020–2023
Case#: 020-2023
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.5312T>C
LegacyVariant:
ClinVar: No
CAID: CA414910786
gnomAD:
002–2005
Case#: 002-2005
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.217T>C
LegacyVariant:
ClinVar: No
CAID: CA414920251
gnomAD:
060–2007
Case#: 060-2007
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: 1% < FVIII:C < 5%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.5399G>A
LegacyVariant:
ClinVar: No
CAID: CA255162
gnomAD:
001–1038
Case#: 001-1038
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.6065G>A
LegacyVariant:
ClinVar: No
CAID: CA414904814
gnomAD:
022–2004
Case#: 022-2004
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.1492G>A
LegacyVariant:
ClinVar: No
CAID: CA255109
gnomAD:
001–2039
Case#: 001-2039
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.5156T>C
LegacyVariant:
ClinVar: No
CAID: CA414913690
gnomAD:
071–2029
Case#: 071-2029
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.1697T>A
LegacyVariant:
ClinVar: No
CAID: CA414911721
gnomAD:
002–2017
Case#: 002-2017
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: 5% < FVIII:C < 40%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.941C>T
LegacyVariant:
ClinVar: No
CAID: CA414917829
gnomAD:
071–2010
Case#: 071-2010
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%, Inhibitor present
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.1208A>C
LegacyVariant:
ClinVar: No
CAID: CA414916134
gnomAD:
047–1020
Case#: 047-1020
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: 1% < FVIII:C < 5%, Inhibitor present
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.3169G>A
LegacyVariant:
ClinVar: No
CAID: CA255144
gnomAD:
003–2024
Case#: 003-2024
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: 5% < FVIII:C < 40%, Inhibitor present
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:
060–2010
Case#: 060-2010
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:
020–2024
Case#: 020-2024
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.437A>C
LegacyVariant:
ClinVar: No
CAID: CA414919724
gnomAD:
020–2006
Case#: 020-2006
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: 5% < FVIII:C < 40%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.1492G>A
LegacyVariant:
ClinVar: No
CAID: CA255109
gnomAD:
035–2022
Case#: 035-2022
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.5954G>A
LegacyVariant:
ClinVar: No
CAID: CA414905715
gnomAD:
020–2027
Case#: 020-2027
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.5253A>C
LegacyVariant:
ClinVar: No
CAID: CA414911240
gnomAD:
091–2008
Case#: 091-2008
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.142A>G
LegacyVariant:
ClinVar: No
CAID: CA414920432
gnomAD:
001–2051
Case#: 001-2051
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.2134C>A
LegacyVariant:
ClinVar: No
CAID: CA414904092
gnomAD:
R46S
Case#: N/A
DiseaseAssertion: Severe Hemophilia B
FamilyInfo: None
ParentalTesting: None
CasePresentingHPOs: HP:0001929
CaseHPOsFreeText: reduced factor IX activity
CaseNotHPOs: N/A
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.138G>T (p.Arg46Ser)
ClinVar: Absent
CAID: CA414435596
gnomAD: Absent/Not Reported
K45N
Case#: N/A
DiseaseAssertion: Severe Hemophilia B
FamilyInfo: None
ParentalTesting: None
CasePresentingHPOs: HP:0001929
CaseHPOsFreeText: reduced factor IX activity
CaseNotHPOs: N/A
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.135G>T (p.Lys45Asn)
ClinVar: Absent
CAID: CA414435576
gnomAD: Absent/Not Reported
Case#: Calgary 4
DiseaseAssertion: Hemophilia B
FamilyInfo: 9 carrier females, 3 affected males, 1 female obligate carrier
ParentalTesting: N/A
CasePresentingHPOs: HP:0001929
CaseHPOsFreeText: reduced factor IX activity
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
Gene: F9
Variant: c.19A>T (p.Ile7Phe)
LegacyVariant: c.48A>T (p.Ile-40Phe)
ClinVar: Absent
CAID: CA10529708
gnomAD: Filtering AF: 0.0007752 (no homozygotes)
Variant: NM_000133.3:c.1150C>T (p.Arg384Ter)
LegacyVariant: c.31133C>T (p.Arg338Ter)
ClinVar: Absent
CAID: CA255399
gnomAD: Absent/Not Reported
c1834C>T
Case#: 15
DiseaseAssertion: Hemophilia A
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FVIII:C 17/19/25% (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.1834C>T (p.Arg612Cys)
ClinVar: 10236 https://www.ncbi.nlm.nih.gov/clinvar/variation/10236/
CAID: CA255129
gnomAD: MAF for Arg612Cys in Latino population 0.0001458<br>https://gnomad.broadinstitute.org/variant/X-154182236-G-A?dataset=gnomad_r2_1
c.6533G>A
Case#: 32
DiseaseAssertion: Hemophilia A
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FVIII:C 28%, 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.6533G>A (p.Arg2178His)
ClinVar: 10319 https://www.ncbi.nlm.nih.gov/clinvar/variation/10319/
CAID: CA255212
gnomAD: MAF for Arg2178His in the African population 0.00007598<br>https://gnomad.broadinstitute.org/variant/X-154091399-C-T?dataset=gnomad_r2_1
c.518C>T
Case#: 43
DiseaseAssertion: Hemophilia B
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FIX:C <1% (Severe 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:c.518C>T (p.Ala173Val)
ClinVar: NA
CAID: CA414439510
gnomAD: Not reported
c.6622C>G
Case#: 33
DiseaseAssertion: Hemophilia A
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FVIII:C 21/29/33/15/20/26%, 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.6622C>G (p.Gln2208Glu)
ClinVar: 811219 https://www.ncbi.nlm.nih.gov/clinvar/variation/811219/
CAID: CA414905992
gnomAD: MAF for Gln2208Glu in the Other population 0.0002208<br>https://gnomad.broadinstitute.org/variant/X-154090094-G-C?dataset=gnomad_r2_1
c.1649G>A
Case#: 14
DiseaseAssertion: Hemophilia A
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FVIII:C 27% (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.1649G>A (p.Arg550His)
ClinVar: 10225 https://www.ncbi.nlm.nih.gov/clinvar/variation/10225/
CAID: CA255115
gnomAD: MAF for Arg550His in European (non-Finnish) population 0.00002442<br> https://gnomad.broadinstitute.org/variant/X-154185335-C-T?dataset=gnomad_r2_1
c.280A>G
Case#: 2
DiseaseAssertion: Hemophilia A
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FVIII:C 32% (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.280A>G (p.Thr94Ala)
ClinVar: NA
CAID: CA10568603
gnomAD: MAF for Thr94Ala in the European (Non-Finnish) population 0.00001222<br> https://gnomad.broadinstitute.org/variant/X-154225356-T-C?dataset=gnomad_r2_1
c.7031G>C
Case#: 38
DiseaseAssertion: Hemophilia A
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FVIII:C 29%, 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:c.7031G>C (p.Gly2344Ala)
ClinVar: NA
CAID: CA414896685
gnomAD: Not reported
c.6118T>G
Case#: 29
DiseaseAssertion: Hemophilia A
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FVIII:C 10/8/14%, 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:c.6118T>G (p.Cys2040Gly)
ClinVar: NA
CAID: CA414904332
gnomAD: Not reported
c.422G>A
Case#: 42
DiseaseAssertion: Hemophilia B
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FIX:C 4% (Moderate 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_000133.4(F9):c.422G>A (p.Cys141Tyr)
ClinVar: 811510 https://www.ncbi.nlm.nih.gov/clinvar/variation/811510/
CAID: CA414438897
gnomAD: Not reported
24.
Case#: 24
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.1193G>A
LegacyVariant:
ClinVar: No
CAID: CA414446384
gnomAD:
29.
Case#: 29
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.1279G>A
LegacyVariant:
ClinVar: No
CAID: CA414447040
gnomAD:
11.
Case#: 11
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.677G>A
LegacyVariant:
ClinVar: No
CAID: CA121128
gnomAD:
32.
Case#: 32
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.1306G>A
LegacyVariant:
ClinVar: No
CAID: CA414447233
gnomAD:
23.
Case#: 23
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.1193G>A
LegacyVariant:
ClinVar: No
CAID: CA414446384
gnomAD:
3.
Case#: 3
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.128G>A
LegacyVariant:
ClinVar: No
CAID: CA414435539
gnomAD:
16.
Case#: 16
DiseaseAssertion: Hemophilia B, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0011858
CaseHPOFreeText: FIX:C = 12%
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.881G>A
LegacyVariant:
ClinVar: No
CAID: CA255368
gnomAD:
10.
Case#: 10
DiseaseAssertion: Hemophilia B, moderate
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0011858
CaseHPOFreeText: FIX:C = 2.5%
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.571C>T
LegacyVariant:
ClinVar: No
CAID: CA255340
gnomAD:
Factor IX San Dima
Case#: Factor IX San Dimas Case
DiseaseAssertion: Severe Hemophilia B
FamilyInfo: None
ParentalTesting: N/A
CasePresentingHPOs: HP:0011858
CaseHPOsFreeText: reduced factor IX activity (FIX:Ag 98%; FIX:C: <0.01)
CaseNotHPOs: N/A
CasePreviousTesting: DNA Seq analysis of the Factor IX gene (FIX:Ag 98%; FIX:C: <0.01)
Gene: F9
Variant: NM_000133.4:c.128G>A (p.Arg43Gln)
LegacyVariant: p.Arg-4Gln
ClinVar: 810864
CAID: CA414435539
gnomAD: Absent/Not Reported
101
Case#: 101, male, 7 years old, Chinese
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 3%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.6611T>C
LegacyVariant:
ClinVar: No
CAID: CA414906072
gnomAD:
73
Case#: 73, male, 67 years old, Chinese
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 6%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.5422C>T
LegacyVariant:
ClinVar: 10278
CAID: CA255166
gnomAD:
42
Case#: 42, male, 24 years old, Chinese
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 1.2%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.901C>T
LegacyVariant:
ClinVar: No
CAID: CA414917990
gnomAD:
36
Case#: 36, male, 10 years old, Chinese
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%, Inhibitor present
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.387G>C
LegacyVariant:
ClinVar: No
CAID: CA414919866
gnomAD:
88
Case#: 88, male, 29 years old, Chinese
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 2%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.6406G>A
LegacyVariant:
ClinVar: No
CAID: CA414899430
gnomAD:
80
Case#: 80, male, 52 years old, Chinese
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 10.9%
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.5707G>A
LegacyVariant:
ClinVar: No
CAID: CA414907751
gnomAD:
56
Case#: 56, male, 12 years old, Chinese
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 29%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.1834C>T
LegacyVariant:
ClinVar: 10236
CAID: CA255129
gnomAD:
69
Case#: 69, male, 11 years old, Chinese
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
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.5321A>T
LegacyVariant:
ClinVar: No
CAID: CA414910719
gnomAD:
34
Case#: 34, male, 25 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.382T>C
LegacyVariant:
ClinVar: 811825
CAID: CA414919878
gnomAD:
75
Case#: 75, male, 14 years old, Chinese
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 16.5%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.5545T>A
LegacyVariant:
ClinVar: No
CAID: CA414908552
gnomAD:
61
Case#: 61, male, 7 years old, Chinese
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.2066T>C
LegacyVariant:
ClinVar: No
CAID: CA414909145
gnomAD:
45
Case#: 45, male, 75 years old, Chinese
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 6.5%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.1172G>A
LegacyVariant:
ClinVar: 10111
CAID: CA120918
gnomAD:
84
Case#: 84, male, 48 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.5821A>C
LegacyVariant:
ClinVar: No
CAID: CA414906679
gnomAD:
C.6515C>T
Case#: 29
DiseaseAssertion: Hemophilia A
FamilyInfo: Positive
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: Severe
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.6515C>T (p.Pro2153Leu)
ClinVar: NA
CAID: CA414907354
gnomAD: Not reported
c.556G>A
Case#: 13
DiseaseAssertion: Hemophilia A
FamilyInfo: Positive
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: Severe
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.556G>A
ClinVar: NA
CAID: CA414919461
gnomAD: Not reported
C.7006A>T
Case#: 31
DiseaseAssertion: Hemophilia A
FamilyInfo: Positive
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.7006A>T (p.Ile2317Phe)
ClinVar: NA
CAID: CA414896884
gnomAD: Not reported
c.5159C>T
Case#: 24
DiseaseAssertion: Hemophilia A
FamilyInfo: Positive
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: Mild
CasePreviousTesting: All 26 exons and exon-intron boundaries of the F8 gene were amplified using primers and PCR, analyzed by direct forward and reverse sequencing using a DNA sequencing kit
Gene: F8
Variant: NM_000132.3:c.5159C>T (p.Ala1701Val)
ClinVar: NA
CAID: CA414913679
gnomAD: Not reported
c.248C>G
Case#: 12
DiseaseAssertion: Hemophilia A
FamilyInfo: Positive
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: Mild
CasePreviousTesting: All 26 exons and exon-intron boundaries of the F8 gene were amplified using primers and PCR, analyzed by direct forward and reverse sequencing using a DNA sequencing kit
Gene: F8
Variant: NM_000132.3:c.248C>G (p.Pro83Arg)
ClinVar: NA
CAID: CA10568618
gnomAD: MAF for Pro83Arg in the Ashkenazi Jewish population 0.0001335<br>https://gnomad.broadinstitute.org/variant/X-154227771-G-C?dataset=gnomad_r2_1
c.1487C>G
Case#: 20
DiseaseAssertion: Hemophilia A
FamilyInfo: Sporadic
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: Severe
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.1487C>G (p.Pro477Arg)
ClinVar: NA
CAID: CA414912766
gnomAD: Not reported
A9 – A11
Case#: A9-A11
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 13, FVIII:AG = 28, 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.1648C>T
LegacyVariant:
ClinVar: No
CAID: CA255113
gnomAD:
B74
Case#: B74
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C Chr = 19, FVIII:AG = 17, 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.5325G>C, NM_000132.4:c.5325G>T
LegacyVariant:
ClinVar: No
CAID: CA255160, CA414910668
gnomAD:
A12
Case#: A12
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 28, FVIII:AG = 54, 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.2045T>C
LegacyVariant:
ClinVar: No
CAID: CA414909247
gnomAD:
A16
Case#: A16
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 7, FVIII:AG = 23, 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.5879G>A
LegacyVariant:
ClinVar: No
CAID: CA255019
gnomAD:
c.138G>C p.Arg46Ser
Case#: Guo_Proband_5 (assumed male; Chinese)
DiseaseAssertion: Severe Hemophilia B
FamilyInfo: N/A
ParentalTesting: None
CasePresentingHPOs: HP:0011858
CaseHPOsFreeText: reduced factor IX activity FIX:C: <1 %; FIX:Ag: 35)
CaseNotHPOs: N/A
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.138G>C (p.Arg46Ser)
ClinVar: Absent
CAID: CA414435594
gnomAD: Absent/Not Reported
Case#: Guo_Family 2_Proband 1 (Chinese, assumed male)
DiseaseAssertion: Moderate Hemophilia B
FamilyInfo: None
ParentalTesting: N/A
CasePresentingHPOs: HP:0011858
CaseHPOsFreeText: FIX:Ag: 1.6%, FIX:C: 2.1%
CaseNotHPOs: N/A
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.59T>C (p.Leu20Ser)
ClinVar: Absent
CAID: CA414434363
gnomAD: Absent/Not Reported
(6372)
Case#: Patient E (assumed male)
DiseaseAssertion: Severe, Familial Hemophilia B
FamilyInfo: Mothers were heterozygous, but patient E’s sister and aunt were non-carriers (homozygous for the cleavage)
ParentalTesting: Mothers were heterozygous, but patient E’s sister and aunt were non-carriers (homozygous for the cleavage)
CasePresentingHPOs: HP:0011858
CasePresentingHPOsFreeText: reduced factor IX activity (FIX:C: <1; FIX:Ag:37/38)
CaseNotHPOs: N/A
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.135G>T (p.Lys45Asn)
ClinVar: Absent/Not Reported
CAID: CA414435576
gnomAD: Absent/Not Reported
Arg- > Gln
Case#: Patient D (assumed male)
DiseaseAssertion: Severe, Sporadic Hemophilia B
FamilyInfo: Patient D's mother is heterozygous and she has had a second, affected son. the maternal grandmother's DNA was also heterozygous
ParentalTesting: Mother was heterozygous for the variant
CasePresentingHPOs: HP:0011858
CasePresentingHPOsFreeText: reduced factor IX activity (FIX:C: <1; FIX:Ag:41)
CaseNotHPOs: N/A
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.128G>A (p.Arg43Gln)
LegacyVariant: c.6365 G>A (p.Arg-4Gln)
ClinVar: 810864
CAID: CA414435539
gnomAD: Absent/Not Reported
Case#: IG2 (Italian, assumed male)
DiseaseAssertion: Severe Hemophilia B
FamilyInfo: Not provided
ParentalTesting: Not provided
CasePresentingHPOs: HP:0011858
CaseHPOsFreeText: reduced factor IX activity (FIX:C: <1%, FIX:Ag: 15-53)
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
Case#: IG13 (Italian, assumed male)
DiseaseAssertion: Severe Hemophilia B
FamilyInfo: Not provided
ParentalTesting: Not provided
CasePresentingHPOs: HP:0011858
CaseHPOsFreeText: reduced factor IX activity (FIX:C: <1%)
CaseNotHPOs: N/A
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.83G>A (p.Cys28Tyr)
LegacyVariant: c.112G>A (p.Cys-19Tyr)
ClinVar: Absent
CAID: CA414434483
gnomAD: Absent/Not Reported
mutations
Case#: Tartary_Proband_998 (assumed male)
DiseaseAssertion: None (FIX:C: 18)
FamilyInfo: None
ParentalTesting: N/A
CasePresentingHPOs: None
CaseNotHPOs: N/A
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.128G>A (p.Arg43Gln)
LegacyVariant: c.6365 G>A (p.Arg-4Gln)
ClinVar: 810864
CAID: CA414435539
gnomAD: Absent/Not Reported
7
Case#: Enayat_Family 7
DiseaseAssertion: Severe Hemophilia B (Familial; from Shiraz, Iran)
FamilyInfo: Affected mothers and some sisters were investigated as the "family"
ParentalTesting:
CasePresentingHPOs: HP:0011858
CaseHPOsFreeText: reduced factor IX activity (FIX:C: < 0.01)
CaseNotHPOs: None
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.128G>A (p.Arg43Gln)
LegacyVariant: c.6365 G>A (p.Arg-4Gln)
ClinVar: 810864
CAID: CA414435539
gnomAD: Absent/Not Reported
c.59T>C
Case#: Salviato_Proband_1164 (male, Chinese)
DiseaseAssertion: Hemophilia B
FamilyInfo: N/A
ParentalTesting: N/A
CasePresentingHPOs: HP:0011858
CaseHPOsFreeText: reduced factor IX activity
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.59T>C (p.Leu20Ser)
ClinVar: Absent
CAID: CA414434363
gnomAD: Absent/Not Reported
UQU-HA35
Case#: UQU-HA35, Male, 2-months-old, Saudi Arabia
DiseaseAssertion: Hemophilia A
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: PTT 118.8, Disabled both knees, Severe
CasePreviousTesting: Screened for inversion 22 by inverse PCR, screened for inversion 1 by multiplexed PCR, capillary sequencing (Sanger method) was performed for factor VIII all 26 exons
Gene: F8
Variant: NM_000132.3:c.1835G>C (p.Arg612Pro)
ClinVar: NA
CAID: CA414910775
gnomAD: Not reported
UQU-HA36
Case#: UQU-HA36, Male, 6-months-old, Saudi Arabia
DiseaseAssertion: Hemophilia A
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: PTT 125.4, Severe, Disabled right knees, left elbow, and ankle
CasePreviousTesting: Screened for inversion 22 by inverse PCR, screened for inversion 1 by multiplexed PCR, capillary sequencing (Sanger method) was performed for factor VIII all 26 exons
Gene: F8
Variant: NM_000132.3:c.409A>C (p.Thr137Pro)
ClinVar: NA
CAID: CA414919795
gnomAD: Not reported
Case#: 043 (GB); Polish origin
DiseaseAssertion: Moderate Hemophilia B
FamilyInfo: Not provided
ParentalTesting: Not provided
CasePresentingHPOs: HP:0011858
CasePresentingHPOsFreeText: FIX:C : 4; FIX:Ag : 4
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
Case#: 014 (AD); Polish origin
DiseaseAssertion: Moderate Hemophilia B
FamilyInfo: Not provided
ParentalTesting: Not provided
CasePresentingHPOs: HP:0011858
CasePresentingHPOsFreeText: FIX:C : 2; FIX:Ag : 65
CaseNotHPOs: N/A
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.138G>T (p.Arg46Ser)
ClinVar: Absent/Not Reported
CAID: CA414435596
gnomAD: Absent/Not Reported
Table 1
Case#: N/A
DiseaseAssertion: Severe/Moderate Hemophilia B
FamilyInfo: N/A
ParentalTesting: None
CasePresentingHPOs: HP:0001929
CaseHPOsFreeText: reduced factor IX activity
CaseNotHPOs: N/A
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.83G>A (p.Cys28Tyr)
ClinVar: Absent
CAID: CA414434483
gnomAD: Absent/Not Reported
15
Case#: 15
DiseaseAssertion: Hemophilia B, moderate
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FIX:C = 2.6%
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.781T>C
LegacyVariant:
ClinVar: No
CAID: CA414443378
gnomAD:
10
Case#: 10
DiseaseAssertion: Hemophilia B, moderate
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FIX:C = 1.8%
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:
LegacyVariant: NM_000133.3:c.880C>T
ClinVar: No
CAID: CA255344
gnomAD:
4
Case#: 4
DiseaseAssertion: Hemophilia B, severe
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.520G>C
LegacyVariant:
ClinVar: No
CAID: CA414439517
gnomAD:
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.68T>C (p.Leu23Pro)
ClinVar: Absent
CAID: CA414434403
gnomAD: Absent/NotReported
Click here for additional data file.
Case#: N/A
DiseaseAssertion: Hemophilia B (severity not specified)
FamilyInfo: Not provided
ParentalTesting: Not provided
CasePresentingHPOs: Not provided
CaseNotHPOs: N/A
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.86C>T (p.Thr29Ile)
ClinVar: Absent
CAID: CA414434494
gnomAD: Absent/NotReported
identify the causative mutation
Case#: Belvini_Proband_13 (male, Italian)
DiseaseAssertion: Severe Hemophilia B
FamilyInfo: N/A
ParentalTesting: N/A
CasePresentingHPOs: HP:0011858
CaseHPOsFreeText: reduced factor IX activity
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.110C>A (p.Ala37Asp)
ClinVar: Absent
CAID: CA414435430
gnomAD: Absent/Not Reported
mutation
Case#: Belvini_Proband_16 (Italian)
DiseaseAssertion: Severe Hemophilia B
FamilyInfo: N/A
ParentalTesting: N/A
CasePresentingHPOs: HP:0011858
CaseHPOsFreeText: reduced factor IX activity
CaseNotHPOs: N/A
CasePreviousTesting: N/A
Gene: F9
Variant:NM_000133.4:c.135G>C (p.Lys45Asn)
ClinVar: Absent
CAID: CA414435574
gnomAD: Absent/Not Reported
Both p.Leu107His substitution (patient P1)
Case#: P1 (female)
DiseaseAssertion: Carrier
FamilyInfo: N/A
ParentalTesting: N/A
CasePresentingHPOs: HP:0003125, HP:0004846, HP:0001892
CaseHPOFreeText: Low FVIII levels (significant decrease in FVIII:C 1.4% ± 0.2 and FVIII:Ag levels 3.9% ± 0.2), prolonged bleeding after surgery, mild bleeding tendency
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: Molecular Analysis included a southern blot assay, PCR, dHPLC and a multiplex ligation-dependent probe amplification analysis. Plasmid mutagenesis, plasmid transfection and in silico analysis were also performed.
Gene: F8
Variant: NM_000132.4:c.320T>A
CAID: CA414920017
gnomAD: Absent/Not Reported
The p.Leu2032Pro
Case Info: P6 (female)
DiseaseAssertion: Carrier
FamilyInfo: N/A
ParentalTesting: N/A
CasePresentingHPOs: HP:0003125, HP:0001928, HP:0001892
CaseHPOFreeText: Low FVIII levels (in vitro results were similar to the WT control and led to a normal specific activity (82.7% ± 9.0)), abnormal blood coagulation, mild bleeding tendency
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.6095T>C
CAID: CA414904631
gnomAD: Absent/Not Reported
9-month old boy was diagnosed with severe haemophilia B
Case1: Male, 9-months at time of diagnosis
DiseaseAssertion: Severe Hemophilia B
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0001933 (Subcutaneous hemorrhage), HP:0007420 (Spontaneous hematomas), HP:0012233 (Intramuscular hematoma), HP:0005261 (Joint hemorrhage)
CaseHPOFreeText: FIX: C <1%, recurrent anaphylactic reactions to FIX (abdominal pain, respiratory arrest, and severe hypotension)
CasePreviousTesting: F9 analysis (revealed a point mutation at exon H)
Gene: F9
Variant: NM_000133.3(F9):c.880C>T (p.Arg294Ter)
LegacyVariant: g 30863 C>T; Arg 248 stop
ClinVar: 10587 https://www.ncbi.nlm.nih.gov/clinvar/variation/10587/
gnomAD: Not reported
g.6365G>A
Case#: Awidi_Variant_1 (9 patients, 2 families)
DiseaseAssertion: Severe Hemophilia B
FamilyInfo: Positive family history
ParentalTesting: Positive family history
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: 810864
CAID: CA414435539
gnomAD: Absent/Not Reported
mutation
Case#: Heit_Proband_HB541 (assumed male, AmerIndian from Peru)
DiseaseAssertion: Severe Hemophilia B
FamilyInfo: N/A
ParentalTesting: N/A
CasePresentingHPOs: HP:0011858
CaseHPOsFreeText: reduced factor IX activity (FIX:C: <1 %)
CaseNotHPOs: N/A
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.128G>A (p.Arg43Gln)
ClinVar: 810864
CAID: CA414435539
gnomAD: Absent/Not Reported
Table S3. F9 mutations
Case#: Miller_Proband 2 (male)
DiseaseAssertion: Severe Hemophilia B
FamilyInfo: N/A
ParentalTesting: N/A
CasePresentingHPOs: HP:0011858
CaseHPOsFreeText: reduced factor IX activity
CaseNotHPOs: N/A
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.128G>A (p.Arg43Gln)
ClinVar: 810864
CAID: CA414435539
gnomAD: Absent/Not Reported
genetic defects
Case#: Lin_Patient 3 (assumed male, Chinese origin)
DiseaseAssertion: Severe Hemophilia B
FamilyInfo: N/A
ParentalTesting: None
CasePresentingHPOs: HP:0011858
CaseHPOsFreeText: reduced factor IX activity (FIX:C: <1 ; FIX:Ag: 38)
CaseNotHPOs: N/A
CasePreviousTesting: None
Gene: F9
Variant: NM_000133.4:c.128G>A (p.Arg43Gln)
ClinVar: 810864
CAID: CA414435539
gnomAD: Absent/Not Reported
2
Case#: Quadros_Proband_ ID_#2
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.112A>C (p.Asn38His)
ClinVar: Absent
CAID: CA414435439
gnomAD: Absent/Not Reported
Case#: Liu_Proband_316 (assumed male; Chinese)
DiseaseAssertion: Severe Hemophilia B
FamilyInfo: N/A
ParentalTesting: N/A
CasePresentingHPOs: HP:0011858
CaseHPOsFreeText: reduced factor IX activity
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.82T>G (p.Cys28Gly)
ClinVar: Absent
CAID: CA414434482
gnomAD: Absent/Not Reported
Case#: 02059, Age 38, Male, Blood type A+ (Table S3)
Disease Assertion: VWD 1
FamilyInfo: Patient is a member of family # 02059. There is one other member of the family (patient 02060). 02060 has the same exonic variant (c.3614G>A), but has a different intronic variant ( c.7438-169G>A).
Parental Genotype: Not listed
CasePresentingHPOs: N/A
CaseHPOFreeText: Bleeding score 12, VWF:Ag: 5.4, VWF:RCo: 6.1, FVIII:C:11, VWF:CB: 4.5
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
Protein Expression: N/A
CasePreviousTesting: 48,48 Access-Array amplification. NGS Molecular analysis was performed. Sanger sequencing was used to validate selected mutations
Gene: VWF
Variant: NM_000552.4:c.3614G>A (p.Arg1205His) and
ClinVar: 308 ClinVar
CAID: CA114160 CAID1
gnomAD:
Case#: 02001, Age 63, Female, Blood Type A+ (Table S3)
Disease Assertion: VWD 1
FamilyInfo:( Family 0201) 8 family members were included in the study. All of them had type VWD type 1. All had the same variant besides patient 02019.
Parental Genotype: Not listed
CasePresentingHPOs: N/A
CaseHPOFreeText: Bleeding Score 14, VWF:Ag: 9.7, VWF:RCo: 2.6, FVIII:C: 19, VWF:CB: 6
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
Protein Expression: N/A
CasePreviousTesting: 48,48 Access-Array amplification. NGS Molecular analysis was performed. Sanger sequencing was used to validate selected mutations.
Gene: VWF
Variant: NM_000552.4:c.3614G>A (p.Arg1205His)
ClinVar: 308 ClinVar
CAID: CA114160
gnomAD: N/A
Case#: 10013, Age 23, Female, Blood Type O+ (Table S3)
Disease Assertion: VWD1
FamilyInfo: The patient is the only member of Family#1011.
Parental Genotype: Not listed
CasePresentingHPOs: N/A
CaseHPOFreeText: Bleeding Score 3, VWF:Ag:7.2, VWF:RCo:5.6, FVIII:C:19, VWF:CB:6.5
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.5198T>C (p.Leu1733Pro)
ClinVar: N/A
CAID: CA383496267 CAID
gnomAD: N/A
Case#: 02047, Age 71, Male, Blood Type: O+ (Table S3)
Disease Assertion:VWD 1
FamilyInfo: Family# 0218; 3 Family members were included in the study. All 3 members had VWD type 1. All 3 have the same variant as patient 02047.
Parental Genotype: Not listed
CasePresentingHPOs: N/A
CaseHPOFreeText: Bleeding Score 9, VWF:Ag: 9.3, VWF:RCo:6.4, FVIII:C: 30, VWF:CB: 6.1
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.5471C>A (p.Pro1824His)
ClinVar: 100430 ClinVar
CAID:CA228725
gnomAD: N/A
Case#: 32010, Age 21, Male, Blood Type not determined (Table S3)
Disease Assertion: VWD 1
FamilyInfo: The patient is one of two members of Family#3210. The second member is a carrier of the variant c.3931C>T.
Parental Genotype: Not listed
CasePresentingHPOs: N/A
CaseHPOFreeText: Bleeding Score 12, VWF:Ag:7.2, VWF:RCo: 5.7, FVIII:C: 21, VWF:CB: 6.8
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.3931C>T (p.Gln1311Ter) and NM_000552.4:c.55G>A (p.Gly19Arg)
ClinVar: 100307 and 100432 ClinVar1 ClinVar
CAID: CA228496 and CA228729 CAID1 CAID2
gnomAD: MAF of 0.0003921 (12/ 30604 alleles) in the South Asian population (CA228496). gnomAD
MAF of 0.0008819 (27/ 30616 alleles) in the South Asian population.
Case#: 06002, Age 39, Female,Blood Type O+ (Table S3)
Disease Assertion: VWD1
FamilyInfo: Two total members in Family #0602. Patient 06003 has the c.2685G>C variant and a seperate intronic variant.
Parental Genotype: Not listed
CasePresentingHPOs: N/A
CaseHPOFreeText: Bleeding score 8, VWF:Ag: 25, VWF:RCo: 19.1, FVIII:C:88, VWF:CB:24
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.2685G>C (p.Gln895His) and NM_000552.4:c.4751A>G (p.Tyr1584Cys)
ClinVar: 310
CAID: CA383519910 and CA114162
gnomAD: MAF of 0.004024 (519/128972 alleles) in the European (non-Finnish) population.
Case#: 13006, Age 66, Male, Blood Type A-
Disease Assertion: VWD 1
FamilyInfo: The patient is the only member of Family# 1304.
Parental Genotype: Not listed
CasePresentingHPOs: N/A
CaseHPOFreeText: Bleeding Score 8, VWF:Ag:10, VWF:RCo: 6, FVIII:C:16, VWF:CB:6.1
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
Protein Expression: N/A
CasePreviousTesting: 48,48 Access-Array amplification. NGS Molecular analysis was performed. Sanger sequencing was used to validate selected mutations
Gene: VWF
Variant: NM_000552.4:c.3614G>A (p.Arg1205His)
ClinVar: 308 ClinVar
CAID: CA114160 CAID
gnomAD: N/A
Case#: 13014, Age20, Male, Blood type O+ (TableS3)
Disease Assertion: VWD 1
FamilyInfo: The patient is the only member of Family#1311.
Parental Genotype: Not listed
CasePresentingHPOs: N/A
CaseHPOFreeText: Bleeding Score 6, VWF:Ag:24, VWF:RCo: 22.5, FVIII:C:40, VWF:CB: 20
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.4751A>G (p.Tyr1584Cys)
ClinVar: 310 ClinVar
CAID: CA114162 CAID
gnomAD: MAF of 0.004024 (519/ 128972 alleles) in the European (non-Finnish) population
Case#: 27012, Age 24, Female, Blood Type O+ (Table S3)
Disease Assertion: VWD 1
FamilyInfo: The patient is the only member of Family #2707.
Parental Genotype: Not listed
CasePresentingHPOs: N/A
CaseHPOFreeText: VWF:Ag: 33, VWF:RCo: 29, FVIII:C: 91, VWF:CB: 32
CaseNotHPOs: N/A
CaseNotHPOFreeText: Bleeding score 0
Protein Expression: N/A
CasePreviousTesting: 48,48 Access-Array amplification. NGS Molecular analysis was performed. Sanger sequencing was used to validate selected mutations.
Gene: VWF
Variant: NM_000552.4:c.3467C>T (p.Thr1156Met) and c.-3151T>G
ClinVar: 100264 ClinVar
CAID: CA228414 CAID
gnomAD:
63 14 M 28 c.3931C.T p.Q1311* Hmz 7.5 ,1 16 - +c.4027A.G p.I1343Vc.4079T.C p.V1360A
Case: 63, M, 14 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): 7.5, VWF:Ag (U/dl): <1, Bleeding Score: 16
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.3931C>T (p.Gln1311*), Exon 28
c.4027A>G (p.Ile1343Val), Exon 28
c.4079T>C (p.Val1360Ala), Exon 28
Homozygous
89 16 F 28 c.4525A.G p.I1509V C.Htz 3.9 3 16 - -
Case: 89, F, 16 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): 3.9, VWF:Ag (U/dl): 3, Bleeding Score: 16
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.4525A>G (p.Ile1509Val), Exon 28
Compound Heterozygous
14 2 F 28 c.3862C.Gp.L1288V Htz 3 2.6 6 + +
Case: 14, F, 2 years, Indian
DiseaseAssertion: VWD type 3
FamilyInfo: family history of disease, Consanguinity: yes
ParentalGenotype: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: FVIII:C: (U/dl): 3, VWF:Ag (U/dl): 2.6, Bleeding Score: 6
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.3862C>G (p.Leu1288Val), Exon 28
Heterozygous
125
Case#: Ahmad_2014_125
DiseaseAssertion: VWD type 2A
FamilyInfo: heterozygous (probably affected according to multimer analysis) mother
ParentalGenotype: heterozygous mother, homozygous wt father and sibling
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:
1 M/10 <1 5 NR 7 c.6634T>Ca p.C2212Ra 38 Homozygous
Case: 1, M, 10, Italian
DiseaseAssertion: VWD type 3
FamilyInfo: Consanguinity: not reported
ParentalGenotype: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: VWF:Ag (IU/dL): <1, FVIII:C (IU/dL): 5, Bleeding Score: 7
CaseNotHPOs: n/a
CaseNotHPOFreeText: Anti-VWF alloantibodies: no
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.6634T>C (p.Cys2212Arg), Exon 38, D4 domain, Homozygous
Note: parents investigated for the probands defects and confirmed to carry the expected mutation at the heterozygous state
24*IranF/171—YesSevere6520T→GC2174G37HomozygousN.A.
Case: 24, F, 17, Iranian
DiseaseAssertion: VWD type 3
FamilyInfo: Consanguinity: Yes
ParentalGenotype: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: VWF:Ag (U/dl): 1, Bleeding symptoms: Severe
CaseNotHPOs: n/a
CaseNotHPOFreeText: Anti-VWF alloantibodies: no
CasePreviousTesting: n/a
Gene: VWF
Variant:
6520T→G (Cys2174Gly), Exon 37, Homozygous
13IranM/8<1—YesMild139G→CD47H3HomozygousNlaIII (+)
Case: 13, M, 8, Iranian
DiseaseAssertion: VWD type 3
FamilyInfo: Consanguinity: Yes
ParentalGenotype: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: VWF:Ag (U/dl): <1, Bleeding symptoms: Mild
CaseNotHPOs: n/a
CaseNotHPOFreeText: Anti-VWF alloantibodies: no
CasePreviousTesting: n/a
Gene: VWF
Variant:
139G→C (Asp47His), Exon 3, Homozygous
28IndiaM/25<1—YesMild421G→AD141N5HomozygousN.A.
Case: 28, M, 25, Indian
DiseaseAssertion: VWD type 3
FamilyInfo: Consanguinity: Yes
ParentalGenotype: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: VWF:Ag (U/dl): <1, Bleeding symptoms: Mild
CaseNotHPOs: n/a
CaseNotHPOFreeText: Anti-VWF alloantibodies: no
CasePreviousTesting: n/a
Gene: VWF
Variant:
421G→A (Asp141Asn), Exon 5, Homozygous
P2
Case: P2, male, 32yo
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 (%) = 32, VWF:RCo(%) = 19, VWF:RCo/VWF:Ag ratio = 0.59, VWF:CIIIB (%) = 35, VWF:CIIIB/VWF:Ag ratio = 1.09, VWF:CVIB (%) = 32, VWF:CVIB/VWF:Ag ratio = 1.00
CaseNOTHPOs: HP:0030132
(Absence of large von Willebrand factor multimers)
CaseNOTHPOFreeText: NA
CasePreviousTesting: NA
GenotypingMethod: NGS
PreviouslyPublished: If applicable.
Gene: VWF
Variant: c.4117G>T (p.Asp1373Tyr)
HGVS: NM_000552.3:c.4117G>T (p.Asp1373Tyr)
ClinVarID: NA
CAID: CA383504503; http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA383504503
gnomAD: MAF = 0.00002891 (1/34588 alleles) in Latino/AdMixed American population; https://gnomad.broadinstitute.org/variant/12-6128467-C-A
P8
Case: Patient 8, male, 9yo
DiseaseAssertion: VWD2M
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0030129, HP:0030130
(Impaired ristocetin cofactor assay activity, Impaired von Willebrand factor collagen binding activity)
CaseHPOFreeText: bleeding score = 3; VWF:Ag (%) = 57, VWF:RCo(%) = 43, VWF:RCo/VWF:Ag ratio = 0.75, VWF:CIIIB (%) = 35, VWF:CIIIB/VWF:Ag ratio = 0.61, VWF:CVIB (%) = 18, VWF:CVIB/VWF:Ag ratio = 0.32
CaseNOTHPOs: HP:0030132
(Absence of large von Willebrand factor multimers)
CaseNOTHPOFreeText: NA
CasePreviousTesting: NA
GenotypingMethod: NGS
PreviouslyPublished: NA
Gene: VWF
Variant: c.4196G>A
HGVS: NM_000552.5(VWF):c.4196G>A
ClinVarID: 293; https://www.ncbi.nlm.nih.gov/clinvar/variation/293/
CAID:
gnomAD: MAF = 0.01670 (173/10360 alleles) in the Ashkenazi Jewish population; https://gnomad.broadinstitute.org/variant/12-6128388-C-T?dataset=gnomad_r2_1
1
Case: 2B-7
DiseaseAssertion: VWD2B
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs: AcuStar RCo/Ag = 0.43; AcuStar CB/Ag = 0.17; ELISA CB/Ag = 0.20
CaseHPOFreeText:
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting:
GenotypingMethod: not described
PreviouslyPublished: 9858249
Gene: VWF
Variant: c.3922C>T (p.Arg1308Cys)
HGVS: NM_000552.5(VWF):c.3922C>T (p.Arg1308Cys)
ClinVarID: 289; https://www.ncbi.nlm.nih.gov/clinvar/variation/289/?new_evidence=false
CAID:
gnomAD: absent
Case: P69, Chinese, male, 12yo
DiseaseAssertion: VWD1
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0012147
(Reduced quantity of VWF)
CaseHPOFreeText: type A blood, bleeding score = 3; VWF:Ag (%) = 2.8, VWF:RCo (%) = 2.5, FVIII:C (%) = 10.5, VWF:CB (%) = 3.2, VWFpp (%) = 2.7, VWF:RCo/VWF:Ag = 0.9, VWF:CB/VWF:Ag = 1.1, VWFpp/VWF:Ag = 1.0, FVIII:C/VWF:Ag = 3.8, RIPA (1.2 mg/ml, %) = 49.7
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: NA
GenotypingMethod: NGS
PreviouslyPublished: NA
Gene: VWF
Variant 1: c.484T>C (p.Cys162Arg)
HGVS: NM_000552.3:c.484T>C (p.Cys162Arg)
ClinVarID: NA
CAID: CA383518153; http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA383518153
gnomAD: absent
Variant 2: c.7884C>G (.Pro2628=) - reported to be a splice site variant
HGVS: NM_000552.5:c.7884C>G (.Pro2628=)
ClinVarID: NA
CAID: CA6401487; http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA6401487
gnomAD: MAF = 0.0002175 (4/18388 alleles) in the East Asian population; https://gnomad.broadinstitute.org/variant/12-6076655-G-C
Case: P5, Chinese, female, 65yo
DiseaseAssertion: VWD2N
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0012147
(Reduced quantity of VWF)
CaseHPOFreeText: type O blood, bleeding score = 14; VWF:Ag (%) = 55.2, VWF:RCo (%) = 51.4, FVIII:C (%) = 1.3, VWF:CB (%) = 58.2, VWFpp (%) = 49.3, VWF:RCo/VWF:Ag = 0.9, VWF:CB/VWF:Ag = 1.1, VWFpp/VWF:Ag = 0.9, FVIII:C/VWF:Ag = 0.0, VWF: FVIIIB (%) = 0.1
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: NA
GenotypingMethod: NGS
PreviouslyPublished: NA
Gene: VWF
Variant 1: c.1911delC - unregistered variant
HGVS: NA
ClinVarID: NA
CAID: NA
gnomAD: NA
Variant 2: c.2446C>T (p.Arg816Trp)
HGVS: NM_000552.4(VWF):c.2446C>T (p.Arg816Trp)
ClinVarID: 295; https://www.ncbi.nlm.nih.gov/clinvar/variation/295/
CAID: NA
gnomAD: MAF = 0.0002541 (9/35418 alleles) in the Latino/Admixed American population; https://gnomad.broadinstitute.org/variant/12-6145654-G-A?dataset=gnomad_r2_1
Case: P85, Chinese, female, 29yo
DiseaseAssertion: VWD2N
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0012147
(Reduced quantity of VWF)
CaseHPOFreeText: type B blood, bleeding score = 2; VWF:Ag (%) = 11.0, VWF:RCo (%) = 10.9, FVIII:C (%) = 6.5, VWF:CB (%) = 11.3, VWFpp (%) = 11.0, VWF:RCo/VWF:Ag = 1.0, VWF:CB/VWF:Ag = 1.0, VWFpp/VWF:Ag = 1.0, FVIII:C/VWF:Ag = 0.6, VWF: FVIIIB (%) = 0.0
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: NA
GenotypingMethod: NGS
PreviouslyPublished: NA
Gene: VWF
Variant 1: c.855G>A (p.Trp285Ter)
HGVS: NM_000552.5:c.855G>A (p.Trp285Ter)
ClinVarID: NA
CAID: CA383508140; http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA383508140
gnomAD: absent
Variant 2: c.2574C>G (p.Cys858Trp)
HGVS: NM_000552.5:c.2574C>G (p.Cys858Trp)
ClinVarID: NA
CAID: CA232299278; http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA232299278
gnomAD: MAF = 0.0001002 (2/19954 alleles) in the East Asian population; https://gnomad.broadinstitute.org/variant/12-6143965-G-C
Case: P82, Chinese, female, 80yo
DiseaseAssertion: VWD2M
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0012147
(Reduced quantity of VWF)
CaseHPOFreeText: type AB blood, bleeding score = 10; VWF:Ag (%) = 15.6, VWF:RCo (%) = 2.7, FVIII:C (%) = 50.8, VWF:CB (%) = 14.9, VWFpp (%) = 13.6, VWF:RCo/VWF:Ag = 0.2, VWF:CB/VWF:Ag = 1.0, VWFpp/VWF:Ag = 0.9, FVIII:C/VWF:Ag = 3.3
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: NA
GenotypingMethod: NGS
PreviouslyPublished: NA
Gene: VWF
Variant 1: c.3365C>T (p.Thr1122Met)
HGVS: NM_000552.4(VWF):c.3365C>T (p.Thr1122Met)
ClinVarID: 453122; https://www.ncbi.nlm.nih.gov/clinvar/variation/453122/
CAID: NA
gnomAD: MAF = 0.003169 (63/19880 alleles) in the East Asian population; https://gnomad.broadinstitute.org/variant/12-6132811-G-A?dataset=gnomad_r2_1
Variant 2: c.3895del
HGVS: NM_000552.5:c.3895del
ClinVarID: NA
CAID: CA603482918; http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA603482918
gnomAD: MAF = 0.00009925 (1/10076 alleles) in Ashkenazi Jewish population; https://gnomad.broadinstitute.org/variant/12-6128686-CA-C
Variant 3: c.5668G>A (p.Gly1890Arg)
HGVS: NM_000552.4(VWF):c.5668G>A (p.Gly1890Arg)
ClinVarID: 672096; https://www.ncbi.nlm.nih.gov/clinvar/variation/627096/
CAID: NA
gnomAD: MAF = 0.00006559 (1/15246 alleles) in European (non-Finnish) population; https://gnomad.broadinstitute.org/variant/12-6120957-C-T?dataset=gnomad_r2_1
Variant 4: c.6424C>T (p.Leu2142Phe)
HGVS: NM_000552.5(VWF):c.6424C>T (p.Leu2142Phe)
ClinVarID: 988881; https://www.ncbi.nlm.nih.gov/clinvar/variation/988881/
CAID: NA
gnomAD: absent
P20
Case: P20, F/33
DiseaseAssertion: VWD1
FamilyInfo: No family history
ParentalGenotype: NA
CaseHPOFreeText: The bleeding score was 4, aPTT was 25 seconds, FVIII:C was 6%, VWF:RCo was 19 IU/dL, and VWF:Ag was 19 IU/dL, with a VWF:RCo/VWF:Ag ratio of 1.0. RIPA was normal, VWF multimer analysis was not tested, and platelet count was 475 × 10⁹/L.
CasePreviousTesting: NA
GenotypingMethod: Direct sequencing of all exons, flanking intronic sequences, and the promoter of VWF was performed.
Gene: VWF
Variant: c.1135T>G, p.C379G, c.7390C>T, p.R2464C. Compound heterozygous
HGVS: NM_000552.5(VWF):c.1135T>G (p.Cys379Gly), NM_000552.5(VWF):c.7390C>T (p.Arg2464Cys)
ClinVar: 100467
CAID: CA6403534 , CA228786
gnomAD: https://gnomad.broadinstitute.org/variant/chr12-6071318-A-C?dataset=gnomad_r4, https://gnomad.broadinstitute.org/variant/chr12-5976158-G-A?dataset=gnomad_r4
P5F/312AYes95634140.3Loss of HMW1210
Case: P5 Female, Korean, 31 years at report
DiseaseAssertion: VWD2A
FamilyInfo: Positive family history, no details provided.
ParentalGenotype: NA
CasePresentingHPOs: HP:0030129, HP:0012147, HP:0030132, HP:0011871
(Impaired ristocetin cofactor assay activity, Reduced quantity of VWF, Absence of large von Willebrand factor multimers, Impaired RIPA)
CaseHPOFreeText: bleeding score 9, FVII:C 3%, VWF:Rco 4 IU/dL, VWF:Ag 14 IU/Dl, VWF:Rco/VWF:Ag 0.3, RIPA 1 ohms
CaseNotHPOs: HP:0003645, HP:0001873
(Prolonged partial thromboplastin time, Thrombocytopenia)
CaseNotHPOFreeText: aPTT 36s, platelets 210x10^9/L
CasePreviousTesting: NA
GenotypingMethod: Direct sequencing of all exons, flanking intronic sequences, and the promoter of VWF was performed.
Gene: VWF
Variant: c.2574C>G p.C858W
HGVS: NM_000552.4:c.2574C>G (p.Cys858Trp)
ClinVar: NA
CAID: CA232299278
gnomAD: MAF of 0.0001002 (2/19954 alleles) in the East Asian population
P18
Case: P18, F/39
DiseaseAssertion: VWD1
FamilyInfo: No family history
ParentalGenotype: NA
CaseHPOFreeText: The bleeding score was 9, aPTT was 40 seconds, FVIII:C was 15%, VWF:RCo was 6 IU/dL, and VWF:Ag was 8 IU/dL, with a VWF:RCo/VWF:Ag ratio of 0.8. The VWF multimer pattern was absent, RIPA was 2 ohms, and the platelet count was 273 × 10⁹/L.
CasePreviousTesting: NA
GenotypingMethod: Direct sequencing of all exons, flanking intronic sequences, and the promoter of VWF was performed.
Gene: VWF
Variant: c.3943C>T, p.R1315C — heterozygous
HGVS: NM_000552.5(VWF):c.3943C>T (p.Arg1315Cys)
ClinVar: 100310
CAID: CA228502
gnomAD: https://gnomad.broadinstitute.org/variant/chr12-6019475-G-A?dataset=gnomad_r4
P17
Case: P17, F/30
DiseaseAssertion: VWD2A
FamilyInfo: No family history
ParentalGenotype: NA
CaseHPOFreeText: The bleeding score was 8, aPTT was 42 seconds, FVIII:C was 23%, VWF:RCo was 20 IU/dL, and VWF:Ag was 11 IU/dL, with a VWF:RCo/VWF:Ag ratio of 1.8. The VWF multimer pattern showed a loss of intermediate and high molecular weight multimers, RIPA was not tested, and the platelet count was 276 × 10⁹/L.
CasePreviousTesting: NA
GenotypingMethod: Direct sequencing of all exons, flanking intronic sequences, and the promoter of VWF was performed.
Gene: VWF
Variant: c.3814T>C, p.C1272R — heterozygous
HGVS: NM_000552.5(VWF):c.3814T>C (p.Cys1272Arg)
ClinVar: 301
CAID: CA114149
gnomAD: absent from gnomad v4.1.0
8
Case: Patient 8 (Family B), female, 49yo
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 = 178, PFA 100 sec = >300, SPA % = 9.5, MADR mg/mL = 0.75, VWF:Ag U/dL = 23.0, VWF:CB U/dL = 4.2, VWF:CB ratio = 0.19, VWF:RCo U/dL = 13.8, VWF:RCo ratio = 0.63, Platelet VWF U/dL = 74.0, FVIII U/dL = 50.0, BAT F/M = 12
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: NA
GenotypingMethod: Sequencing of exon 28 of VWF
PreviouslyPublished: NA
Gene: VWF
Variant: c.3922C>T (p.Arg1308Cys)
HGVS: NM_000552.4(VWF):c.3922C>T (p.Arg1308Cys)
ClinVarID: 289; https://www.ncbi.nlm.nih.gov/clinvar/variation/289/
CAID: NA
gnomAD: absent
3
Case: Patient 3 (Family A), female, 38yo
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 = 207, PFA 100 sec = >300, SPA % = 0, MADR mg/mL = 0.45, VWF:Ag U/dL = 67.9, VWF:CB U/dL = 3.6, VWF:CB ratio = 0.06, VWF:RCo U/dL = 33.1, VWF:RCo ratio = 0.48, Platelet VWF U/dL = 128, FVIII U/dL = 54.5, 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
2
Case: Patient 2 (Family A), female, 75yo
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 = 322, PFA 100 sec = NA, SPA % = 10, MADR mg/mL = 0.6, VWF:Ag U/dL = 133, VWF:CB U/dL = 144.2, VWF:CB ratio = 1.1, VWF:RCo U/dL = 106, VWF:RCo ratio = 0.79, Platelet VWF U/dL = 129.5, FVIII U/dL = 126, BAT F/M = 3
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 C), female, 70yo
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 = 168, PFA 100 sec = >300, SPA % = 15, MADR mg/mL = 0.75, VWF:Ag U/dL = 44.6, VWF:CB U/dL = 10.3, VWF:CB ratio = 0.23, VWF:RCo U/dL = 21.4, VWF:RCo ratio = 0.47, Platelet VWF U/dL = 202.0, FVIII U/dL = 53.2, BAT F/M = 15
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: Patient A
DiseaseAssertion: VWD2N
FamilyInfo: Family 1
ParentalGenotype(s):
CasePresentingHPOs: HP:0012147, HP:0030129, HP:0030130, HP:0011871
CaseHPOFreeText: PTsec = 35.2, FVIII U/dL = 18.5, FVIII ratio = 0.29, VWF:Ag U/dL = 62.9, VWF:FVIIIB U/dL = 10.7, VWF:FVIIIB ratio = 0.17, VWF:CB U/dL = 53.3, VWF:RCo U/dL = 60.4, RIPA % = 74.7, PlatVWF:Ag U/dL = 90.4
CaseNOTHPOs:
CaseNOTHPOFreeText: n/a
CasePreviousTesting: n/a
GenotypingMethod: "Genetic analysis was performed on exons 17-20 of the VWF gene as previously described" (PMID: 12393698)
PreviouslyPublished: n/a
Gene: VWF
Variant: c.2561G>A (p.Arg854Gln); homozygous
HGVS: NM_000552.5(VWF):c.2561G>A (p.Arg854Gln)
ClinVarID: 296; https://www.ncbi.nlm.nih.gov/clinvar/variation/296/?new_evidence=false
CAID: n/a
gnomAD: MAF (European, Finnish) = 0.005692; https://gnomad.broadinstitute.org/variant/12-6143978-C-T
Case: Patient B
DiseaseAssertion: VWD2N
FamilyInfo: Family 2
ParentalGenotype(s):
CasePresentingHPOs: HP:0012147, HP:0030129, HP:0030130, HP:0011871
CaseHPOFreeText: PTsec = 37.2, FVIII U/dL = 36.7, FVIII ratio = 0.33, VWF:Ag U/dL = 109.8, VWF:FVIIIB U/dL = 25.7, VWF:FVIIIB ratio = 0.23, VWF:CB U/dL = 133.8, VWF:RCo U/dL = 94.5, RIPA % = 75.8, PlatVWF:Ag U/dL = 95.4
CaseNOTHPOs:
CaseNOTHPOFreeText: n/a
CasePreviousTesting: n/a
GenotypingMethod: "Genetic analysis was performed on exons 17-20 of the VWF gene as previously described" (PMID: 12393698)
PreviouslyPublished: n/a
Gene: VWF
Variant: c.2561G>A (p.Arg854Gln); homozygous
HGVS: NM_000552.5(VWF):c.2561G>A (p.Arg854Gln)
ClinVarID: 296; https://www.ncbi.nlm.nih.gov/clinvar/variation/296/?new_evidence=false
CAID: n/a
gnomAD: MAF (European, Finnish) = 0.005692; https://gnomad.broadinstitute.org/variant/12-6143978-C-T
II : 2
Case#: F10, II:2
DiseaseAssertion: Type 2 VWD
CaseHPOFreeText: complete loss of high MWM, VWF:Ag = 40; VWF:RCo = 5; VWF:GPIbM = 16; 0.13; 0.40; 3.20
CasePreviousTesting: Not clearly described
Gene: VWF
Variant: p.[R1306W];[=]
HGVS: c.3916C>T (p.Arg1306Trp)
CAID: CA114123
gnomAD: absent from gnomad v4.1.0
III : 1
Case#: F10, III:1
DiseaseAssertion: Type 2 VWD
CaseHPOFreeText: complete loss of high MWM, VWF:Ag = 39; VWF:RCo = 12; VWF:GPIbM = 26; 0.31; 0.67; 2.18
CasePreviousTesting: Not clearly described
Gene: VWF
Variant: p.[R1306W];[=]
HGVS: c.3916C>T (p.Arg1306Trp)
CAID: CA114123
gnomAD: absent from gnomad v4.1.0
II : 1
Case#: F10, II:1
DiseaseAssertion: Type 2 VWD
CaseHPOFreeText: complete loss of high MWM, VWF:Ag = 30; VWF:RCo = 5; VWF:GPIbM = 17; 0.17; 0.57; 3.44
CasePreviousTesting: Not clearly described
Gene: VWF
Variant: p.[R1306W];[=]
HGVS: c.3916C>T (p.Arg1306Trp)
CAID: CA114123
gnomAD: absent from gnomad v4.1.0
6 Type 2A/2N c.2560C > Tc.7448dup Np.Arg854Trpp.Tyr24832044D’-E’C3htzhtzMissenseSmall Dupl.na 9 1 7
Case: 6
DiseaseAssertion: type 2A/2N VWD
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs:
CaseHPOFreeRext: VWF:Ag [IU/dL] = 9; VWF:Ac [IU/dL] = 1; FVIII:C [IU/dL] = 7
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.2560C > T p.Arg854Trp
HGVS:
ClinVarID: not found
CAID: CA228351
gnomAD: 0.00001549 (25 in 1614078) no homozygotes https://gnomad.broadinstitute.org/variant/12-6034813-G-A?dataset=gnomad_r4
MultipleGeneVariants:
Gene: VWF
Variant: c.7448dup p.Tyr2483*
ClinVarID: not found
gnomAD: 0.000001859 (3 in 1614148) no homozygotes https://gnomad.broadinstitute.org/variant/12-5971698-G-GT?dataset=gnomad_r4
10-12Type2A (IIE)c.3296G>AN p.Cys1099Tyr 25 D3-C8-3htz Missense O/na/A131/na/26532/na/44 117
Case: IP #10 (also in row 6 table 6)
DiseaseAssertion: type 2A (IIE) VWD
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs: HP:0032442 - blood group O
CaseHPOFreeRext: VWF:Ag [IU/dL] = 131; VWF:Ac [IU/dL] = 32; FVIII:C [IU/dL] = 117
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
29 Type2Ac.4145T>AN p.Leu1382Gln 28 A1 htz Missense na 19 10 35
Case: IP #29 (also in row 15 table 6)
DiseaseAssertion: type 2A VWD
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs:
CaseHPOFreeRext: VWF:Ag [IU/dL] = 19; VWF:Ac [IU/dL] = 10; FVIII:C [IU/dL] = 35
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting:
GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.
PreviouslyPublished:
Gene: VWF
Variant: c.4145T>A p.Leu1382Gln
HGVS:
ClinVarID: not found
CAID: CA383504402
gnomAD: absent
33 Type2A(IIA)c.4513G>A p.Gly1505Arg 28 A2 htz Missense O 21 4 27
Case: IP #33
DiseaseAssertion: type 2A (IIA) VWD
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs: HP:0032442 - blood group O
CaseHPOFreeRext: VWF:Ag [IU/dL] = 21; VWF:Ac [IU/dL] = 4; FVIII:C [IU/dL] = 27
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting:
GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.
PreviouslyPublished:
Gene: VWF
Variant: c.4513G>A p.Gly1505Arg
HGVS:
ClinVarID: not found
CAID: CA383501612
gnomAD: absent
10,11 c.3922C > A p.Arg1308Ser 28 A1 htz Missense O/A 34/77 na/50 64
Case: IP #10 in type 2B VWD sub-cohort
DiseaseAssertion: type 2B VWD
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs: HP:0032442 - blood group O
CaseHPOFreeRext: VWF:Ag [IU/dL] = 34; VWF:Ac [IU/dL] = n/a; FVIII:C [IU/dL] = 64
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting:
GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.
PreviouslyPublished:
Gene: VWF
Variant: c.3922C>A p.Arg1308Ser
HGVS:
ClinVarID: not found
CAID: CA383506203
gnomAD: absent
7 Type2A (IIC)c.1855C>TN p.Arg619Cys 15 D2-C8-2htz Missense A 28 14 33
Case: IP #7 (also in row 4 table 6)
DiseaseAssertion: type 2A (IIC) VWD
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs: HP:0032370 - blood group A
CaseHPOFreeRext: VWF:Ag [IU/dL] = 28; VWF:Ac [IU/dL] = 14; FVIII:C [IU/dL] = 33
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting:
GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.
PreviouslyPublished:
Gene: VWF
Variant: c.1855C>T p.Arg619Cys
HGVS:
ClinVarID: not found
CAID: CA232310118
gnomAD: 0.000005855 (9 in 1537178) no homozygotes https://gnomad.broadinstitute.org/variant/12-6056947-G-A?dataset=gnomad_r4
66 Type2Ac.7060T>GN p.Cys2354Gly 41 C2 htz Missense na 56 39 89
Case: IP #66 (also in row 25 table 6)
DiseaseAssertion: type 2A VWD
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs:
CaseHPOFreeRext: VWF:Ag [IU/dL] = 56; VWF:Ac [IU/dL] = 39; FVIII:C [IU/dL] = 89
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.7060T>G p.Cys2354Gly
HGVS:
ClinVarID: not found
CAID: CA383491801
gnomAD: 6.196e-7 (1 in 1613900) no homozygotes https://gnomad.broadinstitute.org/variant/12-5983171-A-C?dataset=gnomad_r4
22 2N/1 c.2561G > Ac.2649C > G Np.Arg854Glnp.Tyr8832020D’-E’D3-VWD3htzhtzMissenseNonsensena 63 60 18
Case: IP #22 in type 2N VWD sub-cohort
DiseaseAssertion: type 2N VWD
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs:
CaseHPOFreeRext: VWF:Ag [IU/dL] = 63; VWF:Ac [IU/dL] = 60; FVIII:C [IU/dL] = 18
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting:
GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.
PreviouslyPublished:
Gene: VWF
Variant: c.2561G>A p.Arg854Gln
HGVS:
ClinVarID: 296
CAID:
gnomAD: 0.004956 (8000 in 1614214) 26 homozygotes https://gnomad.broadinstitute.org/variant/12-6034812-C-T?dataset=gnomad_r4
MultipleGeneVariants:
Gene: VWF
Variant: c.2649C>G p.Tyr883*
CAID: CA383520036
gnomAD: 6.195e-7 (1 in 1614176) no homozygotes https://gnomad.broadinstitute.org/variant/12-6034724-G-C?dataset=gnomad_r4
16 c.7694G > A N p.Cys2565Ser 45 C4 htz Missense na 44 31 34 CSA 39
Case: IP #16 in type 2M VWD sub-cohort (also in row 27 table 6)
DiseaseAssertion: type 2M VWD
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs:
CaseHPOFreeRext: VWF:Ag [IU/dL] = 44; VWF:Ac [IU/dL] = 31; FVIII:C [IU/dL] = 34; VWF:CB (IU/dL) = 39
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting:
GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.
PreviouslyPublished:
Gene: VWF
Variant: c.7694G>A p.Cys2565Ser
HGVS:
ClinVarID: not found
CAID: CA383489277
gnomAD: absent
10-12Type2A (IIE)c.3296G>AN p.Cys1099Tyr 25 D3-C8-3htz Missense O/na/A131/na/26532/na/44 117OSCA/na/183
Case: IP #12 (also in row 6 table 6)
DiseaseAssertion: type 2A (IIE) VWD
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs: HP:0032370 - blood group A
CaseHPOFreeRext: VWF:Ag [IU/dL] = 265; VWF:Ac [IU/dL] = 44; FVIII:C [IU/dL] = 183
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
37 Type2A(IIA)c.4541T>CN p.Phe1514Ser 28 A2 htz Missense B 22 14 27
Case: IP #37 ((also in row 17 table 6)
DiseaseAssertion: type 2A (IIA) VWD
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs: HP:0032440 - blood group B
CaseHPOFreeRext: VWF:Ag [IU/dL] = 22; VWF:Ac [IU/dL] = 14; FVIII:C [IU/dL] = 27
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting:
GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.
PreviouslyPublished:
Gene: VWF
Variant: c.4541T>C p.Phe1514Ser
HGVS:
ClinVarID: not found
CAID: CA383501434
gnomAD: absent
42 Type2A(IIA)c.4730A>CN p.Asn1577Thr 28 A2 htz Missense A 45 14.0 41
Case: IP #42 (also in row 20 table 6)
DiseaseAssertion: type 2A (IIA) VWD
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs: HP:0032370 - blood group A
CaseHPOFreeRext: VWF:Ag [IU/dL] = 45; VWF:Ac [IU/dL] = 14.0; FVIII:C [IU/dL] = 41
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting:
GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.
PreviouslyPublished:
Gene: VWF
Variant: c.4730A>C p.Asn1577Thr
HGVS:
ClinVarID: not found
CAID: CA383499838
gnomAD: absent
51-54Type2A(IIA)c.4811T>AN p.Val1604Asp 28 A2 htz Missense O/A/O/O27/24/35/328/9/11/755CSA/57CSA/62CSA/53
Case: IP #54 (also in row 21 table 6)
DiseaseAssertion: type 2A (IIA) VWD
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs: HP:0032442 - blood group O
CaseHPOFreeRext: VWF:Ag [IU/dL] = 32; VWF:Ac [IU/dL] = 7; FVIII:C [IU/dL] = 53
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting:
GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.
PreviouslyPublished:
Gene: VWF
Variant: c.4811T>A p.Val1604Asp
HGVS:
ClinVarID: not found
CAID: CA383499144
gnomAD: absent
213115LMWM−15Mc.1868G>A/c.3712C>Tp.C623T/p.Q1238X15/2816/17N/N
Case: Patient 21, M, Hungarian
DiseaseAssertion: VWD type 3
FamilyInfo: compatible with recessive inheritance
ParentalGenotype(s): n/a
CasePresentingHPOs: n/a
CaseHPOFreeRext: Bleeding score: 15, VWF:Ag (IU dL−1): 1, VWF:CB (IU dL−1): 1, FVIII:C (IU dL−1): 5, VWF:RCo below detection limit (<10 IU dL−1), low‐molecular‐weight multimer on multimer gels
CaseNOTHPOs: n/a
CaseNOTHPOFreeText: no inhibitor detected, did not become refractory to factor replacement therapy
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.1868G>A (p.Cys623Thr), Exon 15
c.3712C>T (p.Gln1238X), Exon 28
Intron 40 VNTR: 16/17
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
24351.57LMWM−14Mc.1786C>Ap.H596N1515/19N
Case: Patient 24, M, Hungarian
DiseaseAssertion: VWD type 3
FamilyInfo: compatible with recessive inheritance
ParentalGenotype(s): n/a
CasePresentingHPOs: n/a
CaseHPOFreeRext: Bleeding score: 14, VWF:Ag (IU dL−1): 5, VWF:CB (IU dL−1): 1.5, FVIII:C (IU dL−1): 7, VWF:RCo below detection limit (<10 IU dL−1), low‐molecular‐weight multimer on multimer gels (distribution of the very small amount of multimers seems almost normal)
CaseNOTHPOs: n/a
CaseNOTHPOFreeText: no inhibitor detected, did not become refractory to factor replacement therapy, gene dosage analysis performed in exon 3 gave normal results
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.1786C>A (p.His596Asn), Exon 15
Intron 40 VNTR: 15/19
SNPs, sequenced throughout the VWF gene (Table S1) were heterozygous and homozygous alternately
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
The proband
Case#: 1, Male, Age 12, Caucasian (Proband), Blood type O
Disease Assertion: VWD2M
FamilyInfo: Mother with clinical symptoms (see case #2). 40 year old father and sister had no bleeding symptoms. Parents had a non-consanguineous relationship, Table 1
Parental Genotype: Heterozygous mother, normal father
CasePresentingHPOs: HP:0000421, HP:0000978, HP:0004846, HP:0000225
(Epistaxis, Bruising susceptibility, Prolonged bleeding after surgery, Gingival bleeding)
CaseHPOFreeText: Bleeding in the central nervous system, Epistaxis required tamponades, bleeding score 14, VWF:RCo: 9 IU/dL, VWF:Ag: 17 IU/dL, RCo/Ag: 0.53, Absence of response to DDAVP infusion
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
Protein Expression: N/A
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) and NM_000552.3:c.4944del (p.Ile1649Serfs?)
ClinVar: 100407 (for c.4944delT) ClinVarID website
CAID: CA6402561 and CA228684
gnomAD: MAF of 0.00006152 (1/16254 alleles) in the African population for CA6402561. MAF of 0.00005440 (1/18384 alleles) in the East Asian population for CA228684.
c.8318 G > C, p.Cys2773Ser mutation
Case: Moreno-Castano_2021_Case_1, female, age 21 at time of study
DiseaseAssertion: VWD2A
FamilyInfo: The phenotypes of the affected propositus, the two unaffected parents, and the unaffected sibling are documented in Table I and Figure 1, while the family relationsihps and genotypes are not shown but described.
ParentalGenotype(s): The parental genotypes are negative for the variant, indicating that the variant is likely de novo in the proband.
CasePresentingHPOs: HP:0030129 (Impaired ristocetin cofactor assay activity), HP:0011871 (Impaired ristocetin-induced platelet aggregation), HP:0040225 (Decrease in high molecular weight von Willebrand factor Multimers), HP:0000978 (Bruising susceptibility), HP:0000421 (Epistaxis)
CaseHPOFreeText: Low VWF:RCo/VWF:Ag ratio
CaseNOTHPOs: HP:0030976 (Abnormal factor VIII activity)
CaseNOTHPOFreeText: Normal / slightly higher VWF antigen level
CasePreviousTesting: Because of the detailed clinical phenotype, genotyping was limited to the VWF locus alone.
GenotypingMethod: Genotyping consisted of PCR amplification and Sanger sequencing of the 52 exons of the VWF gene, as well as linkage analysis using four STRs located within the VWF locus.
PreviouslyPublished: The case appears to have been first published in PMID: 28971901.
Gene: VWF
Variant: NM_000552.5(VWF):c.8318G>C (p.Cys2773Ser)
ClinVarID: 100503
gnomAD: This variant is absent from gnomAD v2.1.1 and v3.1.2.
T076M/12230.010.030.01c.1897T>Cp.Cys633Arg15Homozygous
Case: T076, M, 12
DiseaseAssertion: VWD type 3
FamilyInfo: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: Bleeding Score: 23 (Kruskal–Wallis followed by Mann–Whitney U post-hoc testing Post-hoc testing ), VWF:Ag (IU/ml): 0.01, VWF:RCo (IU/ml): 0.03, FVIII:C (IU/ml): 0.01
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.1897T>C (p.Cys633Arg ), Exon 15, Homozygous
Note: ELISA-based assay for detecting alloantibodies, genomic analysis via sequencing of leukocytes for the VWF gene including exons 1-52 and about 1.5 km of VWF promoter, PCR amplification for variant confirmation, SALSA-MLPAVWF assay evaluation for partial/total gene deletions when sequencing did not reveal pathogenic explanation
T046F/16210.010.040.02c.385C>A, c.813C>Ap.Leu129Met, p.Tyr271*5/7Compound heterozygous
Case: T046, F, 16
DiseaseAssertion: VWD type 3
FamilyInfo: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: Bleeding Score: 21 (Kruskal–Wallis followed by Mann–Whitney U post-hoc testing Post-hoc testing ), VWF:Ag (IU/ml): 0.01, VWF:RCo (IU/ml): 0.04, FVIII:C (IU/ml): 0.02
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.385C>A (p.Leu129Met), Exon 5
c.813C>A (p.Tyr271*), Exon 7
Compound heterozygous
Note: ELISA-based assay for detecting alloantibodies, genomic analysis via sequencing of leukocytes for the VWF gene including exons 1-52 and about 1.5 km of VWF promoter, PCR amplification for variant confirmation, SALSA-MLPAVWF assay evaluation for partial/total gene deletions when sequencing did not reveal pathogenic explanation
6
Case#: 6, male, 20yo
DiseaseAssertion: VWD1
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: HP:0000421, HP:0004846, HP:0012147, HP:0030129, HP:0030130 (Epistaxis, Reduced quantity of VWF, Impaired ristocetin cofactor assay activity, Impaired von Willebrand factor collagen binding activity)
CaseHPOFreeText: posttraumatic muscle and joint bleeds, Type O blood, VWF:Ag (0·55–2 iu/ml) pre = 0·34, VWF:RCo (0·55–2 iu/ml) pre = 0·24, FVIII:C (0·55–2 iu/ml) pre = 0·24, FVIII:C/VWF:Ag ratio = 0·71, VWF:FVIII binding (>20%) = 16%, VWF:FVIII binding/VWF:Ag (>0·7) = 0·47
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
p.Val1316Met
PMID:32618441
Gene: VWF
HGNCID:12726
Case:6 days old female infant
DiseaseAssertion:Type 2B
FamilyInfo:Her family history included no family members with low platelet levels or with bleeding diathesis.
ParentalGenotype(s):Negative for mutation by Sanger sequencing
CasePresentingHPOs:HP:0001873
CaseHPOFreeRext:Petechiae on her body and subependymal hemorrhage and bilateral intraventricular hemorrhage on US
GenotypingMethod:NGS
Gene:VWF
Variant:De Novo p.Val1316Met
HGVS:NP_000543.3:p.Val1316Met
ClinVarID:290
CAID:CA114127
gnomAD:6.20e-7
a missense mutation (p.Arg924Gln) was combined with a large deletion spanning exons 1–5
Case: IP-3
DiseaseAssertion: VWD3
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0000421, HP:0000132
CaseHPOFreeRext: VWF:Ag 1%, VWF:RCo 5% and FVIII:C 1,4%. Repetitive epistaxis, cutaneous and muscles hematomas, postpartum bleedings and a heavy menorrhagia.
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: Direct sequencing of exons 2–52 including exon/intron boundaries of the VWF gene
GenotypingMethod: multiple ligation‐dependent probe amplification (MLPA; using kit P011 and P012; MRC Holland, Amsterdam, the Netherlands) according to the manufacturer’s instructions. The PCR products were run on an ABI PRISM 3130XL sequencer with the GeneScan 500 LIZ size standard and analyzed using GeneMapper Software 5.0 (Applied Biosystems, Darmstadt, Germany). Dosage analysis based on a comparison between deleted and reference wild‐type DNA samples was performed using the Excel‐based software Coffalyser V9.4 (MRC Holland).
PreviouslyPublished: NA
Gene: VWF
Variant: deletion of exons 1-5
HGVS:
ClinVarID:
CAID:
gnomAD:
MultipleGeneVariants:
Gene: VWF
Variant: p.Arg924Gln
HGVS: NM_000552.5:c.2771G>A (p.Arg924Gln)
ClinVarID: 100240
CAID: CA228368
gnomAD: MAF of 0.02225 (26260/118006 alleles) in Eurpoean (non-Finnish)
https://gnomad.broadinstitute.org/variant/12-6031493-C-T?dataset=gnomad_r4
type 3‐VWD patient
Case:44‐year‐old male patient
DiseaseAssertion:type 3‐VWD patient
FamilyInfo:positive family hsiory: The proband and his sister both had low FVIII:C (1 IU/dL) and VWF:Ag (3 IU/dL) levels, confirming the diagnosis of type 3 VWD. His father had nearly normal levels of FVIII:C (58 IU/dL) and VWF:Ag (57 IU/dL). His daughter had type 1 VWD with decreased FVIII:C (46 IU/dL) and VWF:Ag (19 IU/dL)., NGS identified a heterozygous VWF c.2328delT (p.A778Lfs*23) frame shift mutation only in the proband and his sister
ParentalGenotype(s):VWF missense mutation, c.6521G > T (p.C2174F), was found heterozygous in father, but mother not tested
CasePresentingHPOs:BAT score=16, Arterial thrombosis=ischemic stroke, FVIII:C*=1, VWF:Ag=3, Proein S:58, Protein C:100, antithrombin III=106, activated protein C resistance:2.9. CaseHPOFreeRext: Complete blood count showed normocytic anemia (hemoglobin 74 g/L), normal white cell (and differential), and platelet counts. He had prolonged activated partial thromboplastin time (APTT) (89.4 s (s) [reference range (RR), 28.0–44.0 s]) with greatly decreased FVIII:C (1 IU/dL) and VWF:Ag (3 IU/dL) (Table 1). Abdominal ultrasound scanning revealed fatty liver, normal gallbladder, spleen, pancreas, and kidneys. Four hundred ml of virus inactivated fresh frozen plasma (FFP) was transfused, and his VWF:Ag increased to 6 IU/dL. On Day 2 after admission, the patient abruptly experienced numbness and weakness in his right limb.
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting:n.a
GenotypingMethod:NGS
PreviouslyPublished: If applicable.
Gene: VWF
Variant:c.2328delT (p.A778Lfs*23) and c.6521G > T (p.C2174F)
HGVS:n.a.
ClinVarID:n.a.
CAID:n.a.
gnomAD: n.a.
In 1986, a preliminary report described a girl
Case1: Female, 22 years old, ethnicity not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: See Fig 1
ParentalGenotype: The patient's parents revealed reduced concentrations of glycoprotein llb-Illa and were considered to be heterozygotes. See Fig 1
CasePresentingHPOs: HP:0000421, HP:0000225, HP:0000132, HP:0000978
(Severe epistaxis, gingival bleeding, menorrhagia, spontaneous bruising)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
ProteinExpression: Platelets had much reduced alphaIIb3 when estimated by crossed immunoelectrophoresis
PlateletAggregation: Platelet aggregation was absent with ADP, arachidonic acid, and collagen.
CasePreviousTesting: Sequenced all exons and splice sites of ITGA2B and ITGB3
Gene: ITGA2B
Variant: NM_000419.3:c.1073G>A (p.Arg358His) and NM_000419.3:c.1234G>A (p.Gly412Arg)
LegacyVariant: (p.Arg327His) and (p.Gly381Arg)
ClinVar: 2896 and 381748
CAiD: CA115839 and CA8603182
gnomAD: MAF in the Latino population is 0.0001453 https://gnomad.broadinstitute.org/variant/17-42458406-C-T
PreviouslyPublished: PMID: 3762006 proband is mentioned in this article
RS
Case37: Patient RS
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: HP:0000421, HP:0000225, HP:0000132
(Epistaxis, gingival bleeding, menorrhagia)
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.1260G>A and the other variant won't show up in CAR
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA8623200
gnomAD: MAF in the African population is 0.00004005 https://gnomad.broadinstitute.org/variant/17-45368454-G-A
PreviouslyPublished: Reference 60
Substitution49CMVariantHomozygote718C
Case30: Patient CM
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: HP:0000421, HP:0000225, HP:0000132
(Epistaxis, gingival bleeding, menorrhagia)
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.718C>T (p.Arg240Trp)
LegacyVariant: N/A
ClinVar: 13555
CAiD: CA123228
gnomAD: MAF in the East Asian population is 0.00005437 https://gnomad.broadinstitute.org/variant/17-45363729-C-T
PreviouslyPublished: Reference 48 and 49
SH
Case32: Patient SH
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: 20% GPIIIa and GPIIb surface expression
PlateletAggregation: N/A
CasePreviousTesting: N/A
Gene: ITGB3
Variant: NM_000212.2:c.725G>A (p.Arg242Gln)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA291224896
gnomAD: N/A
PreviouslyPublished: Reference number 5 in this article
The patient
Case1: Female, 5 years old, Swiss (from Morocco)
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Affected brother
ParentalGenotype: Mother and father are heterozygous for the variant of interest
CasePresentingHPOs: HP:0001250, HP:0001270, HP:0000967, HP:0001892
(Seizures, retarded motor development, petechia, hemorrhagic diathesis)
CaseHPOFreeText: Subepndymal hematomas, cortical tubera, hydrocephalus internus
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometry protein expression results can be seen in Figure 1
PlateletAggregation: Platelets failed to aggregate with ADP, collagen, or arachidonic acid; however, ristocetin induced platelet agglutination was normal
CasePreviousTesting: Amplified DNA fragments containing exon 11 of the GPIIIa gene were purified by PCR preps DNA purification resin and wizard.
Gene: ITGB3
Variant: NM_000212.2:c.1702T>C (p.Cys568Arg)
LegacyVariant: (p.Cys542Arg)
ClinVar: N/A
CAiD: CA400032350
gnomAD: N/A
G
Case7: Patient ID G, Female, 1 year old, ethnicity not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A (Table 1 does mention family history of bleeding)
ParentalGenotype: N/A (Parents are consangenous)
CasePresentingHPOs: HP:0000978, HP:0004406, HP:0000225)
(Easy bruising, recurrent epistaxis, gingival bleeding)
CaseHPOFreeText: Ear bleeding
CaseNotHPOs: HP:0000967, HP:0000979, HP:0002239, HP:0002239, HP:0000790, HP:0005261, HP:0002248
(Petechiae, purpura, GI bleeding, intracranial hemorrhage, hematuria, hemarthrosis, hematemesis)
CaseNotHPOsFreeText: Hemorrage after dental, hemorrhage after trauma, hematoma
ProteinExpression: N/A
PlateletAggregation: Defective response to ADP, adrenaline, collagen, arachidonic acid, and normal response to ristocetin
CasePreviousTesting: Exon PCR was used to amplify a;; coding regions of the ITGA2B and ITGB3 genes. PCR products were purified and Sanger sequenced. Segregation using parental samples was undertaken when available.
Gene: ITGA2B
Variant: NM_000419.3:c.1652G>A
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA8602986
gnomAD: MAF in South Asian population is 0.00006536 http://gnomad.broadinstitute.org/variant/17-42457470-C-T
PreviouslyPublished: PMID: 19172520
A
Case1: Patient ID A, Male, 6 years old, ethnicity not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A (Parents are consangenous)
CasePresentingHPOs: HP:0000978, HP:0002239
(Easy bruising, gastrointestinal bleeding)
CaseHPOFreeText: N/A
CaseNotHPOs: HP:0000967, HP:0000979, HP:0004406, HP:0000225, HP:0002239, HP:0000790, HP:0005261
(Petechiae, purpura, recurrent epistaxis, gingival bleeding, intracranial hemorrhage, hematuria, hemarthrosis)
CaseNotHPOsFreeText: Hemhorrage after dental, hemhorrage after trauma, ear bleeding, hematoma
ProteinExpression: N/A
PlateletAggregation: Defective response to ADP, adrenaline, collagen, arachidonic acid, and normal response to ristocetin
CasePreviousTesting: Exon PCR was used to amplify a;; coding regions of the ITGA2B and ITGB3 genes. PCR products were purified and Sanger sequenced. Segregation using parental samples was undertaken when available.
Gene: ITGA2B
Variant: NM_000419.3:c.435C>A (p.Asn145Lys) and NM_000419.3:c.531T>A (p.Cys177Ter)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA399805991 and CA290955739
gnomAD: N/A
PreviouslyPublished: PMID: 20020534
Supplementary Tables 1 and 2 combined information:
Case30: GT30, Female, 13
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, HP:0000132
(Bruising, purpura, ecchymosis, epistaxis, gingival bleeding, menorrhagia)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Showed <5% of αIIbβ3 expression measured by flow cytometry
PlateletAggregation: Platelet aggregation showed no response to ADP and collagen but normal response to ristocetin
CasePreviousTesting: All exons from ITGA2B and ITGB3 genes were amplified by PCR using intronic primers. DNA sequencing was determined by Sanger sequencing.
Gene: ITGA2B
Variant: NM_000419.3:c.2330C>A (p.Ala777Asp) and NM_000419.3:c.2602-3C>G (no protein notation given)
LegacyVariant: N/A
ClinVar: 2893 (c.2602-3C>G)
CAiD: CA399796685 (p.Ala777Asp) and CA10575472 (c.2602-3C>G)
gnomAD: MAF for East Asian population: 0.00006523 https://gnomad.broadinstitute.org/variant/17-42453087-G-C
Supplementary Tables 1 and 2 combined information:
Case17a: GT17a, Female, 14 years old, sister of GT17b proband
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Available per supplementary table 1
ParentalGenotype: Parents are not consanguineous, no other genotype information available
CasePresentingHPOs: HP:0000978, HP:0000979, HP:0031364, HP:0000421
(Bruising, purpura, ecchymosis, epistaxis)
CaseHPOFreeText: Post traumatic hemorrhage
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Showed <5% of αIIbβ3 expression measured by flow cytometry
PlateletAggregation: Platelet aggregation showed a small response to ADP and collagen but normal response to ristocetin
CasePreviousTesting: All exons from ITGA2B and ITGB3 genes were amplified by PCR using intronic primers. DNA sequencing was determined by Sanger sequencing.
Gene: ITGA2B
Variant: NM_000419.3:c.799+2T>C and NM_000419.3:c.2671C>T (p.Gln891Ter)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA399805155 (c.799 +2 T>C) and CA8602626 (p.Gln891Ter)
gnomAD: N/A
Supplementary Tables 1 and 2 combined information:
Case25: GT25, Female, 26 years old
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Not available per supplementary table 1
ParentalGenotype: Parents are not consanguineous, no other genotype information available
CasePresentingHPOs: HP:0000421, HP:0000225, HP:0000132, HP:0000789,
(Epistaxis, gingival bleeding, menorrhagia, infertility)
CaseHPOFreeText: Rupture of corpus luteum
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Showed <5% of αIIbβ3 expression measured by flow cytometry
PlateletAggregation: Platelet aggregation showed no response to ADP and collagen but normal response to ristocetin
CasePreviousTesting: All exons from ITGA2B and ITGB3 genes were amplified by PCR using intronic primers. DNA sequencing was determined by Sanger sequencing.
Gene: ITGB3
Variant: NM_000212.2:c.1495T>C (p.Cys499Arg)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA400029525
gnomAD: N/A
Supplementary Tables 1 and 2 combined information:
Case19: GT19, Female, 32 years old
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Not available per Table 1.
ParentalGenotype: Parents are consanguineous, no other genotype information available
CasePresentingHPOs: HP:0000421, HP:0000225, HP:0000790, HP:0000132
(Epistaxis, gingival bleeding, hematuria, menorrhagia)
CaseHPOFreeText: Post traumatic hemorrhage
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Showed <5% of αIIbβ3 expression measured by flow cytometry
PlateletAggregation: Platelet aggregation showed no response to ADP and collagen but normal response to ristocetin
CasePreviousTesting: All exons from ITGA2B and ITGB3 genes were amplified by PCR using intronic primers. DNA sequencing was determined by Sanger sequencing.
Gene: ITGA2B
Variant: NM_000419.3:c.1234G>A (p.Gly412Arg)
LegacyVariant: N/A
ClinVar: 381748
CAiD: CA8603182 (p.Gly412Arg)
gnomAD: MAF in Latino population: 0.0001453 https://gnomad.broadinstitute.org/variant/17-42458406-C-T
Supplementary Table S1 & S2 Proband and Variant Information:
Case68: GT72, Female, 56 years old, French
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: HP:0000421, HP:0031364, HP:0000225, HP:0000132, HP:0002239, HP:0006298
(Epistaxis, ecchymosis, gingival bleeding, menorrhagia, GI bleeding, prolonged bleeding after dental extraction)
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.2951C>A (P.Thr984Lys)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA399790180
gnomAD: N/A
Supplementary Table S1 & S2 Proband and Variant Information:
Case52: GT52, Male, 24 years old, Argentenian/Brazil
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: HP:0000421
(Epistaxis)
CaseHPOFreeText: Hematomas
(Proband's symptoms decreased during adolescence)
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:
Case60: GT62, Female, 58 years old, French
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Affected sister (that is all the information we are given)
ParentalGenotype: N/A
CasePresentingHPOs: HP:0000978, HP:0000225, HP:0000132, HP:0006298
(Easy bruising, gingival bleeding, menorrhagia, bleeding after dental extraction)
CaseHPOFreeText: Esophageal bleeding
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.31T>C (p.Trp11Arg)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA291240306
gnomAD: N/A
Supplementary Table S1 & S2 Proband and Variant Information:
Case15: GT18, Male, 20, French
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: HP:0031364, HP:0000978
(Ecchymosis, easy bruising)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometry showed 10% expression of αIIbβ3 (See Supplementary Table 1)
PlateletAggregation: Residual platelet aggregation (See Supplementary Table 1)
CasePreviousTesting: Sanger sequencing of ITGA2B and ITGB3
Gene: ITGA2B
Variant: NM_000419.3:c.1201G>T (pGly401Cys) andNM_000419.3:c.2800G>T (p.Val934Phe)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA399804280 and CA290946484
gnomAD: N/A
Supplementary Table S1 & S2 Proband and Variant Information:
Case31: GT35a, Female, 18 years old, USA
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Affected sister who is 35 b in this study (See Supplementary Table S1)
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 and ITGB3
Variant: ITGB3: NM_000212.2:c.392G>C (p.Arg131Pro) and NM_000212.2:c.777+1G>A ITGA2B: NM_000419.3:c.2264G>A (p.Arg755Gln)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA8622954, CA8623036, CA8602771
gnomAD: MAF in the African population is 0.00006152 http://gnomad.broadinstitute.org/variant/17-45361839-G-C, MAF in the Latino population is 0.0006774 http://gnomad.broadinstitute.org/variant/17-45363789-G-A, MAF in the Latino population is 0.0001903 http://gnomad.broadinstitute.org/variant/17-42454380-C-T
Supplementary Table S1 & S2 Proband and Variant Information:
Case53: GT53, Male, 16 years old, Argentenian/Brazilian
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: HP:0000421
(Epistaxis)
CaseHPOFreeText: Hematomas
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.356G>A (p.Gly201Ser) and NM_000212.2:c.1697G>A (p.Arg119Gln)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA8622925 and CA400032338
gnomAD: MAF in the African population is http://gnomad.broadinstitute.org/variant/17-45360910-G-A
Patient‐III4
Case1: Male, Israeli-Arab, (age is either 10 or 14)
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: See Fig 1C for pedigree
ParentalGenotype: See Fig 1C for pedigree
CasePresentingHPOs: HP:0000421, HP:0031364, HP:0000967
(Severe epistaxis, ecchymosis, petechiae)
CaseHPOFreeText: Decline of hemoglobin levels to 5 g dl each time epistaxis occurred
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
ProteinExpression: No surface expression of αIIbβ3 was found in patients’ platelets (See Fig 3)
PlateletAggregation: N/A
CasePreviousTesting: DNA fragments containing exons and flanking intronic regions of the aIIb and B3 genes were amplified by PCR using primers
Gene: ITGA2B
Variant: NM_000419.3:c.97A>G (p.Asn2Asp)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA399806951
gnomAD: N/A
brother (3years younger) was quickly shown also to have both GT and MTP (Figure1A) with epistaxis the main cause of his bleedin
Case2:
DiseaseAssertion: Glanzmann Thrombesthenia and Macrothrombocytopenia (MTP)
FamilyInfo: Case1 (his older sister) and no parental information.
ParentalGenotype: N/A
CasePresentingHPOs: HP:0000421, HP:0011877
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: No information for the brother on protein expression.
CasePreviousTesting: As a part of an initial testing of this patient's gene panel (not specified which genes), DNA from this patient was submitted to ThromboGenetics in Cambridge UK. While confirming the two ITGB3 mutations described, an additional finding was a heterozygous mutation in TUBB1.
Gene: ITGB3
Variant: NM_000212.2:c.565C>T and NM_000212.2:c.629G>C
LegacyVariant: N/A
ClinVar: 2890
CAiD: CA291224669 and CA400023389, respectively as written in variant section.
gnomAD: Maximum allele frequency for the variant NM_000212.2:c.565C>T: 0.00002638 https://gnomad.broadinstitute.org/variant/17-45362012-C-T
Patient LD
Case1: (Patient LD) Female, 3 years old, ethnicity not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: See Fig 4 for family pedigree
ParentalGenotype: Father is heterozygous for GC867-G and Mother is heterozygous for T882C (See Fig 4)
CasePresentingHPOs: HP:0000967, HP:0031364, HP:0000978, HP:0000225
(Petechiae, ecchymosis, bruising, gingival bleeding)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Fig 2A shows reduced expression (See Fig2A)
PlateletAggregation: Platelets did not aggregate in response to ADP, epinephrine, or arachidonic acid and showed only shape change in response to collagen. Platelets did agglutinate with ristocetin.
CasePreviousTesting: Genomic DNA was prepared from peripheral blood leukocytes and amplified by polymerase chain reaction (PCR) with Taq polymerase by using oligonucleotide primers from intronic flanking sequences of αIIb and β3. All exons of both genes were sequenced at least twice to exclude Taq errors.
Gene: ITGB3
Variant: NM_000212.2:c.863T>C (p.Leu288Pro) and NM_000212.2:c.847_848del
LegacyVariant: (p.Leu262Pro)
ClinVar: N/A
CAiD: CA400024958 and CA8623068
gnomAD: for c.847_848del https://gnomad.broadinstitute.org/variant/17-45364504-AGC-A
Case10: Patient PL, 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_000419.3:c.1742C>A (p.Ala581Asp)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA399802112
gnomAD: N/A
Case15: Patient CE, 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_000419.3:c.2113T>C (p.Cys705Arg)
LegacyVariant: (p.Arg674Arg)
ClinVar: N/A
CAiD: CA8602816
gnomAD: MAF in the European (non-Finnish) population is 0.000008792 https://gnomad.broadinstitute.org/variant/17-42455140-A-G
GT-30
Case25: (GT-30) Female, age or ethnicity not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Proband GT30 is related to GT29
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Bleeding severity: Moderate (See Supplementary Table 3)
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometry performed and CD41 and CD61 were observed (See Supplementary Table 3)
PlateletAggregation: Minimal information (See Supplementary Table 3)
CasePreviousTesting: DNA was extracted from peripheral blood samples from patients and family members, and Sanger sequencing and PCR was performed. Samples were processed for targeted sequencing using the available SHGp heme panel of 393 genes.
Gene: ITGA2B
Variant: NM_000419.3:c.1651C>T (p.Arg551Trp)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA399802348
gnomAD: MAF in the East Asian population is 0.00005045 http://gnomad.broadinstitute.org/variant/17-42457471-G-A
GT-44b
Case34: (GT-44) Female, age or ethnicity not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Proband GT43-GT44 are related
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Bleeding severity: Information not available (See Supplementary Table 3)
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometry performed and CD41 and CD61 were observed (See Supplementary Table 3)
PlateletAggregation: Minimal information (See Supplementary Table 3)
CasePreviousTesting: DNA was extracted from peripheral blood samples from patients and family members, and Sanger sequencing and PCR was performed. Samples were processed for targeted sequencing using the available SHGp heme panel of 393 genes.
Gene: ITGA2B
Variant: NM_000419.3:c.1620G>C (p.Gln540His) and NM_000419.3:c.1616T>G (p.Leu539Arg)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA399802407 and CA399802416
gnomAD: N/A
GT-73c
Case54: (GT-73) Gender, age, or ethnicity not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Bleeding severity: Information not given (See Supplementary Table 3)
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometry performed and CD41 and CD61 were observed (See Supplementary Table 3)
PlateletAggregation: Minimal information (See Supplementary Table 3)
CasePreviousTesting: DNA was extracted from peripheral blood samples from patients and family members, and Sanger sequencing and PCR was performed. Samples were processed for targeted sequencing using the available SHGp heme panel of 393 genes.
Gene: ITGB3
Variant: NM_000212.2:c.985A>G (p.Asn329Asp)
LegacyVariant: N/A
ClinVar: 323865
CAiD: CA8623107
gnomAD: MAF in Other population 0.0005534 http://gnomad.broadinstitute.org/variant/17-45367092-A-G
GT-14b
Case12: (GT-14) Female, carrier, age or ethnicity not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Probands GT11 -GT13 are related to GT-14 see Table 1
ParentalGenotype: Parents may be included in Table 1; however, not specified so no information
CasePresentingHPOs: N/A
CaseHPOFreeText: Bleeding severity: Not available (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-27
Case23: (GT-27) Male, age or ethnicity not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Proband GT28 is related to this proband GT 27; however, no DNA was available for testing for GT28.
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Bleeding severity: Moderate (See Supplementary Table 3)
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometry performed and CD41 and CD61 were observed (See Supplementary Table 3)
PlateletAggregation: Minimal information (See Supplementary Table 3)
CasePreviousTesting: DNA was extracted from peripheral blood samples from patients and family members, and Sanger sequencing and PCR was performed. Samples were processed for targeted sequencing using the available SHGp heme panel of 393 genes.
Gene: ITGB3
Variant: NM_000212.2:c.1835G>A
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA400032647
gnomAD: N/A
A gastrointestinal patient
Case1: Male, 6 years old, ethnicity not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo:
ParentalGenotype: "No platelet sample from the patient's mother and father were available"
CasePresentingHPOs: N/A
CaseHPOFreeText: Mild spontaneous mucocutaneous bleeding
CaseNotHPOs: N/A
ProteinExpression: Assessment of surface expression of αIIBβ3 D217 and αIIBβ3 V217 by flow cytometry was performed. αIIb and β3 were expressed at normal levels.
Platelet Aggregation: Absence of platelet aggregation in response to agonists such as ADP, epinephrine, or collagen and a normal response to ristocetin
CasePreviousTesting: Sequencing of αIIb and β3 genes revealed a homozygous missense A>T point mutation in the β3 gene leading to a D217Val substitution.
Gene: ITGB3
Variant: NM_000212.2:c.728A>T (p.Asp243Val)
LegacyVariant: (p.Asp217Val)
ClinVar: N/A
CAiD: CA400023604
gnomAD N/A
GT1
Case1: GT-1, Female, Catalan, age not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Affected sister (GT-1) and brother (GT-3)
ParentalGenotype: N/A
CasePresentingHPOs: HP:0000421
(Epistaxis)
CaseHPOFreeText: Hemorrhage associated with deciduous tooth loss
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Standard glycoprotein analysis confirmed the absence of αIIbβ3 in their platelets but while western blotting failed to reveal αIIb, residual β3 was at about 10% of usual levels and of normal migration (illustrated for GT1 in supplemental Figure 1).
PlateletAggregation: Platelets of all 3 patients failed to aggregate in response to a range of physiologic agonists but were agglutinated by ristocetin. Clot retraction was also defective.
CasePreviousTesting: Screened ITGA2B and ITGB3 genes of all three probands. Direct sequencing of all coding regions and splice sites of ITGA2B (30 exons) showed mutation.
Gene: ITGA2B
Variant: NM_000419.3:c.131G>T and NM_000419.3:c.1440-13_1440-1del
LegacyVariant: (p.Gly13Val)
ClinVar: N/A
CAiD: CA399806881 and CA913184940
gnomAD: N/A
M/14
Case6: Male, 14 years old, Tamil Nadu India
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: HP:0000225, HP:0006298, HP:0000967
(Gingival bleeding, prolonged bleeding after tooth extraction, petechiae)
CaseHPOFreeText: N/A
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.1651C>T (p.Arg551Trp)
LegacyVariant: (p.Arg520Trp)
ClinVar: N/A
CAiD: CA399802348
gnomAD: MAF in the East Asian population is 0.00005045https://gnomad.broadinstitute.org/variant/17-42457471-G-A
Supplementary Table S1:
Case34: GT40, Canadian/Pakistani, 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.857T>A (p.Val286Asp)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA399805011
gnomAD: N/A
Supplementary Table S1:
Case6: GT7, French, gender and age not specified
DiseaseAssertion: Glanzmann thrombasthenia type I
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: All patients had a life-long history of mucocutaneous bleeding
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: All patients in this study met the clinical and platelet function requirements for GT-- this includes an absent or strongly reduced expression of alphaIIbBeta3 in platelets
PlateletAggregation: All patients in this study met the clinical and platelet function requirements for GT-- this includes absent or severely reduced platelet aggregation with at least three physiological agonists
CasePreviousTesting: Sanger sequencing was performed. Sanger sequencing ensured coverage of all exons and splice sties of the ITGA2B and ITGB3 genes and extended 300-500 bp into the introns as well as including the UTR. They sequenced 416 bp upstream of the ITGA2B promoter and 463 bp upstream of the ITGB3 promoter. In total they sequenced 51.2% of the ITGA2B gene and 19.4% of the larger ITGB3 gene
Gene: ITGB3
Variant: NM_000212.2:c.187C>T (p.Arg63Cys) and NM_000212.2:c.505C>T (p.Arg169Ter)
LegacyVariant: N/A
ClinVar: 631774
CAiD: CA8622892 and CA291224658
gnomAD: MAF in the East Asian population is 0.00005012 https://gnomad.broadinstitute.org/variant/17-45360741-C-T
GT1
Case1: (GT1), Male, 60 years old, French Gypsy
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Mucocutaneous bleeding defects
CaseNotHPOs: N/A
ProteinExpression: <5% 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.1031A>C (p.Tyr344Ser)
LegacyVariant: (p.Tyr318Ser) (The paper gives legacy and current nomenclature)
ClinVar: N/A
CAiD: CA400025814
gnomAD N/A
Supplemental Table S1:
Case2: Female, India, age not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: N/A
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.1520C>G (p.Pro507Arg)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA399802643
gnomAD: N/A
PreviouslyPublished: PMID: 16463284
Supplemental Table S1:
Case4: Male, India, age not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Bleeding from multiple sites
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.1651C>T (p.Arg551Trp)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA399802348
gnomAD: MAF in the East Asian population is 0.00005045 https://gnomad.broadinstitute.org/variant/17-42457471-G-A
PreviouslyPublished: PMID: 16879215
The patient
Case1: Female, 21 years old, ethnicity not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Blood samples collected from brother, no other information provided
ParentalGenotype: Father heterozygous: NM_000419.3:c.258G>C and mother heterozygous: NM_000419.3:c.2334A>C
CasePresentingHPOs: HP:0000421, HP:0000979
(Epistaxis, purpura)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometry analysis and western blot analysis showed a remarkable reduction in aIIb b3 and aIIb, and a moderate reduction in b3 in the platelets of the patient (data not shown)
PlteletAggregation: N/A
CasePreviousTesting: Nucleotide sequences of aIIb cDNA and b3 cDNA amplified by reverse transcription polymerase chain reaction (RT-PCR) were analyzed
Gene: ITGA2B
Variant: NM_000419.3:c.258G>C (p.Leu86Pro) and NM_000419.3:c.2334A>C
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA500624524 and CA399796662
gnomAD: N/A
GT16
Case20: GT16, Female, India, age of onset is 11 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 60-2
Case36: GT60-2, Female, India, age of onset is 25 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
Patient TK
Case1: (Patient TK) Male, 5 years old, Japanese
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: The (p.His280Pro) mutation was inherited from his mother and the (p.Gly579Ser) mutation was inherited from his father
CasePresentingHPOs: N/A
CaseHPOFreeText: All patients (3 in this study) had suffered from a bleeding diathesis since early childhood
CaseNotHPOs: NA
ProteinExpression: The surface expression of the alphaIIbbeta complex on the patients' platelets was quantitated by flow cytometry. The level of antigen expression for TK was 19.9%
Platelet Aggregation: Absent platelet aggregation in response to ADP, collagen, and epinephrine, but normal platelet agglutination in response to ristocetin
CasePreviousTesting: The nucleotide sequences of the aIIb and b3 coding regions were determined by direct sequencing of RT-PCR products from platelet RNA
Gene: ITGB3
Variant: NM_000212.2:c.917A>C (p.His206Pro) and NM_000212.2:c.1813G>A (p.Gly605Ser) (See Table 1 to see zygosity statement, "double heterozygote for both variants")
LegacyVariant: (p.His280Pro) and (p.Gly579Ser)
ClinVar: N/A
CAiD: CA291224999 and CA291227621
gnomAD MAF in the East Asian population for (p.His206Pro) is 0.00005437 https://gnomad.broadinstitute.org/variant/17-45364575-A-C and MAF in East Asian population for (p.Gly605Ser) is 0.00005437 https://gnomad.broadinstitute.org/variant/17-45376796-G-A
GT45
Case10: (GT45) Gender, age and ethnicity not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Inclusion criteria were patients with a history of mucocutaneous bleeding (Figure 1 shows a bar diagram of all the clinical manifestations in the patient cohort in this article)
CaseNotHPOs: N/A
ProteinExpression: Platelet receptor alphaIIbbeta3 protein was analyzed by flow cytometry followed by western blotting
Platelet Aggregation: Inclusion criteria for probands was absent or reduced platelet aggregation with agonists such as ADP, adrenaline, arachidonic acid, and collagen (no mention of ristocetin here-- this article does not tell us the specific aggregation for each proband in the paper)
CasePreviousTesting: For mutation analysis of ITGA2B and ITGB3 genes, DNA extraction from whole blood, PCR, heteroduplex PCR followed by CSGE and DNA sequencing were performed. All 30 exons of ITGA2B and 15 exons of ITGB3, as well as their promoters, were analyzed by CSGE following heteroduplex PCR.
Gene: ITGA2B
Variant: NM_000419.3:c.1073G>A (p.Arg358His)
LegacyVariant: N/A
ClinVar: 2896
CAiD: CA115839
gnomAD N/A
Mother S
Case2: Mother S
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Assessment of surface PTL expression of GPIIIa-IIb was performed
PlateletAggregation: N/A
CasePreviousTesting: DNA sequence analysis was performed for PCR products corresponding to exon 4 of GPIIb
Gene: ITGA2B
Variant: NM_000419.3:c.480C>G
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA399805892
gnomAD: MAF in the East Asian population is 0.00005507 https://gnomad.broadinstitute.org/variant/17-42463013-G-C
Table 3 Molecular Diagnosis of Patients with Glanzmann Thrombasthenia:
Case1: GT-1, age, gender, ethnicity not specified
DiseaseAssertion: Glanzmann thrombasthenia type II
FamilyInfo: Segregation analysis confirmed in presence of heterozygous mutations in this proband.
ParentalGenotype: Although segregation analysis confirmed, we do not know which variant in particular came from mom or dad.
CasePresentingHPOs: N/A
CaseHPOFreeText: Patients presented with a variable bleeding diathesis; most patients had epistaxis (54%), cutaneous bleeding (58%), and menorrhagia (100% of women) while other common symptoms (oral cavity, GI, following dental extraction of mild injuries, postpartum, or hematomas) were in general milder. There is no specific phenotypes attached to probands in this paper.
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometry showed that αIIbβ3 expression was between 5% and 20%
PlateletAggregation: There was severely impaired aggregation in response to all physiological agonists, and ristocetin induced platelet agglutination was normal or reduced to some extent.
CasePreviousTesting: Total RNA from peripheral blood was used for cDNA synthesis for RT-PCR. Then, using specific oligonucleotides and conditions, they amplified and sequenced ITGA2B and ITGB3 by Sanger sequencing. Every mutation found in cDNA was confirmed in DNA samples.
Gene: ITGB3
Variant: NM_000212.2:c.448A>G (p.Met124Val) and NM_000212.2:c.774_775del (p.Cys258Ter)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA8622961 and CA915940285
gnomAD: MAF in South Asian population is 0.00003266 http://gnomad.broadinstitute.org/variant/17-45361895-A-G
The patient is a 1‐year‐old female from Morocco
Case1: Female, 1 year old, ethnicity not specified (patient from Morocco)
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Her brother is asymptomatic. Her first cousin, (male) died as a result of some unknown bleeding disorder
ParentalGenotype: Parents fully sequenced and
CasePresentingHPOs: HP:0000967, HP:0000978
(Petechia, bruising)
CaseHPOFreeText: Mucocutaneous hemorrhages
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometry showed less than 10% of ITGA2B and ITGB3 complexes
PlateletAggregation: Platelet aggregation in response to ADP, thrombin, collagen and epinephrine was less than 10% of normal platelets and risotcetin induced platelet agglutination was normal
CasePreviousTesting: Complete analysis of ITGA2B and ITGB3 coding sequences were performed (PCR)
Gene: ITGA2B
Variant: NM_000419.3:c.188G>A
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA8603528
gnomAD: MAF in the European (non-Finnish) population is 0.000008803 http://gnomad.broadinstitute.org/variant/17-42466654-C-T
GT13
Case13: GT-13, Swiss, gender or age not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
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: ITGA2B
Variant: NM_000419.3:c.555T>G and NM_000419.3:c.1882C>T
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA399805736 and CA399801310
gnomAD: MAF in the Latino population is 0.00003983 http://gnomad.broadinstitute.org/variant/17-42456075-G-A
Patient 1
Case1: Patient 1, Male, 6 years old
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Affected brother is Patient 2
ParentalGenotype: Mother and father revealed heterozygosity for c.1878G>C mutation. (Parents are consanguineous)
CasePresentingHPOs: HP:0000967, HP:0000421, HP:0000225
(Petechiae, epistaxis, gingival bleeding)
CaseHPOFreeText: Hematomas,
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometry analysis showed that there was no surface expression of GPIIb/IIIa detectable on patient 1's platelets, indicating a lack of platelet GPIIb/IIIa expression
PlateletAggregation: All patients' platelets showed severely reduced platelet aggregation after stimulation with collagen and ADP in contrast to the normal range (See Table 1). Stimulation with epinephrine and arachidonic acid also demonstrated decreased platelet aggregation. In contrast, ristocetin-induced platelet aggregation was within normal range for patient 1
CasePreviousTesting: Sequenced ITGA2B and ITGB3 genes from one patient of each family (Patient 2 and 3) and Patient 1 and 4 were screened for the identified mutation in the corresponding family.
Gene: ITGA2B
Variant: NM_000419.3:c.1878G>C (p.Gln626His)
LegacyVariant: N/A
ClinVar: 2903
CAiD: CA115852
gnomAD: N/A
3.
Case2: Female, Spanish, age not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Mild bleeding
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.1031A>C (p.Tyr344Ser)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA400025814
gnomAD: N/A
Patient Osaka-12
Case1: Female, 21 years old, Japanese (Named Osaka-12 in this study)
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: The substitution was inherited from her father. The molecular genetic defect inherited from her mother remains determined.
CasePresentingHPOs: N/A
CaseHPOFreeText: Moderate mucocutaneous bleeding in childhood
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometry showed revealed a significant reduction in the expression of αIIbβ3 on Osaka-12 platelets
PlateletAggregation: Absent platelet aggregation in response to ADP, epinephrine, and collagen but a normal response to ristocetin
CasePreviousTesting: To identify the molecular genetic defect for the proband of interest, all coding regions of ITGA2B and ITGB3 cDNA amplified by RT-PCR were analyzed
Gene: ITGA2B
Variant: NM_000419.3:c.520T>C (p.Tyr174His)
LegacyVariant: (p.Tyr143His)
ClinVar: N/A
CAiD: CA399805805
gnomAD: N/A
Two male patients
Case1: 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 and need to ask about second variant--made note in google doc to ask
gnomAD: N/A