_000552.4(VWF):c.3916C>T (p.Arg1306Trp)
ClinVarID: 288; https://www.ncbi.nlm.nih.gov/clinvar/variation/288/
CAID: NA
gnomAD: absent
Case: P27, Chinese, female, 3yo
DiseaseAssertion: VWD2N
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0012147
(Reduced quantity of VWF)
CaseHPOFreeText: type B blood, bleeding score = 6; VWF:Ag (%) = 9.5, VWF:RCo (%) = 8.9, FVIII:C (%) = 6.5, VWF:CB (%) = 6.9, VWFpp (%) = 10.8, VWF:RCo/VWF:Ag = 0.9, VWF:CB/VWF:Ag = 0.7, VWFpp/VWF:Ag = 1.1, FVIII:C/VWF:Ag = 0.7, VWF: FVIIIB (%) = 0.0
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: NA
GenotypingMethod: NGS
PreviouslyPublished: NA
Gene: VWF
Variant 1: c.2396G>A (p.Cys799Tyr)
HGVS: NM_000552.5:c.2396G>A (p.Cys799Tyr)
ClinVarID: NA
CAID: CA232300402; http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA232300402
gnomAD: absent
Variant 2: c.3197_3201del - unregistered variant
HGVS: NA
ClinVarID: NA
CAID: NA
gnomAD: NA
Case: P83, Chinese, male, 5yo
DiseaseAssertion: VWD1
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0012147
(Reduced quantity of VWF)
CaseHPOFreeText: patient coexisting with mild haemophilia A; type O blood, bleeding score = 3; VWF:Ag (%) = 44.5, VWF:RCo (%) = 36.7, FVIII:C (%) = 12.6, VWF:CB (%) = 49.2, VWFpp (%) = 35.2, VWF:RCo/VWF:Ag = 0.8, VWF:CB/VWF:Ag = 1.1, VWFpp/VWF:Ag = 0.8, FVIII:C/VWF:Ag = 0.3
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: NA
GenotypingMethod: NGS
PreviouslyPublished: NA
Gene: VWF
Variant: c.6104G>A (p.Gly2035Asp)
HGVS: NM_000552.3:c.6104G>A (p.Gly2035Asp)
ClinVarID: NA
CAID: CA6402069; http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA6402069
gnomAD: MAF = 0.005613 (112/19954 alleles; 2 homozygotes) in the East Asian population; https://gnomad.broadinstitute.org/variant/12-6103733-C-T
Multiple Gene Variants
Gene: F8
Variant: c.943G>T (p.Ala315Ser)
HGVS: NM_000132.3:c.943G>T (p.Ala315Ser)
ClinVarID: NA
CAID: CA414917823; http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA414917823
gnomAD: absent
Case: P29, Chinese, male, 10yo
DiseaseAssertion: VWD2M
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0012147
(Reduced quantity of VWF)
CaseHPOFreeText: type B blood, bleeding score = 5; VWF:Ag (%) = 13.9, VWF:RCo (%) = 5.9, FVIII:C (%) = 37.8, VWF:CB (%) = 17.4, VWFpp (%) = 31.3, VWF:RCo/VWF:Ag = 0.4, VWF:CB/VWF:Ag = 1.3, VWFpp/VWF:Ag = 2.3, FVIII:C/VWF:Ag = 2.7
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: NA
GenotypingMethod: NGS
PreviouslyPublished: NA
Gene: VWF
Variant: c.3943C>T (p.Arg1315Cys)
HGVS: NM_000552.4(VWF):c.3943C>T (p.Arg1315Cys)
ClinVarID: 100310; https://www.ncbi.nlm.nih.gov/clinvar/variation/100310/
CAID: NA
gnomAD: absent
47 2 F 5 c.478G.Ap.G160R Hmz ,1 2.3 6 - +
Case: 47, F, 2 years, Indian
DiseaseAssertion: VWD type 3
FamilyInfo: no family history of disease, Consanguinity: yes
ParentalGenotype: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: FVIII:C: (U/dl): <1, VWF:Ag (U/dl): 2.3, Bleeding Score: 6
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.478G>A (p.Gly160Arg), Exon 5
Homozygous
23 10 F 8 c.954T.A p.N318K Htz 3.1 ,1 8 + +
Case: 23, F, 10 years, Indian
DiseaseAssertion: VWD type 3
FamilyInfo: family history of disease, Consanguinity: yes
ParentalGenotype: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: FVIII:C: (U/dl): 3.1, VWF:Ag (U/dl): <1, Bleeding Score: 8
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.954T>A (p.Asn318Lys), Exon 8
Heterozygous
30
Case: IP #30
DiseaseAssertion: type 2A VWD
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs:
CaseHPOFreeRext: VWF:Ag [IU/dL] = 15; VWF:Ac [IU/dL] = 6; 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.4151T>G p.Leu1384Arg
HGVS:
ClinVarID: not found
CAID: CA383504381
gnomAD: absent
35
Case: IP #35
DiseaseAssertion: type 2A (IIA) VWD
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs: HP:0032370 - blood group A
CaseHPOFreeRext: VWF:Ag [IU/dL] = 65; VWF:Ac [IU/dL] = 10; 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.4517C>T p.Ser1506Leu
HGVS:
ClinVarID: 100369
CAID:
gnomAD: absent
55-57Type2A(IIA)c.4825G>A p.Gly1609Arg 28 A2 htz Missense na/B/O71/46/53 17/12/15 na/60
Case: IP #56
DiseaseAssertion: type 2A (IIA) VWD
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs: HP:0032440 - blood group B
CaseHPOFreeRext: VWF:Ag [IU/dL] = 46; VWF:Ac [IU/dL] = 12; FVIII:C [IU/dL] = 60
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.4825G>A p.Gly1609Arg
HGVS:
ClinVarID: 100395
CAID:
gnomAD: 0.000003098 (5 in 1614130) no homozygotes https://gnomad.broadinstitute.org/variant/12-6018593-C-T?dataset=gnomad_r4
26, 27 Heterozygous2Nc.3673T > G p.Cys1225Gly 27 D3-E3 htz Missense O/A 50/42 29/44 40 CSA /69
Case: IP #27 in type 2N VWD sub-cohort
DiseaseAssertion: type 2N VWD
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs: HP:0032370 - blood group A
CaseHPOFreeRext: VWF:Ag [IU/dL] = 42; VWF:Ac [IU/dL] = 44; FVIII:C [IU/dL] = 69
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.3673T>G p.Cys1225Gly
HGVS:
ClinVarID: 100272
CAID:
gnomAD: absent
40 Type2A(IIA)c.4690C>T p.Arg1564Trp 28 A2 htz Missense A 46 31 57
Case: IP #40
DiseaseAssertion: type 2A (IIA) VWD
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs: HP:0032370 - blood group A
CaseHPOFreeRext: VWF:Ag [IU/dL] = 46; VWF:Ac [IU/dL] = 31; FVIII:C [IU/dL] = 57
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.4690C>T p.Arg1564Trp
HGVS:
ClinVarID: 811702
CAID:
gnomAD: 0.000006818 (11 in 1613330) no homozygotes https://gnomad.broadinstitute.org/variant/12-6018728-G-A?dataset=gnomad_r4
23 Type2Ac.3686T>G*c.3692A>Cp.Val1229Glyp.Asn1231Thr2828D3-E3D3-E3htzhtzConversionO 19 9RCo 37
Case: IP #23
DiseaseAssertion: type 2A VWD
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs: HP:0032442 - blood group O
CaseHPOFreeRext: VWF:Ag [IU/dL] = 19; VWF:Ac [IU/dL] = 9; 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.3686T>G p.Val1229Gly
HGVS:
ClinVarID: 100274
CAID:
gnomAD: 0.002237 (3603 in 1610354) 17 homozygotes https://gnomad.broadinstitute.org/variant/12-6019732-A-C?dataset=gnomad_r4
MultipleGeneVariants:
Gene: VWF
Variant: c.3692A>C p.Asn1231Thr
ClinVarID: 100275
gnomAD:
24–31 U (2A/2M/1C) c.4120C > T p.Arg1374Cys C 28 A1 htz Missense A/A/A/A/O/na/O/A22/ 22/23 /18/11/21/20/3210/8/6/12/4/9/11/1440 CSA /26 CSA /23
Case: IP #26 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] = 23; VWF:Ac [IU/dL] = 6; 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.4120C>T p.Arg1374Cys
HGVS:
ClinVarID: 100329
CAID:
gnomAD: absent
24–31 U (2A/2M/1C) c.4120C > T p.Arg1374Cys C 28 A1 htz Missense A/A/A/A/O/na/O/A22/ 22/23 /18/11/21/20/3210/8/6/12/4/9/11/1440 CSA /26 CSA /23 CSA /22 CSA /11 CSA /42 CSA /27
Case: IP #30 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] = 11; 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.4120C>T p.Arg1374Cys
HGVS:
ClinVarID: 100329
CAID:
gnomAD: absent
8 Type 2A /2N c.2561G > Ac.4811T > A Np.Arg854Glnp.Val1604Asp2028D’-E’A2htzhtzMissenseMissenseA 16 8 12
Case: 8 (also in row 21 table 6)
DiseaseAssertion: type 2A/2N VWD
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs: HP:0032370 - blood group A
CaseHPOFreeRext: VWF:Ag [IU/dL] = 16; VWF:Ac [IU/dL] = 8; FVIII:C [IU/dL] = 12
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting:
GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.
PreviouslyPublished:
Gene: VWF
Variant: c.2561G>A p.Arg854Gln
HGVS:
ClinVarID: 296
CAID:
gnomAD: 0.004956 (8000 in 1614214) 26 homozygotes https://gnomad.broadinstitute.org/variant/12-6034812-C-T?dataset=gnomad_r4
MultipleGeneVariants:
Gene: VWF
Variant: c.4811T>A p.Val1604Asp
CAID: CA383499144
gnomAD: absent
24 2N/1 c.2561G > Ac.6798 þ 2T > A Np.Arg.854Gln-20/38D’-E’C1htzhtzMissenseSplice SiteAB 42 34 16
Case: IP #24 in type 2N VWD sub-cohort (also in row 5 splice variants table 6)
DiseaseAssertion: type 2N/1 VWD
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs: HP:0032441 - blood group AB
CaseHPOFreeRext: VWF:Ag [IU/dL] = 42; VWF:Ac [IU/dL] = 34; FVIII:C [IU/dL] = 16
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting:
GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.
PreviouslyPublished:
Gene: VWF
Variant: c.2561G>A p.Arg854Gln
HGVS:
ClinVarID: 296
CAID:
gnomAD: 0.004956 (8000 in 1614214) 26 homozygotes https://gnomad.broadinstitute.org/variant/12-6034812-C-T?dataset=gnomad_r4
MultipleGeneVariants:
Gene: VWF
Variant: c.6798+2T>A
ClinVarID: 1803122
gnomAD: absent
13 Type2A (IIE)c.3314C>AN p.Ala1105Asp 25 D3-C8-3htz Missense na 23 na 45
Case: IP #13 (also in row 7 table 6)
DiseaseAssertion: type 2A (IIE) VWD
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs:
CaseHPOFreeRext: VWF:Ag [IU/dL] = 23; VWF:Ac [IU/dL] = n/a; FVIII:C [IU/dL] = 45
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.3314C>A p.Ala1105Asp
HGVS:
ClinVarID: 626953
CAID:
gnomAD: absent
67 Type2Ac.7988G>C* p.Arg2663Pro 49 C6 htz Missense na 9,3 4 41
Case: IP #67
DiseaseAssertion: type 2A VWD
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs:
CaseHPOFreeRext: VWF:Ag [IU/dL] = 9,3; VWF:Ac [IU/dL] = 4; FVIII:C [IU/dL] = 41
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.7988G>C p.Arg2663Pro
HGVS:
ClinVarID: 372760
CAID:
gnomAD: 0.001352 (2181 in 1613616) 4 homozygotes https://gnomad.broadinstitute.org/variant/12-5952518-C-G?dataset=gnomad_r4
42 U c.7645T > C N p.Cys2549Arg 45 C4 htz Missense O 9 16 41
Case: IP #42 in type U VWD sub-cohort (also in row 26 table 6)
DiseaseAssertion: unclassified VWD
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs: HP:0032442 - blood group O
CaseHPOFreeRext: VWF:Ag [IU/dL] = 9; VWF:Ac [IU/dL] = 16; FVIII:C [IU/dL] = 41
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.7645T>C p.Cys2549Arg
HGVS:
ClinVarID: not found
CAID: CA383489376
gnomAD: absent
22 U c.4022G > Ac.5801T > Gp.Arg1341Glnc.Val1934Gly2834A1D4htzhtzMissenseMissensena 34 27 RCo 95
Case: IP #22 in type U VWD sub-cohort
DiseaseAssertion: unclassified VWD
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs:
CaseHPOFreeRext: VWF:Ag [IU/dL] = 34; VWF:Ac [IU/dL] = 27; FVIII:C [IU/dL] = 95
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
MultipleGeneVariants:
Gene: VWF
Variant: c.5801T>G p.Val1934Gly
ClinVarID: 627336
gnomAD: 0.00006260 (101 in 1613356) no homozygotes https://gnomad.broadinstitute.org/variant/12-6011658-A-C?dataset=gnomad_r4
2 Type 2A c.-2522C>Tc.3586T>Cp.Cys1196Arg 27 D3-TIL-3htzhtzRegulatoryMissenseA 14 8RCo 34
Case: 2
DiseaseAssertion: type 2A VWD
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs: HP:0032370 - blood group A
CaseHPOFreeRext: VWF:Ag [IU/dL] = 14; VWF:Ac [IU/dL] = 8; FVIII:C [IU/dL] = 34
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.-2522C>T
HGVS:
ClinVarID: not found
CAID: not found
gnomAD:
MultipleGeneVariants:
Gene: VWF
Variant: c.3586T>C
ClinVarID: 100270
65 Type2A(IIA)c.4912G>A p.Glu1638Lys 28 A2 htz Missense na 33 15 na
Case: IP #65
DiseaseAssertion: type 2A (IIA) VWD
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs:
CaseHPOFreeRext: VWF:Ag [IU/dL] = 33; VWF:Ac [IU/dL] = 15; 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.4912G>A p.Glu1638Lys
HGVS:
ClinVarID: 100403
CAID:
gnomAD: absent
37 U (2A/2M) c.4241T > G p.Val1414Gly 28 A1 htz Missense AB/A/O 14/42/15 9/15/7 30 CSA /53 CSA /25
Case: IP #37 in type U VWD sub-cohort
DiseaseAssertion: unclassified (2A/2M) VWD
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs: HP:0032442 - blood group O
CaseHPOFreeRext: VWF:Ag [IU/dL] = 15; VWF:Ac [IU/dL] = 7; 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.4241T>G p.Val1414Gly
HGVS:
ClinVarID: 619752
CAID:
gnomAD: absent
2 c.3847G > A N p.Asp1283Asn 28 A1 htz Missense A 45 9 70 CSA 38
Case: IP #2 in type 2M VWD sub-cohort (also in row 12 table 6)
DiseaseAssertion: type 2M VWD
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs: HP:0032370 - blood group A
CaseHPOFreeRext: VWF:Ag [IU/dL] = 45; VWF:Ac [IU/dL] = 9; FVIII:C [IU/dL] = 70; VWF:CB (IU/dL) = 38
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.3847G>A p.Asp1283Asn
HGVS:
ClinVarID: not found
CAID: CA383506815
gnomAD: absent
9, 10 c.4195C > T p.Arg1399Cys 28 A1 htz Missense B/B 91/73 28/23 105 CSA /79 CSA 88/57
Case: IP #10 in type 2M VWD sub-cohort
DiseaseAssertion: type 2M VWD
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs: HP:0032440 - blood group B
CaseHPOFreeRext: VWF:Ag [IU/dL] = 73; VWF:Ac [IU/dL] = 23; FVIII:C [IU/dL] = 79; VWF:CB (IU/dL) = 57
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.4195C>T p.Arg1399Cys
HGVS:
ClinVarID: 100337
CAID:
gnomAD: 0.00005143 (83 in 1613776) no homozygotes https://gnomad.broadinstitute.org/variant/12-6019223-G-A?dataset=gnomad_r4
23 U (2A/1/M) c.4094T > C p.Leu1365Pro 28 A1 hmz Missense O 12 4 14
Case: IP #23 in type U VWD sub-cohort
DiseaseAssertion: unclassified (2A/1/M) VWD
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs: HP:0032442 - blood group O
CaseHPOFreeRext: VWF:Ag [IU/dL] = 12; VWF:Ac [IU/dL] = 4; FVIII:C [IU/dL] = 14
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.4094T>C p.Leu1365Pro
HGVS:
ClinVarID: 2438545
CAID:
gnomAD: absent
10, 11 U c.3586T > C p.Cys1196Arg 27 D3-TIL-3 htz Missense A/O 21/18 18/12 RCo 55
Case: IP #10 in type U VWD sub-cohort
DiseaseAssertion: unclassified VWD
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs: HP:0032370 - blood group A
CaseHPOFreeRext: VWF:Ag [IU/dL] = 21; VWF:Ac [IU/dL] = 18; 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.3586T>C p.Cys1196Arg
HGVS:
ClinVarID: 100270
CAID:
gnomAD: 0.000001239 (2 in 1614220) no homozygotes https://gnomad.broadinstitute.org/variant/12-6021988-A-G?dataset=gnomad_r4
p.P1162L
Case#: p.P1162L, Female, Age 52, African American
Disease Assertion: Normal Variant
Family Info: Two family members tested with normal clinical phenotype
Parental Genotype: Not listed
CasePresentingHPOs:
CaseHPOFreeText: VWF:RCo/VWF:Ag Ratio 0.50, VWF:GPIbM 98
CaseNotHPOs: HP:0040240
(Increased Ratio of VWF Propeptide to VWF antigen)
CaseNotHPOFreeText:bleeding score 2, VWF:Ag 144 IU/dL, VWF:RCo 72 IU/dL, normal multimer distribution
ProteinExpression:
CasePreviousTesting: VWF Sequencing
Gene:VWF
Variant: NM_000552.4(VWF):c.3485C>T (p.Pro1162Leu)
ClinVar: 256669 ClinVarID
CAID: CA6402756
gnomAD: MAF of 0.2207 (2023/9166 alleles) in the African American population.
p.I1453N
Case#: p.I1453N, Male, Age 25, Caucasian
Disease Assertion: VWD2M
FamilyInfo: No affected family members enrolled in study
Parental Genotype: Not listed
CasePresentingHPOs: N/A
CaseHPOFreeText: bleeding score 11, VWF:RCo/VWF:Ag ratio 0.55, VWF:Ag 20 IU/dL, VWF:RCo 11 IU/dL,
CaseNotHPOs:HP:0040240
(Increased Ratio of VWF Propeptide to VWF antigen)
CaseNotHPOFreeText: Normal multimer distribution
Protein Expression: N/A
CasePreviousTesting: VWF sequencing
Gene: VWF
Variant: NM_000552.4:c.4358T>A (p.Ile1453Asn)
ClinVar: N/A
CAID: CA383502477
gnomAD: N/A
p.D1283Y
Case#: p.D1283Y, Female, Age 85, Caucasian
Disease Assertion: VWD2M
FamilyInfo: Single affected family member with similar bleeding score
Parental Genotype: Not listed
CasePresentingHPOs:
CaseHPOFreeText: VWF:RCo/ VWF:Ag ratio 0.34, bleeding score 12, VWF:RCo 12 IU/dL, VWF:Ag 25 IU/dL
CaseNotHPOs: HP:0040240
(Increased Ratio of VWF Propeptide to VWF antigen)
CaseNotHPOFreeText: Normal multimer distribution
Protein Expression: N/A
CasePreviousTesting: VWF Sequencing
Gene: VWF
Variant: NM_000552.4:c.3847G>T (p.Asp1283Tyr)
ClinVar: N/A
CAID: CA383506819
gnomAD: N/A
Case#: 35003, Age 75, Female, Blood Type A- (Table S3)
Disease Assertion: VWD 1
FamilyInfo: The patient is one of two members in Family# 3502.
Parental Genotype: Not listed
CasePresentingHPOs: N/A
CaseHPOFreeText: VWF:Ag: 6.6, VWF:RCo: 8.5, FVIII:C:13, VWF:CB: 11
CaseNotHPOs: N/A
CaseNotHPOFreeText: Bleeding Score 2
Protein Expression: N/A
CasePreviousTesting: 48,48 Access-Array amplification. NGS Molecular analysis was performed. Sanger sequencing was used to validate selected mutations.
Gene: VWF
Variant: NM_000552.4:c.3614G>A (p.Arg1205His)
ClinVar: 308 ClinVar
CAID: CA114160 CAID
gnomAD: N/A
Case#: 13001, Age 61, Female, Blood Type O+ (Table S3)
Disease Assertion: VWD 1
FamilyInfo: The patient was the only member of Family# 1301.
Parental Genotype: Not listed
CasePresentingHPOs: N/A
CaseHPOFreeText: Bleeding Score 27, VWF:Ag: 11, VWF:RCo: 9.7, FVIII:C: 36, VWF:CB: 12
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
Protein Expression: N/A
CasePreviousTesting: 48,48 Access-Array amplification. NGS Molecular analysis was performed. Sanger sequencing was used to validate selected mutations
Gene: VWF
Variant: NM_000552.4:c.7985A>G
ClinVar: N/A
CAID: CA383487641 CAID
gnomAD: N/A
Case#: 02042, Age 41, Male, Blood Type: O+ (Table S3)
Disease Assertion: VWD 1
FamilyInfo: Family#: 0215; 5 Members of the family were included in the study. 1 was diagnosed type 3 (patient 02039) and the other 4 were carriers for VW
Parental Genotype: Not listed
CasePresentingHPOs:
CaseHPOFreeText: VWF:Ag: 25, VWF:RCo: 21, FVIII:C:77, VWF:CB: 27
CaseNotHPOs:
CaseNotHPOFreeText: Bleeding score 1
Protein Expression:
CasePreviousTesting: 48,48 Access-Array amplification. NGS Molecular analysis was performed. Sanger sequencing was used to validate selected mutations.
Gene: VWF
Variant: NM_000552.4:c.1109G>A
ClinVar: N/A
CAID:CA6403559
gnomAD: MAF of 0.000008802 (1/113608 alleles) in the European (non-Finnish population). gnomAD
Case#: 02074, Age 37, Female, Blood Type A+ (Table S3)
Disease Assertion: VWD 1
FamilyInfo: Patient was the only member of family #0228.
Parental Genotype: Not listed
CasePresentingHPOs: N/A
CaseHPOFreeText: Bleeding Score 3, VWF:Ag: 24, VWF:RCo: 21, FVIII:C: 111, VWF:CB: 29
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
Protein Expression: N/A
CasePreviousTesting: 48,48 Access-Array amplification. NGS Molecular analysis was performed. Sanger sequencing was used to validate selected mutations
Gene: VWF
Variant: NM_000552.4(VWF):c.3426T>C (p.Cys1142=), NM_000552.4:c.6254G>T (p.Cys2085Phe), and NM_000552.4:c.3485_3486inv (p.Pro1162Leu)
ClinVar: 256668 and 619934 ClinVar ClinVar2
CAID: CA6402757, CA383492060, and CA658683073
gnomAD: MAF of 0.2228 (2240/10052 alleles) in the African population (CA6402757).
Case#: 06012, Age 10, Male, Blood Type O+ (Table S3)
Disease Assertion: VWD1
FamilyInfo: Patient is member of Family# 0609, which includes 3 individuals. All members of the family have the same variant.
Parental Genotype: Not listed
CasePresentingHPOs: N/A
CaseHPOFreeText: Bleeding score 10, VWF:Ag: 13, VWF:RCo:14, FVIII:C:40, VWF:CB:13
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
Protein Expression: N/A
CasePreviousTesting: 48,48 Access-Array amplification. NGS Molecular analysis was performed. Sanger sequencing was used to validate selected mutations.
Gene: VWF
Variant: NM_000552.4:c.3363G>T (p.Arg1121Ser)
ClinVar: N/A
CAID: CA383511875 CAID
gnomAD: N/A
Case#: 02064, Age 32, Male, Blood type O- (Table S3)
Disease Assertion: VWD 1
FamilyInfo: Patient is a part of family # 0224. There are 3 other members of the family (02065, 02066, 02067). All members of the family have the same variant.
Parental Genotype: Not listed
CasePresentingHPOs: N/A
CaseHPOFreeText: Bleeding score 13, VWF:Ag: 4.7, VWF:RCo: 5, FVIII:C: 16, VWF:CB:6
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
Protein Expression: N/A
CasePreviousTesting: 48,48 Access-Array amplification. NGS Molecular analysis was performed. Sanger sequencing was used to validate selected mutations
Gene:VWF
Variant: NM_000552.4:c.3614G>A (p.Arg1205His)
ClinVar: 308
CAID: CA114160
gnomAD: N/A
Case#: 27024, Age 56, Female, Blood Type A+ (Table S3)
Disease Assertion: VWD 1
FamilyInfo: The patient is the only member of Family#2713.
Parental Genotype: Not listed
CasePresentingHPOs: N/A
CaseHPOFreeText: VWF:Ag:5.3, VWF:RCo:6, FVIII:C:38, VWF:CB:4.2
CaseNotHPOs: N/A
CaseNotHPOFreeText: Bleeding Score 3
Protein Expression: N/A
CasePreviousTesting: 48,48 Access-Array amplification. NGS Molecular analysis was performed. Sanger sequencing was used to validate selected mutations.
Gene: VWF
Variant: NM_000552.4:c.3467C>T (p.Thr1156Met) and c.-3151T>G
ClinVar: 100264 ClinVar
CAID: CA228414 CAID
gnomAD: N/A
Case#: 02058, Age 64, Female, Blood type A+ (Table S3)
Disease Assertion: VWD1
FamilyInfo: Patient is the only member of family #0221.
Parental Genotype: Not listed
CasePresentingHPOs: N/A
CaseHPOFreeText: Bleeding score 19, VWF:Ag: 7.3, VWF:RCo: 5.9, FVIII:C: 19, VWF:CB: 6.3
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
Protein Expression: N/A
CasePreviousTesting: 48,48 Access-Array amplification. NGS Molecular analysis was performed. Sanger sequencing was used to validate selected mutations.
Gene: VWF
Variant: NM_000552.4:c.3614G>A (p.Arg1205His)
ClinVar: 308 ClinVar
CAID: CA114160 CAID
gnomAD: N/A
Case#: 03035, Age 51, Male (Table S3)
Disease Assertion: VWD1
FamilyInfo: A part of family #03150 along with two other patients.
Parental Genotype: Not listed
CasePresentingHPOs: Not listed
CaseHPOFreeText: Bleeding Score 4, VWF:Ag: 34, VWF:RCo: 26, FVIII:C: 43, VWF:CB 33
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
Protein Expression:N/A
CasePreviousTesting: 48,48 Access-Array amplification. NGS Molecular analysis was performed. Sanger sequencing was used to validate selected mutations
Gene: VWF
Variant: NM_000552.4:c.3467C>T (p.Thr1156Met) and NM_000552.3:c.-3151T>G
ClinVar: 100264 ClinVar
CAID: CA228414 CAID
gnomAD: N/A
Case#: 18001, Age 50, Male, Blood Type B+ (Table S3)
Disease Assertion: VWD 1
FamilyInfo: The patient one of 3 members of Family#1801. All of the patients have the same variant.
Parental Genotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: VWF:Ag:10, VWF:RCo:6.1, FVIII:C:17, VWF:CB:8.2
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
Protein Expression: N/A
CasePreviousTesting: 48,48 Access-Array amplification. NGS Molecular analysis was performed. Sanger sequencing was used to validate selected mutations
Gene: VWF
Variant: NM_000552.4:c.3614G>A (p.Arg1205His) and NM_000552.4:c.6989T>G (p.Val2330Gly)
ClinVar: 308 ClinVar1
CAID: CA114160 and CA6401808 CAID1 CAID2
gnomAD: MAF of 0.000008823 (1/113342 alleles) in the European (non-Finnish population) (CA6401808) gnomAD
Case#: 36008, Age 34, Female, Blood Type O+ (Table S3)
Disease Assertion: VWD 1
FamilyInfo: The patient is the only member of Family#3606.
Parental Genotype: Not listed
CasePresentingHPOs: N/A
CaseHPOFreeText: Bleeding Score 8, VWF:Ag: 34, VWF:RCo:14, FVIII:C: 37, VWF:CB: 25
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
Protein Expression: N/A
CasePreviousTesting: 48,48 Access-Array amplification. NGS Molecular analysis was performed. Sanger sequencing was used to validate selected mutations.
Gene: VWF
Variant: NM_000552.4:c.2771G>A(p.Arg924Gln) and NM_000552.4:c.3390C>T (p.Cys1130=)
ClinVar: 627186 ClinVar
CAID: CA228368 and CA478101454 CAID1 CAID2
gnomAD: MAF of 0.01866 (2411/ 129182 alleles) in the European (non-Finnish) population (CA228368). gnomAD
Case#: 02052, Age 25, Male, Blood type A+ (Table S3)
Disease Assertion: VWD 1
FamilyInfo: Patient is the only family member of family # 0220
Parental Genotype: Not listed
CasePresentingHPOs:N/A
CaseHPOFreeText: Bleeding Score: 11, VWF:Ag: 15, VWF:RCO:12, FVIII:C:20, VWF:CB: 16
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
Protein Expression: N/A
CasePreviousTesting: 48,48 Access-Array amplification. NGS Molecular analysis was performed. Sanger sequencing was used to validate selected mutations.
Gene: VWF
Variant: NM_000552.4:c.1625C>G (p.Ala542Gly) and NM_000552.4:c.6187C>T (p.Pro2063Ser)
ClinVar: 381621 and 100436 ClinVar1
CAID: CA6403319 and CA202650 CAID1
gnomAD: MAF of 0.001355 (48/ 35418 alleles) in the Latino population (CA6403319). MAF of 0.04854 (1486/ 30616 alleles) in the South Asian Population (CA202650).
T086M/130.010.020.01c.1A>G, c.2377C>Tp.Met1Val, p.Gln793*2/18Compound heterozygous
Case: T086, M, 1
DiseaseAssertion: VWD type 3
FamilyInfo: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: Bleeding Score: 3 (Kruskal–Wallis followed by Mann–Whitney U post-hoc testing Post-hoc testing ), VWF:Ag (IU/ml): 0.01, VWF:RCo (IU/ml): 0.02, FVIII:C (IU/ml): 0.01
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.1A>G (p.Met1Val), Exon 2
c.2377C>T (p.Gln793*), Exon 18
Compound Heterozygous
Note: ELISA-based assay for detecting alloantibodies, genomic analysis via sequencing of leukocytes for the VWF gene including exons 1-52 and about 1.5 km of VWF promoter, PCR amplification for variant confirmation, SALSA-MLPAVWF assay evaluation for partial/total gene deletions when sequencing did not reveal pathogenic explanation
T090M/280.010.040.01c.1117C>T, gene conversion (c.3931C>T, c.4027A>G, c.4079T>C, c.4105T>A)p.Arg373*, p.Gln1311*, p.Ile1343Val, p.Val1360Ala, p.Phe1369Ile10/28Compound heterozygous
Case: T090, M, 2
DiseaseAssertion: VWD type 3
FamilyInfo: inherited heterozygous gene conversion from the father
CasePresentingHPOs: n/a
CaseHPOFreeText: Bleeding Score: 8 (Kruskal–Wallis followed by Mann–Whitney U post-hoc testing Post-hoc testing ), VWF:Ag (IU/ml): 0.01, VWF:RCo (IU/ml): 0.04, FVIII:C (IU/ml): 0.01
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.1117C>T (p.Arg373*)
Gene Conversion (
c.3931C>T (p.Gln1311*)
c.4027A>G (p.Ile1343Val)
c.4079T>C (p.Val1360Ala)
c.4105T>A (p.Phe1369Ile)
)
Exon 10/28
Compound heterozygous
Note: ELISA-based assay for detecting alloantibodies, genomic analysis via sequencing of leukocytes for the VWF gene including exons 1-52 and about 1.5 km of VWF promoter, PCR amplification for variant confirmation, SALSA-MLPAVWF assay evaluation for partial/total gene deletions when sequencing did not reveal pathogenic explanation
T028M/34160.010.010.03c.7730-1 G>T, c.7906A>T-, p.Asn7906Tyr46/48HomozygousHeterozygous
Case: T028, M, 34
DiseaseAssertion: VWD type 3
FamilyInfo: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: Bleeding Score: 16 (Kruskal–Wallis followed by Mann–Whitney U post-hoc testing Post-hoc testing ), VWF:Ag (IU/ml): 0.01, VWF:RCo (IU/ml): 0.01, FVIII:C (IU/ml): 0.03
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.7730-1 G>T, Exon 46, Homozygous
c.7906A>T (p.Asn7906Tyr), Exon 48, Heterozygous
Note: ELISA-based assay for detecting alloantibodies, genomic analysis via sequecning of leukocytes for the VWF gene including exons 1-52 and about 1.5 km of VWF promoter, PCR amplification for variant confirmation, SALSA-MLPAVWF assay evaluation for partial/total gene deletions when sequencing did not reveal pathogenic explanation
The p.P1413L variant was detected in a patient with 44 IU/dL VWF:Ag, 58 IU/dL FVIII:C, 39 IU/dL VWF:RCo, and 37 IU/dL VWF:CB levels (Table I).
Case: P1413L heterozygous
DiseaseAssertion: VWD1
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0012147
(Reduced quantity of VWF)
CaseHPOFreeText: FVIII:C = 58 IU/dL, VWF:RCo = 39 IU/dL, VWF:Ag = 44 IU/dL, VWF:CB = 37 IU/dL, VWF:RCo/VWF:Ag = 0.89
CaseNOTHPOs: HP:0030132
(Absence of large von Willebrand factor multimers)
CaseNOTHPOFreeText:
CasePreviousTesting: NA
GenotypingMethod: NA
PreviouslyPublished: PMID: 16985174
Gene: VWF
Variant: c.4238C>T (p.Pro1413Leu)
HGVS: NM_000552.4(VWF):c.4238C>T (p.Pro1413Leu)
ClinVarID: 100342; https://www.ncbi.nlm.nih.gov/clinvar/variation/100342/
CAID:
gnomAD: MAF of 0.00003266 (1/30616 alleles) in the South Asian population
VWD1-115.619.50.807214.0NormalExon 13c.1496A>C‡p.Gln499ProD2Missense
Case: Croatian adult patient
DiseaseAssertion: VWD1
FamilyInfo: Not specified
ParentalGenotype(s): Not specified
CasePresentingHPOs: HP:0001892, HP:0011890, HP:0000132, HP:0002239, HP:0000790, HP:0001342
CaseHPOFreeText: Reduced VWF:Ag of 19.5%, and VWF:GPIbM of 15.6% and VWF:CBA of 14%. Normal FVIII:C of 72%. Normal multimer distribution.
CaseNOTHPOs: Not specified
CaseNOTHPOFreeText: Normal multimer size distribution (tested in Agarose gel).
CasePreviousTesting: Not reported
GenotypingMethod: Illumina NGS, custom designed panel covering all 52 exons as well as intronic flanking regions and promoter region of VWF gene.
PreviouslyPublished: None
Gene: VWF
Variant: c.1496A>C
HGVS: NM_000552.4:c.1496A>C (p.Gln499Pro)
ClinVarID: Not available
CAID: CA383500550
gnomAD: Not available
Supplementary Material
Case: Row 11 in Supplemental Table 1. Data represents 2 patients from 2 families.
DiseaseAssertion: type 1 VWD
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs:
CaseHPOFreeRext: FVIII:C/VWF:Ag = 1.0; 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: 1625C>G A542G
HGVS: VWF:c.1625C>G (p.Ala542Gly)
ClinVarID: 381621
CAID:
gnomAD: 0.001062 (1714 in 1613708) 2 homozygotes https://gnomad.broadinstitute.org/variant/12-6057953-G-C?dataset=gnomad_r4
MultipleGeneVariants:
Gene: VWF
Variant: c.8366C>T p.Thr2789Ile (only present in 1 of the 2 patients)
CAID: CA6401321
gnomAD: absent
1
Case#: 1, female, 44yo
DiseaseAssertion: VWD1
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: HP:0007420, HP:0000132, HP:0004846, HP:0012147, HP:0030129, HP:0030130 (spontaneous hematomas, Menorrhagia, Reduced quantity of VWF, Impaired ristocetin cofactor assay activity, Impaired von Willebrand factor collagen binding activity)
CaseHPOFreeText: Type O blood, VWF:Ag (0·55–2 iu/ml) pre = 0·47, VWF:RCo (0·55–2 iu/ml) pre = 0·5, FVIII:C (0·55–2 iu/ml) pre = 0·16, FVIII:C/VWF:Ag ratio = 0·32, VWF:FVIII binding (>20%) = 7%, VWF:FVIII binding/VWF:Ag (>0·7) = 0·15, patient died after motor vehicle accident
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
ProteinExpression: N/A
CasePreviousTesting: RFLP; confirmatory sequencing
Gene: VWF
Variant 1: NM_000552.4(VWF):c.2561G>A (p.Arg854Gln)
ClinVar: 296; https://www.ncbi.nlm.nih.gov/clinvar/variation/296/
gnomAD: MAF = 0.005692 (European Non-Finnish); https://gnomad.broadinstitute.org/variant/12-6143978-C-T
Variant 2: N/A - stated to be a compound heterozygote for a 2N VWD and a presumed null mutation
3
Case#: 3, female, 19yo
DiseaseAssertion: VWD1
FamilyInfo: brother diagnosed with VWD
ParentalGenotype: N/A
CasePresentingHPOs: HP:0000978; HP:0000132, HP:0004846, HP:0012147, HP:0030129 (Bruising susceptibility, Menorrhagia, Reduced quantity of VWF, Impaired ristocetin cofactor assay activity)
CaseHPOFreeText: Type O blood, VWF:Ag (0·55–2 iu/ml) pre = 0·14, VWF:RCo (0·55–2 iu/ml) pre = 0·15, FVIII:C (0·55–2 iu/ml) pre = 0·1, FVIII:C/VWF:Ag ratio = 0·71, VWF:FVIII binding (>20%) = n/a, VWF:FVIII binding/VWF:Ag (>0·7) = n/a, spinal surgery with VWF concentrate and adequate haemostasis
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
ProteinExpression: N/A
CasePreviousTesting: RFLP; confirmatory sequencing
Gene: VWF
Variant 1: NM_000552.4(VWF):c.2561G>A (p.Arg854Gln)
ClinVar: 296; https://www.ncbi.nlm.nih.gov/clinvar/variation/296/
gnomAD: MAF = 0.005692 (European Non-Finnish); https://gnomad.broadinstitute.org/variant/12-6143978-C-T
Variant 2: N/A - stated to be a compound heterozygote for a 2N VWD and a presumed null mutation
4
Case#: 4, male, 23yo
DiseaseAssertion: VWD1
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: HP:0004846, HP:0012147, HP:0030129 (Reduced quantity of VWF, Impaired ristocetin cofactor assay activity)
CaseHPOFreeText: Haemarthrosis in teens, Delayed bleeding after tonsillectomy (DDAVP given prior to procedure), VWF:Ag (0·55–2 iu/ml) pre = 0·35, VWF:RCo (0·55–2 iu/ml) pre = 0·32, FVIII:C (0·55–2 iu/ml) pre = 0·12, FVIII:C/VWF:Ag ratio = 0·34, VWF:FVIII binding (>20%) = n/a, VWF:FVIII binding/VWF:Ag (>0·7) = n/a, Surgery to repair a syringomyelia defect with VWF concentrate and no bleeding complications
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
ProteinExpression: N/A
CasePreviousTesting: RFLP; confirmatory sequencing
Gene: VWF
Variant 1: NM_000552.4(VWF):c.2561G>A (p.Arg854Gln)
ClinVar: 296; https://www.ncbi.nlm.nih.gov/clinvar/variation/296/
gnomAD: MAF = 0.005692 (European Non-Finnish); https://gnomad.broadinstitute.org/variant/12-6143978-C-T
Variant 2: N/A - stated to be a compound heterozygote for a 2N VWD and a presumed null mutation
1
Case: 2M-2
DiseaseAssertion: VWD2M
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs: AcuStar RCo/Ag = 0.01; AcuStar CB/Ag = 1.16; ELISA CB/Ag = 1.41
CaseHPOFreeText:
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting:
GenotypingMethod: not described
PreviouslyPublished: 1409710
Gene: VWF
Variant: c.3970G>A (p.Gly1324Ser)
HGVS: NM_000552.5(VWF):c.3970G>A (p.Gly1324Ser)
ClinVarID: 300; https://www.ncbi.nlm.nih.gov/clinvar/variation/300/?new_evidence=false
CAID:
gnomAD: MAF = 0.00003267 in South Asian population; https://gnomad.broadinstitute.org/variant/12-6128614-C-T
0.36
Case: 2A-5
DiseaseAssertion: VWD2A
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs: AcuStar RCo/Ag = 0.36; AcuStar CB/Ag = 0.15; ELISA CB/Ag = 0.24
CaseHPOFreeText:
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting:
GenotypingMethod: not described
PreviouslyPublished: PMID: 1537829
Gene: VWF
Variant: c.4789C>T (p.Arg1597Trp)
HGVS: NM_000552.5(VWF):c.4789C>T (p.Arg1597Trp)
ClinVarID: 285; https://www.ncbi.nlm.nih.gov/clinvar/variation/285/?new_evidence=false
CAID:
gnomAD: absent
0.32
Case: 2B-5
DiseaseAssertion: VWD2B
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs: AcuStar RCo/Ag = 0.32; AcuStar CB/Ag = 0.19; ELISA CB/Ag = 0.38
CaseHPOFreeText:
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting:
GenotypingMethod: not described
PreviouslyPublished: 1373334
Gene: VWF
Variant: c.4010C>T (p.Pro1337Leu)
HGVS: NM_000552.5(VWF):c.4010C>T (p.Pro1337Leu)
ClinVarID: 100314; https://www.ncbi.nlm.nih.gov/clinvar/variation/100314/?new_evidence=false
CAID:
gnomAD: MAF = 0.00005440 in East Asian population; https://gnomad.broadinstitute.org/variant/12-6128574-G-A
1
Case: 2B-8
DiseaseAssertion: VWD2B
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs: AcuStar RCo/Ag = 0.99; AcuStar CB/Ag = 1.35; ELISA CB/Ag = 1.02
CaseHPOFreeText:
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting:
GenotypingMethod: not described
PreviouslyPublished: 16985174
Gene: VWF
Variant: c.3797C>T (p.Pro1266Leu)
HGVS: NM_000552.5(VWF):c.3797C>T (p.Pro1266Leu)
ClinVarID: 314; https://www.ncbi.nlm.nih.gov/clinvar/variation/314/?new_evidence=false
CAID:
gnomAD: MAF (European, Finnish) = 0.003667; 1 homozygote; https://gnomad.broadinstitute.org/variant/12-6128787-G-A
1
Case: 2A-7
DiseaseAssertion: VWD2A
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs: AcuStar RCo/Ag = 0.27; AcuStar CB/Ag = 0.10; ELISA CB/Ag = 0.39
CaseHPOFreeText:
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting:
GenotypingMethod: not described
PreviouslyPublished: PMID:1673047
Gene: VWF
Variant: c.4883T>C (p.Ile1628Thr)
HGVS: NM_000552.5(VWF):c.4883T>C (p.Ile1628Thr)
ClinVarID: 284; https://www.ncbi.nlm.nih.gov/clinvar/variation/284/?new_evidence=false
CAID:
gnomAD: absent
0.49
Case: 2A-1
DiseaseAssertion: VWD2A
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs: AcuStar RCo/Ag = 0.49; AcuStar CB/Ag = 0.29; ELISA CB/Ag = 0.33
CaseHPOFreeText:
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting:
GenotypingMethod: not described
PreviouslyPublished: PMID: 8435341
Gene: VWF
Variant: c.4541T>G (p.Phe1514Cys)
HGVS: NM_000552.5(VWF):c.4541T>G (p.Phe1514Cys)
ClinVarID: 304; https://www.ncbi.nlm.nih.gov/clinvar/variation/304/?new_evidence=false
CAID:
gnomAD: absent
0.62
Case: 2B-2
DiseaseAssertion: VWD2B
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs: AcuStar RCo/Ag = 0.62; AcuStar CB/Ag = 0.50; ELISA CB/Ag = 0.47
CaseHPOFreeText:
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting:
GenotypingMethod: not described
PreviouslyPublished: 1373334
Gene: VWF
Variant: c.4010C>T (p.Pro1337Leu)
HGVS: NM_000552.5(VWF):c.4010C>T (p.Pro1337Leu)
ClinVarID: 100314; https://www.ncbi.nlm.nih.gov/clinvar/variation/100314/?new_evidence=false
CAID:
gnomAD: MAF = 0.00005440 in East Asian population; https://gnomad.broadinstitute.org/variant/12-6128574-G-A
P9
Case: P9, M/26
DiseaseAssertion: VWD1
FamilyInfo: No family history
ParentalGenotype: NA
CaseHPOFreeText: The bleeding score was 1, aPTT was 44 seconds, FVIII:C was 9%, VWF:RCo was 13 IU/dL, and VWF:Ag was 6 IU/dL, with a VWF:RCo/VWF:Ag ratio of 2.0. The VWF multimer pattern was normal, RIPA was 3 ohms, and the platelet count was 217 × 10⁹/L.
CasePreviousTesting: NA
GenotypingMethod: Direct sequencing of all exons, flanking intronic sequences, and the promoter of VWF was performed.
Gene: VWF
Variant: c.3614G>A, p.R1205H — heterozygous
HGVS: NM_000552.5(VWF):c.3614G>A (p.Arg1205His)
ClinVar: 308
CAID: CA114160
gnomAD: https://gnomad.broadinstitute.org/variant/chr12-6021960-C-T?dataset=gnomad_r4
P8
Case: P8, M/32
DiseaseAssertion: VWD1
FamilyInfo: Positive family history, no details provided.
ParentalGenotype: NA
CaseHPOFreeText: The bleeding score was 7, aPTT was 39 seconds, FVIII:C was 10%, VWF:RCo was 14 IU/dL, and VWF:Ag was 13 IU/dL, resulting in a VWF:RCo/VWF:Ag ratio of 1.1. The VWF multimer pattern showed a mild loss of high molecular weight multimers, RIPA was not tested, and the platelet count was 286 × 10⁹/L.
CasePreviousTesting: NA
GenotypingMethod: Direct sequencing of all exons, flanking intronic sequences, and the promoter of VWF was performed.
Gene: VWF
Variant: c.2665T>C, p.C889R — heterozygous
HGVS: NM_000552.5(VWF):c.2665T>C (p.Cys889Arg)
ClinVar:
CAID: CA383519992
gnomAD: absent from gnomad v4.1.0
P10
Case: P10, M/2
DiseaseAssertion: VWD1
FamilyInfo: No family history
ParentalGenotype: NA
CaseHPOFreeText: The bleeding score was 1, aPTT was 33 seconds, FVIII:C was 96%, VWF:RCo was 30 IU/dL, and VWF:Ag was 36 IU/dL, resulting in a VWF:RCo/VWF:Ag ratio of 0.8. The VWF multimer pattern was normal, RIPA was not tested, and the platelet count was 222 × 10⁹/L.
CasePreviousTesting: NA
GenotypingMethod: Direct sequencing of all exons, flanking intronic sequences, and the promoter of VWF was performed.
Gene: VWF
Variant: c.3835G>A, p.V1279I — heterozygous
HGVS: NM_000552.5(VWF):c.3835G>A (p.Val1279Ile)
ClinVar: 100288
CAID: CA228459
gnomAD: https://gnomad.broadinstitute.org/variant/chr12-6019583-C-T?dataset=gnomad_r4
9
Case: Patient 9 (Family B), male, 71yo
DiseaseAssertion: VWD2B
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0030132, HP:0030129, HP:0030130, HP:0011871, HP:0012147
(Absence of large von Willebrand factor multimers, impaired ristocetin cofactor assay activity, Impaired von Willebrand factor collagen binding activity, Impaired RIPA, Reduced quantity of VWF)
CaseHPOFreeText: blood group O, Platelet count x103/μl = 56, PFA 100 sec = >300, SPA % = 22, MADR mg/mL = 0.3, VWF:Ag U/dL = 81.2, VWF:CB U/dL = 25.9, VWF:CB ratio = 0.32, VWF:RCo U/dL = 33.75, VWF:RCo ratio = 0.41, Platelet VWF U/dL = 146.2, FVIII U/dL = 52, BAT F/M = NA
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: NA
GenotypingMethod: Sequencing of exon 28 of VWF
PreviouslyPublished: NA
Gene: VWF
Variant: c.3922C>T (p.Arg1308Cys)
HGVS: NM_000552.4(VWF):c.3922C>T (p.Arg1308Cys)
ClinVarID: 289; https://www.ncbi.nlm.nih.gov/clinvar/variation/289/
CAID: NA
gnomAD: absent
3
Case: Patient 3 (Family B), male, 55yo
DiseaseAssertion: VWD2B
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0030129, HP:0030130, HP:0011871, HP:0012147
(impaired ristocetin cofactor assay activity, Impaired von Willebrand factor collagen binding activity, Impaired RIPA, Reduced quantity of VWF)
CaseHPOFreeText: blood group O, Platelet count x103/μl = 204, PFA 100 sec = >300, SPA % = 0, MADR mg/mL = 0.45, VWF:Ag U/dL = 23.4, VWF:CB U/dL = 21.1, VWF:CB ratio = 0.9, VWF:RCo U/dL = 17.2, VWF:RCo ratio = 0.74, Platelet VWF U/dL = 42.6, FVIII U/dL = 60.5, BAT F/M = 20
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: NA
GenotypingMethod: Sequencing of exon 28 of VWF
PreviouslyPublished: NA
Gene: VWF
Variant 1: c.3797C>T (p.Pro1266Leu)
HGVS: NM_000552.4(VWF):c.3797C>T (p.Pro1266Leu)
ClinVarID: 314; https://www.ncbi.nlm.nih.gov/clinvar/variation/314/
CAID: NA
gnomAD: MAF = 0.003667 (92/25086 alleles; 1 homozygote) in the European (Finnish) population; https://gnomad.broadinstitute.org/variant/12-6128787-G-A?dataset=gnomad_r2_1
Variant 2: c.7085G>T (p.Cys2362Phe)
HGVS: NM_000552.4(VWF):c.7085G>T (p.Cys2362Phe)
ClinVarID: 315; https://www.ncbi.nlm.nih.gov/clinvar/variation/315/
CAID: NA
gnomAD: absent
4
Case: Patient 4 (Family C), female, 76yo
DiseaseAssertion: VWD2B
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0030129, HP:0030130, HP:0011871, HP:0012147
(impaired ristocetin cofactor assay activity, Impaired von Willebrand factor collagen binding activity, Impaired RIPA, Reduced quantity of VWF)
CaseHPOFreeText: blood group O, Platelet count x103/μl = 236, PFA 100 sec = >300, SPA % = 8.4, MADR mg/mL = 0.75, VWF:Ag U/dL = 35.4, VWF:CB U/dL = 37.3, VWF:CB ratio = 1.05, VWF:RCo U/dL = 25.4, VWF:RCo ratio = 0.72, Platelet VWF U/dL = 66.8, FVIII U/dL = 32.0, BAT F/M = 16
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: NA
GenotypingMethod: Sequencing of exon 28 of VWF
PreviouslyPublished: NA
Gene: VWF
Variant: c.4135C>T (p.Arg1379Cys)
HGVS: NM_000552.4(VWF):c.4135C>T (p.Arg1379Cys)
ClinVarID: 100333; https://www.ncbi.nlm.nih.gov/clinvar/variation/100333/
CAID: NA
gnomAD: MAF = 0.00003891 (5/128500 alleles) in the European (non-Finnish) population; https://gnomad.broadinstitute.org/variant/12-6128449-G-A?dataset=gnomad_r2_1
1 CASE PRESENTATION
Case#: 32 year old female
DiseaseAssertion: VWD Type 2M
CaseHPOFreeText4: Testing was repeated multiple times, with initial results being untrustworthy. Follow up testing is as follows: VWF:RCo/VWF:Ag ratio = 0.61, VWF:CB = 10. Normal multimers
CasePreviousTesting: Molecular analysis by next generation gene sequencing analysis of VWF, F8, GPIBA and GPIBB.
Gene: VWF
Variant: variant in VWF at exon 31 (c.5347 T > G) that leads to a VWF protein change of p.Ser1783Ala
HGVS: NM_000552.5(VWF):c.5347T>G (p.Ser1783Ala)
ClinVar: 31012
CAID: CA228715
gnomAD: 0.0006918 in South Asian pop
T3-2
Case: T3-2, female, 11yo
DiseaseAssertion: VWD3
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs:
CaseHPOFreeText: Blood type: O+, bleeding score = 13, VWF:Ag (IU/mL) = 0.01; VWF:RCo (IU/mL) = 0.03; FVIII:C (IU/mL) = 0.01
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting:
GenotypingMethod: qRT-PCR
PreviouslyPublished:
Gene: VWF
Variant: c.1897T>C (p.Cys633Arg)
HGVS: NM_000552.5:c.1897T>C (p.Cys633Arg)
ClinVarID: n/a
CAID: CA383496953; https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA383496953
gnomAD: absent
2B
Case: 2B, male, 55yo
DiseaseAssertion: VWD2B
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs:
CaseHPOFreeText: Blood type: O+, bleeding score = 17, VWF:Ag (IU/mL) = 0.40; VWF:RCo (IU/mL) = 0.13; FVIII:C (IU/mL) = 0.46
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting:
GenotypingMethod: qRT-PCR
PreviouslyPublished:
Gene: VWF
Variant: c.3946G>A (p.Val1316Met)
HGVS: NM_000552.5(VWF):c.3946G>A (p.Val1316Met)
ClinVarID: 290; https://www.ncbi.nlm.nih.gov/clinvar/variation/290/?new_evidence=false
CAID:
gnomAD: absent
2M
Case: 2M, female, 25yo
DiseaseAssertion: VWD2M
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs:
CaseHPOFreeText: Blood type: A+, bleeding score = 7, VWF:Ag (IU/mL) = 0.11; VWF:RCo (IU/mL) = 0.03; FVIII:C (IU/mL) = 0.39
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting:
GenotypingMethod: qRT-PCR
PreviouslyPublished:
Gene: VWF
Variant: c.4145T>C (p.Leu1382Pro)
HGVS: NM_000552.5:c.4145T>C (p.Leu1382Pro)
ClinVarID: n/a
CAID: CA383504407; https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA383504407
gnomAD: absent
Val1316Met
Gene:VWF
HGNCID:12726
Case:Preterm female newborn delivered by C/S
DiseaseAssertion:VWD Type 2B
FamilyInfo:Fig. 1 Father with VWD 2B and two paternal half-brothers diagnosed with hematomas after birth
ParentalGenotype(s):heterozygous carrier p.(Val1316Met) confirmed in the father, half-brothers were not tested
CasePresentingHPOs: HP:0001873, HP:0012147
CaseHPOFreeRext:Multiple hematomas, no cerebral hemorrhage
CaseNOTHPOs:HP:0030130
CaseNOTHPOFreeText:analyses showed reduced VWF activity levels (40% at postnatal day 7), whereas VWF antigen was normal (146% at postnatal day 7)
CasePreviousTesting:No . Gene:VWF
Variant:p.Val1316Met
HGVS:NM_000552.4:c.3946G>A
ClinVarID:290
CAID:CA114127
gnomAD:6.20e-7
3*ItalyF/21<1—NoSevere666G→A/823T→AW222X/C275S7/7HeterozygousN.A./BsrI (+)
Case: 3, F, 21, Italian
DiseaseAssertion: VWD type 3
FamilyInfo: Consanguinity: no
ParentalGenotype: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: VWF:Ag (U/dl): <1, Bleeding symptoms: Severe
CaseNotHPOs: n/a
CaseNotHPOFreeText: Anti-VWF alloantibodies: no
CasePreviousTesting: n/a
Gene: VWF
Variant:
666G→A (Trp222X), Exon 7
823T→A (Cys275Ser), Exon 7
Compound Heterozygous
2ItalyF/58<1—NoSevere421G→T/2016del4D141Y/FS5/16HeterozygousBstYI (+)/N.A.
Case: 2, F, 58, Italian
DiseaseAssertion: VWD type 3
FamilyInfo: Consanguinity: no
ParentalGenotype: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: VWF:Ag (U/dl): <1, Bleeding symptoms: Severe
CaseNotHPOs: n/a
CaseNotHPOFreeText: Anti-VWF alloantibodies: no
CasePreviousTesting: n/a
Gene: VWF
Variant:
421G→T (Asp141Tyr), Exon 5
2016del4 (FS), Exon 16
Compound Heterozygous
37IndiaF/29<1—NoMild1896G→A/3212G→TW642X/C1071F15/24HeterozygousMaeIII (+)/N.A.
Case: 37, F, 29, Indian
DiseaseAssertion: VWD type 3
FamilyInfo: Consanguinity: No
ParentalGenotype: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: VWF:Ag (U/dl): <1, Bleeding symptoms: Mild
CaseNotHPOs: n/a
CaseNotHPOFreeText: Anti-VWF alloantibodies: no
CasePreviousTesting: n/a
Gene: VWF
Variant:
1896G→A (Trp642X), Exon 15
3212G→T (Cys1071Phe), Exon 24
Compound Heterozygous
II : 1
Case#: F20, II:1
DiseaseAssertion: Type 2 VWD
CaseHPOFreeText: loss of high and intermediate MWMs, VWF:Ag = 45; VWF:RCo = 7; VWF:GPIbM = 43; 0.16; 0.95; 6.11
CasePreviousTesting: Not clearly described
Gene: VWF
Variant: p.[V1316M];[=]
HGVS: c.3946G>A (p.Val1316Met)
CAID: CA114127
gnomAD: absent from gnomad v4.1.0
I : 1
Case#: F8, I:1
DiseaseAssertion: Type 2 VWD
CaseHPOFreeText: partial loss of high molecular weight multimers, VWF:Ag = 37; VWF:RCo = 21; VWF:GPIbM = 34; 0.57; 0.92; 1.60
CasePreviousTesting: Not clearly described
Gene: VWF
Variant: p.[P1337L];[=]
HGVS: c.4010C>T (p.Pro1337Leu)
CAID: CA228510
gnomAD: https://gnomad.broadinstitute.org/variant/12-6019408-G-A?dataset=gnomad_r4
Case UZ092: 28 year old female (row 93 in supplementary table)
DiseaseAssertion: type 1 VWD
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs: HP:0032442
CaseHPOFreeRext: vWF:Ag (%) = 16; vWF:GPIbR (%) = 12; Act/Ag ratio = 0.75; FVIII:C (%) = 28; Platelets (x10^9/L) = 288
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.4135C>T p.Arg1379Cys
HGVS:
ClinVarID: 100333
CAID:
gnomAD: 0.00002540 (41 in 1613910) no homozygotes https://gnomad.broadinstitute.org/variant/12-6019283-G-A?dataset=gnomad_r4
MultipleGeneVariants:
Gene: F11
Variant: c.1305-2A>G
ClinVarID: 2572126
gnomAD: absent
40 M Type 2 NOS VWD Type 2M VWD c.4195C>T p.Arg1399Cys LP
Case 13: 40 year old male, study ID UZ094 in supplemental table
DiseaseAssertion: type 2 NOS VWD presequencing, type 2M VWD postsequencing
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs: HP:0032442
CaseHPOFreeRext: vWF:Ag (%) = 61.2; vWF:GPIbR (%) = 24.8; Act/Ag ratio = 0.41; FVIII:C (%) = 31.5; Platelets (x10^9/L) = 368; normal multimers
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.4195C>T p.Arg1399Cys
HGVS:
ClinVarID: 100337
CAID:
gnomAD: 0.00005143 (83 in 1613776) no homozygotes https://gnomad.broadinstitute.org/variant/12-6019223-G-A?dataset=gnomad_r4
younger brother (Patient B)
Case: Patient B, male, 11 years old at WIL-29 study entry; ethnicity not reported.
DiseaseAssertion: VWD3. The patient was initially suspected to have VWD2A based on the family history but was reclassified as VWD3 after next-generation sequencing.
FamilyInfo: Patient B and Patient A are brothers from a consanguineous family. Both parents were diagnosed with VWD. Figure 2 shows both parents as heterozygous and Patient A and Patient B as homozygous for the familial VWF variant. The pedigree also includes another brother affected with VWD whose genetic testing was underway and a sister whose VWD diagnosis and genetic testing were pending.
ParentalGenotype: Both parents were heterozygous for the familial VWF variant, as shown in Figure 2.
CasePresentingHPOs: HP:0000421, HP:0030129 (Epistaxis, Impaired ristocetin cofactor assay activity)
CaseHPOFreeText: Recurrent spontaneous epistaxis. Historical VWF:RCo 1%; historical VWF:Ag not measured. VWF:RCo 1 IU/dL at WIL-31 screening. At the month 0 pharmacokinetic visit, pre-injection FVIII 16 IU/dL and VWF:RCo <5 IU/dL; after 60 IU/kg wilate, maximum VWF:RCo 65 IU/dL and in vivo recovery 1.02 kg/dL. VWF inhibitors were confirmed present at WIL-31 study entry; no VWF inhibitor was detectable at the 12-month visit.
CaseNotHPOs: NA
CaseNotHPOFreeText: No anaphylactic reactions or severe treatment-related adverse events were reported.
CasePreviousTesting: Diagnosed with VWD shortly after birth and initially suspected to have VWD2A based on family history. Historical VWF activity testing, and subsequent pharmacokinetic and VWF inhibitor testing, were performed. Historical VWF antigen was not measured. No earlier molecular genetic testing was reported.
GenotypingMethod: Next-generation sequencing performed in Bonn, Germany. Additional technical details regarding the sequencing assay or panel were not provided.
Gene: VWF
Variant: c.4094T>C p.Leu1365Pro, homozygous
HGVS: NM_000552.5:c.4094T>C (p.Leu1365Pro)
ClinVar: 2438545
CAID: NA
gnomAD: Absent (not reported in gnomAD; 0/251040 control chromosomes)
P5
Case: P5, male, 73yo
DiseaseAssertion: VWD2M
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0012147, HP:0030129, HP:0030130
(Reduced quantity of VWF, Impaired ristocetin cofactor assay activity, Impaired von Willebrand factor collagen binding activity)
CaseHPOFreeText: bleeding score = 8; VWF:Ag (%) = 46, VWF:RCo(%) = 8.5, VWF:RCo/VWF:Ag ratio = 0.18, VWF:CIIIB (%) = 19.5, VWF:CIIIB/VWF:Ag ratio = 0.4, VWF:CVIB (%) = 15, VWF:CVIB/VWF:Ag ratio = 0.33
CaseNOTHPOs: HP:0030132
(Absence of large von Willebrand factor multimers)
CaseNOTHPOFreeText: NA
CasePreviousTesting: NA
GenotypingMethod: NGS
PreviouslyPublished: NA
Gene: VWF
Variant: c.4121G>A (p.Arg1374His)
HGVS: NM_000552.4(VWF):c.4121G>A (p.Arg1374His)
ClinVarID: 100330; https://www.ncbi.nlm.nih.gov/clinvar/variation/100330/
CAID:
gnomAD: absent
P7
Case: P7, male, 9yo
DiseaseAssertion: VWD2M
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0030129, HP:0030130
(Impaired ristocetin cofactor assay activity, Impaired von Willebrand factor collagen binding activity)
CaseHPOFreeText: bleeding score = 7; VWF:Ag (%) = 56, VWF:RCo(%) = 32, VWF:RCo/VWF:Ag ratio = 0.58, VWF:CIIIB (%) = 37, VWF:CIIIB/VWF:Ag ratio = 0.67, VWF:CVIB (%) = 17.4, VWF:CVIB/VWF:Ag ratio = 0.31
CaseNOTHPOs: HP:0030132
(Absence of large von Willebrand factor multimers)
CaseNOTHPOFreeText: NA
CasePreviousTesting: NA
GenotypingMethod: NGS
PreviouslyPublished: NA
Gene: VWF
Variant: c.4195C>T (p.Arg1399Cys)
HGVS: NM_000552.4(VWF):c.4195C>T (p.Arg1399Cys)
ClinVarID: 100337; https://www.ncbi.nlm.nih.gov/clinvar/variation/100337/
CAID:
gnomAD: MAF = 0.0001386 (1/7214 alleles) in the Other population; https://gnomad.broadinstitute.org/variant/12-6128389-G-A?dataset=gnomad_r2_1
In family 1, the proposita (1A)
Case#: 1A
DiseaseAssertion:
FamilyInfo: Family 1. Her 2 offspring, 1B (son) and 1C (daughter), reported minor bleeding symptoms that had not required treatment. 1B was found to be heterozygous for Trp1745Cys only and 1C was heterozygous for Arg760His only, confirming that these mutations are in trans in 1A.
CaseHPOFreeText4: was an elderly woman with lifelong bleeding episodes, including epistaxis, ecchymosis, menorrhagia, and prolonged bleeding after dental extractions, requiring multiple medical interventions. The coexistence of both mutations appears to produce a more significant bleeding disorder as the bleeding score in 1A (8) was higher than that in either of her children (4 and 2). The position of Trp1745 in the A3 domain is shown in Figure 2. Both persons with this mutation (1A and 1B) had markedly reduced ratios of VWF collagen-binding activity to VWF antigen (CB:Ag) with type III collagen (0.1 and 0.3, respectively) and type I collagen (0.2 and 0.3, respectively). The ratio of VWF:RCo to VWF:Ag (RCo:Ag) was near unity in both persons, and VWF multimer analysis (Figure 1B) and RIPA were normal. Closure times in the PFA-100 were mildly prolonged with the ADP cartridge (1A = 173 seconds, 1B = 189 seconds, NR < 112 seconds). With the epinephrine cartridge, the closure time was prolonged in 1A only (1A = 271 seconds, 1B = 90 seconds, NR < 179 seconds).
CasePreviousTesting: Fifty-one primer sets were used to amplify the essential regions of VWF (52 exons, flanking intronic regions, 5′ promoter region, and the 3′ untranslated region).
Gene: VWF
Variant: 1A demonstrated compound heterozygosity for 2 mutations in the VWF gene. The first is a novel mutation in exon 30:c.5235 G → T resulting in Trp1745Cys and the second is c.2279 G → A resulting in Arg760His.
HGVS: NM_000552.5(VWF):c.5235G>T (p.Trp1745Cys), NM_000552.5(VWF):c.2279G>A (p.Arg760His)
ClinVar: 100421, 31011
CAID: CA228706, CA228316
gnomAD: 8.474e-7 in the european non finnish pop, 0.00002669 in the African American population
55-year-old Italian man
Case: 55-year-old Italian, male
DiseaseAssertion: VWD, Type 2B
FamilyInfo: Patient did not report any family history of bleeding and his daughter did not show any menorrhagia and hemorrhagic disorder. Genotyping for daughter was negative for variants of interest. Paternity of daughter established. Testing performed on both daughter and wife.
ParentalGenotype(s): No genotyping available on parents, as they were deceased.
CasePresentingHPOs: HP:0000421, HP:0004846, HP:0012147, HP:0030129, HP:0030130, . HP:0030132, HP:0011871, HP:0003645
CaseHPOFreeRext: aPTT,s=45.4, Fibrinogen,mg/dL=349, VFG:Ag, IU/dL=23.4, VWF:RCo, IU/dL=8.5, VWF:CBA, IU/dL=7.2, FVIII:C, IU/dL=28.2, VWFpp, %=63.4, VWF:RCo/VWF:Ag =0.36, VWF:CBA/VWF:Ag=0.31, VWFpp/VWF:Ag=2.7, FVIII/VWF:Ag=1.2,FVIII/VWF:binding, %=127.8, ADAMTS-13 act, U/dL=110.1, Platelets, ×109/L=121-166, Hb, g/dL=8.1-15.1, Blood group= A-Rh +Rh phenotype: ccDEe Kell/Cellano phenotype: kk
CaseNOTHPOs: none
CaseNOTHPOFreeText: none
CasePreviousTesting: none
GenotypingMethod: Molecular genetic analysis of the VWF gene was performed using 3100-Avant Genetic Analyzer. Sanger-sequencing procedures were carried out to validate the identified genetic variants.
PreviouslyPublished:
1) PMID: 27007659
2) PMID: 20492463
Gene: VWF
Variant:
1) c.2771G>A p.R924Q, exon 21, D′D3 domain,cis heterozygous
2) c.6532G>T p.A2178S, exon 37, cis heterozygous
HGVS:
1) NC_000012.12:g.6031493C>T, NC_000012.11:g.6140659C>T, NG_009072.2:g.98178G>A, NM_000552.5:c.2771G>A, NM_000552.4:c.2771G>A, NM_000552.3:c.2771G>A, XM_047429501.1:c.2771G>A, NP_000543.3:p.Arg924Gln, XP_047285457.1:p.Arg924Gln
2) NC_000012.12:g.5993928C>A, NC_000012.12:g.5993928C>T, NC_000012.11:g.6103094C>A, NC_000012.11:g.6103094C>T, NG_009072.2:g.135743G>T, NG_009072.2:g.135743G>A, NM_000552.5:c.6532G>T, NM_000552.5:c.6532G>A, NM_000552.4:c.6532G>T, NM_000552.4:c.6532G>A, NM_000552.3:c.6532G>T, NM_000552.3:c.6532G>A, XM_047429501.1:c.6532G>T, XM_047429501.1:c.6532G>A, NP_000543.3:p.Ala2178Ser, NP_000543.3:p.Ala2178Thr, XP_047285457.1:p.Ala2178Ser, XP_047285457.1:p.Ala2178Thr
ClinVarID:
1) 100240
2) 619942
CAID:
1) CA228368
2) CA6401974
gnomAD:
1) European (non-Finnish) 0.02225 https://gnomad.broadinstitute.org/variant/12-6031493-C-T?dataset=gnomad_r4
2) European (non-Finnish) 0.02318 https://gnomad.broadinstitute.org/variant/12-5993928-C-A?dataset=gnomad_r4
homozygous c.2311A>G
Gene:VWF
HGNCID:12726
Case:13 yo female
DiseaseAssertion: Type 2N
FamilyInfo:Fig. 1, family 2, patient 7
ParentalGenotype(s):Unknown, obligate carriers
CasePresentingHPOs:HP:0000421, HP:0004846, HP:0012147 HP:0030132, HP:0030130
CaseHPOFreeRext:Oral cavity and joint bleeding, VWF:Ag 0.07 U/mL, VWF:Ac 0 U/mL, VWF:CB 0.05 U/mL, FVIII 0.04 U/mL, No VWF Multimers
GenotypingMethod: NGS
Gene:VWF
Variant:c.2311A>G
HGVS:NM_000552.5(VWF):c.2311A>G
ClinVarID:1065273
CAID:CA383522481
homozygous c.2311A>G
Gene:VWF
HGNCID:12726
Case:27 yo male
DiseaseAssertion: Type 2N
FamilyInfo:Fig. 1, family 1, patient 2
ParentalGenotype(s):Unknown, obligate carriers
CasePresentingHPOs:HP:0000421, HP:0012147 HP:0030132, HP:0030130
CaseHPOFreeRext:Skin, oral cavity, and joint bleeding, Bleeding after tooth extractions and small wounds, VWF: Ag 0.07 U/mL, VWF:Act 0.05 U/mL, VWF:CB <0.05 U/mL, FVIII:C 0.01 U/mL, Less VWF Multimers
GenotypingMethod: NGS
Gene:VWF
Variant:c.2311A>G
HGVS:NM_000552.5(VWF):c.2311A>G
ClinVarID:1065273
CAID:CA383522481
homozygous c.2311A>G
Gene:VWF
HGNCID:12726
Case:17 yo male
DiseaseAssertion: Type 2N
FamilyInfo:Fig. 1, family 1, patient 3
ParentalGenotype(s):Unknown, obligate carriers
CasePresentingHPOs:HP:0000421, HP:0012147 HP:0030132, HP:0030130
CaseHPOFreeRext:Oral cavity, skin, and muscle bleeding, Bleeding after tooth extractions, VWF: Ag 0.09 U/mL, VWF:Act 0.05 U/mL, VWF:CB 0.04 U/mL, FVIII:C 0.01 U/mL, No VWF Multimers
GenotypingMethod: NGS
Gene:VWF
Variant:c.2311A>G
HGVS:NM_000552.5(VWF):c.2311A>G
ClinVarID:1065273
CAID:CA383522481
15*3113−−NDFc.3379+1G>A/c.3379+1G>ASplice/Splice25/2518/18PD/PD
Case: Patient 15, F, Hungarian
DiseaseAssertion: VWD type 3
FamilyInfo: compatible with recessive inheritance
ParentalGenotype(s): n/a
CasePresentingHPOs: n/a
CaseHPOFreeRext: VWF:Ag (IU dL−1): 1, VWF:CB (IU dL−1): 1, FVIII:C (IU dL−1): 3, VWF:RCo below detection limit (<10 IU dL−1), not detectable VWF on multimer gels, bleeding episode severity increased after the menarche
CaseNOTHPOs: n/a
CaseNOTHPOFreeText: no inhibitor detected, did not become refractory to factor replacement therapy
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.3379+1G>A (Splice), Exon 25, Homozygous
(p.Arg924Gln), Exon 21, Homozygous
Intron 40 VNTR 18/18
Note: multimer electrophoresis, Recombinant VWF antigen concentrations and Collagen binding activity (VWF:CB) measured by ELISA, direct sequencing of the 51 exons and the exon‐intron boundaries, Breakpoint analysis and breakpoint‐specific PCR
GTa, a 37-year-old female IrishCaucasian
Case1: (GTa) Female, 27 years old, Irish Caucasian
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: No family history of bleeding
ParentalGenotype: N/A
CasePresentingHPOs: HP:0000978
(Bruising)
CaseHPOFreeText: Excessive bleeding after a normal delivery
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Reduced expression of GPIIb/IIIa
PlateletAggregation: Platelet aggregation to ADP, thrombin receptor activating peptide, thrombin and U46619 was less than 10% and ristocetin induced agglutination was normal
CasePreviousTesting: Total RNA isolated from the proband's platelets was used as a template for RT PCR. Seven primer pairs were used to amplify overlapping regions of the entire GPIIIa coding sequence using cDNA template
Gene: ITGB3
Variant: NM_000212.2:c.655G>A (p.Val219Met)
LegacyVariant: (p.Val193Met)
ClinVar: N/A
CAiD: CA8623016
gnomAD: MAF in the South Asian population is 0.00003266 http://gnomad.broadinstitute.org/variant/17-45363666-G-A
patient 9
Case1: Patient 9, Female, 10 years old
DiseaseAssertion: Glanzmann thrombasthenia III (Diagnosed at 3 months of age)
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Bleeding phenotypes are not specified per patient in this article, rather, it states: "Petechia, epistaxis, and prolonged bleeding after trauma were the most common symptoms among studied patients"
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: This patient has type III Glanzmann thrombasthenia; therefore, according to this article, this proband showed normal or near-nromal levels of the GPIIb/IIIa complex via flow cytometry.
PlateletAggregation: Prolonged bleeding time, abnormal clot retraction, impaired platelet aggregation induced by most physiological agonists (ADP, epinephrine, and collagen) except ristocetin, mucosal bleeding, easy bruising, epistaxis, as well as normal prothrombin/acivated partial thromboplastin time, and normal platelet count. (This is among inclusion criteria for this study)
CasePreviousTesting: To identify the underlying molecular mechanism of GPIIb/IIIa complex abnormalities among probands in this study, all the 30 exons of ITGA2B and the 15 exons of ITGB3 were analyzed using PCR–CSGE and DNA sequencing.
Gene: ITGB3
Variant: NM_000212.2:c.719G>A (p.Arg240Gln)
LegacyVariant: N/A
ClinVar: 13553
CAiD: CA123224
gnomAD: N/A
GT3
Case3: GT-3, Male, Catalan, age not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Affected sisters (GT-1) and (GT-2)
ParentalGenotype: N/A
CasePresentingHPOs: HP:0000421
(Epistaxis)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Standard glycoprotein analysis confirmed the absence of αIIbβ3 in their platelets but while western blotting failed to reveal αIIb, residual β3 was at about 10% of usual levels and of normal migration (illustrated for GT1 in supplemental Figure 1).
PlateletAggregation: Platelets of all 3 patients failed to aggregate in response to a range of physiologic agonists but were agglutinated by ristocetin. Clot retraction was also defective.
CasePreviousTesting: Screened ITGA2B and ITGB3 genes of all three probands. Direct sequencing of all coding regions and splice sites of ITGA2B (30 exons) showed mutation.
Gene: ITGA2B
Variant: NM_000419.3:c.131G>T and NM_000419.3:c.1440-13_1440-1del
LegacyVariant: (p.Gly13Val)
ClinVar: N/A
CAiD: CA399806881 and CA913184940
gnomAD: N/A
GT2
Case2: GT-2, Female, Catalan, age not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Affected sister (GT-1) and brother (GT-3)
ParentalGenotype: N/A
CasePresentingHPOs: HP:0011891
(Post-partum hemorrhage)
CaseHPOFreeText: N/A
CaseNotHPOs:
CaseNotHPOsFreeText:
ProteinExpression: Standard glycoprotein analysis confirmed the absence of αIIbβ3 in their platelets but while western blotting failed to reveal αIIb, residual β3 was at about 10% of usual levels and of normal migration (illustrated for GT1 in supplemental Figure 1).
PlateletAggregation: Platelets of all 3 patients failed to aggregate in response to a range of physiologic agonists but were agglutinated by ristocetin. Clot retraction was also defective.
CasePreviousTesting: Screened ITGA2B and ITGB3 genes of all three probands. Direct sequencing of all coding regions and splice sites of ITGA2B (30 exons) showed mutation.
Gene: ITGA2B
Variant: NM_000419.3:c.131G>T and NM_000419.3:c.1440-13_1440-1del
LegacyVariant: (p.Gly13Val)
ClinVar: N/A
CAiD: CA399806881 and CA913184940
gnomAD: N/A
Supplementary Tables 1 and 2 combined information:
Case8: GT8, Male, 9 years old
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Not available per supplementary table 1
ParentalGenotype: Parents are not consanguineous, no other genotype information available
CasePresentingHPOs: HP:0000978, HP:0000979, HP:0031364, HP:0000421
(Bruising, purpura, ecchymosis, epistaxis)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Showed <5% of αIIbβ3 expression measured by flow cytometry
PlateletAggregation: Platelet aggregation showed no response to ADP and collagen but normal response to ristocetin
CasePreviousTesting: All exons from ITGA2B and ITGB3 genes were amplified by PCR using intronic primers. DNA sequencing was determined by Sanger sequencing.
Gene: ITGA2B
Variant: NM_000419.3:c.1651C>T (p.Arg551Trp) and NM_000419.3:c.2236G>T (p.Glu746Ter)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA399802348 (p.Arg551Trp) and CA399798321 (p.Glu746Ter)
gnomAD: N/A
Supplementary Tables 1 and 2 combined information:
Case38: GT38, Female, 23 years old
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Not available per supplementary table 1
ParentalGenotype: Parents are not consanguineous, no other genotype information available
CasePresentingHPOs: HP:0000978, HP:0000979, HP:0031364, HP:0000132
(Bruising, purpura, ecchymosis, menorrhagia)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Showed <5% of αIIbβ3 expression measured by flow cytometry
PlateletAggregation: Platelet aggregation showed no response to ADP and collagen but normal response to ristocetin
CasePreviousTesting: All exons from ITGA2B and ITGB3 genes were amplified by PCR using intronic primers. DNA sequencing was determined by Sanger sequencing.
Gene: ITGA2B and ITGB3
Variant: NM_000419.3:c.2613del in ITGA2B (p.Leu872Cysfs*38) and NM_000212.2:c.1646G>C in ITGB3 (p.Cys549Ser)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA915940594 (p.Leu872Cysfs*38) and CA400030198 (p.Cys549Ser)
gnomAD: MAF of (p.Cys549Ser) in the East Asian population: 0.00005453 https://gnomad.broadinstitute.org/variant/17-45369890-G-C
Supplementary Tables 1 and 2 combined information:
Case33: GT33, Female, 12 years old
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Not available per supplementary table 1
ParentalGenotype: Parents are consanguineous, no other genotype information available
CasePresentingHPOs: HP:0000978, HP:0000979, HP:0031364, HP:0000421
(Bruising, purpura, ecchymosis, epistaxis)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Showed <5% of αIIbβ3 expression measured by flow cytometry
PlateletAggregation: Platelet aggregation showed a small response to ADP, no response to collagen but normal response to ristocetin
CasePreviousTesting: All exons from ITGA2B and ITGB3 genes were amplified by PCR using intronic primers. DNA sequencing was determined by Sanger sequencing.
Gene: ITGB3
Variant: NM_000212.2:c.719G>A (p.Arg240Gln)
LegacyVariant: N/A
ClinVar: 13553
CAiD: CA123224
gnomAD: N/A
Supplementary Tables 1 and 2 combined information:
Case31: GT31, Female, 13 years old
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Not available per supplementary table 1
ParentalGenotype: Parents are not consanguineous, no other genotype information available
CasePresentingHPOs: HP:0000978, HP:0000979, HP:0031364, HP:0000421, HP:0000225
(Bruising, purpura, ecchymosis, epistaxis, gingival bleeding)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Showed <5% of αIIbβ3 expression measured by flow cytometry
PlateletAggregation: Platelet aggregation showed no response to ADP and collagen but normal response to ristocetin
CasePreviousTesting: All exons from ITGA2B and ITGB3 genes were amplified by PCR using intronic primers. DNA sequencing was determined by Sanger sequencing.
Gene: ITGA2B and ITGB3
Variant: NM_000419.3:c.1022C>T (p.Ala341Val) in ITGA2B and NM_000212.2:c.412G>A (p.Val138Met) in ITGB3
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA399804629 (p.Ala341Val) and CA400021826 (p.Val139Met)
gnomAD: N/A
Supplementary Tables 1 and 2 combined information:
Case23: GT23, Female, 11 years old
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Not available per supplementary table 1
ParentalGenotype: Parents are consanguineous, no other genotype information available
CasePresentingHPOs: HP:0000978, HP:0000979, HP:0031364, HP:0000421, HP:0000225, HP:0000132
(Bruising, purpura, ecchymosis, epistaxis, gingival bleeding, menorrhagia)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Showed <5% of αIIbβ3 expression measured by flow cytometry
PlateletAggregation: Platelet aggregation showed a small response to ADP, no response to collagen but normal response to ristocetin
CasePreviousTesting: All exons from ITGA2B and ITGB3 genes were amplified by PCR using intronic primers. DNA sequencing was determined by Sanger sequencing.
Gene: ITGB3
Variant: NM_000212.2:c.1980C>A (p.Tyr660Ter) and NM_000212.2:c.2147G>T (p.Gly716Val)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA400032983 (p.Tyr660Ter) and CA400033923 (p.Gly716Val)
gnomAD: N/A
GT-20b
Case18: (GT-20) Female, age or ethnicity not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Probands GT15-GT19 are related to GT-20 see Table 1
ParentalGenotype: Parents may be included in Table 1; however, not specified so no information
CasePresentingHPOs: N/A
CaseHPOFreeText: Bleeding severity: Information not available on bleeding phenotype/severity (See Supplementary Table 3)
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometry performed and CD41 and CD61 were observed (See Supplementary Table 3)
PlateletAggregation: Minimal information (See Supplementary Table 3)
CasePreviousTesting: DNA was extracted from peripheral blood samples from patients and family members, and Sanger sequencing and PCR was performed. Samples were processed for targeted sequencing using the available SHGp heme panel of 393 genes.
Gene: ITGB3
Variant: NM_000212.2:c.727G>C (p.Asp243His)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA400023600
gnomAD: N/A
GT-19b
Case17: (GT-19) Male, carrier status, age or ethnicity not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Probands GT15-GT20 are related to GT-19 see Table 1
ParentalGenotype: Parents may be included in Table 1; however, not specified so no information
CasePresentingHPOs: N/A
CaseHPOFreeText: Bleeding severity: Information not available on bleeding phenotype/severity (See Supplementary Table 3)
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometry performed and CD41 and CD61 were observed (See Supplementary Table 3)
PlateletAggregation: Minimal information (See Supplementary Table 3)
CasePreviousTesting: DNA was extracted from peripheral blood samples from patients and family members, and Sanger sequencing and PCR was performed. Samples were processed for targeted sequencing using the available SHGp heme panel of 393 genes.
Gene: ITGB3
Variant: NM_000212.2:c.727G>C (p.Asp243His)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA400023600
gnomAD: N/A
GT-72c
Case53: (GT-72) Gender, age, or ethnicity not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Bleeding severity: Information not given (See Supplementary Table 3)
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometry performed and CD41 and CD61 were observed (See Supplementary Table 3)
PlateletAggregation: Minimal information (See Supplementary Table 3)
CasePreviousTesting: DNA was extracted from peripheral blood samples from patients and family members, and Sanger sequencing and PCR was performed. Samples were processed for targeted sequencing using the available SHGp heme panel of 393 genes.
Gene: ITGB3
Variant: NM_000212.2:c.662C>T (p.Thr221Met)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA8623017
gnomAD: MAF in European Finnish population 0.0001386 http://gnomad.broadinstitute.org/variant/17-45363673-C-T
GT-56
Case45: (GT-56) Female, age or ethnicity not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Bleeding severity: Moderate (See Supplementary Table 3)
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometry performed and CD41 and CD61 were observed (See Supplementary Table 3)
PlateletAggregation: Minimal information (See Supplementary Table 3)
CasePreviousTesting: DNA was extracted from peripheral blood samples from patients and family members, and Sanger sequencing and PCR was performed. Samples were processed for targeted sequencing using the available SHGp heme panel of 393 genes.
Gene: ITGA2B
Variant: NM_000419.3:c.985G>T (p.Val329Phe)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA399804719
gnomAD: N/A
GT-16
Case14: (GT-16) Male, age or ethnicity not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Probands GT15-GT20 are related to GT-16 see Table 1
ParentalGenotype: Parents may be included in Table 1; however, not specified so no information
CasePresentingHPOs: N/A
CaseHPOFreeText: Bleeding severity: Severe (See Supplementary Table 3)
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometry performed and CD41 and CD61 were observed (See Supplementary Table 3)
PlateletAggregation: Minimal information (See Supplementary Table 3)
CasePreviousTesting: DNA was extracted from peripheral blood samples from patients and family members, and Sanger sequencing and PCR was performed. Samples were processed for targeted sequencing using the available SHGp heme panel of 393 genes.
Gene: ITGB3
Variant: NM_000212.2:c.727G>C (p.Asp243His)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA400023600
gnomAD: N/A
GT12
Case6: (GT12) Gender, age and ethnicity not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Inclusion criteria were patients with a history of mucocutaneous bleeding (Figure 1 shows a bar diagram of all the clinical manifestations in the patient cohort in this article)
CaseNotHPOs: N/A
ProteinExpression: Platelet receptor alphaIIbbeta3 protein was analyzed by flow cytometry followed by western blotting
Platelet Aggregation: Inclusion criteria for probands was absent or reduced platelet aggregation with agonists such as ADP, adrenaline, arachidonic acid, and collagen (no mention of ristocetin here-- this article does not tell us the specific aggregation for each proband in the paper)
CasePreviousTesting: For mutation analysis of ITGA2B and ITGB3 genes, DNA extraction from whole blood, PCR, heteroduplex PCR followed by CSGE and DNA sequencing were performed. All 30 exons of ITGA2B and 15 exons of ITGB3, as well as their promoters, were analyzed by CSGE following heteroduplex PCR.
Gene: ITGA2B
Variant: NM_000419.3:c.641T>C (p.Leu214Pro)
LegacyVariant: N/A
ClinVar: 2901
CAiD: CA115848
gnomAD N/A
Case25: Patient CD, gender and age are not specified, all of these patients are Caucasian (either Italian or European)
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: All patients presented with a current or past history of bleeding and a bleeding time >15 min. Bleeding symptoms were evaluated by examining available hospital records. Mild bleeders were defined as those who bled only after trauma or surgery or had minor symptoms, such as epistaxis. Moderate/severe bleeders were defined as those with a history of spontaneous or life threatening hemorrhages, such as gastrointestinal bleeding, or who had repeated episodes requiring platelet transfusions
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: See Table 1
PlateletAggregation: See Table 1
CasePreviousTesting: To identify point mutations responsible for GT, we have sequenced all coding regions of Ib and 3 genes and intron/exon boundaries.
Gene: ITGA2B
Variant: NM_000212.2:c.1801T>C
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA8623361
gnomAD: MAF in the European non Finnish population is 0.00001758 https://gnomad.broadinstitute.org/variant/17-45376784-T-C
Case5: Patient DRP, gender and age are not specified, all of these patients are Caucasian (either Italian or European)
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: All patients presented with a current or past history of bleeding and a bleeding time >15 min. Bleeding symptoms were evaluated by examining available hospital records. Mild bleeders were defined as those who bled only after trauma or surgery or had minor symptoms, such as epistaxis. Moderate/severe bleeders were defined as those with a history of spontaneous or life threatening hemorrhages, such as gastrointestinal bleeding, or who had repeated episodes requiring platelet transfusions
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: See Table 1
PlateletAggregation: See Table 1
CasePreviousTesting: To identify point mutations responsible for GT, we have sequenced all coding regions of Ib and 3 genes and intron/exon boundaries.
Gene: ITGA2B
Variant: This variant has a typo in the paper the real variant is this: NM_000419.3:c.800 G>A and NM_000419.3:c.2930del
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA399805147 and CA915940386
gnomAD: N/A
MU
Case3: Patient MU, gender age and ethnicity not specified
DiseaseAssertion: Glanzmann thrombasthenia type I
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Bleeding symptoms were evaluated by examining available hospital records. Mild bleeders were defined as those who had minor symptoms, such as epistaxis or gum bleeds, and moderate bleeders suffered, in addition, from bleeding complications after surgery and trauma. Severe bleeders were defined as those with a history of spontaneous or life-threatening hemorrhages, such as gastrointestinal bleeding, or who had repeated episodes requiring platelet transfusion. See Table 1.
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: See Table 6
PlateletAggregation: See Table 6
CasePreviousTesting: To ascertain the mutations, we sequenced the coding regions of the αIIb and β3 subunits including the exon/intron boundaries
Gene: ITGA2B
Variant: NM_000419.3:c.641T>C (p.Leu214Pro)
LegacyVariant: N/A
ClinVar: 2901
CAiD: CA115848
gnomAD: N/A
11
Case9: No assertion made on age, gender or ethnicity
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Table 1 mentions family history available for this proband.
ParentalGenotype: The identified variants were heterozygote in parents.
CasePresentingHPOs: HP:0030402, HP:0005542
(Abnormal platelet aggregation, prolonged clotting time)
CaseHPOFreeText: Bleeding time greater than 20 minutes and hematocrit of 38.1%.
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: N/A
CasePreviousTesting: Genetic study of patient was conducted using direct sequencing of entire coding and exon-intron boundaries of the ITGA2B and ITGB3 genes.
Gene: ITGA2B
Variant: NM_000419.3:c.286T>A (p.Cys96Ser)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA8603504
gnomAD: N/A
proband‐III2
Case3: Male, Israeli-Arab, (age is either 10 or 14)
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: See Fig 1C for pedigree
ParentalGenotype: See Fig 1C for pedigree
CasePresentingHPOs: HP:0000421, HP:0031364, HP:0000967
(Severe epistaxis, ecchymosis, petechiae)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
ProteinExpression: No surface expression of αIIbβ3 was found in patients’ platelets (See Fig 3)
PlateletAggregation: Absent platelet aggregation in response to ADP, epinephrine, collagen and normal ristocetin-induced platelet agglutination
CasePreviousTesting: DNA fragments containing exons and flanking intronic regions of the aIIb and B3 genes were amplified by PCR using primers
Gene: ITGA2B
Variant: NM_000419.3:c.97A>G (p.Asn2Asp)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA399806951
gnomAD: N/A
CC
Case9: Patient CC
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs:
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: αIIbβ3 expression
PlateletAggregation: N/A
CasePreviousTesting: The amplification of DNA fragments using PCR and their electrophoretic migration through a denaturing gradient was used to scan the entire coding region, splice site junctions and promoter regions of the GPIIb and GPIIIa genes for all 20 patients in this study
Gene: ITGA2B
Variant: NM_000419.3:c.666C>A (p.Phe222Leu)
LegacyVariant: (p.Phe191Leu)
ClinVar: N/A
CAiD: CA399805465
gnomAD: N/A
7
Case7: Male, 1.5 years old, Indian
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: HP:0031364, HP:0000421 (Ecchymosis, epistaxis)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
ProteinExpression: Diagnosis of GT was made on the basis of quantitive determination of receptor count by flow cytometric analysis of GPIIb-IIIa
PlateletAggregation: Diagnosis of GT was made on the basis of impaired platelet aggregation (platelet aggregation was tested against ristocetin, ADP, collagen, epinephrine and arachidonic acid)
CasePreviousTesting: Multiplex PCR by using GPIIb primers and CSGE analysis were performed
Gene: ITGA2B
Variant: NM_000419.3:c.2315C>G (p.Pro772Arg)
LegacyVariant: (p.Pro741Arg)
ClinVar: N/A
CAiD: CA8602740
gnomAD: MAF in the South Asian population is 0.0002613 https://gnomad.broadinstitute.org/variant/17-42453709-G-C
6
Case6: Female, 7 years old, Indian
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: HP:0000225 (Gingival bleeding)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
ProteinExpression: Diagnosis of GT was made on the basis of quantitive determination of receptor count by flow cytometric analysis of GPIIb-IIIa
PlateletAggregation: Diagnosis of GT was made on the basis of impaired platelet aggregation (platelet aggregation was tested against ristocetin, ADP, collagen, epinephrine and arachidonic acid)
CasePreviousTesting: Multiplex PCR by using GPIIb primers and CSGE analysis were performed
Gene: ITGA2B
Variant: NM_000419.3:c.1374C>G (p.Ile458Met)
LegacyVariant: (p.Ile427Met)
ClinVar: N/A
CAiD: CA8603157
gnomAD: MAF in the South Asian population is 0.003658 https://gnomad.broadinstitute.org/variant/17-42458266-G-C
5
Case5: Female, 3 years old, Indian
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: HP:0000421, HP:0000225
(Epistaxis, gingival bleeding)
CaseHPOFreeText: Severe epistaxis and mild gum bleeding
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
ProteinExpression: Diagnosis of GT was made on the basis of quantitive determination of receptor count by flow cytometric analysis of GPIIb-IIIa
PlateletAggregation: Diagnosis of GT was made on the basis of impaired platelet aggregation (platelet aggregation was tested against ristocetin, ADP, collagen, epinephrine and arachidonic acid)
CasePreviousTesting: Multiplex PCR by using GPIIb primers and CSGE analysis were performed
Gene: ITGA2B
Variant: NM_000419.3:c.859G>C (p.Gly287Arg)
LegacyVariant: (p.Gly256Arg)
ClinVar: N/A
CAiD: CA399805008
gnomAD: N/A
4
Case4: Female, 18 years old, Indian
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: HP:0000225, HP:0000132
(Gingival bleeding, menorrhagia)
CaseHPOFreeText: Menorrhagia only during puberty
CaseNotHPOs: N/A
CaseNotHPOFreeText:N/A
ProteinExpression: Diagnosis of GT was made on the basis of quantitive determination of receptor count by flow cytometric analysis of GPIIb-IIIa
PlateletAggregation: Diagnosis of GT was made on the basis of impaired platelet aggregation (platelet aggregation was tested against ristocetin, ADP, collagen, epinephrine and arachidonic acid)
CasePreviousTesting: Multiplex PCR by using GPIIb primers and CSGE analysis were performed
Gene: ITGA2B
Variant: NM_000419.3:c.2264G>C (p.Arg755Pro)
LegacyVariant: (p.Arg724Pro)
ClinVar: N/A
CAiD: CA8602772
gnomAD: MAF in the European (non-Finnish) population is 0.00001060 https://gnomad.broadinstitute.org/variant/17-42454380-C-G
I
Case9: Patient ID I, Female, 3 years old, ethnicity not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Related to Patient's J and K (See Table 1)
ParentalGenotype: N/A (Parents are consangenous)
CasePresentingHPOs: HP:0000967, HP:0000979, HP:0000978, HP:0004406
(Petechiae, purpura, easy bruising, recurrent epistaxis)
CaseHPOFreeText: N/A
CaseNotHPOs: HP:0000225, HP:0002239, HP:0002239, HP:0000790, HP:0005261, HP:0002248
(Gingival bleeding, GI bleeding, intracranial hemorrhage, hematuria, hemarthrosis, hematemesis)
CaseNotHPOsFreeText: Hemorrhage after dnetal, hemorrhage after trauma, ear bleeding, hematoma
ProteinExpression: N/A
PlateletAggregation: Defective response to ADP, adrenaline, collagen, arachidonic acid, and normal response to ristocetin
CasePreviousTesting: Exon PCR was used to amplify coding regions of the ITGA2B and ITGB3 genes. PCR products were purified and Sanger sequenced. Segregation using parental samples was undertaken when available.
Gene: ITGA2B
Variant: NM_000419.3:c.1652G>A
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA8602986
gnomAD: MAF in South Asian population is 0.00006536 http://gnomad.broadinstitute.org/variant/17-42457470-C-T
PreviouslyPublished: PMID: 19172520
GT 04
Case15: GT04, Female, India, age of onset is 11 years old
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: Menorrhagia HP:0000132
CaseHPOFreeText: Patients were recruited as they presented consecutively from 1996 to 1998 for evaluation of a mucocutaneous bleeding disorder
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: N/A
PlateletAggregation: All patients examined had defective ADP, epinephrine, and collagen induced aggregation and normal ristocetin induced aggregation
CasePreviousTesting: Mutations were detected by the method of single strand conformation polymorphism (SSCP) analysis, followed by nucleotide sequencing and confirmation by restriction fragment length polymorphism (RFLP) assays. The sequences of the primers employed and the reaction conditions for PCR amplification of the exons, adjacent intronic regions, and 50 and 30 untranslated regions of the aIIb and b3 gene
Gene: ITGB3
Variant: NM_000212.2:c.262C>T (p.Arg88Ter) and NM_000212.2:c.356G>A (p.Arg119Gln)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA400020703 and CA8622925
gnomAD: MAF in the Other population is 0.0001385 https://gnomad.broadinstitute.org/variant/17-45360816-C-T and MAF in the African population is 0.0002470 https://gnomad.broadinstitute.org/variant/17-45360910-G-A
Supplementary Table S1:
Case59: GT69, French, age and gender are not specified here
DiseaseAssertion: Glanzmann thrombasthenia type I
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: All patients had a life-long history of mucocutaneous bleeding
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: All patients in this study met the clinical and platelet function requirements for GT-- this includes an absent or strongly reduced expression of alphaIIbBeta3 in platelets
PlateletAggregation: All patients in this study met the clinical and platelet function requirements for GT-- this includes absent or severely reduced platelet aggregation with at least three physiological agonists
CasePreviousTesting: Sanger sequencing was performed. Sanger sequencing ensured coverage of all exons and splice sties of the ITGA2B and ITGB3 genes and extended 300-500 bp into the introns as well as including the UTR. They sequenced 416 bp upstream of the ITGA2B promoter and 463 bp upstream of the ITGB3 promoter. In total they sequenced 51.2% of the ITGA2B gene and 19.4% of the larger ITGB3 gene
Gene: ITGA2B
Variant: NM_000419.3:c.1878G>C (p.Gln626His/ p.Asp585_Gln626del)
LegacyVariant: N/A
ClinVar: 2903
CAiD: CA115852
gnomAD: N/A
Supplementary Table S1:
Case37: GT43a, Morrocco, gender and age not specified
DiseaseAssertion: Glanzmann thrombasthenia type I
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: All patients had a life-long history of mucocutaneous bleeding
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: All patients in this study met the clinical and platelet function requirements for GT-- this includes an absent or strongly reduced expression of alphaIIbBeta3 in platelets
PlateletAggregation: All patients in this study met the clinical and platelet function requirements for GT-- this includes absent or severely reduced platelet aggregation with at least three physiological agonists
CasePreviousTesting: Sanger sequencing was performed. Sanger sequencing ensured coverage of all exons and splice sties of the ITGA2B and ITGB3 genes and extended 300-500 bp into the introns as well as including the UTR. They sequenced 416 bp upstream of the ITGA2B promoter and 463 bp upstream of the ITGB3 promoter. In total they sequenced 51.2% of the ITGA2B gene and 19.4% of the larger ITGB3 gene
Gene: ITGB3
Variant: NM_000212.2:c.614+1G>T and NM_000212.2:c.683G>A (p.Arg228His)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA400023344 and CA8623025
gnomAD: MAF in the African population is 0.00008012 https://gnomad.broadinstitute.org/variant/17-45363694-G-A
Supplementary Table S1:
Case11: GT12, French, age and gender not specified
DiseaseAssertion: Glanzmann thrombasthenia type I
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: All patients had a life-long history of mucocutaneous bleeding
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: All patients in this study met the clinical and platelet function requirements for GT-- this includes an absent or strongly reduced expression of alphaIIbBeta3 in platelets
PlateletAggregation: All patients in this study met the clinical and platelet function requirements for GT-- this includes absent or severely reduced platelet aggregation with at least three physiological agonists
CasePreviousTesting: Sanger sequencing was performed. Sanger sequencing ensured coverage of all exons and splice sties of the ITGA2B and ITGB3 genes and extended 300-500 bp into the introns as well as including the UTR. They sequenced 416 bp upstream of the ITGA2B promoter and 463 bp upstream of the ITGB3 promoter. In total they sequenced 51.2% of the ITGA2B gene and 19.4% of the larger ITGB3 gene
Gene: ITGB3
Variant: NM_000212.2:c.565C>T (p.Pro189Ser)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA291224669
gnomAD: MAF in the European (non-Finnish) population is 0.00002638 https://gnomad.broadinstitute.org/variant/17-45362012-C-T
56-year-old Algerian woman
Case1: Female, 56 years old, Algerian
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: HP:0004406, HP:0000132
(Recurrent epistaxis, menorrhagia)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: No platelet αIIbβ3 expression (mentioned briefly in abstract)
PlateletAggregation: The patient shows all the typical signs of GT with no platelet aggregation in response to physiologic agonists and an absence of clot retraction. No mention of ristocetin
CasePreviousTesting: N/A
Gene: ITGA2B
Variant: NM_000419.3:c.1063G>A (p.Glu355Lys)
LegacyVariant: p.Glu324Lys
ClinVar: 2899
CAiD: CA115844
gnomAD: MAF in European (non-Finnish population 0.00001978 http://gnomad.broadinstitute.org/variant/17-42461008-C-T
PreviouslyPublished: Proband 9 in PMID: 2180491
6CabGT-6
Case6: (Proband, CabGT-6), Male, age not specified, Caucasian
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
ProteinExpression: Flow cytometry showed <5% surface expression of GPIIIa and GPIIb
Platelet Aggregation: N/A
CasePreviousTesting: Promoter and exon sequences of aIIb and b3 genes were amplified and directly sequence
Gene: ITGA2B
Variant: NM_000419.3:c.1413C>G (p.Tyr471Ter) and NM_000419.3:c.2800G>T (p.Val934Phe)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA290950376 (p.Tyr471Ter) and CA290946484 (p.Val934Phe)
gnomAD MAF in the European (non-Finnish) population is 0.000008791 https://gnomad.broadinstitute.org/variant/17-42457994-G-C
15CabGT-15
Case15: (Proband CabGT-15)
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
ProteinExpression: N/A
Platelet Aggregation: N/A
CasePreviousTesting: Promoter and exon sequences of aIIb and b3 genes were amplified and directly sequence
Gene: ITGA2B
Variant: NM_000419.3:c.2800G>T (p.Val934Phe)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA290946484
gnomAD N/A
Supplementary Table S1 & S2 Proband and Variant Information:
Case13: GT14, Female, 10, French
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: HP:0000979 and HP:0006298
(Purpura, prolonged bleeding after dental extraction)
CaseHPOFreeText: Moderate cutaneous bleeding from birth
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometry showed <5% variant expression of αIIbβ3 (See Supplementary Table 1)
PlateletAggregation: Absent platelet aggregation (See Supplementary Table 1)
CasePreviousTesting: Sanger sequencing of ITGA2B and ITGB3
Gene: ITGA2B
Variant: NM_000419.3:c.423G>T (p.Trp141Cys) and NM_000419.3:c.2902del (p.Tyr968Metfs*163)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA399806022 and CA915940332
gnomAD: N/A
Supplementary Table S1 & S2 Proband and Variant Information:
Case58: GT60, Male, 54 years old, French/Italian
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: HP:0000421, HP:0000978, HP:0002239, HP:0000225
(Epistaxis, easy bruising, GI bleeding, gingival bleeding)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometry showed <5% expression of αIIbβ3 (See Supplementary Table 1)
PlateletAggregation: Absent platelet aggregation (See Supplementary Table 1)
CasePreviousTesting: Sanger sequencing of ITGA2B and ITGB3
Gene: ITGB3
Variant: NM_000212.2:c.1801T>C (p.Cys601Arg)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA8623361
gnomAD: MAF in the European (non-Finnish) population is 0.00001758 https://gnomad.broadinstitute.org/variant/17-45376784-T-C
2
Case2: Female, 67 years old, Japanese
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A per Table 1
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Prolonged ivy bleeding times, bleeding diathesis since early childhood
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
ProteinExpression: Surface expression of αIIbβ3 was analyzed by flow cytometry which was < 5% of normal
PlateletAggregation: Aggregation in response to ADP, epinephrine and collagen was absent but normal in response to ristocetin
CasePreviousTesting: Nucleotide sequences of the αIIb and β3 coding regions were determined by direct sequencing of RT-PCR products from platelet RNA.
Gene: ITGA2B
Variant: NM_000419.3:c.1063G>A (p.Glu355Lys)
LegacyVariant: (p.Glu324Lys)
ClinVar: 2899
CAiD: CA115844
gnomAD: MAF in the European (non-Finnish) population is 0.00001978 https://gnomad.broadinstitute.org/variant/17-42461008-C-T
Supplemental Table S1:
Case12: Male, Italy, age not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: Moderate bleeding
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: <5% αIIbβ3 expression
PlateletAggregation: Absent platelet aggregation (all the information that is provided in Supp. Table S1)
CasePreviousTesting: Sanger sequencing of exons, splice sites and untranslated regions of the ITGA2B and ITGB3 genes was performed
Gene: ITGA2B
Variant: NM_000419.3:c.1742C>A (p.Ala581Asp)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA399802112
gnomAD: N/A
PreviouslyPublished: PMID: 12083483
Mother L
Case1: Mother L
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Assessment of surface PTL expression of GPIIIa-IIb was performed
PlateletAggregation: N/A
CasePreviousTesting: DNA sequence analysis was performed -- direct sequence analysis of the PCR products corresponding to exon 10 was performed here
Gene: ITGA2B
Variant: NM_000212.2:c.1447T>C
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA400029321
gnomAD: N/A
GT12
Case12: GT-12, Caucasian, gender or age not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: Mother: c.2326_2331dupGAGGCC and Father: deceased
CasePresentingHPOs: N/A
CaseHPOFreeText: Bleeding symptoms are severe and bleeding time is pathogenic (See Table 1) Abstract mentions patients' bleeding signs include epistaxis, mucocutaneous bleeding, haematomas, petechiae, GI bleeding and menorrhagia; however, not specified per proband.
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometry was performed and expression is stated as pathogenic in Table 1
PlateletAggregation: Platelet aggregation was performed and is stated as pathogenic in Table 1; however, no specific agonists mentioned
CasePreviousTesting: All exons of ITGA2B and ITGB3 genes as well as surrounding intron regions were amplified by PCR using intronic primers as pre-viously described (12). The purified DNA fragments were then di-rectly sequenced.
Gene: ITGA2B
Variant: NM_000419.3:c.957T>A and NM_000419.3:c.2326_2331dupGAGGCC
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA399804780 and CA915940324
gnomAD: N/A
GT5
Case5: GT-5, Caucasian, gender or age not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Bleeding symptoms are severe and bleeding time is pathogenic (See Table 1) Abstract mentions patients' bleeding signs include epistaxis, mucocutaneous bleeding, haematomas, petechiae, GI bleeding and menorrhagia; however, not specified per proband.
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometry was performed and expression is stated as pathogenic in Table 1
PlateletAggregation: Platelet aggregation was performed and is stated as pathogenic in Table 1; however, no specific agonists mentioned
CasePreviousTesting: All exons of ITGA2B and ITGB3 genes as well as surrounding intron regions were amplified by PCR using intronic primers as pre-viously described (12). The purified DNA fragments were then di-rectly sequenced.
Gene: ITGA2B
Variant: NM_000419.3:c.408G>C and NM_000419.3:c.1787T>C
LegacyVariant: N/A
ClinVar: 2900
CAiD: CA500624244 and CA115846
gnomAD: MAF in the European (non-Finnish) population 0.00006484 http://gnomad.broadinstitute.org/variant/17-42463192-C-G and MAF in European (non-Finnish) population is 0.0001325 http://gnomad.broadinstitute.org/variant/17-42457148-A-G