020–2071
Case#: 020-2071
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.1492G>A
LegacyVariant:
ClinVar: No
CAID: CA255109
gnomAD:
066–2002
Case#: 066-2002
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.5399G>A
LegacyVariant:
ClinVar: No
CAID: CA255162
gnomAD:
071–2025
Case#: 071-2025
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.2167G>A
LegacyVariant:
ClinVar: No
CAID: CA255138
gnomAD:
020–2070
Case#: 020-2070
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.558C>G
LegacyVariant:
ClinVar: No
CAID: CA414919454
gnomAD:
035–2020
Case#: 035-2020
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.5275G>A
LegacyVariant:
ClinVar: No
CAID: CA414911087
gnomAD:
020–2021
Case#: 020-2021
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.1396T>C
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
022–2003
Case#: 022-2003
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.278C>T
LegacyVariant:
ClinVar: No
CAID: CA414920106
gnomAD:
020–2065
Case#: 020-2065
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:
060–2006
Case#: 060-2006
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.1618C>A
LegacyVariant:
ClinVar: No
CAID: CA414911950
gnomAD:
001–2026
Case#: 001-2026
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.986G>A
LegacyVariant:
ClinVar: No
CAID: CA255089
gnomAD:
047–2002
Case#: 047-2002
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.6011C>A
LegacyVariant:
ClinVar: No
CAID: CA414905140
gnomAD:
c.128G>A
Case#: Variant #24 (no specific case; 5 patients and 5 families have variant)
DiseaseAssertion: Severe (2), Moderate (1), Mild (2)
FamilyInfo: N/A
ParentalTesting: None
CasePresentingHPOs: HP:0011858
CaseHPOsFreeText: reduced factor IX activity
CaseNotHPOs: None
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.128G>A (p.Arg43Gln)
ClinVar: Absent/Not Reported
CAID: CA414435539
gnomAD: Absent/Not Reported
The final list of mutations is provided in Supplementary Table S1.
Case#: N/A
DiseaseAssertion: Severe Hemophilia B
FamilyInfo: N/A
ParentalTesting: N/A
CasePresentingHPOs: N/A
CaseHPOsFreeText: N/A
CaseNotHPOs: N/A
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.110C>A (p.Ala37Asp)
ClinVar: Absent
CAID: CA414435430
gnomAD: Absent/NotReported
66
Case#: 66, male, 16 years old, Chinese
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 11.8%
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.2167G>A
LegacyVariant:
ClinVar: 10246
CAID: CA255138
gnomAD:
43
Case#: 43, male, 22 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.902G>A
LegacyVariant:
ClinVar: 10192
CAID: CA255079
gnomAD:
47
Case#: 47, male, 19 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.1241A>G
LegacyVariant:
ClinVar: No
CAID: CA414915839
gnomAD:
90
Case#: 90, male, 12 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.6406G>A
LegacyVariant:
ClinVar: No
CAID: CA414899430
gnomAD:
85
Case#: 85, male, 31 years old, Chinese
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 9%
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.6103G>A
LegacyVariant:
ClinVar: 381561
CAID: CA16609159
gnomAD:
49
Case#: 49, male, 56 years old, Chinese
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 5.1%
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.1660A>C
LegacyVariant:
ClinVar: No
CAID: CA414911810
gnomAD:
105
Case#: 105, male, 8 years old, Chinese
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 49%
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.6683G>A
LegacyVariant:
ClinVar: 10098
CAID: CA255016
gnomAD:
98
Case#: 98, male, 31 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.6544C>T
LegacyVariant:
ClinVar: 10321
CAID: CA255214
gnomAD:
58
Case#: 58, male, 8 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.1909A>G
LegacyVariant:
ClinVar: No
CAID: CA414909856
gnomAD:
91
Case#: 91, male, 7 years old, Chinese
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: Noted Family History
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.6437T>C
LegacyVariant:
ClinVar: 627110
CAID: CA414908033
gnomAD:
H (karachi
Case#: Nawaz_Proband_H (karachi) (Pakistan resident)14 y/o)
DiseaseAssertion: Hemophilia B (no severity assertion made)
FamilyInfo: None
ParentalTesting: None
CasePresentingHPOs: N/A
CaseNotHPOs: N/A
CasePreviousTesting: None
Gene: F9
Variant: NM_000133.4:c.127C>T (p.Arg43Trp)
ClinVar: 811505
CAID: CA414435537
gnomAD: Absent/Not Reported
c.6623A>G
Case#: 34
DiseaseAssertion: Hemophilia A
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FVIII:C 23%, Mild 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.6623A>G (p.Gln2208Arg)
ClinVar: 368117 https://www.ncbi.nlm.nih.gov/clinvar/variation/368117/
CAID: CA10567784
gnomAD: MAF for Gln2208Arg in the European (non-Finnish) population 0.00004320<br>https://gnomad.broadinstitute.org/variant/X-154090093-T-C?dataset=gnomad_r2_1
c.1345C>T
Case#: 43
DiseaseAssertion: Hemophilia B
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FIX:C 30% (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.1345C>T (p.Arg449Trp)
ClinVar: 626990 https://www.ncbi.nlm.nih.gov/clinvar/variation/626990/
CAID: CA10529890
gnomAD: MAF for Arg449Trp in the European (non-Finnish) population 0.00006494<br>https://gnomad.broadinstitute.org/variant/X-138644189-C-T?dataset=gnomad_r2_1
c.575T>C
Case#: 5
DiseaseAssertion: Hemophilia A
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FVIII:C 26% (Mild 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.575T>C (p.Ile192Thr)
ClinVar: 618637 https://www.ncbi.nlm.nih.gov/clinvar/variation/618637/
CAID: CA414919417
gnomAD: Not reported
mutations
Case#: Ghanem_Caen (assumed male, from Caen)
DiseaseAssertion: Moderate Hemophilia B
FamilyInfo: N/A
ParentalTesting: None
CasePresentingHPOs: HP:0011858
CaseHPOsFreeText: reduced factor IX activity (FIX:C: 2 ; FIX:Ag: 52
CaseNotHPOs: None
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.128G>T (p.Arg43Leu)
ClinVar: 993549
CAID: CA414435545
gnomAD: Absent Not Reported
S10
Case#: S10, Iranian
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%, Mucosal bleeding
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.1931T>G
LegacyVariant:
ClinVar: No
CAID: CA414909677
gnomAD:
mutation
Case#: Cases 1464
DiseaseAssertion: Familial Severe Hemophilia B
FamilyInfo: In 16 cases, the family pedigree showed more than one affected individual (familial cases) and 12 cases were sporadic. In 17 cases, familial data was not available.
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.128G>A (p.Arg43Gln)
ClinVar: 810864
CAID: CA414435539
gnomAD: Absent/Not Reported
13.
Case#: 13
DiseaseAssertion: Hemophilia B, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0011858
CaseHPOFreeText: FIX:C = 6.6%
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.797C>T
LegacyVariant:
ClinVar: No
CAID: CA414443482
gnomAD:
19.
Case#: 19
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.1129G>T
LegacyVariant:
ClinVar: No
CAID: CA414446072
gnomAD:
26.
Case#: 26
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.1234G>T
LegacyVariant:
ClinVar: No
CAID: CA414446705
gnomAD:
c.839G>A
Case#: 17, Spanish
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.839G>A (p.Gly261Asp)
ClinVar: NA
CAID: CA414918260
gnomAD: Not reported
c.782T>C
Case#: 16, Spanish
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.782T>C (p.Leu242Pro)
ClinVar: NA
CAID: CA414918925
gnomAD: Not reported
Twenty-five novel mutations of the factor IX gene in haemophilia B
Case#: Wulff_Proband_2252 and Wulff_Proband_2270
DiseaseAssertion: Severe Hemophilia B
FamilyInfo: N/A
ParentalTesting: None
CasePresentingHPOs: HP:0011858
CaseHPOsFreeText: reduced factor IX activity
CaseNotHPOs: None
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.128G>T (p.Arg43Leu)
ClinVar: 993549
CAID: CA414435545
gnomAD: Absent/Not Reported
17
Case#: 17
DiseaseAssertion: Hemophilia B, moderate
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FIX:C = 1%
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.172G>C
LegacyVariant:
ClinVar: No
CAID: CA414435830
gnomAD:
A13
Case#: A13
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 10, FVIII:AG = 60, 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.5303G>A
LegacyVariant:
ClinVar: No
CAID: CA10568007
gnomAD:
B14 – B16
Case#: B14 - B16
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C Chr = 10, FVIII:AG = 18, 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.1293G>C, NM_000132.4:c.1293G>T
LegacyVariant:
ClinVar: No
CAID: CA414915298, CA255100
gnomAD:
B32 – B44
Case#: B32 - B44
DiseaseAssertion: NA
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C Chr = 94, FVIII:AG = 88, 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.2215G>A
LegacyVariant:
ClinVar: No
CAID: CA255139
gnomAD:
A5 – A8
Case#: A5 - A8
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 26, FVIII:AG = 60, 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.1649G>A
LegacyVariant:
ClinVar: No
CAID: CA255115
gnomAD:
mutation
Case#: Attali_LY23 (assumed male, from France)
DiseaseAssertion: Severe Hemophilia B
FamilyInfo: None
ParentalTesting: None
CasePresentingHPOs: HP:0011858
CasePresentingHPOsFreeText: reduced factor IX activity (FIX:C: <1 ; FIX:Ag: 44)
CaseNotHPOs: N/A
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.128G>A (p.Arg43Gln)
ClinVar: 810864
CAID: CA414435539
gnomAD: Absent/Not Reported
mutations
Case#: Wulff_Proband_031 & Wulff_Proband_048
DiseaseAssertion: Severe Hemophilia B
FamilyInfo: N/A
ParentalTesting: None
CasePresentingHPOs: HP:0011858
CaseHPOsFreeText: reduced factor IX activity (Proband_031: FIX:C: <1 FIX:Ag: 48 ; Proband_048 FIX:C <1 FIX:Ag: 52
CaseNotHPOs: None
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.128G>A (p.Arg43Gln)
ClinVar: 810864
CAID: CA414435539
gnomAD: Absent/Not Reported
Cysteine 19--arginine (in patient HB13O) alters thesignal peptide. The factor IX activity (20%) in thepatient record suggests mild disease
Case#: Family HB130
DiseaseAssertion: Mild Hemophilia B
FamilyInfo: N/A
ParentalTesting: N/A
CasePresentingHPOs: HP:0011858
CaseHPOsFreeText: reduced factor IX activity (FIX:C : 20%)
CaseNotHPOs: N/A
CasePreviousTesting:
Gene: F9
Variant: NM_000133.4:c.82T>C (p.Cys28Arg)
LegacyVariant: c.111T>C (p.Cys-19Arg)
ClinVar: 10657
CAID: CA255450
gnomAD: Absent/Not Reported
Table S3. F9 mutations.
Case#: Miller_Proband 1 (male)
DiseaseAssertion: Moderate 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.82T>C (p.Cys28Arg)
ClinVar: 10657
CAID: CA255450
gnomAD: Absent/Not Reported
Ala-10 residue (Ala[GCC) to Val[GCT]
Case#: Oldenburg_Patient_A and Oldenburg_Patient_C
DiseaseAssertion: Mild Hemophilia B (exacerbated due to phenprocoumon administration)
FamilyInfo: The parents of patients A and C emigrated from the same region in North-Eastern Europe (North Poland)
ParentalTesting: N/A
CasePresentingHPOs: HP:0011858
CaseHPOsFreeText: reduced factor IX activity, severe bleeding at each oral anticoagulation with phenprocoumon occurrence, bleeding in muscles of the upper leg
CaseNotHPOs: N/A
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.110C>T (p.Ala37Val)
ClinVar: Absent
CAID: CA414435437
gnomAD: Allele Frequency in European (non-Finnish) population: 0.00002186
The p.Pro521Leu substitution (patient P3)
Case#: P3 (female)
DiseaseAssertion: Carrier
FamilyInfo: N/A
ParentalTesting: Father was tested; has mild HA
CasePresentingHPOs: HP:0003125, HP:0001928
CaseHPOFreeText: Low FVIII levels (significant decrease in FVIII:C (48.4% ± 6.1, P < 0.01) and FVIII:Ag (36.6% ± 2.7, P < 0.01)), abnormal blood coagulation
CaseNotHPOs: N/A
CaseNotHPOsFreeText: 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.1562C>T
CAID: CA414912242
gnomAD: Absent/Not Reported
homozygous c.2311A>G
Gene:VWF
HGNCID:12726
Case:11 yo female
DiseaseAssertion: Type 2N
FamilyInfo:Fig. 1, family 1, patient 4
ParentalGenotype(s):Unknown, obligate carriers
CasePresentingHPOs:HP:0000421, HP:0012147 HP:0030132, HP:0030130
CaseHPOFreeRext:Oral cavity and joint bleeding, Bleeding from small wounds and after tooth extraction, VWF:Ag 0.07 U/mL, VWF:Ac 0.08 U/mL, VWF:CB <0.05 U/mL, FVIII 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
homozygous c.2311A>G
Gene:VWF
HGNCID:12726
Case:29 yo female
DiseaseAssertion: Type 2N
FamilyInfo:Fig. 1, family 1, patient 1
ParentalGenotype(s):Unknown, obligate carriers
CasePresentingHPOs:HP:0000421, HP:0000132, HP:0012147 HP:0030132, HP:0030130
CaseHPOFreeRext:Skin, GI, muscle, oral cavity, and joint bleeding, VWF: Ag 0.07 U/mL, VWF:Ac 0.08 U/mL, VWF:CB 0.05 U/mL, FVIII 0.02 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
97 10 F 45 c.7604G.Ap.R2535Q Hmz 9 2.3 6 - -
Case: 97, F, 10 years, Indian
DiseaseAssertion: VWD type 3
FamilyInfo: no family history of disease, Consanguinity: no
ParentalGenotype: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: FVIII:C: (U/dl): 9, VWF:Ag (U/dl): 2.3, Bleeding Score: 6
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.7604G>A (p.Arg2535Gln), Exon 45
Homozygous
10 42 M 20 c.2560C.T p.R854W Htz ,1 ,1 34 + -
Case: 10, M, 42 years, Indian
DiseaseAssertion: VWD type 3
FamilyInfo: family history of disease, Consanguinity: no
ParentalGenotype: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: FVIII:C: (U/dl): <1, VWF:Ag (U/dl): <1, Bleeding Score: 34
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.2560C>T (p.Arg854Trp), Exon 20
Heterozygous
87 16 F 28 c.5001G.Cp.Q1667H Hmz ,1 5.3 12 - +
Case: 87, F, 16 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): 5.3, Bleeding Score: 12
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.5001G>C (p.Gln1667His), Exon 28
Homozygous
64 2 M 28 c.3835G.A p.V1279I Hmz 5.2 ,1 6 - +c.3931C.T p.Q1311*
Case: 64, M, 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): 5.2, VWF:Ag (U/dl): <1, Bleeding Score: 6
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.3835G>A (p.Val1279Ile), Exon 28
c.3931C>T (p.Gln1311*), Exon 28
Homozygous
69 1.5 F 34 c.5793G.Cp.Q1931H Hmz ,1 ,1 2 - -
Case: 69, F, 1.5 years, Indian
DiseaseAssertion: VWD type 3
FamilyInfo: no family history of disease, Consanguinity: no
ParentalGenotype: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: FVIII:C: (U/dl): <1, VWF:Ag (U/dl): <1, Bleeding Score: 2
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.5793G>C (p.Gln1931His), Exon 34
Homozygous
38 Type2A(IIA)c.4589T>GN p.Val1530Gly 28 A2 htz Missense na 30 na na
Case: IP #38 (also in row 18 table 6)
DiseaseAssertion: type 2A (IIA) VWD
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs:
CaseHPOFreeRext:
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.4589T>G p.Val1530Gly
HGVS:
ClinVarID: not found
CAID: CA383501045
gnomAD: absent
10-12Type2A (IIE)c.3296G>AN p.Cys1099Tyr 25 D3-C8-3htz Missense O/na/A131/na/26532/na/44 117OSCA/na
Case: IP #11 (also in row 6 table 6)
DiseaseAssertion: type 2A (IIE) VWD
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs:
CaseHPOFreeRext:
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.3296G>A p.Cys1099Tyr
HGVS:
ClinVarID: not found
CAID: CA383512195
gnomAD: absent
3 Type 2A c.1324C>TNc.6536C>Tp.Arg442Cysp.Ser2179PheC1237D2-VWD2D4-C8-4htzhtzMissenseMissensena na 17 15
Case: 3 (Also in row 1 table 6)
DiseaseAssertion: type 2A VWD
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs:
CaseHPOFreeRext: VWF:Ag [IU/dL] = n/a; VWF:Ac [IU/dL] = 17; FVIII:C [IU/dL] = 15
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting:
GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.
PreviouslyPublished:
Gene: VWF
Variant: c.1324C>T p.Arg442Cys
HGVS:
ClinVarID: 806808
CAID:
gnomAD: 0.00003098 (50 in 1614024) no homoztygotes https://gnomad.broadinstitute.org/variant/12-6064354-G-A?dataset=gnomad_r4
MultipleGeneVariants:
Gene: VWF
Variant: c.6536C>T p.Ser2179Phe
ClinVarID: 100442
gnomAD: 6.196e-7 (1 in 1614072) no homozygotes https://gnomad.broadinstitute.org/variant/12-5993924-G-A?dataset=gnomad_r4
51-54Type2A(IIA)c.4811T>AN p.Val1604Asp 28 A2 htz Missense O/A/O/O27/24/35/328/9/11/755CSA/57
Case: IP #52 (also in row 21 table 6)
DiseaseAssertion: type 2A (IIA) VWD
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs: HP:0032370 - blood group A
CaseHPOFreeRext: VWF:Ag [IU/dL] = 24; VWF:Ac [IU/dL] = 9; 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.4811T>A p.Val1604Asp
HGVS:
ClinVarID: not found
CAID: CA383499144
gnomAD: absent
28 Type2Ac.4078G>TN p.Val1360Phe 28 A1 htz Missense A 39 7 61
Case: IP #28 (also in row 14 table 6)
DiseaseAssertion: type 2A VWF
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs: HP:0032370 - blood group A
CaseHPOFreeRext: VWF:Ag [IU/dL] = 39; VWF:Ac [IU/dL] = 7; FVIII:C [IU/dL] = 61
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.4078G>T p.Val1360Phe
HGVS:
ClinVarID: 1809581
CAID:
gnomAD: absent
9 Type2Ac.2771G>A* p.Arg924Gln 21 D3-VWD3htz Missense na 17 10 51
Case: IP #9
DiseaseAssertion: type 2A VWD
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs:
CaseHPOFreeRext: VWF:Ag [IU/dL] = 17; VWF:Ac [IU/dL] = 10; FVIII:C [IU/dL] = 51
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting:
GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.
PreviouslyPublished:
Gene: VWF
Variant: c.2771G>A p.Arg924Gln
HGVS:
ClinVarID: 100240
CAID:
gnomAD: 0.01774 (28642 in 1614096) 297 homozygotes https://gnomad.broadinstitute.org/variant/12-6031493-C-T?dataset=gnomad_r4
34
Case: IP #34
DiseaseAssertion: type 2A (IIA) VWD
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs:
CaseHPOFreeRext: VWF:Ag [IU/dL] = 55; VWF:Ac [IU/dL] = 35; 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.4517C>T p.Ser1506Leu
HGVS:
ClinVarID: 100369
CAID:
gnomAD: absent
26, 27 Heterozygous2Nc.3673T > G p.Cys1225Gly 27 D3-E3 htz Missense O/A 50/42 29/44 40
Case: IP #26 in type 2N VWD sub-cohort
DiseaseAssertion: type 2N VWD
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs: HP:0032442 - blood group O
CaseHPOFreeRext: VWF:Ag [IU/dL] = 50; VWF:Ac [IU/dL] = 29; FVIII:C [IU/dL] = 40
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting:
GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.
PreviouslyPublished:
Gene: VWF
Variant: c.3673T>G p.Cys1225Gly
HGVS:
ClinVarID: 100272
CAID:
gnomAD: absent
12–15 c.5191T > A p.Ser1731Thr 30 A3 htz Missense O/A/na/na23/47/94/na 21/46/89/50 52 CSA /86 CSA /126 CSA /nana/na/49/25
Case: IP #15 in type 2M VWD sub-cohort
DiseaseAssertion: type 2M VWD
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs:
CaseHPOFreeRext: VWF:Ag [IU/dL] = n/a; VWF:Ac [IU/dL] = 50; FVIII:C [IU/dL] = n/a; VWF:CB (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.5191T>A p.Ser1731Thr
HGVS:
ClinVarID: 100420
CAID:
gnomAD: 0.001158 (1870 in 1614210) 5 homozygotes https://gnomad.broadinstitute.org/variant/12-6016636-A-T?dataset=gnomad_r4
33 U c.4120C > A p.Arg1374Ser 28 A1 htz Missense O 11 4 10
Case: IP #33 in type U VWD sub-cohort
DiseaseAssertion: unclassified VWD
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs: HP:0032442 - blood group O
CaseHPOFreeRext: VWF:Ag [IU/dL] = 11; VWF:Ac [IU/dL] = 4; FVIII:C [IU/dL] = 10
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting:
GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.
PreviouslyPublished:
Gene: VWF
Variant: c.4120C>A p.Arg1374Ser
HGVS:
ClinVarID: 100328
CAID:
gnomAD: absent
55-57Type2A(IIA)c.4825G>A p.Gly1609Arg 28 A2 htz Missense na/B/O71/46/53 17/12/15 na
Case: IP #55
DiseaseAssertion: type 2A (IIA) VWD
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs:
CaseHPOFreeRext: VWF:Ag [IU/dL] = 71; VWF:Ac [IU/dL] = 17; 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.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
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
Case: IP #29 in type U VWD sub-cohort
DiseaseAssertion: unclassified (2A/2M/1C) VWD
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs:
CaseHPOFreeRext: VWF:Ag [IU/dL] = 21; VWF:Ac [IU/dL] = 9; FVIII:C [IU/dL] = 42
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
12 U (2M/2B/1) c.3835G > A p.Val1279Ile 28 A1 htz Missense na 7 na 8
Case: IP #12 in type U VWD sub-cohort
DiseaseAssertion: unclassified (2M/2B/1) VWD
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs:
CaseHPOFreeRext: VWF:Ag [IU/dL] = 7; VWF:Ac [IU/dL] = n/a; FVIII:C [IU/dL] = 8
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.3835G>A p.Val1279Ile
HGVS:
ClinVarID: 100288
CAID:
gnomAD: 0.0003751 (605 in 1612942) 1 homozygote https://gnomad.broadinstitute.org/variant/12-6019583-C-T?dataset=gnomad_r4
58 Type2A(IIA)c.4880C>GN p.Pro1627Arg 28 A2 htz Missense O 19 4 21
Case: IP #58 (also in row 22 table 6)
DiseaseAssertion: type 2A (IIA) VWD
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs: HP:0032442 - blood group O
CaseHPOFreeRext: VWF:Ag [IU/dL] = 19; VWF:Ac [IU/dL] = 4; FVIII:C [IU/dL] = 21
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting:
GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.
PreviouslyPublished:
Gene: VWF
Variant: c.4880C>G p.Pro1627Arg
HGVS:
ClinVarID: not found
CAID: CA383498774
gnomAD: absent
4 c.4037A > C N p.Gln1346Pro 28 A1 htz Missense O 20 5 22 CSA 20
Case: IP #4 in type 2M VWD sub-cohort (also in row 13 table 6)
DiseaseAssertion: type 2M VWD
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs:
CaseHPOFreeRext: VWF:Ag [IU/dL] = 20; VWF:Ac [IU/dL] = 5; FVIII:C [IU/dL] = 22; VWF:CB (IU/dL) = 20
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting:
GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.
PreviouslyPublished:
Gene: VWF
Variant: c.4037A>C p.Gln1346Pro
HGVS:
ClinVarID: not found
CAID: CA383505695
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
Case: IP #25 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] = 22; VWF:Ac [IU/dL] = 8; FVIII:C [IU/dL] = 26
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting:
GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.
PreviouslyPublished:
Gene: VWF
Variant: c.4120C>T p.Arg1374Cys
HGVS:
ClinVarID: 100329
CAID:
gnomAD: absent
22 Type2A (IIE)c.3518G>T p.Cys1173Phe 26 D3-TIL-3htz Missense na 23 16 37
Case: IP #22
DiseaseAssertion: type 2A (IIE) VWD
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs:
CaseHPOFreeRext: VWF:Ag [IU/dL] = 23; VWF:Ac [IU/dL] = 16; 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.3518G>T p.Cys1173Phe
HGVS:
ClinVarID: not found
CAID: CA383511188
gnomAD: absent
Case#: 23015, Age 74, Male, Blood Type A+ (Table S3)
Disease Assertion: VWD1
FamilyInfo: The patient is the only member of Family# 2310.
Parental Genotype: Not listed
CasePresentingHPOs: N/A
CaseHPOFreeText:VWF:Ag: 18, VWF:RCo:17.3, FVIII:C:19, VWF:CB:13
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.2546+132G>A(p.=) and NM_000552.4:c.3614G>A (p.Arg1205His)
ClinVar: 308 ClinVar
CAID: CA232299449 and CA114160 CAID1 CAID2
gnomAD: MAF of 0.001179 ( 1/848 alleles) in the Latino population (CA232299449). gnomAD
Case#: 01010, Age 55, Male, Blood Type O+ (Table S3)
Disease Assertion:VWD1
FamilyInfo: Not listed
Parental Genotype:Not listed
CasePresentingHPOs:
CaseHPOFreeText: Bleeding score 5, VWF:Ag 27, VWF:RCo: 30, FVIII:C 51, VWF:CB: 32
CaseNotHPOs:
CaseNotHPOFreeText:
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(VWF):c.4751A>G (p.Tyr1584Cys)
ClinVar: 310
CAID: CA114162
gnomAD: MAF of 0.004024 (519/128972 alleles) in the European (non-Finnish) population.
Case#: 32005, Age 28, Female, Blood Type O- (Table S3)
Disease Assertion: VWD 1
FamilyInfo: The patient is the only member of Family# 3205.
Parental Genotype: Not listed
CasePresentingHPOs: N/A
CaseHPOFreeText: VWF:Ag: 30, VWF:RCo: 25, FVIII:C: 25, VWF:CB: 32
CaseNotHPOs: N/A
CaseNotHPOFreeText: Bleeding Score 4
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.2546+132G>A (p.=) and NM_000552.4:c.4751A>G (p.Tyr1584Cys)
ClinVar: 310
CAID: CA232299449 and CA114162 CAID1 CAID2
gnomAD: MAF of 0.001179 (1/848 alleles) in the Latino population (CA232299449) gnomAD
MAF of 0.004024 (519/ 128972 alleles) in the European (non-Finnish) population. gnomAD
Case#: 02023, Age 28, Female, Blood type O+ (Table S3)
Disease Assertion: VWD 1
FamilyInfo: Family# 0206. 3 family members were included in the study. Everyone in the family have the same variant and all have type 1 VWD.
Parental Genotype: Not listed
CasePresentingHPOs:
CaseHPOFreeText: Bleeding score 18, VWF:Ag: 5.5, VWF:RCo: 8, FVIII:C: 11, VWF:CB: 4.2
CaseNotHPOs:
CaseNotHPOFreeText:
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.3614G>A (p.Arg1205His)
ClinVar: 308 ClinVar
CAID: CA114160 CAID
gnomAD: N/A
Case#: 21006, Age 40, Male, Blood Type O+ (Table S3)
Disease Assertion: VWD 1
FamilyInfo: The patient is one of 4 members of Family# 2103. Each patient has the p.Gly2083Asp variant. Some of the patients have a second variant.
Parental Genotype: Not listed
CasePresentingHPOs: N/A
CaseHPOFreeText: Bleeding Score 8, VWF:Ag: 11, VWF:RCo: 10, FVIII:C:29, VWF:CB: 10.3
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.6248G>A (p.Gly2083Asp)
ClinVar: N/A
CAID: CA383492072 CAID
gnomAD: N/A
Case#: 30008, Age 24, Female, Blood Type A+ (Table S3)
Disease Assertion: VWD 1
FamilyInfo: The patient is one of two members of Family #3006. Both patients have the same variant.
Parental Genotype: Not listed
CasePresentingHPOs: N/A
CaseHPOFreeText: Bleeding Score 12, VWF:Ag:18, VWF:RCo:19.3, FVIII:C: 35, VWF:CB: 21
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.6536C>T (p.Ser2179Phe)
ClinVar: 100442 ClinVar
CAID: CA228746 CAID
gnomAD: N/A
Case#: 35008, Age 64, Male, Blood Type A+ (Table S3)
Disease Assertion: VWD 1
FamilyInfo: The patient is the only member of Family# 3503.
Parental Genotype: Not listed
CasePresentingHPOs: N/A
CaseHPOFreeText: VWF:Ag: 5.3, VWF:RCo:5, FVIII:C: 10, VWF:CB: 4.9
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.1625C>G (p.Ala542Gly), NM_000552.4:c.5198T>C (p.Leu1733Pro), and NM_000552.4:c.6187C>T (p.Pro2063Ser)
ClinVar: 381621 and 100436 ClinVar1 ClinVar2
CAID: CA6403319, CA383496267, and CA202650 CAID1 CAID2 CAID3
gnomAD: MAF of 0.001355 (48/ 35418 alleles) in the Latino population (CA6403319). gnomAD
MAF of 0.04854 (1486/30616 alleles) in the South Asian population (CA202650). gnomAD
Case#: 37005, Age 39, Female, Blood Type O+ (Table S3)
Disease Assertion: VWD 1
FamilyInfo: The patient is the only member of Family#3705.
Parental Genotype: Not listed
CasePresentingHPOs: N/A
CaseHPOFreeText: Bleeding Score 9, VWF:Ag:26, VWF:RCo: 18, FVIII:C: 44, VWF:CB: 18
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.2878C>T (p.Arg960Trp)
ClinVar: N/A
CAID: CA6402916 CAID
gnomAD: MAF of 0.0004900 (50/ 30612 alleles) in the South Asian population. gnomAD
Case#: 30006, Age 70, Female, Blood Type A- (Table S3)
Disease Assertion: VWD 1
FamilyInfo: The patient is the only member of Family#3005.
Parental Genotype: Not listed
CasePresentingHPOs: N/A
CaseHPOFreeText: Bleeding Score 17, VWF:Ag: 24, VWF:RCo: 29.4, FVIII:C:30, VWF:CB: 28
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.5336G>T(p.Arg1779Leu)
ClinVar: N/A
CAID: CA383495656 CAID
gnomAD: MAF of 0.00002891 ( 1/ 34592 alleles) in the Latino population. gnomAD
I : 1
Case#: F7, I:1
DiseaseAssertion: Type 2 VWD
CaseHPOFreeText: partial loss of high molecular weight multimers, VWF:Ag = 88; VWF:RCo = 46; VWF:GPIbM = 81; 0.52; 0.93; 1.77
CasePreviousTesting: Not clearly described
Gene: VWF
Variant: p.[I1309V];[=]
HGVS: c.3925A>G (p.Ile1309Val)
CAID: CA228492
gnomAD: absent from gnomad v4.1.0
I : 1
Case#: F6, I:1
DiseaseAssertion: Type 2 VWD
CaseHPOFreeText: partial loss of high molecular weight multimers, VWF:Ag = 56; VWF:RCo = 29; VWF:GPIbM = 75; 0.51; 1.34; 2.63
CasePreviousTesting: Not clearly described
Gene: VWF
Variant: p.[H1268D];[=]
HGVS: c.3802C>G (p.His1268Asp)
CAID: CA228445
gnomAD: absent from gnomad v4.1.0
I : 1
Case#: F20, I:1
DiseaseAssertion: Type 2 VWD
CaseHPOFreeText: loss of high and intermediate MWMs, VWF:Ag = 34; VWF:RCo = 8; VWF:GPIbM = 23; 0.22; 0.68; 3.08
CasePreviousTesting: Not clearly described
Gene: VWF
Variant: p.[V1316M];[=]
HGVS: c.3946G>A (p.Val1316Met)
CAID: CA114127
gnomAD: absent from gnomad v4.1.0
II : 1
Case#: F5, II:1
DiseaseAssertion: Type 2 VWD
CaseHPOFreeText: all mutimers present, VWF:Ag = 56; VWF:RCo = 48; VWF:GPIbM = 49; 0.86; 0.87; 1.01
CasePreviousTesting: Not clearly described
Gene: VWF
Variant: p.[I1372S];[=]
HGVS: c.4115T>G (p.Ile1372Ser)
CAID: CA228535
gnomAD: https://gnomad.broadinstitute.org/variant/12-6019303-A-C?dataset=gnomad_r4
I : 1
Case#: F19, I:1
DiseaseAssertion: Type 2 VWD
CaseHPOFreeText: loss of high and intermediate MWMs, VWF:Ag = 35; VWF:RCo = 5; VWF:GPIbM = 28; 0.14; 0.81; 5.68
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#: F5, I:1
DiseaseAssertion: Type 2 VWD
CaseHPOFreeText: all mutimers present, VWF:Ag = 105; VWF:RCo = 90; VWF:GPIbM = 87; 0.86; 0.82; 0.96
CasePreviousTesting: Not clearly described
Gene: VWF
Variant: p.[I1372S];[=]
HGVS: c.4115T>G (p.Ile1372Ser)
CAID: CA228535
gnomAD: https://gnomad.broadinstitute.org/variant/12-6019303-A-C?dataset=gnomad_r4
I : 1
Case#: F18, I:1
DiseaseAssertion: Type 2 VWD
CaseHPOFreeText: loss of high and intermediate MWMs, VWF:Ag = 95; VWF:RCo = 30; VWF:GPIbM = 70; 0.32; 0.73; 2.31
CasePreviousTesting: Not clearly described
Gene: VWF
Variant: p.[R1308C];[=]
HGVS: c.3922C>T (p.Arg1308Cys)
CAID: CA114125
gnomAD: absent from gnomad v4.1.0
I : 1
Case#: F17, I:1
DiseaseAssertion: Type 2 VWD
CaseHPOFreeText: loss of high and intermediate MWMs, VWF:Ag = 30; VWF:RCo = 8; VWF:GPIbM = 23; 0.27; 0.75; 2.81
CasePreviousTesting: Not clearly described
Gene: VWF
Variant: p.[R1308C];[=]
HGVS: c.3922C>T (p.Arg1308Cys)
CAID: CA114125
gnomAD: absent from gnomad v4.1.0
I : 1
Case#: F16, I:1
DiseaseAssertion: Type 2 VWD
CaseHPOFreeText: loss of high and intermediate MWMs, VWF:Ag = 48; VWF:RCo = 13; VWF:GPIbM = 48; 0.27; 1.00; 3.65
CasePreviousTesting: Not clearly described
Gene: VWF
Variant: p.[R1308C];[=]
HGVS: c.3922C>T (p.Arg1308Cys)
CAID: CA114125
gnomAD: absent from gnomad v4.1.0
I : 1
Case#: F15, I:1
DiseaseAssertion: Type 2 VWD
CaseHPOFreeText: loss of high and intermediate MWMs, VWF:Ag = 43; VWF:RCo = 12; VWF:GPIbM = 30; 0.28; 0.70; 2.56
CasePreviousTesting: Not clearly described
Gene: VWF
Variant: p.[R1308C];[=]
HGVS: c.3922C>T (p.Arg1308Cys)
CAID: CA114125
gnomAD: absent from gnomad v4.1.0
II : 2
Case#: F14, II:2
DiseaseAssertion: Type 2 VWD
CaseHPOFreeText: loss of high and intermediate MWMs, VWF:Ag = 12; VWF:RCo = 3; VWF:GPIbM = 9; 0.21; 0.71; 3.31
CasePreviousTesting: Not clearly described
Gene: VWF
Variant: p.[C275R];[P1337L]
HGVS: c.823T>C (p.Cys275Arg), c.4010C>T (p.Pro1337Leu)
CAID: CA228836, CA228510
gnomAD: absent from gnomad, https://gnomad.broadinstitute.org/variant/12-6019408-G-A?dataset=gnomad_r4
6
Case: Patient 6 (Family C), male, 53yo
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 = 193, PFA 100 sec = 199, SPA % = 5.2, MADR mg/mL = 0.75, VWF:Ag U/dL = 47.1, VWF:CB U/dL = 44.6, VWF:CB ratio = 0.94, VWF:RCo U/dL = 38.0, VWF:RCo ratio = 0.80, Platelet VWF U/dL = 47.4, FVIII U/dL = 43.8, BAT F/M = 0
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
6
Case: Patient 6 (Family B), male, 15yo
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 A, Platelet count x103/μl = 180, PFA 100 sec = >300, SPA % = 0, MADR mg/mL = 0.6, VWF:Ag U/dL = 30.9, VWF:CB U/dL = 12.5, VWF:CB ratio = 0.41, VWF:RCo U/dL = 11.4, VWF:RCo ratio = 0.37, Platelet VWF U/dL = 79.1, FVIII U/dL = 49.3, BAT F/M = 4
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
1
Case: Patient 1 (Family A), female, 48yo
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 A, Platelet count x103/μl = 232, PFA 100 sec = NA, SPA % = 12, MADR mg/mL = 0.45, VWF:Ag U/dL = 160.6, VWF:CB U/dL = 135.6, VWF:CB ratio = 0.84, VWF:RCo U/dL = 132.8, VWF:RCo ratio = 0.83, Platelet VWF U/dL = 92.0, FVIII U/dL = 78.0, BAT F/M = 6
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: NA
GenotypingMethod: Sequencing of exon 28 of VWF
PreviouslyPublished: NA
Gene: VWF
Variant: c.4115T>G (p.Ile1372Ser)
HGVS: NM_000552.4(VWF):c.4115T>G (p.Ile1372Ser)
ClinVarID: 100327; https://www.ncbi.nlm.nih.gov/clinvar/variation/100327/
gnomAD: MAF = 0.00006175 (7/113356 alleles) in the European (non-Finnish) population; https://gnomad.broadinstitute.org/variant/12-6128469-A-C?dataset=gnomad_r2_1
10
Case: Patient 10 (Family D), female, 24yo
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 AB, Platelet count x103/μl = 231, PFA 100 sec = 223, SPA % = 6, MADR mg/mL = 0.75, VWF:Ag U/dL = 46.0, VWF:CB U/dL = 49.1, VWF:CB ratio = 1.07, VWF:RCo U/dL = 40.5, VWF:RCo ratio = 0.83, Platelet VWF U/dL = 55.6, FVIII U/dL = 64.8, BAT F/M = NA
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
11
Case: Patient 11 (Family C), male, 80yo
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 = 182, PFA 100 sec = >300, SPA % = 0, MADR mg/mL = 0.45, VWF:Ag U/dL = 39.5, VWF:CB U/dL = 9.3, VWF:CB ratio = 0.24, VWF:RCo U/dL = 23.3, VWF:RCo ratio = 0.59, Platelet VWF U/dL = 113.90, FVIII U/dL = 52.1, BAT F/M = 14
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
7
Case: Patient 7 (Family B), male, 81yo
DiseaseAssertion: VWD2B
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0030132, HP:0030129, HP:0030130, HP:0011871
(Absence of large von Willebrand factor multimers, impaired ristocetin cofactor assay activity, Impaired von Willebrand factor collagen binding activity, Impaired RIPA)
CaseHPOFreeText: blood group A, Platelet count x103/μl = 165, PFA 100 sec = >300, SPA % = NA, MADR mg/mL = 0.6, VWF:Ag U/dL = 166.4, VWF:CB U/dL = 30.0, VWF:CB ratio = 0.18, VWF:RCo U/dL = 112.0, VWF:RCo ratio = 0.67, Platelet VWF U/dL = NA, FVIII U/dL = 136.0, 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
17
Case: Patient 17 (Family E), female, 24yo
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 = 65, PFA 100 sec = >300, SPA % = 22.5, MADR mg/mL = 0.15, VWF:Ag U/dL = 35.9, VWF:CB U/dL = 15.6, VWF:CB ratio = 0.44, VWF:RCo U/dL = 14.4, VWF:RCo ratio = 0.40, Platelet VWF U/dL = 140.3, FVIII U/dL = 35.9, BAT F/M = 13
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: NA
GenotypingMethod: Sequencing of exon 28 of VWF
PreviouslyPublished: NA
Gene: VWF
Variant: c.3946G>A (p.Val1316Met)
HGVS: NM_000552.4(VWF):c.3946G>A (p.Val1316Met)
ClinVarID: 290; https://www.ncbi.nlm.nih.gov/clinvar/variation/290/
CAID: NA
gnomAD: absent
4
Case: Patient 4 (Family A), male, 43yo
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 A, Platelet count x103/μl = 163, PFA 100 sec = >300, SPA % = 0, MADR mg/mL = 0.6, VWF:Ag U/dL = 42.8, VWF:CB U/dL = 10.6, VWF:CB ratio = 0.25, VWF:RCo U/dL = 25.2, VWF:RCo ratio = 0.58, Platelet VWF U/dL = 132.7, FVIII U/dL = 47.1, BAT F/M = 10
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
Case: P53, Chinese, female, 70yo
DiseaseAssertion: VWD2A
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs:
CaseHPOFreeText: HP:0012147
(Reduced quantity of VWF)
CaseNOTHPOs: type O blood, bleeding score = 9; VWF:Ag (%) = 32.1, VWF:RCo (%) = 6.0, FVIII:C (%) = 50.8, VWF:CB (%) = 14.7, VWFpp (%) = 56.9, VWF:RCo/VWF:Ag = 0.2, VWF:CB/VWF:Ag = 0.5, VWFpp/VWF:Ag = 1.8, FVIII:C/VWF:Ag = 1.6
CaseNOTHPOFreeText:
CasePreviousTesting: NA
GenotypingMethod: NGS
PreviouslyPublished: NA
Gene: VWF
Variant: c.4790G>T (p.Arg1597Leu)
HGVS: NM_000552.4(VWF):c.4790G>T (p.Arg1597Leu)
ClinVarID: 100392; https://www.ncbi.nlm.nih.gov/clinvar/variation/100392/
CAID: NA
gnomAD: absent
Case: P9, Chinese, male, 11yo
DiseaseAssertion: VWD1
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0012147
(Reduced quantity of VWF)
CaseHPOFreeText: type A blood, bleeding score = 2; VWF:Ag (%) = 5.3, VWF:RCo (%) = 4.7, FVIII:C (%) = 10.7, VWF:CB (%) = 4.5, VWFpp (%) = 4.1, VWF:RCo/VWF:Ag = 0.9, VWF:CB/VWF:Ag = 0.9, VWFpp/VWF:Ag = 0.8, FVIII:C/VWF:Ag = 2.0, RIPA (1.2 mg/ml, %) = 51.0
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: NA
GenotypingMethod: NGS
PreviouslyPublished: NA
Gene: VWF
Variant 1: c.4414G>C (p.Asp1472His)
HGVS: NM_000552.4(VWF):c.4414G>C (p.Asp1472His)
ClinVarID: 256679; https://www.ncbi.nlm.nih.gov/clinvar/variation/256679/
CAID: NA
gnomAD: MAF = 0.5077 (12039/23712 alleles; 3078 homozygotes) in the African/African-American population; https://gnomad.broadinstitute.org/variant/12-6128170-C-G?dataset=gnomad_r2_1
Variant 2: c.8079C>A (p.Cys2693Ter)
HGVS: NM_000552.5:c.8079C>A (p.Cys2693Ter)
ClinVarID: NA
CAID: CA383487414; http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA383487414
gnomAD: absent
Case: P75, Chinese, female, 25yo
DiseaseAssertion: VWD1
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0012147
(Reduced quantity of VWF)
CaseHPOFreeText: type O blood, bleeding score = 2; VWF:Ag (%) = 53.6, VWF:RCo (%) = 55.9, FVIII:C (%) = 74.0, VWF:CB (%) = 53.8, VWFpp (%) = 57.7, VWF:RCo/VWF:Ag = 1.0, VWF:CB/VWF:Ag = 1.0, VWFpp/VWF:Ag = 1.1, FVIII:C/VWF:Ag = 1.4
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: P44, Chinese, male, 6yo
DiseaseAssertion: VWD2A
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0012147
(Reduced quantity of VWF)
CaseHPOFreeText: type A blood, bleeding score = 6; VWF:Ag (%) = 43.6, VWF:RCo (%) = 18.3, FVIII:C (%) = 38.7, VWF:CB (%) = 16.7, VWFpp (%) = 64.8, VWF:RCo/VWF:Ag = 0.4, VWF:CB/VWF:Ag = 0.4, VWFpp/VWF:Ag = 1.5, FVIII:C/VWF:Ag = 0.9
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: NA
GenotypingMethod: NGS
PreviouslyPublished: NA
Gene: VWF
Variant 1: c.1870G>A (p.Gly624Ser)
HGVS: NM_000552.4(VWF):c.1870G>A (p.Gly624Ser)
ClinVarID: 619737; https://www.ncbi.nlm.nih.gov/clinvar/variation/619737/
CAID: NA
gnomAD: MAF = 0.004886 (59/12076 alleles; 1 homozygote) in the East Asian population; https://gnomad.broadinstitute.org/variant/12-6166098-C-T?dataset=gnomad_r2_1
Variant 2: c.4883T>C (p.Ile1628Thr)
HGVS: NM_000552.4(VWF):c.4883T>C (p.Ile1628Thr)
ClinVarID: 284; https://www.ncbi.nlm.nih.gov/clinvar/variation/284/
CAID: NA
gnomAD: absent
Case: P24, Chinese, male, 6yo
DiseaseAssertion: VWD3
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0012147
(Reduced quantity of VWF)
CaseHPOFreeText: type A blood, bleeding score = 13; VWF:Ag (%) = 0.9, VWF:RCo (%) = 0.7, FVIII:C (%) = 5.0, VWF:CB (%) = 0.7, VWFpp (%) = 0.9, VWF:RCo/VWF:Ag = 0.8, VWF:CB/VWF:Ag = 0.8, VWFpp/VWF:Ag = 1.0, FVIII:C/VWF:Ag = 5.6
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: NA
GenotypingMethod: NGS
PreviouslyPublished: NA
Gene: VWF
Variant: c.478G>C (p.Gly160Arg)
HGVS: NM_000552.5:c.478G>C (p.Gly160Arg)
ClinVarID: NA
CAID: CA383518174; http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA383518174
gnomAD: absent
Case: P19, Chinese, male, 35yo
DiseaseAssertion: VWD2M
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0012147
(Reduced quantity of VWF)
CaseHPOFreeText: type O blood, bleeding score = 4; VWF:Ag (%) = 17.5, VWF:RCo (%) = 5.1, FVIII:C (%) = 35.9, VWF:CB (%) = 16.9, VWFpp (%) = 45.3, VWF:RCo/VWF:Ag = 0.3, VWF:CB/VWF:Ag = 1.0, VWFpp/VWF:Ag = 2.6, FVIII:C/VWF:Ag = 2.1
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: NA
GenotypingMethod: NGS
PreviouslyPublished: NA
Gene: VWF
Variant: c.4120C>T (p.Arg1374Cys)
HGVS: NM_000552.4(VWF):c.4120C>T (p.Arg1374Cys)
ClinVarID: 100329; https://www.ncbi.nlm.nih.gov/clinvar/variation/100329/
CAID: NA
gnomAD: MAF = 0.000008824 (1/113322 alleles) in the European (non-Finnish) population; https://gnomad.broadinstitute.org/variant/12-6128464-G-A?dataset=gnomad_r2_1
Case: P89, Chinese, female, 51yo
DiseaseAssertion: VWD2N
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0012147
(Reduced quantity of VWF)
CaseHPOFreeText: type O blood, bleeding score = 7; VWF:Ag (%) = 125.8, VWF:RCo (%) = 119.6, FVIII:C (%) = 9.8, VWF:CB (%) = 127.8, VWFpp (%) = 109.8, VWF:RCo/VWF:Ag = 1.0, VWF:CB/VWF:Ag = 1.0, VWFpp/VWF:Ag = 0.9, FVIII:C/VWF:Ag = 0.1, VWF: FVIIIB (%) = 0.1
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: NA
GenotypingMethod: NGS
PreviouslyPublished: NA
Gene: VWF
Variant: c.2446C>T (p.Arg816Trp)
HGVS: NM_000552.4(VWF):c.2446C>T (p.Arg816Trp)
ClinVarID: 295; https://www.ncbi.nlm.nih.gov/clinvar/variation/295/
CAID: NA
gnomAD: MAF = 0.0002541 (9/35418 alleles) in the Latino/Admixed American population; https://gnomad.broadinstitute.org/variant/12-6145654-G-A?dataset=gnomad_r2_1
Case: P28, Chinese, male, 15yo
DiseaseAssertion: VWD2B
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0012147
(Reduced quantity of VWF)
CaseHPOFreeText: type A blood, bleeding score = 4; VWF:Ag (%) = 17.7, VWF:RCo (%) = 4.9, FVIII:C (%) = 25.5, VWF:CB (%) = 5.1, VWFpp (%) = 45.3, VWF:RCo/VWF:Ag = 0.3, VWF:CB/VWF:Ag = 0.3, VWFpp/VWF:Ag = 2.6, FVIII:C/VWF:Ag = 1.4, RIPA (0.5 mg/ml, %) = 20.5, PLT(×109/l) = 112
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: NA
GenotypingMethod: NGS
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
Case: P47, Chinese, female, 23yo
DiseaseAssertion: VWD1
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0012147
(Reduced quantity of VWF)
CaseHPOFreeText: type O blood, bleeding score = 12; VWF:Ag (%) = 4.5, VWF:RCo (%) = 3.3, FVIII:C (%) = 36.5, VWF:CB (%) = 4.2, VWFpp (%) = 5.3, VWF:RCo/VWF:Ag = 0.7, VWF:CB/VWF:Ag = 0.9, VWFpp/VWF:Ag = 1.2, FVIII:C/VWF:Ag = 8.1, RIPA (1.2 mg/ml, %) = 55.9
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: NA
GenotypingMethod: NGS
PreviouslyPublished: NA
Gene: VWF
Variant 1: c.100C>T (p.Arg34Ter)
HGVS: NM_000552.4(VWF):c.100C>T (p.Arg34Ter)
ClinVarID: 100171; https://www.ncbi.nlm.nih.gov/clinvar/variation/100171/
CAID: NA
gnomAD: MAF = 0.00002645 (3/113436 alleles) in the European (non-Finnish) population; https://gnomad.broadinstitute.org/variant/12-6230460-G-A?dataset=gnomad_r2_1
Variant 2: 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: P81, Chinese, female, 30yo
DiseaseAssertion: VWD1
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0012147
(Reduced quantity of VWF)
CaseHPOFreeText: type A blood, bleeding score = 7; VWF:Ag (%) = 5.0, VWF:RCo (%) = 5.3, FVIII:C (%) = 6.1, VWF:CB (%) = 6.8, VWFpp (%) = 46.0, VWF:RCo/VWF:Ag = 1.1, VWF:CB/VWF:Ag = 1.4, VWFpp/VWF:Ag = 9.2, FVIII:C/VWF:Ag = 1.2, RIPA (1.2 mg/ml, %) = 85.4
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: NA
GenotypingMethod: NGS
PreviouslyPublished: NA
Gene: VWF
Variant: c.3614G>A (p.Arg1205His)
HGVS: NM_000552.4(VWF):c.3614G>A (p.Arg1205His)
ClinVarID: 308; https://www.ncbi.nlm.nih.gov/clinvar/variation/308/
CAID: NA
gnomAD: absent
Case: P63, Chinese, female, 23yo
DiseaseAssertion: VWD3
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0012147
(Reduced quantity of VWF)
CaseHPOFreeText: type A blood, bleeding score = 15; VWF:Ag (%) = 1.2, VWF:RCo (%) = 0.5, FVIII:C (%) = 5.9, VWF:CB (%) = 0.6, VWFpp (%) = 0.5, VWF:RCo/VWF:Ag = 0.4, VWF:CB/VWF:Ag = 0.5, VWFpp/VWF:Ag = 0.4, FVIII:C/VWF:Ag = 4.9
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: NA
GenotypingMethod: NGS
PreviouslyPublished: NA
Gene: VWF
Variant 1: c.817C>T (p.Arg273Trp)
HGVS: NM_000552.4(VWF):c.817C>T (p.Arg273Trp)
ClinVarID: 100493; https://www.ncbi.nlm.nih.gov/clinvar/variation/100493/
CAID: NA
gnomAD: MAF = 0.00005288 (6/113462 alleles) in the European (non-Finnish) population; https://gnomad.broadinstitute.org/variant/12-6184558-G-A?dataset=gnomad_r2_1
Variant 2: c.5335C>T (p.Arg1779Ter)
HGVS: NM_000552.4(VWF):c.5335C>T (p.Arg1779Ter)
ClinVarID: 100425; https://www.ncbi.nlm.nih.gov/clinvar/variation/100425/
CAID: NA
gnomAD: absent
Case UZ053: 28 year old female (row 54 in supplemental table)
DiseaseAssertion: type 1 VWD
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs:
CaseHPOFreeRext:vWF:Ag (%) = 20.4; vWF:GPIbR (%) = 22.1; Act/Ag ratio = 1.08; FVIII:C (%) = 58.9; Platelets (x10^9/L) = 261
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.449T>C p.Leu150Pro
HGVS:
ClinVarID: 100363
CAID:
gnomAD: 0.000001239 (2 in 1614236) no homozygotes https://gnomad.broadinstitute.org/variant/12-6110457-A-G?dataset=gnomad_r4
43 F Type 2 NOS VWD Type 2A/M VWD c.4120C>T p.Arg1374Cys P
Case 14: 43 year old female, study ID UZ101 in supplemental table
DiseaseAssertion: type 2 NOS VWD presequencing, type 2A/M VWD postsequencing
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs:
CaseHPOFreeRext: vWF:Ag (%) = 23.6; vWF:GPIbR (%) = 9; Act/Ag ratio = 0.38; FVIII:C (%) = 35.3; Platelets (x10^9/L) = 244
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.4120C>T p.Arg1374Cys
HGVS:
ClinVarID: 100329
CAID:
gnomAD: 0.000003098 (5 in 1613796) no homozygotes https://gnomad.broadinstitute.org/variant/12-6019298-G-A?dataset=gnomad_r4
Case UZ090: 4 year old female (row 91 in supplemental table)
DiseaseAssertion: type 1 VWD
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs: HP:0032370
CaseHPOFreeRext: vWF:Ag (%) = 15; vWF:GPIbR (%) = 14.1; Act/Ag ratio = 0.94; FVIII:C (%) = 9.1; Platelets (x10^9/L) = 395
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.2573G>T p.Cys858Phe
HGVS:
ClinVarID: 100229
CAID:
gnomAD: absent
MultipleGeneVariants:
Gene: VWF
Variant: c.7437+5G>A
ClinVarID: not found
gnomAD: 0.000001859 (3 in 1613728) no homozygotes https://gnomad.broadinstitute.org/variant/12-5976106-C-T?dataset=gnomad_r4
6 F Type 2 NOS VWD Type 2M VWD c.4195C>T p.Arg1399Cys LP
Case 8: 6 y.o. female, study ID UZ026 in supplemental table
DiseaseAssertion: type 2 NOS VWD presequencing, type 2M VWD postsequencing
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs: HP:0032442
CaseHPOFreeRext: vWF:Ag (%) = 30.2; vWF:GPIbR (%) = 8.5; Act/Ag ratio = 0.28; FVIII:C (%) = 32.4; Platelets (x10^9/L) = 503
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 (83/1613776) 0 homozygotes https://gnomad.broadinstitute.org/variant/12-6019223-G-A?dataset=gnomad_r4
37 F Type 2 NOS VWD Type 2A VWD c.3569G>A p.Cys1190Tyr LP
Case 11: 37 year old female, study ID UZ022 in supplemental table
DiseaseAssertion: type 2 NOS VWD presequencing, type 2A VWD postsequencing
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs:
CaseHPOFreeRext: vWF:Ag (%) = 54.1; vWF:GPIbR (%) = 10.5; Act/Ag ratio = 0.19; FVIII:C (%) = 56.6; Platelets (x10^9/L) = 291
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.3569G>A p.Cys1190Tyr
HGVS:
ClinVarID: 626960
CAID:
gnomAD: 6.195e-7 (1 in 1614212) no homozygotes https://gnomad.broadinstitute.org/variant/12-6022005-C-T?dataset=gnomad_r4
MultipleGeneVariants: F7:c.977G>A p.Arg326Gln (VUS)
1
Case: 2A-9
DiseaseAssertion: VWD2A
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs: AcuStar RCo/Ag = 0.32; AcuStar CB/Ag = 0.34; ELISA CB/Ag = 0.40
CaseHPOFreeText:
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting:
GenotypingMethod: not described
PreviouslyPublished: PMID:20351307
Gene: VWF
Variant: c.3296G>A (p.Cys1099Tyr)
HGVS: NM_000552.5:c.3296G>A (p.Cys1099Tyr)
ClinVarID: n/a
CAID: CA383512195; https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA383512195
gnomAD: absent
1
Case: 2A-8
DiseaseAssertion: VWD2A
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs: AcuStar RCo/Ag = 0.43; AcuStar CB/Ag = 0.28; ELISA CB/Ag = 0.39
CaseHPOFreeText:
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting:
GenotypingMethod: not described
PreviouslyPublished: PMID:16985174
Gene: VWF
Variant: c.8313C>G (p.Cys2771Trp)
HGVS: NM_000552.5:c.8313C>G (p.Cys2771Trp)
ClinVarID: n/a
CAID: CA383486665; https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA383486665
gnomAD: absent
0.55
Case: 2B-4
DiseaseAssertion: VWD2B
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs: AcuStar RCo/Ag = 0.55; AcuStar CB/Ag = 0.44; ELISA CB/Ag = 0.44
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
0.39
Case: 2A-4
DiseaseAssertion: VWD2A
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs: AcuStar RCo/Ag = 0.39; AcuStar CB/Ag = 0.17; ELISA CB/Ag = 0.20
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
0.74
Case: 2B-10
DiseaseAssertion: VWD2B
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs: AcuStar RCo/Ag = 0.74; AcuStar CB/Ag = 0.97; ELISA CB/Ag = 1.13
CaseHPOFreeText:
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting:
GenotypingMethod: not described
PreviouslyPublished: 11325649
Gene: VWF
Variant: c.4135C>T (p.Arg1379Cys)
HGVS: NM_000552.5(VWF):c.4135C>T (p.Arg1379Cys)
ClinVarID: 100333; https://www.ncbi.nlm.nih.gov/clinvar/variation/100333/?new_evidence=false
CAID:
gnomAD: MAF (European, non-Finnish) = 0.00003891; 0 homozygotes; https://gnomad.broadinstitute.org/variant/12-6128449-G-A
Case: Case 2, male, newborn
DiseaseAssertion: VWD2B
FamilyInfo: First child of consanguineous parents (first cousins), no family history of bleeding, search of maternal platelet autoantibodies was negative; parents had VWF measurements showed decreased VWF:RCo, ratio FVIII:C/VWF:Ag < 0.5, and enhanced RIPA
ParentalGenotype(s): both parents heterozygous for both variants
CasePresentingHPOs: HP:0012330, HP:0001873, HP:0000967, HP:0030129
(Pyelonephritis, thrombocytopenia, petechiae, impaired ristocetin cofactor assay activity)
CaseHPOFreeText: born at 40wks, thrombocytopenia: 5 GL−1 at birth, platelets clumps in citrate tube, normal platelet morphology, no platelet incompatibility between the mother and the child in HPA groups 1, 3, 5, and 15, Allo- and autoantibodies on the mother and child and cross-match between father and mother serum were negative; bone marrow aspiration showed hyperplasia of megakaryocyte line, with all stages of maturation, consistent with peripheral origin, normal development; VWF:RCo = 13 IU dL−1, VWF:Ag = 47 IU dL−1, VWF:RCo /VWF:Ag= 0.3, FVIII:C = 22 IU dL−1, FVIII/VWF:Ag= 0.6, VWF:FVIII = 10 IU dL−1< RIPA analysis could not be performed
CaseNOTHPOs: HP:0032169, HP:0001892
(infection, abnormal bleeding)
CaseNOTHPOFreeText: DIC
CasePreviousTesting: NA
GenotypingMethod: Sequencing of exon 20 and 28 of VWF gene
PreviouslyPublished: NA
Gene: VWF
Variant 1: c.4010C>T (p.Pro1337Leu); exon 28, homozygous
HGVS: NM_000552.4(VWF):c.4010C>T (p.Pro1337Leu)
ClinVarID: 100314; https://www.ncbi.nlm.nih.gov/clinvar/variation/100314/
CAID: NA
gnomAD: MAF = 0.00005440 (1/18384 alleles) in East Asian population; https://gnomad.broadinstitute.org/variant/12-6128574-G-A?dataset=gnomad_r2_1
Variant 2: c.2561G>A (p.Arg854Gln); exon 20; homozygous
HGVS: NM_000552.4(VWF):c.2561G>A (p.Arg854Gln)
ClinVarID: 296; https://www.ncbi.nlm.nih.gov/clinvar/variation/296/
CAID: NA
gnomAD: MAF = 0.005692 (143/25122 alleles, 4 homozygotes) in European (non-Finnish) population; https://gnomad.broadinstitute.org/variant/12-6143978-C-T?dataset=gnomad_r2_1
660
Case#: Ahmad_2014_660
DiseaseAssertion: VWD type 2A
FamilyInfo: heterozygous (probably affected according to multimer analysis) mother and sibling
ParentalGenotype: heterozygous mother and sibling, homozygous wt father
CasePresentingHPOs: none described
CaseHPOFreeText: none described
CaseNotHPOs:
CaseNotHPOFreeText:
CasePreviousTesting: not reported
GenotypingMethod: PCR, restriction digest
Gene: VWF
Variant: NM_000552.5(VWF):c.4883T>C (p.Ile1628Thr)
HGVS:
ClinVarID: 284
CAID:
gnomAD: not reported
MultipleGeneVariants:
His 30‐year‐old mother had epistaxis, easy bruising, gum bleeding, and abnormal menstrual score according to the Pictorial Bleeding Assessment Chart4 (PBAC = 192, nv < 185).
Case#: 2, Female, Age 30, blood type B, Mother of Proband
Disease Assertion: VWD1
FamilyInfo: Mother of proband, No family history
Parental Genotype: not listed
CasePresentingHPOs: HP:0000421, HP:0000978, HP:0000225
(Epistaxis, Bruising susceptibility, Gingival bleeding)
CaseHPOFreeText: abnormal menstrual score (PBAC= 192, nv<185), VWF:Ag: 45, VWF:RCo: 46, bleeding score 5
CaseNotHPOs:
CaseNotHPOFreeText:
Protein Expression:
CasePreviousTesting: Forward and reverse strands sequenced by automated sequencing technology, PCR techniques used to analyze exons 17, 26-31, and 52 of VWF gene
Gene: VWF
Variant:NM_000552.3:c.4276C>T (p.Arg1426Cys)
ClinVar:. N/A
CAID: CA6402561 CA6402561
gnomAD: MAF of 0.00006152 (1/16254 alleles) in the African population for CA6402561.
The older brother (hereafter called Patient A)
Case: Patient A, male, 14 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 A and Patient B 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, HP:0012147 (Epistaxis, Impaired ristocetin cofactor assay activity, Reduced quantity of VWF)
CaseHPOFreeText: Recurrent spontaneous epistaxis. Historical VWF:RCo 1% and VWF:Ag 10%. VWF:RCo 1 IU/dL at WIL-31 screening. At the month 0 pharmacokinetic visit, pre-injection FVIII 12 IU/dL and VWF:RCo <5 IU/dL; after 60 IU/kg wilate, virtually no rise in VWF activity (maximum VWF:RCo 9 IU/dL, in vivo recovery 0.07 kg/dL). VWF inhibitors were confirmed present at WIL-31 study entry, and the patient remained inhibitor-positive 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 and antigen testing, and subsequent pharmacokinetic and VWF inhibitor testing, were performed. 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)
Case presentation A 27-year-old woman
Case: Proband, female, 27 years old at report; ethnicity not reported.
DiseaseAssertion: VWD2A. The authors confirmed type 2A VWD based on VWF:Ac/VWF:Ag ratio <0.7 (excluding types 1C, 2N, and 3), RIPA negative for increased platelet affinity (excluding type 2B), and multimer analysis showing HMWM deletion with IMWM reduction (excluding type 2M).
FamilyInfo: The patient denied a family history of abnormal bleeding. The father carried VWF c.2281+1G>A and was not diagnosed with VWD (VWF:Ag 61%, VWF:Ac 60.6%, FVIII activity 82%, VWF:Ac/VWF:Ag ratio 0.9). The mother carried VWF c.4654T>A and was diagnosed by the authors as having low VWF per British Committee for Standards in Haematology criteria (VWF:Ag 40%, VWF:Ac 26.6%, FVIII activity 66%, VWF:Ac/VWF:Ag ratio 0.6). Neither parent had a history of abnormal bleeding. Parental laboratory results and genotypes are reported in Table 2.
ParentalGenotype: Both parents were genotyped. The father was heterozygous for c.2281+1G>A and the mother was heterozygous for c.4654T>A (Table 2). The authors report that the two variants were inherited separately from each parent, establishing compound heterozygosity. Note: Figure 2 shows Sanger sequencing validation for c.2281+1G>A only, confirming the variant in the patient and father and a normal genotype at that locus in the mother. No confirmatory sequencing trace is shown for the maternal c.4654T>A variant; that genotype is reported only in Table 2.
CasePresentingHPOs: HP:0000421, HP:0000132, HP:0004846, HP:0012147, HP:0030132, HP:0011871 (Epistaxis, Menorrhagia, Prolonged bleeding after surgery, Reduced quantity of VWF, Absence of large von Willebrand factor multimers, Impaired RIPA)
CaseHPOFreeText: Gingival bleeding persisted for two days after tooth extraction. History of frequent epistaxis and one episode of heavy menorrhagia in 2007 treated with plasma transfusion. ISTH-BAT bleeding score 7 (epistaxis score 1, bleeding after tooth extraction score 2, heavy menorrhagia with plasma transfusion score 4). VWF:Ag 26.2%, VWF:Ac 5.7%, FVIII activity 43%, VWF:Ac/VWF:Ag ratio 0.21. Low-concentration RIPA 23.7% (reference 30.0-70.0%). VWF multimer analysis demonstrated deletion of high-molecular-weight multimers and reduction of intermediate-molecular-weight multimers (Figure 1). Arachidonic acid-induced platelet aggregation was impaired, with a maximal aggregation rate of 14.3%.
CaseNotHPOs: HP:0003645, HP:0001873 (Prolonged partial thromboplastin time, Thrombocytopenia)
CaseNotHPOFreeText: APTT 39.2 s (reference 32.0-45.0), platelets 183x10^9/L (reference 125-350), PT 13.6 s (reference 11.0-15.0), and fibrinogen 2.71 g/L (reference 2.0-4.0) were all within reference ranges, as was thrombin time. High-concentration RIPA 52.9% (reference 40.0-80.0), normal. Systemic physical examination unremarkable with no active bleeding on admission. Prior laparoscopic surgery for luteal rupture without a remarkable increase in bleeding. Hemoglobin 125 g/L was marginally below the stated reference range (130-175), although the authors described the complete blood count as normal.
CasePreviousTesting: Whole-exome sequencing was performed, which is a genome-wide method. No genes other than VWF were reported as tested or implicated. No earlier molecular genetic testing was reported.
GenotypingMethod: Whole-exome sequencing followed by one-generation (Sanger) sequencing validation, performed on the proband and both parents.
Variant 1
Gene: VWF
Variant: c.2281+1G>A, heterozygous, inherited from the father. Intron 17 canonical splice donor site; the authors describe the affected region as lying between the D2 and D' domains. Classified as pathogenic by the authors per ACMG guidelines.
HGVS: NM_000552.5:c.2281+1G>A
ClinVar: NA
CAID: CA383523243
gnomAD: Absent (gnomAD v4.1.1; variant not found, region adequately covered)
Variant 2
Gene: VWF
Variant: c.4654T>A (p.Phe1552Ile), heterozygous, inherited from the mother. Exon 28, A2 domain; missense. Classified as a variant of uncertain significance by the authors per ACMG guidelines. Note: the article gives the protein consequence as p.Phe1152Ile in the Case Presentation and p.Phe1552Ile in the Discussion; these are internally inconsistent. p.Phe1552Ile is correct, as confirmed by HGVS validation and by the ClinGen Allele Registry record (NP_000543.3:p.Phe1552Ile), and is consistent with the stated exon 28 location.
HGVS: NM_000552.5:c.4654T>A (p.Phe1552Ile)
ClinVar: NA
CAID: CA383500446
gnomAD: Absent (gnomAD v4.1.1; variant not found, region adequately covered)
An infant with presumed maternal immune thrombocytopenic purpura had persistent thrombocytopenia with platelet clumping. The patient had no significant bleeding symptoms in the first year of life and von Willebrand antigen and ristocetin cofactor activity were normal. Absent high molecular weight multimers ultimately led to a genetically proven diagnosis of type 2B von Willebrand disease (3964G>A VWF exon 28), highlighting the challenges of establishing this diagnosis in infants.
Case: Rotz Proband, female, reported at birth
DiseaseAssertion: VWD2b
FamilyInfo: Mother was 30yo reported with new onset thrombocytopenia during labor, diagnosed with maternal ITP; mother also had history of menorrhagia and excessive bleeding with minor trauma; VWF profile revealed a Factor VIII activity=49 IU/dL, VWF antigen=32 IU/dL, and undetectable RCo
ParentalGenotype(s): mother also carried c.3964G>A unregistered variant
CasePresentingHPOs: HP:0001873, HP:0030132, HP:0000967, HP:0000421, HP:0001892, HP:0001903, HP:0001981
(thrombocytopenia, Absence of large von Willebrand factor multimers, Petechiae, epistaxis, abnormal bleeding, anemia, schistocyte)
CaseHPOFreeText: small hematoma at IV puncture site, platelet count was 9×109/L, ultrasound showed no hemorrhage, hemoglobin=7.6 g/dL
CaseNOTHPOs: HP:0012147, HP:0030129
(Reduced quantity of VWF, impaired ristocetin cofactor assay activity)
CaseNOTHPOFreeText: no unusual findings on physical exam
CasePreviousTesting: NA
GenotypingMethod: Sequencing of VWF exon 28
PreviouslyPublished: NA
Gene: VWF
Variant: c.3964G>A unregistered variant
HGVS: NA
ClinVarID: NA
CAID: NA
gnomAD: NA
P9
Case: P9, female, 28yo
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 = 7; VWF:Ag (%) = 35, VWF:RCo(%) = 24, VWF:RCo/VWF:Ag ratio = 0.69, VWF:CIIIB (%) = 11, VWF:CIIIB/VWF:Ag ratio = 0.31, VWF:CVIB (%) = 19.2, VWF:CVIB/VWF:Ag ratio = 0.54
CaseNOTHPOs: HP:0030132
(Absence of large von Willebrand factor multimers)
CaseNOTHPOFreeText: NA
CasePreviousTesting: NA
GenotypingMethod: NGS
PreviouslyPublished: NA
Gene: VWF
Variant: c.5140G>C (p.Ala1714Pro)
HGVS: NM_000552.3:c.5140G>C (p.Ala1714Pro)
ClinVarID: NA
CAID: CA383496428; http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA383496428
gnomAD: absent
P6
Case: P6, female, 31yo
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 = 3; VWF:Ag (%) = 23, VWF:RCo(%) = 4, VWF:RCo/VWF:Ag ratio = 0.17, VWF:CIIIB (%) = 9.4, VWF:CIIIB/VWF:Ag ratio = 0.4, VWF:CVIB (%) = 4, VWF:CVIB/VWF:Ag ratio = 0.17
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
Case: Row 1 Supplemental Table 1.
DiseaseAssertion: type 1 VWD
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs:
CaseHPOFreeRext: FVIII:C/VWF:Ag ratio = 1.5; VWFpp/ VWF:Ag = 2.0
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting:
GenotypingMethod: 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: 55G>A G19R
HGVS: c.55G>A p.G19R
ClinVarID: 100432
CAID:
gnomAD: 0.00007062 (114 in 1614206) no homozygotes https://gnomad.broadinstitute.org/variant/12-6123142-C-T?dataset=gnomad_r4
Supplementary Material
Case: Row 3 in Supplemental Table 1. Represents 2 patients in 2 families.
DiseaseAssertion: type 1 VWD
FamilyInfo:
ParentalGenotype(s): Both patients also had R2313C (novel)
CasePresentingHPOs:
CaseHPOFreeRext: FVIII:C/VWF:Ag = 2.5 (2.4-2.5); VWFpp/VWF:Ag = 1.8 (1.3-2.3)
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: 421G>A D141N
HGVS: c.421G>A p.Asp141Asn
ClinVarID: 100338
CAID:
gnomAD: absent
Case: Row 12 in Supplemental Table 1.
DiseaseAssertion: type 2A VWD
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs:
CaseHPOFreeRext: FVIII:C/VWF:Ag = 3.3; VWFpp/VWF:Ag = 1.9
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting:
GenotypingMethod: Genetic analysis was performed at the laboratory of hematology of the Radboud University Medical Center in Nijmegen. Ion semiconductor sequencing (Ion-Torrent) was used to analyze the VWF gene from peripheral blood obtained in EDTA tubes or from saliva samples. The 52 exons of VWF gene were analyzed including ±20 bp exon-intron boundaries. If no VWF gene variant was detected, multiplex ligation-dependent probe amplification (MLPA) analysis was performed to find large deletions or duplications. Thus, MLPA was performed in 183 patients (46.9%). All variants were confirmed with Sanger sequencing.
PreviouslyPublished:
Gene: VWF
Variant: 1708T>C C570R
HGVS: VWF:c.1708T>C (p.Cys570Arg)
ClinVarID: 1695347
CAID:
gnomAD: absent
38-yr-old Nepalese woman
Case: 38 year old Napalese woman
DiseaseAssertion: type 2N VWD
FamilyInfo: mother and elder brother had bleeding manifestations since childhood.
CasePresentingHPOs: HP:0005261, HP:0012233, HP:0000132, HP:0003645, HP:0003125
CaseHPOFreeRext: diagnosed as hemophilia A with factor VIII level of 3.6%. normal CBC; bleeding time, 2 min; PT, 14.9 sec (11-14 sec); aPTT, 51.2 sec (24-38 sec); and factor VIII, 4.9% (50-150%)
CaseNOTHPOFreeText: No abnormalities were found in the vWF antigen level (71.3%), ristocetin cofactor assay (130.4%), and multimer assay
GenotypingMethod: direct DNA sequencing of the VWF gene
Gene: VWF
Variant: c.2446C>T (p.Arg816Trp)
HGVS: NM_000552.5:c.2446C>T p.(Arg816Trp)
ClinVarID: 295
gnomAD: MAF of 0.0001667 (10/59984) in Admixed American population https://gnomad.broadinstitute.org/variant/12-6036488-G-A?dataset=gnomad_r4
Case: Case Report, female, 63yo
DiseaseAssertion: VWD2B
FamilyInfo: sister exhibited thrombocytopenia and mother had suffered from acute subdural hematoma in the context of chronic thrombocytopenia
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0002138, HP:0011854, HP:0001873, HP:0032044, HP:0030132
(Subarachnoid hemorrhage, Hemoperitoneum, thrombocytopenia, Decreased vigilance, Absence of large von Willebrand factor multimers)
CaseHPOFreeText: thrombocytopenia with pregnancy, platelet count fluctuated between 3 and 200 G/l, subarachnoid hemorrhage associated with a subdural hematoma after falling, hemostasis results were normal, meningeal hemorrhage, cephalalgia; FVIII:C: 1.63 IU/ml; VWF:RCo: 0.7 IU/ml; VWF:Ag: 1.8 IU/ml, ratio VWF:Rco/VWF/Ag: 0.39; Ristocetin-induced platelet agglutination could not be performed due to the severe thrombocytopenia
CaseNOTHPOs: NA
CaseNOTHPOFreeText: NA
CasePreviousTesting: tests for autoimmune disease negative
GenotypingMethod: NGS of exon 28 of VWF gene; variant confirmed via Sanger sequencing
PreviouslyPublished: NA
Gene: VWF
Variant: c.3946G>A (p.Val1316Met)
HGVS: NM_000552.4(VWF):c.3946G>A (p.Val1316Met)
ClinVarID: 290; https://www.ncbi.nlm.nih.gov/clinvar/variation/290/
CAID:
gnomAD: absent
16*3115−−24Fc.3379+1G>A/c.3379+1G>ASplice/Splice25/2518/18PD/PD
Case: Patient 16, F, Hungarian
DiseaseAssertion: VWD type 3
FamilyInfo: compatible with recessive inheritance
ParentalGenotype(s): n/a
CasePresentingHPOs: n/a
CaseHPOFreeRext: Bleeding score: 24, VWF:Ag (IU dL−1): 1, VWF:CB (IU dL−1): 1, VWF:RCo below detection limit (<10 IU dL−1), FVIII:C (IU dL−1): 5, 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
5
Case#: 5, male, 65yo
DiseaseAssertion: VWD1
FamilyInfo: grandson diagnosed with VWD
ParentalGenotype: N/A
CasePresentingHPOs: HP:0000978, HP:0004846, HP:0012147, HP:0030129, HP:0030130 (Bruising susceptibility, Reduced quantity of VWF, Impaired ristocetin cofactor assay activity, Impaired von Willebrand factor collagen binding activity)
CaseHPOFreeText: Bleeding after oral surgery, ESRD awaiting renal transplantation, Type A blood, VWF:Ag (0·55–2 iu/ml) pre = 0·41, VWF:RCo (0·55–2 iu/ml) pre = 0·29, FVIII:C (0·55–2 iu/ml) pre = 0·31, FVIII:C/VWF:Ag ratio = 0·75, VWF:FVIII binding (>20%) = 12%, VWF:FVIII binding/VWF:Ag (>0·7) = 0·29, Uncomplicated kidney transplant with VWF concentrate replacement
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
P3
Case: P3, M/36
DiseaseAssertion: VWD2A
FamilyInfo: Positive family history, no details provided.
ParentalGenotype: NA
CaseHPOFreeText: The bleeding score was 4, aPTT was 43 seconds, FVIII:C was 22%, VWF:RCo was not determined, and VWF:Ag was 14 IU/dL. The VWF:RCo/VWF:Ag ratio was not available. RIPA showed a loss of intermediate and high molecular weight multimers, VWF multimer analysis was 2, and platelet count was 265 × 10⁹/L.
CasePreviousTesting: NA
GenotypingMethod: Direct sequencing of all exons, flanking intronic sequences, and the promoter of VWF was performed.
Gene: VWF
Variant: c.3538+1G>A — heterozygous
HGVS: NM_000552.5(VWF):c.3538+1G>A
ClinVar: 100267
CAID: CA228420
gnomAD: absent from gnomad v4.1.0
9.6y
Case: Patient 2, female, 9.6yo
DiseaseAssertion: VWD2A
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0012147, HP:0030129, HP:0030130, HP:0030132
(Reduced quantity of VWF, impaired ristocetin cofactor assay activity, Impaired von Willebrand factor collagen binding activity, Absence of large von Willebrand factor multimers)
CaseHPOFreeText: VWF:Ag = 27%, undetectable VWF:RCo and VWF:CB; Platelets (*109/L) = 274, Mean Platelet Volume (fL) = 10, FVIII:C (\%) = 34, VWF:CB (\%) <5, VWF:RCo (\%) = <5, aPTT (sec) = 51.6, PT (\%) =724
CaseNOTHPOs: HP:0001873
(Thrombocytopenia)
CaseNOTHPOFreeText:
CasePreviousTesting: NA
GenotypingMethod: sequencing of exon 28 of the VWF
PreviouslyPublished: NA
Gene: VWF
Variant: c.4373G>A (p.Cys1458Tyr)
HGVS: NM_000552.4(VWF):c.4373G>A (p.Cys1458Tyr)
ClinVarID: 100351; https://www.ncbi.nlm.nih.gov/clinvar/variation/100351/
CAID: NA
gnomAD: absent
Case#: Elayaperumal_2018_V-282, F, 2 y.o. (onset), origin in India
DiseaseAssertion: VWD type 3
FamilyInfo: reportedly not-consanguineous. No family history of bleeding.
ParentalGenotype: not reported
CasePresentingHPOs:
CaseHPOFreeText: bleeding score of 17, VWF:Ag of 0, FVIII:C 4.3%
CaseNotHPOs:
CaseNotHPOFreeText:
CasePreviousTesting: not reported
GenotypingMethod: CSGE and Sanger sequencing of VWF gene only.
Gene: VWF
Variant: heterozygous c.2683C>T (Gln895), c.3835G>A (p.Val1279Ile), c.3931C>T (p.Gln1311)
HGVS: NM_000552.3:c.2683C>T, NM_000552.3:c.3835G>A, NM_000552.3:c.3931C>T
ClinVarID: -,100288,100307
CAID: -, CA228459, CA228496
gnomAD: 1: not found 2: MAF of 0.002604 (27/10370 allele, Ashkenazi Jewish) https://gnomad.broadinstitute.org/variant/12-6128749-C-T?dataset=gnomad_r2_1 3:
MultipleGeneVariants:
31
Case#: Melo-Nava_2007,31, F, 7 y.o. (report), Mestizo Mexican and French ancestry reported
DiseaseAssertion: VWD type 3
FamilyInfo: No consanguinity
ParentalGenotype: NR
CasePresentingHPOs:
CaseHPOFreeText: low 42% VWF:Ag, low FVIII:C 40%, low RIPA 24%, moderate bleeding severity
CaseNotHPOs: abnormal platelet count
CaseNotHPOFreeText:
CasePreviousTesting: not reported
GenotypingMethod: PCR
Gene: VWF
Variant:
HGVS: NM_000552.5(VWF):c.4883T>C (p.Ile1628Thr)
ClinVarID: 284
CAID:
gnomAD: Not found
MultipleGeneVariants:
F2Proband P2K157E C1165RCompound heterozygous1.951.040.893.02.13.06
Case: Proband 2 (P2)
DiseaseAssertion: VWD III
FamilyInfo:
Father
Lys157Glu impaired multimerization of von Willebrand factor; reduced oxidoreductase activity
VWF are retained in the ER and fail to be transported to the Golgi
APTT ratio (seconds): 0.94
PT ratio (seconds): 1.02
TT ratio (seconds): 0.98
VWF: Ag (IU/dL): 87.2
VWF:RCo (IU/dL): 80.3
FVIII:C (IU/dL): 97.8
BS: 1
Mother
Cys379Gly impaired multimerization of von Willebrand factor; reduced oxidoreductase activity
VWF are retained in the ER and fail to be transported to the Golgi
APTT ratio (seconds): 1.05
PT ratio (seconds): 1.17
TT ratio (seconds): 1.07
VWF: Ag (IU/dL): 8.0
VWF:RCo (IU/dL): 5.9
FVIII:C (IU/dL): 13.1
BS: 9
ParentalGenotype: n/a
Father: Lys157Glu, Heterozygous
Mother: Cys379Gly, Heterozygous
CasePresentingHPOs: n/a
CaseHPOFreeText:
Lys157Glu impaired multimerization; reduced oxidoreductase activity; undetectable von Willebrand factor (VWF) multimer
VWF are retained in the ER and fail to be transported to the Golgi
APTT ratio (seconds): 1.95
PT ratio (seconds): 1.04
TT ratio (seconds): 0.89
VWF: Ag (IU/dL): 3.0
VWF:RCo (IU/dL): 2.1
FVIII:C (IU/dL): 3.0
BS: 6
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
CasePreviousTesting: n/a
Gene: VWF
Variant:
Lys157Glu
Cys1165Arg
Compound heterozygous
GT 08
Case17: GT08, Male, India, age of onset is 8 years old
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
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.428T>G (p.Leu143Trp)
LegacyVariant: N/A
ClinVar: 13567
CAiD: CA123252
gnomAD: MAF in the Other population is 0.0001629 https://gnomad.broadinstitute.org/variant/17-45361875-T-G
GT 50
Case32: GT50, Male, India, age of onset is 2 years old
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
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.428T>G (p.Leu143Trp)
LegacyVariant: N/A
ClinVar: 13567
CAiD: CA123252
gnomAD: MAF in the Other population is 0.0001629 https://gnomad.broadinstitute.org/variant/17-45361875-T-G)
GT17
Case21: GT17, Female, India, age of onset is 21 years old
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
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.652C>T , (p.His218Tyr)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA400023445
gnomAD: N/A
1
Case1: No assertion made on age, gender, or ethnicity
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Table 1 states family history is available.
ParentalGenotype: The identified variants were heterozygote in parents and were not present as homozygote in their healthy members of the family as expected in cases where mutations are deleterious.
CasePresentingHPOs: N/A
CaseHPOFreeText: Bleeding time is 20 minutes and hematocrit is 35.5%
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: ITGB3
Variant: NM_000212.2:c.2T>C (p.Met1Thr)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA400028186 (c.2T>C)
gnomAD: N/A
6
Case6: No assertion made on age, gender or ethnicity
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: The identified variants were heterozygote in parents.
CasePresentingHPOs: HP:0005542, HP:0000132, HP:0000421, HP:0000979
(Prolonged clotting, menorrhagia, epistaxis, purpura)
CaseHPOFreeText: Bleeding time of 17 minutes, upper GI bleeding
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: ITGB3
Variant: NM_000212.2:c.1990G>T (p.1990G>T)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA400033003
gnomAD: N/A
Two male patients
Case2: Male, age not specified, ethnicity not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: See Fig 3
ParentalGenotype: Both mutations were found to be heterozygous in all family members that includes parents
CasePresentingHPOs:
(Gum bleeding, ecchymosis, epistaxis)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometry showed that the surface expression of GPIIb/IIIa in patients was 0% and both parents also showed reduced expression as well.
PlateletAggregation: Platelet aggregation in response to all the agonists except risocetin was completely absent in the patient
CasePreviousTesting: Mutation screening by conformational sensitive gel electrophoresis was performed in all the 30 exons of ITGA2B and 15 exons of ITGB3 gene in this patient
Gene: ITGA2B
Variant: NM_000419.3:c.1028T>C (p.Leu343Pro) and a promoter variant g.951G>A
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA399804619
gnomAD: N/A
SK
PreviouslyPublished: PMID: 1317725
This proband has been previously published in the PMID listed above --> see that paper to get patient information. This patient can also be found in the GT database: https://glanzmann.mcw.edu/
FLD
Case5: Patient FLD (found in the GT database) gender and age are not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: HP:0000421, HP:0031364, HP:0006298
(Epistaxis, Ecchymosis, Prolonged bleeding after tooth extraction)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: 2-5% GPIIIa and GPIIb surface expression
PlateletAggregation: N/A
CasePreviousTesting: N/A
Gene: ITGA2B
Variant: NM_000419.3:c.818G>A (p.Gly273Asp)
LegacyVariant: (p.Gly242Asp)
ClinVar: 2894
CAiD: CA115837
gnomAD: N/A
PreviouslyPublished: 8282784
N
Case26: Patient NR
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: HP:0000421, HP:0000225, HP:0000978
(Epistaxis, gingival bleeding, bruising)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: N/A
PlateletAggregation: N/A
CasePreviousTesting: N/A
Gene: ITGB3
Variant: NM_000212.2:c.433G>T (p.Asp145Tyr)
LegacyVariant: N/A
ClinVar: 13554
CAiD: CA123226
gnomAD: N/A
PreviouslyPublished: Ref 43
6BLIIHomozygote563C
Case27: Patient BL
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: HP:0000978, HP:0000421, HP:0000225
(Bruising, epistaxis, gingival bleeding)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: 30% GPIIIa and GPIIb surface expression
PlateletAggregation: N/A
CasePreviousTesting: N/A
Gene: ITGB3
Variant: NM_000212.2:c.563C>T (p.Ser188Leu)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA8622981
gnomAD: MAF in the European non Finnish population is 0.000008793 https://gnomad.broadinstitute.org/variant/17-45362010-C-T
PreviouslyPublished: Reference 44
Chinese 20
Case35: Patient Chinese 20 (found in GT database)
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: HP:0000421, HP:0000132, HP:0000979, HP:0000967
(Epistaxis, menorrhagia, purpura/petechiae)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: <15% GPIIIa and GPIIb surface expression
PlateletAggregation: N/A
CasePreviousTesting: N/A
Gene: ITGB3
Variant: NM_000212.2:c.1199G>A (Cys400Tyr)
LegacyVariant: N/A
ClinVar: 13562
CAiD: CA123244
gnomAD: N/A
PreviouslyPublished: References 57 and 58
Patient P
Case40: Patient P
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: 44% GPIIIa and GPIIb surface expression
PlateletAggregation: N/A
CasePreviousTesting: N/A
Gene: ITGB3
Variant: NC_000017.11:g.47310169T>C
LegacyVariant: N/A
ClinVar: 13556
CAiD: CA123230
gnomAD: N/A
PreviouslyPublished: References 63-65
Supplementary Tables 1 and 2 combined information:
Case15b: Male, 9 years old, brother to GT15a
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Available per Table 1, brother to GT15a
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 10-20% of αIIbβ3 expression measured by flow cytometry
PlateletAggregation: Platelet aggregation showed a small 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: ITGB3
Variant: NM_000212.2:c.1525del (p.Gln509Argfs*160) and NM_000212.2:c.1199G>A (p.Cys400Tyr)
LegacyVariant: N/A
ClinVar: 13562 (p.Cys400Tyr)
CAiD: CA915940237 (p.Gln509Argfs*160) and CA123244 (p.Cys400Tyr)
gnomAD: N/A
Supplementary Tables 1 and 2 combined information:
Case24: GT24, Female, 7 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 10-20% 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: ITGA2B
Variant: NM_000419.3:c.2333A>C (p.Gln778Pro) and NM_000419.3:c.1750C>T (p.Arg584Ter) This article is still being done-Meera)
LegacyVariant: N/A
ClinVar: 225393 (p.Gln778Pro) and 2892 (p.Arg584Ter)
CAiD: CA290947544 (p.Gln778Pro) and CA115834 (p.Arg584Ter)
gnomAD: MAF in East Asian population: 0.0002176 (p.Arg584Ter) https://gnomad.broadinstitute.org/variant/17-42457372-G-A and MAF in East Asian population for p.Gln778Pro 0.0001087 https://gnomad.broadinstitute.org/variant/17-42453691-T-G
Supplemental Table S1:
Case1: Male, China, age not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: HP:0004406, HP:0000225, HP:0000979
(Recurrent epistaxis, gingival bleeding, and purpura)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: 14% 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.1429G>C (p.Ala477Pro)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA399803370
gnomAD: N/A
PreviouslyPublished: PMID: 15946231
Supplemental Table S1:
Case25: Female, Italy, age not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Severe bleeding
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.2051T>G (p.Leu684Arg)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA399799849
gnomAD: N/A
PreviouslyPublished: PMID: 21113249
GT-11
Case11: GT-11, gender, age, ethnicity not specified
DiseaseAssertion: Glanzmann thromasthenia
FamilyInfo: N/A
ParentalGenotype: Segregation analysis confirmed the presence of heterozygous mutations in carrier parents
CasePresentingHPOs: N/A
CaseHPOFreeText: Article mentions patients presented with variable bleeding diathesis and Table 1 shows the several phenotypes that were seen among the cohort of 13 patients in this study (this article does not state a specific bleeding phenotype for each proband) "Most of the patients had gross blood loss due to epistaxis (54%), cutaneous bleeding (58%) and menorrhagia (100% of women), while other common symptoms (oral cavity, gastrointestinal, following dental extraction or mild injuries, postpartum, or hematomas) were in general milder."
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometry showed this proband classified as variant GT (50% expression but receptor being not functional according to LTA and clot retraction)
PlateletAggregation: Article mentions the disorder was indentified by platelet testing consisting in severely impaired aggregation in response to all physiological agonists and also TMA (See Table 4). Ristocetin-induced platelet aggregation was normal or reduced to some extent.
CasePreviousTesting: To detect mutations in ITGA2B or ITGB3, total RNA from peripheral blood was used for cDNA synthesis for RT-PCR. Using specific oligonucleotides and conditions, they amplified and sequenced ITGA2B and ITGB3 by Sanger sequencing, and every mutation found in cDNA was confirmed on DNA samples
Gene: ITGB3
Variant: NM_000212.2:c.647A>G (p.Tyr216Cys) and NM_000212.2:c.665T> (Leu222Pro))
LegacyVariant: (p.Tyr190Cys) and (p.Leu196Pro)
ClinVar: N/A
CAiD: CA400023432 and CA291224887
gnomAD: N/A
PreviouslyPublished: 11897046 (p.Leu196Pro)
GT-7
Case7: GT-7, gender, age, ethnicity not specified
DiseaseAssertion: Glanzmann thrombasthenia type II
FamilyInfo: N/A
ParentalGenotype: Segregation analysis confirmed the presence of heterozygous mutations in carrier parents
CasePresentingHPOs: N/A
CaseHPOFreeText: Article mentions patients presented with variable bleeding diathesis and Table 1 shows the several phenotypes that were seen among the cohort of 13 patients in this study (this article does not state a specific bleeding phenotype for each proband) "Most of the patients had gross blood loss due to epistaxis (54%), cutaneous bleeding (58%) and menorrhagia (100% of women), while other common symptoms (oral cavity, gastrointestinal, following dental extraction or mild injuries, postpartum, or hematomas) were in general milder."
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometry showed αIIbβ3 expression to be between 5% and 20%
PlateletAggregation: Article mentions the disorder was indentified by platelet testing consisting in severely impaired aggregation in response to all physiological agonists and also TMA (See Table 4). Ristocetin-induced platelet aggregation was normal or reduced to some extent.
CasePreviousTesting: To detect mutations in ITGA2B or ITGB3, total RNA from peripheral blood was used for cDNA synthesis for RT-PCR. Using specific oligonucleotides and conditions, they amplified and sequenced ITGA2B and ITGB3 by Sanger sequencing, and every mutation found in cDNA was confirmed on DNA samples
Gene: ITGB3
Variant: NM_000212.2:c.431T>G (p.Met144Arg)
LegacyVariant: (p.Met118Arg)
ClinVar: N/A
CAiD: CA291224645
gnomAD: N/A
GT-6
Case6: GT-6, gender, age, ethnicity not specified
DiseaseAssertion: Glanzmann thrombasthenia type II
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Article mentions patients presented with variable bleeding diathesis and Table 1 shows the several phenotypes that were seen among the cohort of 13 patients in this study (this article does not state a specific bleeding phenotype for each proband) "Most of the patients had gross blood loss due to epistaxis (54%), cutaneous bleeding (58%) and menorrhagia (100% of women), while other common symptoms (oral cavity, gastrointestinal, following dental extraction or mild injuries, postpartum, or hematomas) were in general milder."
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometry showed αIIbβ3 expression to be <5%
PlateletAggregation: Article mentions the disorder was indentified by platelet testing consisting in severely impaired aggregation in response to all physiological agonists and also TMA (See Table 4). Ristocetin-induced platelet aggregation was normal or reduced to some extent.
CasePreviousTesting: To detect mutations in ITGA2B or ITGB3, total RNA from peripheral blood was used for cDNA synthesis for RT-PCR. Using specific oligonucleotides and conditions, they amplified and sequenced ITGA2B and ITGB3 by Sanger sequencing, and every mutation found in cDNA was confirmed on DNA samples
Gene: ITGA2B
Variant: NM_000419.3:c.2944G>A (p.Val982Met) and NM_000419.3:c.2965G>A (p.Ala989Thr) and NM_000419.3:c.1612G>T (p.Glu538Ter)
LegacyVariant: (p.Val951Met) and (p.Ala958Thr) and (p.Glu507Ter)
ClinVar: 381747 and 417951
CAiD: CA16608466 (p.Val951Met) and CA8602498 (p.Ala958Thr) and CA399802424 (p.Glu538Ter)
gnomAD: MAF in European (non-Finnish population) 0.00006486 http://gnomad.broadinstitute.org/variant/17-42451838-C-T and MAF in other population is 0.001939 http://gnomad.broadinstitute.org/variant/17-42451817-C-T
PreviouslyPublished: PMID: 15099289(p.Val951Met) and (p.Ala958Thr)
Supplementary Table S1 & S2 Proband and Variant Information:
Case18: GT21, Female, 61, French
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: HP:0000421, HP:0002239
(Epistaxis, GI 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: ITGA2B
Variant: NM_000419.3:c.1440-13_1440-1del (p.Arg480Serfs*106) and NM_000419.3:c.2864T>A (p.Leu955Gln)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA913184940 and CA399791171
gnomAD: N/A
Supplementary Table S1 & S2 Proband and Variant Information:
Case43: GT43a, Female, 7 years old, Moroccan (this proband died from epistaxis-see Supp Table S1)
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Affected brother is 43b (See Supplementary Table S1)
ParentalGenotype: N/A
CasePresentingHPOs: HP:0000421
(Severe epistaxis)
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.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 http://gnomad.broadinstitute.org/variant/17-45363694-G-A
Supplementary Table S1 & S2 Proband and Variant Information:
Case39: GT40, Female, 17 years old, Pankistani
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: HP:0000421, HP:0030140
(Epistaxis, bleeding from mouth)
CaseHPOFreeText: Heavy bleeding at menarche
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: ITGA2B
Variant: NM_000419.3:c.857T>A (p.Val286Asp)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA399805011
gnomAD: N/A
Supplementary Table S1 & S2 Proband and Variant Information:
Case4: GT5, Male, 7, French
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: 1 brother, that is all Supp table S1 states
ParentalGenotype: N/A
CasePresentingHPOs: HP:0000421, HP:0000978, HP:0002138
(Epistaxis, easy bruising, subararachnoid hemorrhoid)
CaseHPOFreeText: Post-traumatic bleeding
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: N/A
PlateletAggregation: Absent platelet aggregation (See Supplementary Table 1)
CasePreviousTesting: Sanger sequencing of ITGA2B and ITGB3
Gene: ITGB3
Variant: NM_000212.2:c.565C>T (p.Pro189Ser) and NM_000212.2:c.2113del (p.Leu705Cysfs*4)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA291224669 and CA8623443
gnomAD: MAF in the European (non-Finnish) population is 0.00002638 http://gnomad.broadinstitute.org/variant/17-45362012-C-T and MAF in the East Asian population is 0.0001087 http://gnomad.broadinstitute.org/variant/17-45380183-TC-T
Supplementary Table S1 & S2 Proband and Variant Information:
Case2: GT3, Female, 32, French
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: HP:0000421, HP:0031364, HP:0000979, HP:0002239
(Epistaxis, ecchymosis, purpura, GI bleeding,)
CaseHPOFreeText: Excessive menstrual bleeding, proband sometimes hospitalized with severe symptoms
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.353T>A, NM_000212.2:c.709_710del, NM_000212.2:c.1732G>A
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA291224511, CA8623029 and CA8623343
gnomAD: MAF in the European non Finnish populationis 0.00001796 http://gnomad.broadinstitute.org/variant/17-45363717-CAG-C and MAF in the Other popualation is 0.0008149 http://gnomad.broadinstitute.org/variant/17-45376715-G-A
Supplementary Table S1 & S2 Proband and Variant Information:
Case57: GT58, Male, 14, Argentinian/European
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: HP:0000421, HP:0000967, HP:0000225, HP:0011886
(Epistaxis, petechia, gingival bleeding, hyphema)
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: ITGA2B
Variant: NM_000419.3:c.601G>A (p.Gly201Ser)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA399805612
gnomAD: N/A
Supplementary Table S1 & S2 Proband and Variant Information:
Case49: GT49, Female, 16 years old, French/Spanish
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: HP:0031364, HP:0000421
(Ecchymosis, epistaxis)
CaseHPOFreeText: Post-traumatic hematomas, proband has severe epistaxis
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometry showed 5-10% 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.1440-13_1440-1del (p.Arg480Serfs*106) and NM_000419.3:c.2113T>C (p.Clys705Arg)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA913184940 and CA8602816
gnomAD: MAF in the European (non-Finnish) population is 0.000008792 http://gnomad.broadinstitute.org/variant/17-42455140-A-G
The Glanzmann thrombasthenia patient
Case1: Female, age or ethnicity not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: HP:0000979 (Purpura)
CaseHPOFreeText: Frequent hematomas
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: N/A
PlateletAggregation: Platlets failed to aggregate or support clot retraction
CasePreviousTesting: N/A
Gene: ITGB3
Variant: NM_000212.2:c.940G>T (p.Asp314Tyr)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA400025612
gnomAD: N/A
PreviouslyPublished: 22837472 (Proband GT-2 in this article harbors same variant)
The proband is a 6-month-old Caucasian female
Case1: Female, 6 months old, Caucasian
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo:
ParentalGenotype: Mother: Met124Val and Father: Asp119Tyr
CasePresentingHPOs: HP:0003010
(Prolonged bleeding time)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Diminished platelet content of αIIbβ3 in the proband (See Figure 1A)
PlateletAggregation: The platelets from the patient did not show aggregation upon stimulation with collagen, ADP, adrenaline, or arachidonic acid, but a response to ristocetin was observed
CasePreviousTesting: The entire coding sequences of ITGA2B and ITGB3 were determined by PCR amplification of overlapping fragments from total RNA
Gene: ITGB3
Variant: NM_000212.2:c.433G>T (p.Asp119Tyr) and NM_000212.2:c.448A>G (p.Met124Val)
LegacyVariant: N/A
ClinVar: 13554
CAiD: CA123226 and CA8622961
gnomAD: MAF in the South Asian population is 0.00003266 http://gnomad.broadinstitute.org/variant/17-45361895-A-G
Proband 2 was a 6-year-old girl diagnosed with recurrent hematemesis (upper gastrointestinal bleeding added up to five times) at age 2.
Case2: 6 year old, Female, Chinese
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Case1 is sister of this proband. Additional family information found in table 1.
ParentalGenotype: Father: Heterozygous for the p.Cys549Ser variant and did not find the p.Gln254Lys variant. Mother: Did not find the p.Cys549Ser variant but she is heterozygous for the p.Gln254Lys variant.
CasePresentingHPOs: HP:0002248
CaseHPOFreeText: Upper gastrointestinal bleeding added up to five times at age 2.
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: The expression of CD41 and CD61 was detected by platelet immunofluorescence test-flow cytometry. The expression of CD41 and CD61 of Case1 was remarkably lower than other family members (261.90 and 355.45 respectively).
CasePreviousTesting: DNA was isolated and ITGB3 and ITGA2B gene sequences were amplified by PCR with a high fidelity Taq Polymerase.
Gene: ITGB3
Variant: NM_000212.2:c.1646G>C (p.Cys549Ser), and NM_000212.2:c.760C>A (p.Gln254Lys)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA400030198 (p.Cys549Ser) and CA400023674 (p. Gln254Lys)
gnomAD: MAF: 0.00005453 (p.Cys549Ser) https://gnomad.broadinstitute.org/variant/17-45369890-G-C and MAF not available for (p.Gln254Lys)
Proband1 was a 5-year-old girl diagnosed with recurrent epistaxis and hematuria.
Case1: 5 year old, Female, Chinese
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Case2 is the sister of this proband, additional family information found in Table 1
ParentalGenotype: Father: Did not find the p.Cys549Ser variant and is heterozygous for p.Leu705CysfsTer4 variant. Mother: Heterozygous for the p.Cys549Ser variant and did not find the p.Leu705CysfsTer4 variant.
CasePresentingHPOs: HP:0004406, HP:0000790
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: The expression of CD41 and CD61 was detected by platelet immunofluorescence test-flow cytometry. The expression of CD41 and CD61 of Case1 was remarkably lower than other family members (261.90 and 355.45 respectively).
CasePreviousTesting: DNA was isolated according to the manufacturer's instruction-- ITGA2B and ITGB3 gene sequences were amplified by PCR with a high fidelity TAQ Polymerase.
Gene: ITGB3
Variant: NM_000212.2:c.1646G>C (p.Cys549Ser), and NM_000212.2:c.2113del (p.Leu705CysfsTer4)
LegacyVariant: N/A
ClinVar: Not available for either of the two variants.
CAiD: CA400030198 (p.Cys549Ser), CA8623443 (p.Leu705CysfsTer4)
gnomAD: MAF: 0.00005453 (p.Cys549Ser) https://gnomad.broadinstitute.org/variant/17-45369890-G-C and MAF: 0.0001087 (p.Leu705CysfsTer4) https://gnomad.broadinstitute.org/variant/17-45380183-TC-T
GT19
Case36: (GT19) Gender, age and ethnicity are not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: One brother is homozygous for the mutation and the other brother is heterozygous for the mutation
ParentalGenotype: Mother and father are heterozygous for the mutation
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: There seems to be a typo in this variant, asked Shruthi NM_000419.3:c.937G>A
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA290954329
gnomAD MAF in the European (non-Finnish) population is 0.000008888 https://gnomad.broadinstitute.org/variant/17-42461461-C-T
GT3
Case18: (GT3) Gender, age and ethnicity are not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Has one brother and sister without the mutation and has one brother that is heterozygous for the variant
ParentalGenotype: Mother and father are both heterozygous for the mutation
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: ITGB3
Variant: NM_000212.2:c.2315T>C (p.Leu772Pro)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA400034691
gnomAD MAF in the African population is 0.00006152 https://gnomad.broadinstitute.org/variant/17-45387518-T-C
GT2
Case14: (GT2), Gender, age and ethnicity not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: His sister is heterozygous for this mutation
ParentalGenotype: Father and mother are both heterozygous for this mutation
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: ITGB3
Variant: NM_000212.2:c.725G>A (p.Arg242Gln) There is a typo in the paper-- it says that the c. is c.752G>A however it is 725
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA291224896
gnomAD N/A
Patient Chinese‐57
Case1: (Patient Chinese-57) Male, 5 years old, Chinese
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: HP:0004406, HP:0000225, HP:0000979
(Recurrent epistaxis, gingival bleeding, purpura)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
ProteinExpression: "Markedly decreased αIIbβ3 expression"
Platelet Aggregation: Absent platelet aggregation in response to ADP, epinephrine, collagen and normal response to ristocetin
CasePreviousTesting: They performed PCR SSCP analysis of the coding sequences and splice sites of ITGA2B and ITBG3
Gene: ITGA2B
Variant: NM_000419.3:c.1429G>C (p.Ala477Pro)
LegacyVariant: (p.Ala446Pro)
ClinVar: N/A
CAiD: CA399803370
gnomAD N/A
The patient (R.M.)
Case1: (Patient RM), Male, 73 years old, from Southwest of France
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Other family members were his mother (M.M), his son (J.M.M), and his sister (A.M)
ParentalGenotype: Mother is heterozygous for the mutation
CasePresentingHPOs: HP:0000421 (Epistaxis)
CaseHPOFreeText: Life-long history of mucocutaneous bleeding
CaseNotHPOs: N/A
ProteinExpression: Flow cytometric analysis shows a reduced aIIbb3 expression in the platelets of the proband and other family members (See Fig. 6)
Platelet Aggregation: Absent platelet aggregation in response to ADP, collagen, arachidonic acid and thrombin receptor activated peptide. Ristocetin induced platelet agglutination was normal
CasePreviousTesting: Screening of the aIIb and b3 genes by PCR-SSCP revealed aheterozygous mutation at position 685 in exon 5 of the b3 gene leading to a 1 96Leu to Pro substitution.
Gene: ITGB3
Variant: NM_000212.2:c.665T>C (p.Leu6656Pro)
LegacyVariant: (p.Leu196Pro)
ClinVar: N/A
CAiD: CA291224887
gnomAD MAF in the European (non-Finnish) population is 0.00006482 https://gnomad.broadinstitute.org/variant/17-45363676-T-C
propositusisanAshkenaziJewishfemale
Case: Female, Ashkenazi Jewish, 2 days old at presentation
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: consanguineous marriage, pedigree in Figure 4
ParentalGenotype: Mother carrier of Gly273Asp. Father carrier of Gly273Asp.
CasePresentingHPOs: HP:0100309, HP:0000978, HP:0003010, HP:0004866, HP:0008320, HP:0008148, HP:0000421, HP:0001975
(subdural bleeding, extensive ecchymoses, prolonged cutaneous bleeding time, absent platelet aggregation in response to ADP, absent platelet aggregation in response to collagen, absent platelet aggregation in response to epinephrine, occasional epistaxis, markedly decreased number of GPIIb-IIIa heterodimers)
CaseHPOFreeText: NA
CaseNotHPOs: HP:0011873, HP:0011871
(normal platelet count, normal platelet agglutination in response to ristocetin)
CaseNotHPOFreeText: NA
ProteinExpression: <5% of the normal amount of GPIIb-GPIIIa; measured by flow cytometry
CasePreviousTesting: PCR amplification of genomic DNA and DNA sequence analysis of the GPIIb coding sequence only.
Gene: ITGA2B
Variant: NM_000419.3:c.818G>A p.(Gly273Asp)
LegacyVariant: NA
ClinVar: 2894
CAID: CA115837
gnomAD: NA
Supplementary Table S1:
Case54: GT64, French, age and gender are 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: ITGA2B
Variant: NM_000419.3:c.257T>C (p.Leu86Pro) and NM_000419.3:c.1440-13_1440-1del (p.Arg480SerfsTer106)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA290956162 and CA913184940
gnomAD: N/A
Supplementary Table S1:
Case50: GT58, Argentinian/European, gender and age are 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: ITGA2B
Variant: NM_000419.3:c.601G>A (p.Gly201Ser)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA399805612
gnomAD: N/A
Supplementary Table S1:
Case61: GT72, French, age and ethnicity are 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: ITGA2B
Variant: NM_000419.3:c.2951C>A (p.Thr984Lys)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA399790180
gnomAD: N/A
Supplementary Table S1:
Case4: GT5, French, age and ethnicity 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) and NM_000212.2:c.2113del (p.Leu705Cysfs*4)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA291224669 and CA8623443
gnomAD: MAF in the European (non-Finnish) population is 0.00002638 https://gnomad.broadinstitute.org/variant/17-45362012-C-T and MAF in the East Asian population is 0.0001087 https://gnomad.broadinstitute.org/variant/17-45380183-TC-T
Supplementary Table S1:
Case20: GT23, French, gender and age are 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.1031A>C (p.Tyr344Ser)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA400025814
gnomAD: N/A
Supplementary Table S1:
Case45: GT52, Argentina/Brazil, 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: ITGA2B
Variant: NM_000419.3:c.601G>A (p.Gly201Ser)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA399805612
gnomAD: N/A
7.
Case7: Female, elderly (age not specified)
DiseaseAssertion: Glanzmann thrombasthenia type 1
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Severe bleeding when younger
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: N/A
PlateletAggregation: Minimal information, not specific enough
CasePreviousTesting: Sanger sequencing identified disease-causing variants in 18 out of 20 patients (Probands 6 and 14 excluded) with istoantibodies to αIIbβ3. The mutations were evenly distributed between ITGB3 and ITGA2B.
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
18
Case18: (Proband CabGT-18), Gender, age and ethnicity were not specified
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.2944G>A (p.Val982Met) and NM_000419.3:c.2965G>A (p.Ala989Thr)
LegacyVariant: N/A
ClinVar: 381747 (p.Val982Met) and 417951 (p.Ala989Thr)
CAiD: CA16608466 (p.Val982Met) and CA8602498 (p.Ala989Thr)
gnomAD MAF in the European (non-Finnish) population is 0.00006486 https://gnomad.broadinstitute.org/variant/17-42451838-C-T and MAF in the Other popeulation for (p.Ala989Thr) is 0.001939 https://gnomad.broadinstitute.org/variant/17-42451817-C-T
13CabGT-13
Case13: (Proband CabGT-13) Male, age not specified, Japanese
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
ProteinExpression: Flow cytometry showed <5% of GPIIIa and GPIIb surface expression
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.2333A>C (p.Gln778Pro)
LegacyVariant: N/A
ClinVar: 225393
CAiD: CA290947544
gnomAD MAF in the East Asian population is 0.0001087 https://gnomad.broadinstitute.org/variant/17-42453691-T-G
The patient,
Case1: Male, 52 years old, Japanese
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: HP:0002584
(Intestinal bleeding)
CaseHPOFreeText: Bleeding tendency since childhood
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Fly cytometry analysis demonstrated no detectable amounts of GPIIb-IIIa complexes or GPIIb on the surface of transfected 293-T cells, whereas normal expression was observed with the wild type GPIIb. GPIIIa was detected, although the expression level was low
PlateletAggregation: Platelet aggregation showed no response to ADP or collagen but did show a normal response to ristocetin
CasePreviousTesting: Genomic DNA was extracted from peripheral blood mononuclear cells, and the flanking region of exon 3 of the GPIIb gene was amplified by PCR. Primers were synthesized according to the method described in a previous report [7]. PCR products were then subjected to direct sequencing
Gene: ITGA2B
Variant: NM_000419.3:c.399C>G (p.Asp133Glu)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA399806084
gnomAD: N/A
Therefore, we wondered whether DTT could expose the fibrinogen binding site on platelets isolated from a patient with GTV. The all& on the platelets of this patient have an Arg + Trp mutation at position 214 of P3, and the platelets fail to aggregate or to bind fibrinogen in response to physiologic agonists despite sufficient surface expression of the complex."
Case1: (M.S) Female, 19 years old, Caucasian
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: The mutation has been inherited from proband's parents who are heterozygous for the same mutation the proband has.
CasePresentingHPOs: HP:0000978 (Bruising)
CaseHPOFreeText: Intracerebral hematoma
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: See Fig 4 for flow cytometry analysis of protein expression
PlateletAggregation: Absence of platelet aggregation in response to all agonists tested i.e. ADP, collagen, platelet activating factor acether thrombin, and arachidonic acid; however, ristocetin induced platelet aggregation was normal
CasePreviousTesting: Sequenced patient's GPIIIa exons encompasing a highlight conserved reion of GPIIIa.
Gene: ITGB3
Variant: NM_000212.2:c.718C>T (p.Arg240Trp)
LegacyVariant: (p.Arg214Trp)
ClinVar: 13555
CAiD: CA123228
gnomAD: MAF in the East Asian population is 0.00005437 http://gnomad.broadinstitute.org/variant/17-45363729-C-T
PreviouslyPublished: PMID: 1602006
Case22: Patient DOM, 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
GT-17
Case15: (GT-17) Female, age or ethnicity not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Probands GT15-GT20 are related to GT-17 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
GT-15
Case13: (GT-15) Male, carrier, age or ethnicity not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Probands GT16-GT20 are related to GT-15 see Table 1
ParentalGenotype: Parents may be included in Table 1; however, not specified so no information
CasePresentingHPOs: N/A
CaseHPOFreeText: Bleeding severity: Mild (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
Patient 4
Case4: Male, 4 years old, Korean
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: Figure 1 shows haplotype analysis
CasePresentingHPOs: HP:0000978, HP:0000967
(Easy bruising, petechiae)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometry analyses revealed decreased expression at a level of 7.5%(type II GT)
PlateletAggregation: Platelet aggregation tests were performed to evaluate responses to ADP, collagen, epinephrine, and ristocetin agonists
CasePreviousTesting: Polymerase chain reaction for all exons of ITGA2Band/orITGB3were performed using primers. Sequence analysis was performed with reference to M_000419.3 andNP_000410.2 for ITGA2B and NM_000212.2 and NP_000203.2 for ITGB3.
Gene: ITGA2B
Variant: NM_000419.3:c.2333A>C (p.Gln778Pro) and NM_000419.3:c.1750C>T (p.Arg584Ter)
LegacyVariant: N/A
ClinVar: 225393 and 2892
CAiD: CA290947544 and CA115834
gnomAD: MAF in the East Asian population is 0.0001087 http://gnomad.broadinstitute.org/variant/17-42453691-T-G and MAF in the East Asian population is 0.0002176 http://gnomad.broadinstitute.org/variant/17-42457372-G-A
M/6
Case3: Male, 6 years old, Andra Pradesh India
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: HP:0031364, HP:0000225
(Ecchymosis, gingival bleeding)
CaseHPOFreeText: Bleeding during tooth extraction
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: See Table 1 for values
PlateletAggregation: See Table 1 for values
CasePreviousTesting: PCR amplification of ITAG2B and ITGB3
Gene: ITGA2B
Variant: NM_000419.3:c.952T>A (p.Ser318Leu)
LegacyVariant: (p.Ser287Leu)
ClinVar: N/A
CAiD: CA399804792
gnomAD: N/A
18-year-old woman
Case1: Female, 18 years old, ethnicity not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometry showed mutated CD41 protein and lack of CD61 surface expression
PlateletAggregation: Platlets were stimulated by ADP and thromboxane A2 and stained with PAC-1, which specifically detects only the activated conformation of αIIbβ3. GT platelets from both sources showed diminished PAC-1 binding after both agonist treatments compared to corresponding CTR cells
CasePreviousTesting: PCR primers used for sequencing of exons containing mutations in ITGA2B gene
Gene: ITGA2B
Variant: NM_000419.3:c.1922C>T (p.Pro641Leu) and NM_000419.3:c.2478dup (p.Gly827Trp)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA399801154 and CA915940290
gnomAD: N/A
GT4
Case4: (GT4), Female, 72 years old, French
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Mucocutaneous bleeding
CaseNotHPOs: N/A
ProteinExpression: 10% surface expression levels of αIIbβ3
Platelet Aggregation: Absent platelet aggregation to all agonists (no mention for which agonists or response to ristocetin)
CasePreviousTesting: All the information we are given is "mutation screening of the ITGA2B and ITGB3 genes" the method for sequencing etc. was not stated
Gene: ITGB3
Variant: NM_000212.2:c.724C>T (p.Arg242Ter) and NM_000212.2:c.1871G>A (p.Cys624Tyr)
LegacyVariant: (p.Arg216Ter) and (p.Cys598Tyr) (The paper gives legacy and current nomenclature)
ClinVar: N/A
CAiD: CA400023596 (p.Arg242Ter) and CA400032726 (p.Cys624Tyr)
gnomAD MAF in the European (non-Finnish) population is 0.00006483 https://gnomad.broadinstitute.org/variant/17-45363735-C-T
GT8
Case8: GT-8, Caucasian, gender or age not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: Mother: none and Father: c.118C>T heterozygous
CasePresentingHPOs: N/A
CaseHPOFreeText: Bleeding symptoms are moderate (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: ITGB3
Variant: NM_000212.2:c.118C>T
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA400031679
gnomAD: N/A
patient LM
Case1: Patient LM --very minimal info on this patient
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: αIIbβ3 expression
PlateletAggregation: N/A
CasePreviousTesting: N/A
Gene: ITGA2B
Variant: NM_000419.3:c.1346G>A (p.Gly449Asp)
LegacyVariant: Gly418Asp
ClinVar: N/A
CAiD: CA399803552
gnomAD: N/A
4-year-old Japanese girl
Case1: Female, 4 years old, Japanese
DiseaseAssertion: Thrombocytopenia
FamilyInfo: 4-generation pedigree available
ParentalGenotype: See Figure 1 A for parents in the pedigree
CasePresentingHPOs: HP:0004406, HP:0000979
(Recurrent epistaxis, purpura)
CaseHPOFreeText: Mild bleeding tendency
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometry showed reduced expression levels
PlateletAggregation: Platelet aggregation induced by ADP and collagen was markedly reduced but agglutination induced by ristocetin was within the normal range.
CasePreviousTesting: Direct sequencing analysis around T2231 in exon 14 of the ITGB3 gene. Genomic DNA extracted from the affected and unaffected individuals of the pedigree were amplified by PCR and sequenced (See Figure 2)
Gene: ITGB3
Variant: NM_000212.2:c.2231T>C (p.Leu744Pro)
LegacyVariant: p.Leu718Pro
ClinVar: 50229
CAiD: CA143712
gnomAD: N/A
Across 2,384 individuals with ASD, we identified 1,418 missense variants affecting 1,269 unique genes and annotated the impact of the variants using evolutionary action scores (Table S1)
Case#: ProbandID:14248
DiseaseAssertion: autism spectrum disorder
FamilyInfo: n/a
ParentalGenotype: this variant was asserted to be de novo.
CasePresentingHPO: n/a
PlateletAggregation: n/a
CaseHPOFreeText: n/a
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
ProteinExpression: n/a
CasePreviousTesting: n/a
Gene: ITGA2B
Variant: M1018T
HGVS: NM_000419.3:c.3053T>C
ClinVar: Not reported
CAID: CA399788190
gnomAD: not found in v4.1.0
Glanzmann patient (LM
Case1: (Patient LM) Gender, age, and ethnicity not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A (Immunoblot analysis of parents is the only thing available)
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
ProteinExpression: Immunoblot analysis was performed see Fig 1
PlateletAggregation: N/A
CasePreviousTesting: Sequence analysis of PCR amplified GPIIIb mRNA
Gene: ITGA2B
Variant: NM_000419.3:c.1346G>A (p.Gly449Asp)
LegacyVariant: (p.Gly418Asp)
ClinVar: 691627
CAiD: CA399803552
gnomAD: N/A
patient ET,
Case1: Patient ET, gender, age, and ethnicity is not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
ProteinExpression: "However, ET platelets exhibited a normal surface expression of a-granule thrombospondin" this is all of the information we are given in this article; however Reference 13 might mention more on the protein expression. However, access is not available for article 13 at this time.
PlateletAggregation: ET's platelets fail to aggregate in response to stimuli (the article does not state which agonists/stimuli and does not mention response to ristocetin)
CasePreviousTesting: Two regions of ITGB3 were selected for amplification and sequence analysis. The first region, corresponding to exonIII encodes a fragment from D96 to D179 and the second region corresponding to exon IV, encodes a fragment from M180 to D233.
Gene: ITGB3
Variant: (NM_000212.2:c.719G>A (p.Arg240Gln)
LegacyVariant: (p.Arg214Gln)
ClinVar: 13553
CAiD: CA123224
gnomAD: N/A
PreviouslyPublished: Patient ET may have been previously published in PMID: 2512684; however, access is not available to this article