S30
Case#: S30, Iranian
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: 5% < FVIII:C < 30%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The F8 gene was directly sequenced for all 26 exons using the Sanger sequencing method. PCR was performed and subsequently analyzed
Gene: F8
Variant: NM_000132.3:c.2090T>C
LegacyVariant:
ClinVar: No
CAID: CA414909005
gnomAD:
S21
Case#: S21, Iranian
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: Family history of HA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125, HP:0005261
CaseHPOFreeText: FVIII:C < 1%, Inhibitor present
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The F8 gene was directly sequenced for all 26 exons using the Sanger sequencing method. PCR was performed and subsequently analyzed
Gene: F8
Variant: NM_000132.3:c.6213A>T
LegacyVariant:
ClinVar: No
CAID: CA414903164
gnomAD:
B76
Case#: B76
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C Chr = 7, FVIII:AG = 10, 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.5398C>G
LegacyVariant:
ClinVar: No
CAID: CA255164
gnomAD:
B45 – B72
Case#: B45 - B72
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C Chr = 9, FVIII:AG = 16, 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.5096A>T
LegacyVariant:
ClinVar: No
CAID: CA255022
gnomAD:
B17 – B27
Case#: B17 - B27
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C Chr = 31, FVIII:AG = 90, 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.1636C>T
LegacyVariant:
ClinVar: No
CAID: CA255112
gnomAD:
C.6317A>C
Case#: 27
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.6317A>C (p.Gln2087Pro)
ClinVar: NA
CAID: CA414900070
gnomAD: Not reported
c.1706C>G
Case#: 22
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.1706C>G (p.Pro550Arg)
ClinVar: NA
CAID: CA414911701
gnomAD: Not reported
C.6301C>G
Case#: 26
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(F8):c.6301C>G (p.His2101Asp)
ClinVar: 804137 https://www.ncbi.nlm.nih.gov/clinvar/variation/804137/
CAID: CA414900220
gnomAD: Not reported
c.584T>C
Case#: 14, Spanish
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.584T>C (p.Leu195Pro)
ClinVar: NA
CAID: CA414919399
gnomAD: Not reported
c.5286T>A
Case#: 25
DiseaseAssertion: Hemophilia A
FamilyInfo: Sporadic
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: Moderate
CasePreviousTesting: All 26 exons and exon-intron boundaries of the F8 gene were amplified using primers and PCR, analyzed by direct forward and reverse sequencing using a DNA sequencing kit
Gene: F8
Variant: NM_000132.3:c.5286T>A (p.Phe1743Leu)
ClinVar: NA
CAID: CA414910973
gnomAD: Not reported
c.1538G>T
Case#: 21
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.1538G>T (p.Gly494Val)
ClinVar: NA
CAID: CA414912397
gnomAD: Not reported
Thr37 mutation
Case#: Pezeshkpoor_Patient_M (male, 58 y/o, from Switzerland)
DiseaseAssertion: Hemophilia B
FamilyInfo: N/A
ParentalTesting: N/A
CasePresentingHPOs: HP:0011858
CaseHPOsFreeText: spontaneous bleeding symptoms from the blood, the mouth, the tongue, and epiglottis, low FIX:C levels
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.109G>A (p.Ala37Thr)
ClinVar: 804089
CAID: CA10529736
gnomAD: Allele Frequency in population where variant was found in the highest (South Asian population): 0.0001128
25.
Case#: 25
DiseaseAssertion: Hemophilia B, moderate
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0011858
CaseHPOFreeText: FIX:C = 2%
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.1204G>A
LegacyVariant:
ClinVar: No
CAID: CA414446446
gnomAD:
12.
Case#: 12
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.761G>A
LegacyVariant:
ClinVar: No
CAID: CA414443235
gnomAD:
5
Case#: 5
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.305G>T
LegacyVariant:
ClinVar: No
CAID: CA414437422
gnomAD:
17.
Case#: 17
DiseaseAssertion: Hemophilia B, moderate
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0011858
CaseHPOFreeText: FIX:C = 3%
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.1025C>T
LegacyVariant:
ClinVar: No
CAID: CA255381
gnomAD:
4.
Case#: 4
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.160G>C
LegacyVariant:
ClinVar: No
CAID: CA414435755
gnomAD:
mutations in the factor IX gene resulting in hemophilia B
Case#: Gostout_Proband_189 (assumed male, Asian (from India))
DiseaseAssertion: Severe Hemophilia B
FamilyInfo: N/A
ParentalTesting: None
CasePresentingHPOs: HP:0011858
CaseHPOsFreeText: reduced factor IX activity (FIX:C: 3%)
CaseNotHPOs: None
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.127C>T (p.Arg43Trp)
LegacyVariant: c.6364C>T (p.Arg-4Trp)
ClinVar: 811505
CAID: CA414435537
gnomAD: Absent/Not Reported
UQU-HB4
Case#: UQU-HB4, Male, 6-months-old, Saudi Arabia
DiseaseAssertion: Hemophilia B
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: Severe, PTT 60.1
CasePreviousTesting: Screened for all factor IX exons by capillary sequencing
Gene: F9
Variant: NM_000133.3(F9):c.1025C>T (p.Thr342Met)
ClinVar: 10607 https://www.ncbi.nlm.nih.gov/clinvar/variation/10607/
CAID: CA255381
gnomAD: Not reported
UQU-HB2
Case#: UQU-HB2, Male, 2-months-old, Saudi Arabia
DiseaseAssertion: Hemophilia B
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: Severe, PTT 74.5, Disabled right knee
CasePreviousTesting: Screened for all factor IX exons by capillary sequencing
Gene: F9
Variant: NM_001313913.1:c.580G>A (p.Asp194Asn)
ClinVar: NA
CAID: CA414441211
gnomAD: Not reported
UQU-HA38
Case#: UQU-HA36, Male, 1-months-old, Saudi Arabia
DiseaseAssertion: Hemophilia A
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0001892 (Abnormal bleeding)
CaseHPOFreeText: Mild, FVIII: 1 to <5% (moderate HA) based on text
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.99G>T (p.Trp33Cys)
ClinVar: NA
CAID: CA414920529
gnomAD: Not reported
UQU-HB1
Case#: UQU-HB1, Male, 2-months-old, Saudi Arabia
DiseaseAssertion: Hemophilia B
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: Severe, PTT 74.5
CasePreviousTesting: Screened for all factor IX exons by capillary sequencing
Gene: F9
Variant: NM_000133.3(F9):c.1136G>A (p.Arg379Gln)
ClinVar: 10613 https://www.ncbi.nlm.nih.gov/clinvar/variation/10613/
CAID: CA255394
gnomAD: Not reported
UQU-HB8
Case#: UQU-HB8, Male, 1-months-old, Saudi Arabia
DiseaseAssertion: Hemophilia B
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: Severe, Disabled both knees , PTT 105.1
CasePreviousTesting: Screened for all factor IX exons by capillary sequencing
Gene: F9
Variant: NM_001313913.1:c.580G>A
ClinVar: NA
CAID: CA414441211
gnomAD: Not reported
8
Case#: 8
DiseaseAssertion: Hemophilia B, moderate
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FIX:C = 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: All exons, UTRs, exon-intron junction regions, and the promotor of F9 were amplified by PCR and analyzed by direct DNA sequencing
Gene: F9
Variant: NM_000133.3:c.349T>C
LegacyVariant:
ClinVar: No
CAID: CA414437669
gnomAD:
16
Case#: 16
DiseaseAssertion: Hemophilia B, moderate
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FIX:C = 1.5%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: All exons, UTRs, exon-intron junction regions, and the promotor of F9 were amplified by PCR and analyzed by direct DNA sequencing
Gene: F9
Variant: NM_000133.3:c.427C>G
LegacyVariant:
ClinVar: No
CAID: CA414438921
gnomAD:
11
Case#: 11
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.676C>T
LegacyVariant:
ClinVar: No
CAID: CA255350
gnomAD:
071–2001
Case#: 071-2001
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.901C>T
LegacyVariant:
ClinVar: No
CAID: CA414917990
gnomAD:
035–2013
Case#: 035-2013
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: 1% < FVIII:C < 5%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.5275G>A
LegacyVariant:
ClinVar: No
CAID: CA414911087
gnomAD:
091–2010
Case#: 091-2010
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.1475A>G
LegacyVariant:
ClinVar: No
CAID: CA337334224
gnomAD:
071–2023
Case#: 071-2023
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: 1% < FVIII:C < 5%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.2167G>A
LegacyVariant:
ClinVar: No
CAID: CA255138
gnomAD:
091–2005
Case#: 091-2005
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.5393C>A
LegacyVariant:
ClinVar: No
CAID: CA414909064
gnomAD:
020–2054
Case#: 020-2054
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.1899G>T
LegacyVariant:
ClinVar: No
CAID: CA414910251
gnomAD:
060–2004
Case#: 060-2004
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.272T>C
LegacyVariant:
ClinVar: No
CAID: CA414920117
gnomAD:
020–2063
Case#: 020-2063
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: 5% < FVIII:C < 40%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.558C>G
LegacyVariant:
ClinVar: No
CAID: CA414919454
gnomAD:
001–2025
Case#: 001-2025
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.986G>A
LegacyVariant:
ClinVar: No
CAID: CA255089
gnomAD:
020–2038
Case#: 020-2038
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:
015–2011
Case#: 015-2011
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.1241A>G
LegacyVariant:
ClinVar: No
CAID: CA414915839
gnomAD:
086–2006
Case#: 086-2006
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.1537G>C
LegacyVariant:
ClinVar: No
CAID: CA414912560
gnomAD:
001–2041
Case#: 001-2041
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.2167G>A
LegacyVariant:
ClinVar: No
CAID: CA255138
gnomAD:
004–2009
Case#: 004-2009
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.1899G>T
LegacyVariant:
ClinVar: No
CAID: CA414910251
gnomAD:
003–2003
Case#: 003-2003
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.5275G>A
LegacyVariant:
ClinVar: No
CAID: CA414911087
gnomAD:
071–1037
Case#: 071-1037
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:
c.127C>T
Case#: Meireles_Proband_4 (assumed male)
DiseaseAssertion: Severe Hemophilia B
FamilyInfo: None
ParentalTesting: None
CasePresentingHPOs: HP:0011858
CaseHPOsFreeText: reduced factor IX activity
CaseNotHPOs: N/A
CasePreviousTesting: None
Gene: F9
Variant: NM_000133.4:c.127C>T (p.Arg43Trp)
ClinVar: 811505
CAID: CA414435537
gnomAD: Absent/Not Reported
Hb15
Case#: HB15 (assumed male, Tunisian)
DiseaseAssertion: Severe Hemophilia B
FamilyInfo: None
ParentalTesting: None
CasePresentingHPOs: HP:0011858
CaseHPOsFreeText: reduced factor IX activity (FIX: <1)
CaseNotHPOs: None
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.128G>A (p.Arg43Gln)
ClinVar: 810864
CAID: CA414435539
gnomAD: Absent/Not Reported
6365
Case#: Patient B (assumed male)
DiseaseAssertion: Moderate, Sporadic Hemophilia B
FamilyInfo: Patient B is deceased and only a DNA sample was available; his two sisters and mother are carriers
ParentalTesting: Mother was heterozygous for the variant
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
c.689G>A
Case#: 45
DiseaseAssertion: Hemophilia B
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FIX:C 5% (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_000133.3:c.689G>A (p.Gly230Glu)
ClinVar: NA
CAID: CA414441179
gnomAD: Not reported
c.5123G>A
Case#: 20
DiseaseAssertion: Hemophilia A
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FVIII:C 18%, 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.5123G>A (p.Arg1708His)
ClinVar: 10266 https://www.ncbi.nlm.nih.gov/clinvar/variation/10266/
CAID: CA255154
gnomAD: MAF for Arg1708His in the South Asian population 0.00005507<br> https://gnomad.broadinstitute.org/variant/X-154156942-C-T?dataset=gnomad_r2_1
c.6845C>G
Case#: 36
DiseaseAssertion: Hemophilia A
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FVIII:C 33/30%, 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.6845C>G (p.Ser2282Cys)
ClinVar: NA
CAID: CA414903435
gnomAD: Not reported
c.396A>C
Case#: 3
DiseaseAssertion: Hemophilia A
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FVIII:C 18% (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.396A>C (p.Glu132Asp)
ClinVar: 10171 https://www.ncbi.nlm.nih.gov/clinvar/variation/10171/
CAID: CA255060
gnomAD: MAF for Glu132Asp in Other population 0.0003762<br> https://gnomad.broadinstitute.org/variant/X-154221416-T-G?dataset=gnomad_r2_1
c.1291T>G
Case#: 41
DiseaseAssertion: Hemophilia B
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FIX:C 2/2% (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_000133.3:c.1291T>G (p.Trp431Gly)
ClinVar: NA
CAID: CA414447127
gnomAD: Not reported
c.580G>A
Case#: 44
DiseaseAssertion: Hemophilia B
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FIX:C 23% (Mild Phenotype)
CasePreviousTesting: Screened for IVS-22 and IVS-1, sample was blinded for NGS and the sequencing component was validated by comparing results with Sanger Sequencing
Gene: F9
Variant: NM_001313913.1:c.580G>A (p.Asp194Asn)
ClinVar: NA
CAID: CA414441211
gnomAD: Not reported
c.2043G>A
Case#: 16
DiseaseAssertion: Hemophilia A
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FVIII:C 31% (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.2043G>A (p.Met681Ile)
ClinVar: NA
CAID: CA414909257
gnomAD: Not reported
c.1219T>C
Case#: 40
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.1219T>C (p.Cys407Arg)
ClinVar: NA
CAID: CA414446562
gnomAD: Not reported
89
Case#: 89, male, 36 years old, Chinese
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.6406G>A
LegacyVariant:
ClinVar: No
CAID: CA414899430
gnomAD:
30
Case#: 30, male, 27 years old, Chinese
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: NA
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 4.1%
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.361G>A
LegacyVariant:
ClinVar: No
CAID: CA414919926
gnomAD:
81
Case#: 81, male, 19 years old, Chinese
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 7.1%
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.5707G>A
LegacyVariant:
ClinVar: No
CAID: CA414907751
gnomAD:
62
Case#: 62, male, 50 years old, Chinese
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 38.5%
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.2111C>T
LegacyVariant:
ClinVar: No
CAID: CA414908864
gnomAD:
46
Case#: 46, male, 21 years old, Chinese
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 2.3%
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.1172G>A
LegacyVariant:
ClinVar: 10111
CAID: CA120918
gnomAD:
53
Case#: 53, male, 21 years old, Chinese
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 15.9%
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.1834C>T
LegacyVariant:
ClinVar: 10236
CAID: CA255129
gnomAD:
70
Case#: 70, male, 16 years old, Chinese
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: NA
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.5398C>T
LegacyVariant:
ClinVar: 10275
CAID: CA255163
gnomAD:
31
Case#: 31, male, 41 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.361G>A
LegacyVariant:
ClinVar: No
CAID: CA414919926
gnomAD:
94
Case#: 94, male, 8 years old, Chinese
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 8.5%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.6448G>A
LegacyVariant:
ClinVar: No
CAID: CA414907951
gnomAD:
27
Case#: 27, male, 30 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.266G>C
LegacyVariant:
ClinVar: No
CAID: CA414920127
gnomAD:
97
Case#: 97, male, 66 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.6517A>G
LegacyVariant:
ClinVar: No
CAID: CA414907348
gnomAD:
108
Case#: 108, male, 36 years old, Chinese
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 3.3%
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.6870G>T
LegacyVariant:
ClinVar: No
CAID: CA414903147
gnomAD:
40
Case#: 40, male, 32 years old, Chinese
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 24.5%
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.871G>A
LegacyVariant:
ClinVar: No
CAID: CA414918134
gnomAD:
6364 C→T
Case#: Ivaskevicius_Proband_LT65 (assumed male, Lithuanian)
DiseaseAssertion: Severe Hemophilia B
FamilyInfo: N/A
ParentalTesting: N/A
CasePresentingHPOs: HP:0011858
CaseHPOsFreeText: reduced factor IX activity (FIX:C: 0)
CaseNotHPOs: N/A
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.127C>T (p.Arg43Trp)
LegacyVariant: c.6364C>T (p.Arg-4Trp)
ClinVar: 811505
CAID: CA414435537
gnomAD: Absent/Not Reported
The final list of mutations is provided in Supplementary Table S1.
Case#: N/A
DiseaseAssertion: Severe Hemophilia B
FamilyInfo: N/A
ParentalTesting: N/A
CasePresentingHPOs: N/A
CaseHPOsFreeText: N/A
CaseNotHPOs: N/A
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.71T>C (p.Leu24Pro)
ClinVar: Absent
CAID: CA414434410
gnomAD: Absent/NotReported
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.59T>C (p.Leu20Ser)
ClinVar: Absent
CAID: CA414434363
gnomAD: Absent/NotReported
Table S1
Case#: Li_Proband_1 (male)
DiseaseAssertion: Moderate Hemophilia B
FamilyInfo: Not provided
ParentalTesting: Not provided
CasePresentingHPOs: N/A
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#: Patient A (assumed male)
DiseaseAssertion: Severe (sporadic) Hemophilia B
FamilyInfo: Variant also localized in affected brother, mother (Native American descent) is deceased but maternal grandmother and two maternal aunts screened negative, researchers believe this de novo mutation originated during either grandparent’s gametogenesis.
ParentalTesting: Mother deceased, no mention of father
CasePresentingHPOs: HP:0011858
CaseHPOsFreeText: FIX Clotting Activity (U/dl): < 1, Antigen Level (U/dl): < 1
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.50T>A (p.Ile17Asn)
LegacyVariant: c.79T>A (p.Ile-30Asn)
ClinVar: Absent
CAID: CA414434315
gnomAD: Absent/Not Reported
Case#: Liu_Proband_56/439/440/486/830 (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.128G>A (p.Arg43Gln)
ClinVar: Absent
CAID: CA414435539
gnomAD: Absent/Not Reported
Case#: Liu_Proband_438 (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.127C>T (p.Arg43Trp)
ClinVar: Absent
CAID: CA414435537
gnomAD: Absent/Not Reported
c.83G>A
Case#: Salviato_Proband_2164 (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.83G>A (p.Cys28Tyr)
ClinVar: Absent
CAID: CA414434483
gnomAD: Absent/Not Reported
mutant factor IX
Case#: Salle_Proband_J-C L (male, 23 y/o, white)
DiseaseAssertion: Severe Hemophilia B
FamilyInfo: family history is negative for any haemostatic disorder
ParentalTesting: family history is negative for any haemostatic disorder
CasePresentingHPOs: HP:0011858, HP:0012233, HP:0000421
CaseHPOsFreeText: reduced factor IX activity (FIX:C: <0.01 % FIX:Ag: 0.46), muscular haematoma, haemarthrosis, nose bleeding
CaseNotHPOs: N/A
CasePreviousTesting: None
Gene: F9
Variant: NM_000133.4:c.128G>A (p.Arg43Gln)
ClinVar: 810864
CAID: CA414435539
gnomAD: Absent/Not Reported
c.83G>A/p.Cys28Tyr
Case#: Nummi_Proband_6 (assumed male)
DiseaseAssertion: Moderate Hemophilia B
FamilyInfo: N/A
ParentalTesting: None
CasePresentingHPOs: HP:0001929 (FIX baseline clotting activity: 1
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
Case#: Oldenburg Cases A, B and C (A: 66 y/o, B: 38 y/o, C: 30 y/o (all in Germany))
DiseaseAssertion: Mild Hemophilia B
FamilyInfo: No bleeding tendency noted in any of these patients family history
ParentalTesting: N/A
CasePresentingHPOs: HP:0011858
CaseHPOsFreeText: severe bleeding at each occasion of oral anticoagulation with phenoprocoumon, bleeding was located in the muscles of the upper leg (patients A and C) and scrotum, left calf and thigh musles (patient B), reduced factor IX levels
CaseNotHPOs: N/A
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.109G>A (p.Ala37Thr)
LegacyVariant: p.Ala-10Thr
ClinVar: 804089
CAID: CA10529736
gnomAD: Allele Frequency in population where variant was found in the highest (South Asian population): 0.0001128
AdditionalCaseInfo: all patients were unrelated up to the third generation. However, the parents of patients A and C emigrated from the same region in North-Eastern Europe (North Poland)
p.Ala315dup (patient P2)
CaseInfo: P2 (female)
DiseaseAssertion: Carrier
FamilyInfo: N/A
ParentalTesting: N/A
CasePresentingHPOs: HP:0003125, HP:0004846, HP:0001892
CaseHPOFreeText: Low FVIII levels (undetectable FVIII:C levels and significant decrease in FVIII:Ag levels: 1.7% ± 1.1), prolonged bleeding after surgery, 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 were also performed.
Gene: F8
Variant: NM_000132.3:c.943del
CAID: CAID:CA255085
gnomAD: Absent/Not Reported
p.Cys28Trp
Case#: N/A
DiseaseAssertion: Severe Hemophilia B
FamilyInfo: None
ParentalTesting: N/A
CasePresentingHPOs: HP:0001929
CasePresentingHPOsFreeText: reduced factor IX activity
CaseNotHPOs: None
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.84T>G (p.Cys28Trp)
ClinVar: Absent
CAID: CA414434487
gnomAD: Absent/Not Reported
Mutations
Case#: Weinmann_Family 9248
DiseaseAssertion: Severe Hemophilia B
FamilyInfo: 16 of the families were from the Pacific Northwest, 4 from Colorado, and 6 were referred from elsewhere in the United States
ParentalTesting: N/A
CasePresentingHPOs: HP:0011858
CaseHPOsFreeText: reduced factor IX activity (FIX:C: <1%, FIX:Ag: 37)
CaseNotHPOs: N/A
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.127C>T (p.Arg43Trp)
LegacyVariant: c.6364C>T
ClinVar: 811505
CAID: CA414435537
gnomAD: Absent/Not Reported
identify the causative mutation
Case#: Belvini_Proband_15 (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.128G>A (p.Arg43Gln)
ClinVar: 810864
CAID: CA414435539
gnomAD: Absent/Not Reported
Fig. 1
Case#: 12 year old male
DiseaseAssertion: Hemophilia B, moderate
FamilyInfo: Mother was a carrier. Maternal uncle has the same hemizygous mutation
ParentalTesting: Family Pedigree reveals that the mother was a carrier of the variant identified in the proband
CasePresentingHPOs: HP:0011858, HP:0030839
CaseHPOFreeText: FIX:C = 1%, proband had a history of soft tissue hemorrhages since 7 years of age
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: Direct nucleotide sequencing was completed
Gene: F9
Variant: NM_000133.3:c.157G>C
LegacyVariant:
ClinVar: No
CAID: CA414435729
gnomAD:
37, G-IA
Case#: Riegelsberg (male)
DiseaseAssertion: Severe Hemophilia B
FamilyInfo: Mother carries only the G-to-A transition (age at conception: 30 y/o). Origin of variant cannot be proved, since maternal grandparents were deceased at time of report.
ParentalTesting: Mother carries only the G-to-A transition, father shows to not be affected (figure 1)
CasePresentingHPOs: HP:0011858
CaseHPOsFreeText: FIX Coagulant %: < 1, FIX Antigen %: < 1
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.8G>A (p.Arg3His)
LegacyVariant: c.37G>A
ClinVar: 695909
CAID: CA10529706
gnomAD: Filtering AF: 0.0002304 (no homozygotes)
Case: Patient D
DiseaseAssertion: VWD2N
FamilyInfo: Family 3
ParentalGenotype(s):
CasePresentingHPOs: HP:0012147, HP:0030129, HP:0030130, HP:0011871
CaseHPOFreeText: PTsec = 37.9, FVIII U/dL = 31.1, FVIII ratio = 0.33, VWF:Ag U/dL = 95.0, VWF:FVIIIB U/dL = 23.8, VWF:FVIIIB ratio = 0.25, VWF:CB U/dL = 101.6, VWF:RCo U/dL = 112.4, RIPA % = 73.4, PlatVWF:Ag U/dL = 87.2
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 C
DiseaseAssertion: VWD2N
FamilyInfo: Family 2
ParentalGenotype(s):
CasePresentingHPOs: HP:0012147, HP:0030129, HP:0030130, HP:0011871
CaseHPOFreeText: PTsec = 38.0, FVIII U/dL = 37.6, FVIII ratio = 0.26, VWF:Ag U/dL = 146.2, VWF:FVIIIB U/dL = 34.0, VWF:FVIIIB ratio = 0.20, VWF:CB U/dL = 157.5, VWF:RCo U/dL = 137.4, RIPA % = 87.9, PlatVWF:Ag U/dL = 102.7
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
5
Case: Patient 5 (Family B), male, 26yo
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 = 176, PFA 100 sec = >300, SPA % = 8, MADR mg/mL = 0.6, VWF:Ag U/dL = 17.6, VWF:CB U/dL = 9.2, VWF:CB ratio = 0.52, VWF:RCo U/dL = 10.4, VWF:RCo ratio = 0.59, Platelet VWF U/dL = 76.6, FVIII U/dL = 38.8, BAT F/M = 8
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
19
Case: Patient 19 (Family F), male, 44yo
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 = 116, PFA 100 sec = >300, SPA % = 15.7, MADR mg/mL = 0.3, VWF:Ag U/dL = 44.7, VWF:CB U/dL = 11.8, VWF:CB ratio = 0.48, VWF:RCo U/dL = 11.4, VWF:RCo ratio = 0.71, Platelet VWF U/dL = 130, FVIII U/dL = 27.7, BAT F/M = 10
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: NA
GenotypingMethod: Sequencing of exon 28 of VWF
PreviouslyPublished: NA
Gene: VWF
Variant: c.3916C>T (p.Arg1306Trp)
HGVS: NM_000552.4(VWF):c.3916C>T (p.Arg1306Trp)
ClinVarID: 288; https://www.ncbi.nlm.nih.gov/clinvar/variation/288/
CAID: NA
gnomAD: absent
21
Case: Patient 21 (Family H), male, 40yo
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 = 158, PFA 100 sec = >300, SPA % = NA, MADR mg/mL = 0.45, VWF:Ag U/dL = 32.5, VWF:CB U/dL = 14.7, VWF:CB ratio = 0.45, VWF:RCo U/dL = 18.7, VWF:RCo ratio = 0.59, Platelet VWF U/dL = 130, FVIII U/dL = 39.0, BAT F/M = NA
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: NA
GenotypingMethod: Sequencing of exon 28 of VWF
PreviouslyPublished: NA
Gene: VWF
Variant: c.3916C>T (p.Arg1306Trp)
HGVS: NM_000552.4(VWF):c.3916C>T (p.Arg1306Trp)
ClinVarID: 288; https://www.ncbi.nlm.nih.gov/clinvar/variation/288/
CAID: NA
gnomAD: absent
13
Case: Patient 13 (Family C), male, 37yo
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 = 132, PFA 100 sec = >300, SPA % = 0, MADR mg/mL = 0.6, VWF:Ag U/dL = 51.9, VWF:CB U/dL = 10.6, VWF:CB ratio = 0.20, VWF:RCo U/dL = 25.2, VWF:RCo ratio = 0.48, Platelet VWF U/dL = 133.4, FVIII U/dL = 34.5, BAT F/M = 17
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
15
Case: Patient 15 (Family C), female, 14yo
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 = 126, PFA 100 sec = >300, SPA % = 0, MADR mg/mL = 0.45, VWF:Ag U/dL = 35.0, VWF:CB U/dL = 4.0, VWF:CB ratio = 0.11, VWF:RCo U/dL = 12.7, VWF:RCo ratio = 0.38, Platelet VWF U/dL = 141, FVIII U/dL = 46.0, BAT F/M = 6
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
I : 3
Case#: F4, I:3
DiseaseAssertion: Type 2 VWD
CaseHPOFreeText: all mutimers present, VWF:Ag = 34; VWF:RCo = 21; VWF:GPIbM = 31; 0.62; 0.92; 1.49
CasePreviousTesting: Not clearly described
Gene: VWF
Variant: p.[R1308L];[=]
HGVS: c.3923G>T (p.Arg1308Leu)
CAID: CA6402650
gnomAD: https://gnomad.broadinstitute.org/variant/12-6019495-C-A?dataset=gnomad_r4
I : 2
Case#: F4, I:2
DiseaseAssertion: Type 2 VWD
CaseHPOFreeText: all mutimers present, VWF:Ag = 40; VWF:RCo = 25; VWF:GPIbM = 38; 0.63; 0.95; 1.52
CasePreviousTesting: Not clearly described
Gene: VWF
Variant: p.[R1308L];[=]
HGVS: c.3923G>T (p.Arg1308Leu)
CAID: CA6402650
gnomAD: https://gnomad.broadinstitute.org/variant/12-6019495-C-A?dataset=gnomad_r4
II : 1
Case#: F3, II:1
DiseaseAssertion: Type 2 VWD
CaseHPOFreeText: all mutimers present, VWF:Ag = 45; VWF:RCo = 38; VWF:GPIbM = 45; 0.84; 1.00; 1.19
CasePreviousTesting: Not clearly described
Gene: VWF
Variant: p.[P1266L];[=]
HGVS: NM_000552.5(VWF):c.3797C>T (p.Pro1266Leu)
CAID: CA114170
gnomAD: https://gnomad.broadinstitute.org/variant/12-6019621-G-A?dataset=gnomad_r4
I : 1
Case#: F13, I:1
DiseaseAssertion: Type 2 VWD
CaseHPOFreeText: complete loss of high MWM, VWF:Ag = 69; VWF:RCo = 50; VWF:GPIbM = 71; 0.72; 1.04; 1.43
CasePreviousTesting: Not clearly described
Gene: VWF
Variant: p.[R1341Q];[=]
HGVS: c.4022G>A (p.Arg1341Gln)
CAID: CA114129
gnomAD: https://gnomad.broadinstitute.org/variant/12-6019396-C-T?dataset=gnomad_r4
I : 1
Case#: F3, I:1
DiseaseAssertion: Type 2 VWD
CaseHPOFreeText: all mutimers present, VWF:Ag = 60; VWF:RCo = 57; VWF:GPIbM = 59; 0.95; 0.98; 1.03
CasePreviousTesting: Not clearly described
Gene: VWF
Variant: p.[P1266L];[=]
HGVS: NM_000552.5(VWF):c.3797C>T (p.Pro1266Leu)
CAID: CA114170
gnomAD: https://gnomad.broadinstitute.org/variant/12-6019621-G-A?dataset=gnomad_r4
II : 1
Case#: F2, II:1
DiseaseAssertion: Type 2 VWD
CaseHPOFreeText: all mutimers present, VWF:Ag = 68; VWF:RCo = 66; VWF:GPIbM = 61; 0.97; 0.90; 0.93
CasePreviousTesting: Not clearly described
Gene: VWF
Variant: p.[P1266L];[=]
HGVS: NM_000552.5(VWF):c.3797C>T (p.Pro1266Leu)
CAID: CA114170
gnomAD: https://gnomad.broadinstitute.org/variant/12-6019621-G-A?dataset=gnomad_r4
II : 1
Case#: F12, II:1
DiseaseAssertion: Type 2 VWD
CaseHPOFreeText: complete loss of high MWM, VWF:Ag = 52; VWF:RCo = 18; VWF:GPIbM = 52; 0.34; 1.00; 2.92
CasePreviousTesting: Not clearly described
Gene: VWF
Variant: p.[R1341Q];[=]
HGVS: c.4022G>A (p.Arg1341Gln)
CAID: CA114129
gnomAD: https://gnomad.broadinstitute.org/variant/12-6019396-C-T?dataset=gnomad_r4
I : 1
Case#: F2, I:1
DiseaseAssertion: Type 2 VWD
CaseHPOFreeText: all mutimers present, VWF:Ag = 30; VWF:RCo = 29; VWF:GPIbM = 24; 0.97; 0.81; 0.84
CasePreviousTesting: Not clearly described
Gene: VWF
Variant: p.[P1266L];[=]
HGVS: NM_000552.5(VWF):c.3797C>T (p.Pro1266Leu)
CAID: CA114170
gnomAD: https://gnomad.broadinstitute.org/variant/12-6019621-G-A?dataset=gnomad_r4
I : 1
Case#: F11, I:1
DiseaseAssertion: Type 2 VWD
CaseHPOFreeText: complete loss of high MWM, VWF:Ag = 35; VWF:RCo = 5; VWF:GPIbM = 27; 0.14; 0.78; 5.44
CasePreviousTesting: Not clearly described
Gene: VWF
Variant: p.[R1306W];[=]
HGVS: c.3916C>T (p.Arg1306Trp)
CAID: CA114123
gnomAD: absent from gnomad v4.1.0
II : 3
Case#: F10, II:3
DiseaseAssertion: Type 2 VWD
CaseHPOFreeText: complete loss of high MWM, VWF:Ag = 53; VWF:RCo = 13; VWF:GPIbM = 37; 0.25; 0.69; 2.82
CasePreviousTesting: Not clearly described
Gene: VWF
Variant: p.[R1306W];[=]
HGVS: c.3916C>T (p.Arg1306Trp)
CAID: CA114123
gnomAD: absent from gnomad v4.1.0
78 14 F 28 c.4525A.G p.I1509V Htz ,1 ,1 18 - -
Case: 78, F, 14 years, Indian
DiseaseAssertion: VWD type 3
FamilyInfo: no family history of disease, Consanguinity: no
ParentalGenotype: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: FVIII:C: (U/dl): <1, VWF:Ag (U/dl): <1, Bleeding Score: 18
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.4525A>G (p.Ile1509Val), Exon 28
Heterozygous
46 5 F 28 c.3686T.G p.V1229G Htz 2.5 3.4 32 + -c.3692A.C p.N1231Tc.3789G.A p.S1263Sc.3797C.T p.P1266Lc.3835G.A p.V1279Ic.3862C.G p.L1288V
Case: 46, F, 5 years, Indian
DiseaseAssertion: VWD type 3
FamilyInfo: family history of disease, Consanguinity: no
ParentalGenotype: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: FVIII:C: (U/dl): 2.5, VWF:Ag (U/dl): 3.4, Bleeding Score: 32
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.3686T>G (p.Val1229Gly), Exon 28
c.3692A>C (p.Asn1231Thr), Exon 28
c.3789G>A (p.Ser1263Ser), Exon 28
c.3797C>T (p.Pro1266Leu), Exon 28
c.3835G>A (p.Val1279Ile), Exon 28
c.3862C>G (p.Leu1288Val), Exon 28
Heterozygous
67 13 M 28 c.3686T.G p.V1229G Hmz ,1 2.6 7 + +c.3692A.C p.N1231Tc.3931C.T p.Q1311*
Case: 67, M, 13 years, Indian
DiseaseAssertion: VWD type 3
FamilyInfo: family history of disease, Consanguinity: yes
ParentalGenotype: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: FVIII:C: (U/dl): <1, VWF:Ag (U/dl): 2.6, Bleeding Score: 7
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.3686T>G (p.Val1229Gly), Exon 28
c.3692A>C (p.Asn1231Thr), Exon 28
c.3931C>T (p.Gln1311*), Exon 28
Homozygous
85 6 F 28 c.4578G.Tp.Q1526H Htz ,1 2 2 - +
Case: 85, F, 6 years, Indian
DiseaseAssertion: VWD type 3
FamilyInfo: no family history of disease, Consanguinity: yes
ParentalGenotype: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: FVIII:C: (U/dl): <1, VWF:Ag (U/dl): 2, Bleeding Score: 2
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.4578G>T (p.Gln1526His), Exon 28
Heterozygous
Case: P1,Chinese, female, 17yo
DiseaseAssertion: VWD1
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0012147
(Reduced quantity of VWF)
CaseHPOFreeText: type O blood, bleeding score = 8; VWF:Ag (%) = 38.0, VWF:RCo (%) = 35.2, FVIII:C (%) = 59.0, VWF:CB (%) = 33.2, VWFpp (%) = 52.9, VWF:RCo/VWF:Ag = 0.9, VWF:CB/VWF:Ag = 0.9, VWFpp/VWF:Ag = 1.4, FVIII:C/VWF:Ag = 1.6
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: NA
GenotypingMethod: NGS
PreviouslyPublished: NA
Gene: VWF
Variant: c.6860G>A (p.Arg2287Gln)
HGVS: NM_000552.3:c.6860G>A (p.Arg2287Gln)
ClinVarID: NA
CAID: CA6401877; http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA6401877
gnomAD: MAF = 0.005415 (108/19946 alleles) in the East Asian population; https://gnomad.broadinstitute.org/variant/12-6094770-C-T
Case: P55, Chinese, female, 24yo
DiseaseAssertion: VWD2A
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0012147
(Reduced quantity of VWF)
CaseHPOFreeText: type O blood, bleeding score = 8; VWF:Ag (%) = 35.2, VWF:RCo (%) = 14.5, FVIII:C (%) = 57.9, VWF:CB (%) = 6.5, VWFpp (%) = 21.5, VWF:RCo/VWF:Ag = 0.4, VWF:CB/VWF:Ag = 0.2, VWFpp/VWF:Ag = 0.6, FVIII:C/VWF:Ag = 1.6
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: NA
GenotypingMethod: NGS
PreviouslyPublished: NA
Gene: VWF
Variant 1: c.1099T>G (p.Cys367Gly)
HGVS: NM_000552.5:c.1099T>G (p.Cys367Gly)
ClinVarID: NA
CAID: CA383505165; http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA383505165
gnomAD: absent
Variant 2: c.1450_1451delinsAG (p.His484Se) - Unregisted Variant
HGVS: NA
ClinVarID: NA
CAID: NA
gnomAD: NA
Variant 3: c.2423G>A (p.Cys808Tyr)
HGVS: NM_000552.5:c.2423G>A (p.Cys808Tyr)
ClinVarID: NA
CAID: CA383521928; http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA383521928
gnomAD: absent
Case: P68, Chinese, female, 12yo
DiseaseAssertion: VWD2A
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0012147
(Reduced quantity of VWF)
CaseHPOFreeText: type A blood, bleeding score = 6; VWF:Ag (%) = 14.1, VWF:RCo (%) = 1.3, FVIII:C (%) = 42.3, VWF:CB (%) = 7.3, VWFpp (%) = 16.9, VWF:RCo/VWF:Ag = 0.1, VWF:CB/VWF:Ag = 0.5, VWFpp/VWF:Ag = 1.2, FVIII:C/VWF:Ag = 3.0
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: NA
GenotypingMethod: NGS
PreviouslyPublished: NA
Gene: VWF
Variant: c.3830A>G (p.Asp1277Gly)
HGVS: NM_000552.5:c.3830A>G (p.Asp1277Gly)
ClinVarID: NA
CAID: CA383506912; http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA383506912
gnomAD: absent
193< 1< 13−−20Mc.241A>G/c.5315insGAp.R81G/p.D1772EfsX114/3116/17N/N
Case: Patient 19, M, Hungarian
DiseaseAssertion: VWD type 3
FamilyInfo: compatible with recessive inheritance
ParentalGenotype(s): n/a
CasePresentingHPOs: n/a
CaseHPOFreeRext: Bleeding score: 20, VWF:Ag (IU dL−1): < 1, VWF:CB (IU dL−1): < 1, FVIII:C (IU dL−1): 3, VWF:RCo below detection limit (<10 IU dL−1), not detectable VWF on multimer gels
CaseNOTHPOs: n/a
CaseNOTHPOFreeText: no inhibitor detected, did not become refractory to factor replacement therapy
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.241A>G (p.Arg81Gly), Exon 4
c.5315insGA (p.Asp1772GlufsX11), Exon 31
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
39 U c.4943C > T N p.Pro1648Leu 28 A2 htz Missense A 59 55 57
Case: IP #39 in type U VWD sub-cohort (also in row 23 table 6)
DiseaseAssertion: unclassified VWD
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs: HP:0032370 - blood group A
CaseHPOFreeRext: VWF:Ag [IU/dL] = 59; VWF:Ac [IU/dL] = 55; FVIII:C [IU/dL] = 57
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting:
GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.
PreviouslyPublished:
Gene: VWF
Variant: c.4943C>T p.Pro1648Leu
HGVS:
ClinVarID: not found
CAID: CA6402436
gnomAD: 0.000008056 (13 in 1613708) no homozygotes https://gnomad.broadinstitute.org/variant/12-6018475-G-A?dataset=gnomad_r4
41 Type2A(IIA)c.4718G>TN p.Gly1573Val 28 A2 htz Missense B 56 28 70
Case: IP #41 (also in row 19 table 6)
DiseaseAssertion: type 2A (IIA) VWD
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs: HP:0032440 - blood group B
CaseHPOFreeRext: VWF:Ag [IU/dL] = 56; VWF:Ac [IU/dL] = 28; FVIII:C [IU/dL] = 70
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.4718G>T p.Gly1573Val
HGVS:
ClinVarID: not found
CAID: CA383499940
gnomAD: absent
11 c.3922C > A p.Arg1308Ser 28 A1 htz Missense O/A 34/77 na/50 64 CSA /82
Case: IP #11 in type 2B VWD sub-cohort
DiseaseAssertion: type 2B VWD
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs: HP:0032370 - blood group A
CaseHPOFreeRext: VWF:Ag [IU/dL] = 77; VWF:Ac [IU/dL] = 50; FVIII:C [IU/dL] = 82
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting:
GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.
PreviouslyPublished:
Gene: VWF
Variant: c.3922C>A p.Arg1308Ser
HGVS:
ClinVarID: not found
CAID: CA383506203
gnomAD: absent
51-54Type2A(IIA)c.4811T>AN p.Val1604Asp 28 A2 htz Missense O/A/O/O27/24/35/328/9/11/755
Case: IP #51 (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] = 27; VWF:Ac [IU/dL] = 8; FVIII:C [IU/dL] = 55
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting:
GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.
PreviouslyPublished:
Gene: VWF
Variant: c.4811T>A p.Val1604Asp
HGVS:
ClinVarID: not found
CAID: CA383499144
gnomAD: absent
Type 2A c.1681_1684dup Nc.5278G > Ap.Leu562Argfsp.Val1760Ile C1430D2-VWD2A3htzhtzSmall Dupl.Missensena 64 39 104
Case: 4
DiseaseAssertion: type 2A VWD
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs:
CaseHPOFreeRext: VWF:Ag [IU/dL] = 64; VWF:Ac [IU/dL] = 39; FVIII:C [IU/dL] = 104
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.1681_1684dup p.Leu562Argfs
HGVS:
ClinVarID: not found
CAID: absent
gnomAD: absent
MultipleGeneVariants:
Gene: VWF
Variant: c.5278G > A p.Val1760Ile
CAID: CA228708
gnomAD: 0.001050 (1695 in 1614194) 4 homozygotes https://gnomad.broadinstitute.org/variant/12-6016549-C-T?dataset=gnomad_r4
41 U (A/1) c.6981T > G p.Cys2327Trp 41 C1 htz Missense O 37 32 103
Case: IP #41 in type U VWD sub-cohort
DiseaseAssertion: unclassified (A/1) VWD
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs: HP:0032442 - blood group O
CaseHPOFreeRext: VWF:Ag [IU/dL] = 37; VWF:Ac [IU/dL] = 32; FVIII:C [IU/dL] = 103
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.6981T>G
HGVS:
ClinVarID: not found
CAID: CA383492037
gnomAD: absent
14 Type2A (IIE)c.3362G>T p.Arg1121Met 25 D3-C8-3htz Missense A 11 5 21
Case: IP #14
DiseaseAssertion: type 2A (IIE) VWD
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs: HP:0032370 - blood group A
CaseHPOFreeRext: VWF:Ag [IU/dL] = 11; VWF:Ac [IU/dL] = 5; FVIII:C [IU/dL] = 21
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting:
GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.
PreviouslyPublished:
Gene: VWF
Variant: c.3362G>T p.Arg1121Met
HGVS:
ClinVarID: not found
CAID: CA383511879
gnomAD: absent
p.Y1349C
Case#: p.Y1349C, Female, Age 29, Caucasian
Disease Assertion: VWD2M
FamilyInfo: 5 affected family members with varied bleeding scores (range 4-14)
Parental Genotype: Not listed
CasePresentingHPOs:
CaseHPOFreeText: bleeding score 8, VWF:Rco/VWF:Ag ratio 0.35, VWF:Rco 17 IU/dL, VWF:Ag 49 IU/dL,
CaseNotHPOs:HP:0040240
(Increased Ratio of VWF Propeptide to VWF antigen)
CaseNotHPOFreeText: normal multimer distribution
Protein Expression:
CasePreviousTesting:VWF Sequencing
Gene: VWF
Variant: NM_000552.4:c.4046A>G (p.Tyr1349Cys)
ClinVar: N/A
CAID: CA383505652
gnomAD: N/A
p.R1374C
Case: p.R1374C, Male, Age 39, Caucasian
Disease Assertion: VWD2M
FamilyInfo: 25 family members tested, 1 with high bleeding score, some affected by VWD (number not defined)
Parental Genotype: Not listed
CasePresentingHPOs:
CaseHPOFreeText: VWF:RCo 12 IU/dL, VWF:GPIbM 18 U/dL, VWF:CB3 19 IU/dL, VWF:CB4 14 U/dL, VWF:RCo/VWF:Ag ratio 0.55
CaseNotHPOs: HP:0040240
(Increased Ratio of VWF Propeptide to VWF antigen)
CaseNotHPOFreeText:bleeding score 2, normal multimer distribution,VWF:Ag 22 IU/dL
Protein Expression:
CasePreviousTesting: VWF sequencing
Gene: VWF
Variant: NM_000552.4(VWF):c.4120C>T (p.Arg1374Cys)
ClinVar: 100329 ClinVarID
CAID: CA228539
gnomAD: MAF of 0.000008824 (1/113322 alleles) in the European (non-Finnish) population.
Case#: 01030, Age 12, Female, Blood type:O+ (Table S3)
Disease Assertion: VWD 1
FamilyInfo: Not listed
Parental Genotype: Not listed
CasePresentingHPOs: N/A
CaseHPOFreeText: VWF:Ag: 23, VWF:RCo: 33, FVIII:C: 51, VWF:CB: 33
CaseNotHPOs: N/A
CaseNotHPOFreeText: Bleeding score 2
Protein Expression: N/A
CasePreviousTesting: 48,48 Access-Array amplification. NGS Molecular analysis was performed. Sanger sequencing was used to validate selected mutations.
Gene: VWF
Variant: NM_000552.4:c.2561G>A (p.Arg854Gln)
ClinVar: 296
CAID: CA114139
gnomAD:MAF of 0.005692 (143/25122 alleles) in the European (Finnish) population.
Case#: 30035, Age 55, Female, Blood Type A+ (Table S3)
Disease Assertion: VWD 1
FamilyInfo: The patient is the only member of Family# 3012.
Parental Genotype: Not listed
CasePresentingHPOs: N/A
CaseHPOFreeText: VWF:Ag:25, VWF:RCo:16, FVIII:C:38, VWF:CB: 19
CaseNotHPOs: N/A
CaseNotHPOFreeText: Bleeding Score 1
Protein Expression: N/A
CasePreviousTesting: 48,48 Access-Array amplification. NGS Molecular analysis was performed. Sanger sequencing was used to validate selected mutations.
Gene: VWF
Variant: NM_000552.4:c.5336G>T (p.Arg1779Leu)
ClinVar: N/A
CAID:CA383495656 CAID
gnomAD: MAF of 0.00002891 (1/ 34592 alleles) in the Latino population. gnomAD
Case#: 14003, Age 40, Female, Blood Type O+,
Disease Assertion: VWD 1
FamilyInfo: The patient is the only member of Family#1403.
Parental Genotype: Not listed
CasePresentingHPOs: N/A
CaseHPOFreeText: VWF:Ag:28. VWF:RCo:20,FVIII:C:61, VWF:CB:18
CaseNotHPOs: N/A
CaseNotHPOFreeText: Bleeding Score 6
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.221-70G>T and NM_000552.4:c.478G>A
ClinVar: N/A
CAID: CA923726380 and CA383518171 CAID1 CAID2
gnomAD: N/A
Case#: 35011, Age 46, Male, Blood Type O+ (Table S3)
Disease Assertion: VWD 1
FamilyInfo: The patient is one of 3 members of Family#3505. All have VWD type 1 and patient# 35013 has an additional intronic variant that the other two family members don't have.
Parental Genotype: Not listed
CasePresentingHPOs: N/A
CaseHPOFreeText: VWF:Ag: 18, VWF:RCo: 14, FVIII:C: 42, VWF:CB: 12
CaseNotHPOs: N/A
CaseNotHPOFreeText: Bleeding Score 2
Protein Expression: N/A
CasePreviousTesting: 48,48 Access-Array amplification. NGS Molecular analysis was performed. Sanger sequencing was used to validate selected mutations.
Gene: VWF
Variant: NM_000552.4:c.5198T>C (p.Leu1733Pro) and NM_000552.4(VWF):c.6187C>T (p.Pro2063Ser)
ClinVar: 100436 ClinVar
CAID: CA383496267 and CA202650 CAID1 CAID2
gnomAD: MAF of 0.04854 (1486/30616 alleles) in the South Asian population (CA202650). gnomAD
Case#: 05008, Age 30, Male, Blood Type A+ (Table S3)
Disease Assertion: VWD1
FamilyInfo: Patient is the only member of Family #0507
Parental Genotype: Not listed
CasePresentingHPOs: N/A
CaseHPOFreeText: Bleeding Score 2, VWF:Ag: 5.8, VWF:RCo:5, FVIII:C: 7.4, 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#: 16001, Age 50, Female, Blood Type A+
Disease Assertion: VWD 1
FamilyInfo: The patient is one of two members of Family#1616. Both patients have the same variants. (Patient#16002)
Parental Genotype: Not listed
CasePresentingHPOs: N/A
CaseHPOFreeText: Bleeding Score 7, VWF:Ag:21, VWF:RCo: 16, FVIII:C:108, 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.1110-26T>A (p.=) and NM_000552.4:c.5695T>C (p.Cys1899Arg)
ClinVar: N/A
CAID: CA6403542 and CA6402177 CAID1 CAID2
gnomAD: MAF of 0.008911 (222/ 24914 alleles) in the African Population ( CA6403542). MAF of 0.00006892 (1/14510 alleles) in the African population (CA6402177)
Case#: 05012, Age 10, Female, Blood Type O+ (Table S3)
Disease Assertion: VWD1
FamilyInfo: Patient is the only member of Family# 0511.
Parental Genotype: Not listed
CasePresentingHPOs: N/A
CaseHPOFreeText:Bleeding Score 4, VWF:Ag: 15, VWF:RCo:12.3, FVIII:C: 45, VWF:CB: 25
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
Protein Expression: N/A
CasePreviousTesting: 48,48 Access-Array amplification. NGS Molecular analysis was performed. Sanger sequencing was used to validate selected mutations
Gene: VWF
Variant: NM_000552.4:c.2119T>C
ClinVar: N/A
CAID: CA383494546 CAID
gnomAD: N/A
Case#: 13018, Age 5, Male, Blood type not determined (TableS3)
Disease Assertion: VWD 1
FamilyInfo: The patient is the only member of Family#1314.
Parental Genotype: Not listed
CasePresentingHPOs: N/A
CaseHPOFreeText: Bleeding Score 0, VWF:Ag:18, VWF:RCo:21, FVIII:C:39, VWF:CB: 15
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.4238C>T (p.Pro1413Leu)
ClinVar: 100342 ClinVar
CAID: CA228565 CAID
gnomAD: MAF of 0.00003266 ( 1/30616 alleles) in the South Asian population. gnomAD
Case: Case 1, female, newborn
DiseaseAssertion: VWD2B
FamilyInfo: second child of couple without family history of bleeding, Detection of maternal alloantibodies against HPA antigens present on paternal platelets showed weak cross reactivity, Analysis of platelet genotype for HPA-1, 2, 3, 5, and HPA-15 alleles by PCR-SSP performed in both parents, showed a possible incompatibility in HPA-1b and HPA-5b, No maternal anti-HPA antibody was detected using monoclonal antibody-specific immobilization of platelet antigen method directed against HPA-1, 3, 4, HPA-2, and HPA-5 antigens
ParentalGenotype(s): variant absent in both parents
CasePresentingHPOs: HP:0000967, HP:0001873, HP:0030129
(petechia, thrombocytopenia, impaired ristocetin cofactor assay activity)
CaseHPOFreeText: Delivered at 40wks, VWF:RCo = 8 IU dL−1, VWF:Ag = 105 IU dL−1, VWF:RCo/VWF:Ag < 0.1, FVIII:C = 94 IU dL−1, RIPA not tested due to low platelet count
CaseNOTHPOs: HP:0032169
(infection)
CaseNOTHPOFreeText: DIC, spontaneous bleeding
CasePreviousTesting: NA
GenotypingMethod: sequencing of the whole exon 28 of VWF gene
PreviouslyPublished: NA
Gene: VWF
Variant: c.4379T>C (Leu1460Pro)
HGVS: NM_000552.3:c.4379T>C (Leu1460Pro)
ClinVarID: NA
CAID: CA383502290; http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA383502290
gnomAD: absent
P7
Case: P7, M/41
DiseaseAssertion: VWD2A
FamilyInfo: Positive family history, no details provided.
ParentalGenotype: NA
CaseHPOFreeText: The bleeding score was 7, aPTT was 36 seconds, FVIII:C was 36%, VWF:RCo was not determined, and VWF:Ag was 25 IU/dL. The VWF:RCo/VWF:Ag ratio was not applicable. The VWF multimer pattern showed a mild loss of high molecular weight multimers, RIPA was 4 ohms, and the platelet count was 301 × 10⁹/L.
CasePreviousTesting: NA
GenotypingMethod: Direct sequencing of all exons, flanking intronic sequences, and the promoter of VWF was performed.
Gene: VWF
Variant: c.4789C>T, p.R1597W — heterozygous
HGVS: NM_000552.5(VWF):c.4789C>T (p.Arg1597Trp)
ClinVar: 285
CAID: CA114117
gnomAD: https://gnomad.broadinstitute.org/variant/chr12-6018629-G-A?dataset=gnomad_r4
P1
Case: P1, M/5
DiseaseAssertion: VWD1
FamilyInfo: No
ParentalGenotype: NA
CaseHPOFreeText: The bleeding score was 0, aPTT was 41 seconds, FVIII:C was 60%, VWF:RCo was 22 IU/dL, and VWF:Ag was 27 IU/dL, resulting in a VWF:RCo/VWF:Ag ratio of 0.8. RIPA was nearly absent, VWF multimer analysis was not tested, and the platelet count was 250 × 10⁹/L.
CasePreviousTesting: NA
GenotypingMethod: Direct sequencing of all exons, flanking intronic sequences, and the promoter of VWF was performed.
Gene: VWF
Variant: c.6579G>C, p.W2193C — heterozygous
HGVS: NM_000552.5(VWF):c.6579G>C (p.Trp2193Cys)
ClinVar:
CAID: CA383490665
gnomAD: absent from gnomad v4.1.0
P22
Case: P22, F/5
DiseaseAssertion: VWD2A
FamilyInfo: Positive family history, no details provided.
ParentalGenotype: NA
CaseHPOFreeText: The bleeding score was 3, aPTT was 43 seconds, FVIII:C was 47%, VWF:RCo was 122 IU/dL, and VWF:Ag was 20 IU/dL, with a VWF:RCo/VWF:Ag ratio of 0.1. RIPA was normal, VWF multimer analysis was 2, and platelet count was 270 × 10⁹/L.
CasePreviousTesting: NA
GenotypingMethod: Direct sequencing of all exons, flanking intronic sequences, and the promoter of VWF was performed.
Gene: VWF
Variant: c.4825G>A, p.G1609R — heterozygous
HGVS: NM_000552.5(VWF):c.4825G>A (p.Gly1609Arg)
ClinVar: 100395
CAID: CA228665
gnomAD: https://gnomad.broadinstitute.org/variant/chr12-6018593-C-T?dataset=gnomad_r4
P21
Case: P21, F/5
DiseaseAssertion: VWD2M
FamilyInfo: Positive family history, no details provided.
ParentalGenotype: NA
CaseHPOFreeText: The bleeding score was 2, aPTT was 53 seconds, FVIII:C was 30%, and VWF:RCo was 25 IU/dL. The VWF:RCo/VWF:Ag ratio indicated a mild loss of high molecular weight multimers. RIPA was 4, VWF multimer analysis was 301, and platelet count was not specified.
CasePreviousTesting: NA
GenotypingMethod: Direct sequencing of all exons, flanking intronic sequences, and the promoter of VWF was performed.
Gene: VWF
Variant: c.4121G>T, p.R1374L — heterozygous
HGVS: NM_000552.5(VWF):c.4121G>T (p.Arg1374Leu)
ClinVar: 100331
CAID: CA228543
gnomAD: https://gnomad.broadinstitute.org/variant/chr12-6019297-C-A?dataset=gnomad_r4
c.4136 G>T
Gene:VWF
HGNCID:12726
PMID33550910
Case:38-year-old woman from Saudi Arabia
DiseaseAssertion:VWD type 2B
FamilyInfo:Mother and brother suffered from epistaxis (no genotypes). Two sons and one daughter: both sons carry the same mutation, but only one presents with minimal epistaxis.
ParentalGenotype(s):Not available
CasePresentingHPOs:HP:0001934, HP:0004846, HP:0011871
CaseNOTHPOs:HP:0000421, HP:0000132
CaseNOTHPOFreeText:multiple dental extractions without bleeding complications
CaseHPOFreeRext:RIPA (+) Rist 0.5 mg/mL
CasePreviousTesting:No
GenotypingMethod:NGS
Gene:VWF
Variant:c.4136 G>T (p. R1379 L)
HGVS:NC_000012.12:g.6019282C>A
ClinVarID:
CAID:CA383504438
gnomAD:
0.33
Case: 2A-3
DiseaseAssertion: VWD2A
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs: AcuStar RCo/Ag = 0.33; AcuStar CB/Ag = 0.08; ELISA CB/Ag = 0.25
CaseHPOFreeText:
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting:
GenotypingMethod: not described
PreviouslyPublished: PMID: 1537829
Gene: VWF
Variant: c.4789C>T (p.Arg1597Trp)
HGVS: NM_000552.5(VWF):c.4789C>T (p.Arg1597Trp)
ClinVarID: 285; https://www.ncbi.nlm.nih.gov/clinvar/variation/285/?new_evidence=false
CAID:
gnomAD: absent
T1-1
Case: T1-1, female, 33yo
DiseaseAssertion: VWD1
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs:
CaseHPOFreeText: Blood type: O+, bleeding score = 4, VWF:Ag (IU/mL) = 0.27; VWF:RCo (IU/mL) = 0.19; FVIII:C (IU/mL) = 0.53
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting:
GenotypingMethod: qRT-PCR
PreviouslyPublished:
Gene: VWF
Variant: c.1897T>C (.Cys633Arg)
HGVS: NM_000552.5:c.1897T>C (.Cys633Arg)
ClinVarID: n/a
CAID: CA383496953; https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA383496953
gnomAD: absent
2N
Case: 2N, female, 33yo
DiseaseAssertion: VWD2N
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs:
CaseHPOFreeText: Blood type: A, bleeding score = 8, VWF:Ag (IU/mL) = 0.97; VWF:RCo (IU/mL) = 1.20; FVIII:C (IU/mL) = 0.44
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting:
GenotypingMethod: qRT-PCR
PreviouslyPublished:
Gene: VWF
Variant 1: c.2561G>A (p.Arg854Gln)
Variant 2: unknown
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:
gnomAD: MAF = 0.005692 in European (Finnish) population; 2 homozygotes
F1Proband P1G39R D141NCompound heterozygous2.241.070.971.02.32.06
Case: Proband 1 (P1)
DiseaseAssertion: VWD III
FamilyInfo:
Father
Asp141Asn impaired multimerization of von Willebrand factor; reduced oxidoreductase activity
VWF are retained in the ER and fail to be transported to the Golgi
APTT ratio (seconds): 1.09
PT ratio (seconds): 1.15
TT ratio (seconds): 1.24
VWF: Ag (IU/dL): 48.4
VWF:RCo (IU/dL): 50.2
FVIII:C (IU/dL): 73.5
BS: 0
Mother
Gly39Arg impaired multimerization of von Willebrand factor; reduced oxidoreductase activity
VWF are retained in the ER and fail to be transported to the Golgi
APTT ratio (seconds): 1.12
PT ratio (seconds): 1.05
TT ratio (seconds): 0.91
VWF: Ag (IU/dL): 30.3
VWF:RCo (IU/dL): 36.4
FVIII:C (IU/dL): 50.6
BS: 1
ParentalGenotype: n/a
Father: Asp141Asn, Heterozygous
Mother: Gly39Arg, Heterozygous
CasePresentingHPOs: n/a
CaseHPOFreeText:
Asp141Asn and Gly39Arg impaired multimerization; reduced oxidoreductase activity; undetectable von Willebrand factor (VWF) multimer
VWF are retained in the ER and fail to be transported to the Golgi
APTT ratio (seconds): 2.24
PT ratio (seconds): 1.07
TT ratio (seconds): 0.97
VWF: Ag (IU/dL): 1.0
VWF:RCo (IU/dL): 2.3
FVIII:C (IU/dL): 2.0
BS: 6
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
CasePreviousTesting: n/a
Gene: VWF
Variant:
Asp141Asn
Gly39Arg
Compound heterozygous
VWD1-1228.727.21.064318.0NormalExon 37c.6596G>A‡p.Cys2199TyrD4Missense
Case: Croatian adult patient
DiseaseAssertion: VWD1
FamilyInfo: Not specified
ParentalGenotype(s): Not specified
CasePresentingHPOs: HP:0001892, HP:0011890, HP:0000132, HP:0002239, HP:0000790, HP:0001342
CaseHPOFreeText: Reduced VWF:Ag of 27.2%, VWF:GPIbM of 28.7%, FVIII:C of 43% and VWF:CBA of 18%. Normal multimer distribution.
CaseNOTHPOs: Not specified
CaseNOTHPOFreeText: Normal multimer size distribution (tested in Agarose gel).
CasePreviousTesting: Not reported
GenotypingMethod: Illumina NGS, custom designed panel covering all 52 exons as well as intronic flanking regions and promoter region of VWF gene.
PreviouslyPublished: None
Gene: VWF
Variant: c.6596G>A
HGVS: NM_000552.4:c.6596G>A (p.Cys2199Tyr)
ClinVarID: Not available
CAID: CA383490627
gnomAD: Not available
c.571T>C
Case: Croatian adult patient
DiseaseAssertion: VWD3
FamilyInfo: Not specified
ParentalGenotype(s): Not specified
CasePresentingHPOs: HP:0001892, HP:0011890, HP:0000132, HP:0002239, HP:0000790, HP:0001342
CaseHPOFreeText: <4.0% VWF:Ag, <4.0% VWF:GPIbM, 5% FVIII:C and <1% VWF:CBA.
CaseNOTHPOs: Not specified
CaseNOTHPOFreeText: Not specified.
CasePreviousTesting: Not reported
GenotypingMethod: Illumina NGS, custom designed panel covering all 52 exons as well as intronic flanking regions and promoter region of VWF gene.
PreviouslyPublished: None
Gene: VWF
Variant: c.571T>C
HGVS: NM_000552.4:c.571T>C (p.Trp191Arg)
ClinVarID: Not available
CAID: CA383514932
gnomAD: Not available
patient with the p.L881R variation was also a compound heterozygote for the p.N1421K mutation
Case: L881R/N1421K heterozygous proband
DiseaseAssertion: VWD1
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0012147
(Reduced quantity of VWF)
CaseHPOFreeText: FVIII:C = 30 IU/dL, VWF:RCo = 3 IU/dL, VWF:Ag = 27 IU/dL, VWF:CB = 22 IU/dL, VWF:RCo/VWF:Ag = 0.11
CaseNOTHPOs: HP:0030132
(Absence of large von Willebrand factor multimers)
CaseNOTHPOFreeText:
CasePreviousTesting: NA
GenotypingMethod: NA
PreviouslyPublished: PMID: 16985174
Gene: VWF
Variant 1: c.2642T>G (p.Leu881Arg)
HGVS: NM_000552.5:c.2642T>G
ClinVarID: NA
CAID: CA383520052; http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA383520052
gnomAD: absent
Variant 2: c.4263C>G (p.Asn1421Lys)
HGVS: NM_000552.4(VWF):c.4263C>G (p.Asn1421Lys)
ClinVarID: 100345; https://www.ncbi.nlm.nih.gov/clinvar/variation/100345/
gnomAD: absent
We report on the coinheritance of mild haemophilia A and type 1 von Willebrand disease (VWD) in a genetically characterized Italian family. The proband is a 56-year-old man carrying both the c.2167G>A mutation in the factor VIII (FVIII) gene (responsible for p.A723T substitution) and the c.4751A>G mutation (p.Y1584C) in the von Willebrand factor (VWF) gene.
Case: Proband (II-1), male, 56yo, Italian
DiseaseAssertion: VWD1 and Hemophilia A
FamilyInfo: Pedigree in Fig. 1 - Father had VWD1 and Mother had Hemophilia A - parents have normal or higher VWF levels, and normal FVIII/VWF:Ag ratios, as well as a normal bleeding score; 2 daughters carry F8 variant
ParentalGenotype(s): Paternal = NM_000552.4(VWF):c.4751A>G (p.Tyr1584Cys); Maternal = NM_000132.3(F8):c.2167G>A (p.Ala723Thr)
CasePresentingHPOs: HP:0012147, HP:0030129, HP:0030130, HP:0001892, HP:0000421, HP:0000978, HP:0004846, HP:0000225, HP:0005261, HP:0040242
(Reduced quantity of VWF, Impaired ristocetin cofactor assay activity, Impaired von Willebrand factor collagen binding activity, abnormal bleeding, epistaxis, Bruising susceptibility, Prolonged bleeding after surgery, bleeding gums, joint hemorrhage, muscle hemorrhage)
CaseHPOFreeText: blood group = 0, aPTT = 0.56sec, FVIII = 9.8 IU/dL, VWF:Ag = 43.2 IU/dL, VWF:CB = 35.6 IU/dL, VWF:Rco = 42.1 IU/dL, VWF:FVIIIB = 41.3 IU/dL, Platelet VWF:Ag = 58.2 IU/dL, bleeding score = 27
CaseNOTHPOs: HP:0011871
(Impaired RIPA)
CaseNOTHPOFreeText:
CasePreviousTesting:
GenotypingMethod: PCR and direct sequencing of VWF and FVIII
PreviouslyPublished: NA
Gene: VWF
Variant: c.4751A>G (p.Tyr1584Cys)
HGVS: NM_000552.4(VWF):c.4751A>G (p.Tyr1584Cys)
ClinVarID: 310; https://www.ncbi.nlm.nih.gov/clinvar/variation/310/
CAID: NA
gnomAD: MAF = 0.004024 (519/128972 alleles, 4 homozygotes) in European (non-Finnish) population
MultipleGeneVariants:
Gene: F8
Variant: c.2167G>A (p.Ala723Thr)
HGVS: NM_000132.3(F8):c.2167G>A (p.Ala723Thr)
ClinVarID: 10246; https://www.ncbi.nlm.nih.gov/clinvar/variation/10246/
CAid: NA
gnomAD: MAF = 0.00005257 (1/19022 alleles, 1 hemizygote) in South Asian population
6.3y
Case: Patient 1, female, 6.3yo
DiseaseAssertion: VWD2A
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0012147, HP:0030129, HP:0030130, HP:0030132
(Reduced quantity of VWF, impaired ristocetin cofactor assay activity, Impaired von Willebrand factor collagen binding activity, Absence of large von Willebrand factor multimers)
CaseHPOFreeText: VWF:Ag = 22%, undetectable VWF:RCo and VWF:CB; Platelets (*109/L) = 194, Mean Platelet Volume (fL) = 11.6, FVIII:C (\%) = 23, VWF:CB (\%) <5, VWF:RCo (\%) = <5, aPTT (sec) = 47.6, PT (\%) = 94
CaseNOTHPOs: HP:0001873
(Thrombocytopenia)
CaseNOTHPOFreeText:
CasePreviousTesting: NA
GenotypingMethod: sequencing of exon 28 of the VWF
PreviouslyPublished: NA
Gene: VWF
Variant: c.3816C>G (p.Cys1272Trp)
HGVS: NM_000552.3:c.3816C>G (p.Cys1272Trp)
ClinVarID: NA
CAID: CA383506988; http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA383506988
gnomAD: absent
7 M/34 <1 3 No 13 c.6551G>Ca/? p.C2184Sa/? 37/? Heterozygous
Case: 7, M, 34, Italian
DiseaseAssertion: VWD type 3
FamilyInfo: Consanguinity: no
ParentalGenotype: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: VWF:Ag (IU/dL): <1, FVIII:C (IU/dL): 3, Bleeding Score: 13
CaseNotHPOs: n/a
CaseNotHPOFreeText: Anti-VWF alloantibodies: no
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.6551G>C (p.Cys2184Ser), Exon 37, D4 domain
Compound Heterozygous
Note: The second mutant allele is unknown
GT-4
Case4: GT-4, gender, age, ethnicity not specified
DiseaseAssertion: Glanzmann thrombasthenia type I
FamilyInfo: N/A
ParentalGenotype: Segregation analysis confirmed the presence of heterozygous mutations in carrier parents
CasePresentingHPOs: N/A
CaseHPOFreeText: Article mentions patients presented with variable bleeding diathesis and Table 1 shows the several phenotypes that were seen among the cohort of 13 patients in this study (this article does not state a specific bleeding phenotype for each proband) "Most of the patients had gross blood loss due to epistaxis (54%), cutaneous bleeding (58%) and menorrhagia (100% of women), while other common symptoms (oral cavity, gastrointestinal, following dental extraction or mild injuries, postpartum, or hematomas) were in general milder."
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometry showed αIIbβ3 expression to be <5%
PlateletAggregation: Article mentions the disorder was indentified by platelet testing consisting in severely impaired aggregation in response to all physiological agonists and also TMA (See Table 4). Ristocetin-induced platelet aggregation was normal or reduced to some extent.
CasePreviousTesting: To detect mutations in ITGA2B or ITGB3, total RNA from peripheral blood was used for cDNA synthesis for RT-PCR. Using specific oligonucleotides and conditions, they amplified and sequenced ITGA2B and ITGB3 by Sanger sequencing, and every mutation found in cDNA was confirmed on DNA samples
Gene: ITGB3
Variant: M_000212.2:c.647A>G (p.Tyr216Cys)
LegacyVariant: (p.Tyr190Cys)
ClinVar: N/A
CAiD: CA400023432
gnomAD: N/A
GT-3
Case3: GT-3, gender, age, ethnicity not specified
DiseaseAssertion: Glanzmann thrombasthenia type II
FamilyInfo: N/A
ParentalGenotype: Segregation analysis confirmed the presence of heterozygous mutations in carrier parents
CasePresentingHPOs: N/A
CaseHPOFreeText: Article mentions patients presented with variable bleeding diathesis and Table 1 shows the several phenotypes that were seen among the cohort of 13 patients in this study (this article does not state a specific bleeding phenotype for each proband) "Most of the patients had gross blood loss due to epistaxis (54%), cutaneous bleeding (58%) and menorrhagia (100% of women), while other common symptoms (oral cavity, gastrointestinal, following dental extraction or mild injuries, postpartum, or hematomas) were in general milder."
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometry showed αIIbβ3 expression between 5% and 20%
PlateletAggregation: Article mentions the disorder was indentified by platelet testing consisting in severely impaired aggregation in response to all physiological agonists and also TMA (See Table 4). Ristocetin-induced platelet aggregation was normal or reduced to some extent.
CasePreviousTesting: To detect mutations in ITGA2B or ITGB3, total RNA from peripheral blood was used for cDNA synthesis for RT-PCR. Using specific oligonucleotides and conditions, they amplified and sequenced ITGA2B and ITGB3 by Sanger sequencing, and every mutation found in cDNA was confirmed on DNA samples
Gene: ITGA2B
Variant: NM_000419.3:c.2113T>C (p.Cys705Arg)
LegacyVariant: (p.Cys674Arg) +31=705
ClinVar: N/A
CAiD: CA8602816
gnomAD: MAF in European (non-Finnish) population is 0.000008792 http://gnomad.broadinstitute.org/variant/17-42455140-A-G
PreviouslyPublished PMID: 9920835
GT-2
Case2: GT-2, gender, age, ethnicity not specified
DiseaseAssertion: Glanzmann thrombasthenia type I
FamilyInfo: N/A
ParentalGenotype: Segregation analysis confirmed the presence of heterozygous mutations in carrier parents
CasePresentingHPOs: N/A
CaseHPOFreeText: Article mentions patients presented with variable bleeding diathesis and Table 1 shows the several phenotypes that were seen among the cohort of 13 patients in this study (this article does not state a specific bleeding phenotype for each proband) "Most of the patients had gross blood loss due to epistaxis (54%), cutaneous bleeding (58%) and menorrhagia (100% of women), while other common symptoms (oral cavity, gastrointestinal, following dental extraction or mild injuries, postpartum, or hematomas) were in general milder."
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometry showed <5% αIIbβ3 expression
PlateletAggregation: Article mentions the disorder was indentified by platelet testing consisting in severely impaired aggregation in response to all physiological agonists and also TMA (See Table 4). Ristocetin-induced platelet aggregation was normal or reduced to some extent.
CasePreviousTesting: To detect mutations in ITGA2B or ITGB3, total RNA from peripheral blood was used for cDNA synthesis for RT-PCR. Using specific oligonucleotides and conditions, they amplified and sequenced ITGA2B and ITGB3 by Sanger sequencing, and every mutation found in cDNA was confirmed on DNA samples
Gene: ITGA2B
Variant: NM_000419.3:c.641T>C (p.Leu214Pro) and NM_000419.3:c.2473_2481delinsTCACCTGGTC c.2473_2481delinsTCACCTGGTC
LegacyVariant: (p.Leu183Pro) + 31= 214
ClinVar: 2901
CAiD: CA115848 and CA915940289
gnomAD: N/A
PreviouslyPublished PMID: 9473221 (p.Leu214Pro)
GT-1
Case1: GT-1, gender, age, ethnicity not specified
DiseaseAssertion: Glanzmann thrombasthenia type II
FamilyInfo: N/A
ParentalGenotype: Segregation analysis confirmed the presence of heterozygous mutations in carrier parents
CasePresentingHPOs: N/A
CaseHPOFreeText: Article mentions patients presented with variable bleeding diathesis and Table 1 shows the several phenotypes that were seen among the cohort of 13 patients in this study (this article does not state a specific bleeding phenotype for each proband) "Most of the patients had gross blood loss due to epistaxis (54%), cutaneous bleeding (58%) and menorrhagia (100% of women), while other common symptoms (oral cavity, gastrointestinal, following dental extraction or mild injuries, postpartum, or hematomas) were in general milder."
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometry revealed αIIbβ3 expression between 5% and 20%
PlateletAggregation: Article mentions the disorder was indentified by platelet testing consisting in severely impaired aggregation in response to all physiological agonists and also TMA (See Table 4). Ristocetin-induced platelet aggregation was normal or reduced to some extent.
CasePreviousTesting: To detect mutations in ITGA2B or ITGB3, total RNA from peripheral blood was used for cDNA synthesis for RT-PCR. Using specific oligonucleotides and conditions, they amplified and sequenced ITGA2B and ITGB3 by Sanger sequencing, and every mutation found in cDNA was confirmed on DNA samples
Gene: ITGB3
Variant: NM_000212.2:c.448A>G (p.Met150Val) and NM_000212.2:c.774_775del (p.Cys258Ter)
LegacyVariant: (p.Met124Val)
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
PreviouslyPublished PMID: 15583747 (p.Met124Val)
Table 3 Molecular Diagnosis of Patients with Glanzmann Thrombasthenia:
Case4: GT-4, age, gender, ethnicity not specified
DiseaseAssertion: Glanzmann thrombasthenia type I
FamilyInfo: N/A
ParentalGenotype: N/A
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 less than 5%
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.569A>G (p.Tyr190Cys)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA400023236
gnomAD: N/A
Case report The patient is a 5‐year‐old son of non‐consaguinous Swiss parents
Case1: Male, 5 years old, Swiss
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Family pedigree provided in Figure 1- blood samples for the study were obtained from the patient, his parents and 5 other members of his family and none of the other studied family members have experienced abnormal bleeding
ParentalGenotype: Studied and no mutation detected
CasePresentingHPOs: N/A
CaseHPOFreeText: Frequent mucocutaneous bleeding with transfusion being required shortly after birth
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
ProteinExpression: <2% of the normal platelet content of GPIIb-IIIa as determined by flow cytometry
PlateletAggregation: Absence of platelet aggregation in response to ADP, epinephrine, thrombin and collagen; however, normal platelet agglutination with ristocetin
CasePreviousTesting: Using a PCR‐SSCP procedure and direct sequence analysis of PCR‐amplified DNA fragments, we have examined all exons and splice sites of the GPIIb and GPIIIa genes
Gene: ITGA2B
Variant: NM_000419.3:c.1063G>A (p.Glu355Lys) and NM_000419.3:c.1787T>C (p.Ile596Thr)
LegacyVariant: (p.Glu324Lys) and (p.Ile565Thr)
ClinVar: 2899 and 2900, respectively
CAiD: CA115844 and CA115846, respectively
gnomAD: MAF in the European (non-Finnish) population is 0.00001978 https://gnomad.broadinstitute.org/variant/17-42461008-C-T and the MAF in the European (non-Finnish) population is 0.0001325 https://gnomad.broadinstitute.org/variant/17-42457148-A-G
LeuFC
Case10: Patient FC
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs:
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: N/A
PlateletAggregation: N/A
CasePreviousTesting: The amplification of DNA fragments using PCR and their electrophoretic migration through a denaturing gradient was used to scan the entire coding region, splice site junctions and promoter regions of the GPIIb and GPIIIa genes for all 20 patients in this study
Gene: ITGA2B
Variant: NM_000419.3:c.2540T>C (p.Leu847Pro)
LegacyVariant: (p.Leu816Pro)
ClinVar: N/A
CAiD: CA399794666
gnomAD: MAF in the African population is 0.00006443 https://gnomad.broadinstitute.org/variant/17-42453262-A-G
LeuSsab
Case12: Patient Ssab
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: N/A
CasePreviousTesting: The amplification of DNA fragments using PCR and their electrophoretic migration through a denaturing gradient was used to scan the entire coding region, splice site junctions and promoter regions of the GPIIb and GPIIIa genes for all 20 patients in this study
Gene: ITGB3
Variant: NM_000212.2:c.1955A>T (p.His652Leu)
LegacyVariant: (p.His626Leu)
ClinVar: N/A
CAiD: CA400032927
gnomAD: N/A
Supplementary Table S1:
Case2: GT3, French, age and gender not specified
DiseaseAssertion: Glanzmann thrombasthenia type I
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: All patients had a life-long history of mucocutaneous bleeding
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: All patients in this study met the clinical and platelet function requirements for GT-- this includes an absent or strongly reduced expression of alphaIIbBeta3 in platelets
PlateletAggregation: All patients in this study met the clinical and platelet function requirements for GT-- this includes absent or severely reduced platelet aggregation with at least three physiological agonists
CasePreviousTesting: Sanger sequencing was performed. Sanger sequencing ensured coverage of all exons and splice sties of the ITGA2B and ITGB3 genes and extended 300-500 bp into the introns as well as including the UTR. They sequenced 416 bp upstream of the ITGA2B promoter and 463 bp upstream of the ITGB3 promoter. In total they sequenced 51.2% of the ITGA2B gene and 19.4% of the larger ITGB3 gene
Gene: ITGB3
Variant: NM_000212.2:c.353T>A (p.Leu118His) and NM_000212.2:c.709_710del (p.Ser237Cysfs*13) and NM_000212.2:c.1732G>A (p.Asp578Asn)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA291224511 (p.Leu118His) and CA8623029 (p.Ser237Cysfs*13) and CA8623343 (p.Asp578Asn)
gnomAD: MAF in the European (non-Finnish) population in (p.Ser237Cysfs*13) is 0.00001796 https://gnomad.broadinstitute.org/variant/17-45363717-CAG-C and MAF in the Other population for (p.Asp578Asn) is 0.0008149 https://gnomad.broadinstitute.org/variant/17-45376715-G-A
Supplementary Table S1:
Case19: GT22, 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: ITGA2B
Variant: NM_000419.3:c.408+11C>A and NM_000419.3:c.1259T>C (p.Va;420Ala)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA915940333 and CA399803733
gnomAD: N/A
Supplementary Table S1:
Case42: GT49, French/Spanish, 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.1440-13_1440-1del (p.Arg480SerfsTer106) and NM_000419.3:c.2113T>C (p.Cys705Arg)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA913184940 and CA8602816
gnomAD: MAF in the European (non-Finnish) population is 0.000008792 https://gnomad.broadinstitute.org/variant/17-42455140-A-G for the (p.Cys705Arg) variant
Supplementary Table S1:
Case45: GT53, Argentina/Brazil, gender and age not specified
DiseaseAssertion: Glanzmann thrombasthenia type I
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: All patients had a life-long history of mucocutaneous bleeding
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: All patients in this study met the clinical and platelet function requirements for GT-- this includes an absent or strongly reduced expression of alphaIIbBeta3 in platelets
PlateletAggregation: All patients in this study met the clinical and platelet function requirements for GT-- this includes absent or severely reduced platelet aggregation with at least three physiological agonists
CasePreviousTesting: Sanger sequencing was performed. Sanger sequencing ensured coverage of all exons and splice sties of the ITGA2B and ITGB3 genes and extended 300-500 bp into the introns as well as including the UTR. They sequenced 416 bp upstream of the ITGA2B promoter and 463 bp upstream of the ITGB3 promoter. In total they sequenced 51.2% of the ITGA2B gene and 19.4% of the larger ITGB3 gene
Gene: ITGB3
Variant: NM_000212.2:c.356G>A (p.Arg119Gln) and NM_000212.2:c.1697G>A (p.Gly566Asp)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA8622925 and CA400032338
gnomAD: MAF in the African population is 0.0002470 https://gnomad.broadinstitute.org/variant/17-45360910-G-A
Supplementary Table S1:
Case24: GT27, French, gender and age were not specified here
DiseaseAssertion: Glanzmann thrombasthenia type I
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: All patients had a life-long history of mucocutaneous bleeding
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: All patients in this study met the clinical and platelet function requirements for GT-- this includes an absent or strongly reduced expression of alphaIIbBeta3 in platelets
PlateletAggregation: All patients in this study met the clinical and platelet function requirements for GT-- this includes absent or severely reduced platelet aggregation with at least three physiological agonists
CasePreviousTesting: Sanger sequencing was performed. Sanger sequencing ensured coverage of all exons and splice sties of the ITGA2B and ITGB3 genes and extended 300-500 bp into the introns as well as including the UTR. They sequenced 416 bp upstream of the ITGA2B promoter and 463 bp upstream of the ITGB3 promoter. In total they sequenced 51.2% of the ITGA2B gene and 19.4% of the larger ITGB3 gene
Gene: ITGA2B
Variant: NM_000419.3:c.1413C>G (p.Tyr471Ter) and NM_000419.3:c.2468G>A (p.Gly823Glu)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA290950376 and CA399795351
gnomAD: MAF in the European (non-Finnish) population is 0.000008791 for (p.Tyr471Ter) MAF in the African population is 0.000 for p.Gly823Glu) https://gnomad.broadinstitute.org/variant/17-42453334-C-T
12
Case1: Female, 15, ethnicity not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: "This mutation was confirmed in the proband and parents."
CasePresentingHPOs: HP:0000225 (Gingival bleeding)
CaseHPOFreeText: Site of bleeding: skin, menstrual
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
ProteinExpression: See Table 1 (information provided)
PlateletAggregation: See Table 1 (information provided)
CasePreviousTesting: Screened mutations in ITGA2B and ITGB3 by multiplex polymerase chain reaction (PCR) amplification (MPCR) and conformation-sensitive gel electrophoresis
Gene: ITGB3
Variant: NM_000212.2:c.646T>C (p.Tyr216His)
LegacyVariant: (p.Tyr190His)
ClinVar: N/A
CAiD: CA400023428
gnomAD: N/A
Supplementary Tables 1 and 2 combined information:
Case27: GT27, Male, 29 years old
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Available per Table 1; however, very minimal information
ParentalGenotype: Parents are not consanguineous, no other genotype information available
CasePresentingHPOs: HP:0000978, HP:0000979, HP:0031364
(Bruising, purpura, ecchymosis)
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.2333A>C (p.Gln778Pro) This article is not completed-Meera
LegacyVariant: N/A
ClinVar: 225393
CAiD: CA290947544
gnomAD: MAF in East Asian population: 0.0001087 https://gnomad.broadinstitute.org/variant/17-42453691-T-G
Supplementary Tables 1 and 2 combined information:
Case15a: Male, 15 years old, brother to GT15b
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Available per Table 1, brother to GT15b
ParentalGenotype: Parents are not consanguineous, no other genotype information available
CasePresentingHPOs: HP:0000978, HP:0000979, HP:0031364, HP:0000421, HP:0000225
(Bruising, purpura, ecchymosis, epistaxis, gingival bleeding)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Showed 10-20% of αIIbβ3 expression measured by flow cytometry
PlateletAggregation: Platelet aggregation showed no response to ADP, a small response to collagen but normal response to ristocetin
CasePreviousTesting: All exons from ITGA2B and ITGB3 genes were amplified by PCR using intronic primers. DNA sequencing was determined by Sanger sequencing.
Gene: ITGB3
Variant: NM_000212.2:c.1525del (p.Gln509Argfs*160) and NM_000212.2:c.1199G>A (p.Cys400Tyr)
LegacyVariant: N/A
ClinVar: 13562 (p.Cys400Tyr)
CAiD: CA915940237 (p.Gln509Argfs*160) and CA123244 (p.Cys400Tyr)
gnomAD: N/A
Supplementary Tables 1 and 2 combined information:
Case1: GT1, Female, 5 years old
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Not available per supplementary table 1
ParentalGenotype: Parents are not consanguineous, no other genotype information available
CasePresentingHPOs: HP:0000978, HP:0000979, HP:0031364, HP:0000421
(Bruising, purpura, ecchymosis, epistaxis)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Showed <5% of αIIbβ3 expression measured by flow cytometry
PlateletAggregation: Platelet aggregation showed no response to ADP and collagen but normal response to ristocetin
CasePreviousTesting: All exons from ITGA2B and ITGB3 genes were amplified by PCR using intronic primers. DNA sequencing was determined by Sanger sequencing.
Gene: ITGA2B
Variant: NM_000419.3:c.1051C>T (p.Arg351Ter) and NM_000419.3:c.2029G>A (p.Glu677Lys)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA290954030 (p.Arg351Ter) and CA399800002 (p.Glu677Lys)
gnomAD: N/A
Supplementary Tables 1 and 2 combined information:
Case39: GT39, Male, 25 years old
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Available per Table 1; however, very minimal information
ParentalGenotype: Parents are not consanguineous, no other genotype information available
CasePresentingHPOs: HP:0100309 (Subdural hematoma)
CaseHPOFreeText: Post traumatic hemorrhage
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Showed 50-100% (variant) 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.2570G>T (p.Cys857Phe) and NM_000419.3:c.1769G>A (p.Arg590Gln)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA399794409 (p.Cys857Phe) and CA8602943 (p.Arg590Gln)
gnomAD: MAF for (p.Arg590Gln) in the Latino population 0.0002314 https://gnomad.broadinstitute.org/variant/17-42457166-C-T
Supplementary Tables 1 and 2 combined information:
Case14: GT14, Female, 5 years old
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Not available per supplementary table 1
ParentalGenotype: Parents are not consanguineous, no other genotype information available
CasePresentingHPOs: HP:0000978, HP:0000979, HP:0031364, HP:0000421, HP:0000225
(Bruising, purpura, ecchymosis, epistaxis, gingival bleeding)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Showed <5% of αIIbβ3 expression measured by flow cytometry
PlateletAggregation: Platelet aggregation showed no response to ADP and collagen but normal response to ristocetin
CasePreviousTesting: All exons from ITGA2B and ITGB3 genes were amplified by PCR using intronic primers. DNA sequencing was determined by Sanger sequencing.
Gene: ITGA2B
Variant: NM_000419.3:c.2333A>C
LegacyVariant: N/A
ClinVar: 225393
CAiD: CA290947544
gnomAD: N/A
Supplementary Tables 1 and 2 combined information:
Case7: GT7, Female, 31 years old
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Not available per supplementary table 1
ParentalGenotype: Parents are consanguineous, no other genotype information available
CasePresentingHPOs: HP:0000978, HP:0000979, HP:0031364, HP:0000421, HP:0000132
(Bruising, purpura, ecchymosis, epistaxis, 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.1652G>A (p.Arg551Gln)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA8602986 (p.Arg551Gln)
gnomAD: MAF in South Asian population: 0.00006536 https://gnomad.broadinstitute.org/variant/17-42457470-C-T
Supplementary Tables 1 and 2 combined information:
Case5: GT5, Female, 25 years old; however, now deceased
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Not available per supplementary table 1
ParentalGenotype: Parents are consanguineous, no other genotype information available
CasePresentingHPOs: HP:0000132, HP:0000421, HP:0002239, HP:0002170
(Menorrhagia, epistaxis, gastrointestinal bleeding, intracranial hemorrhage)
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.1750C>T (p.Arg584Ter) and NM_000419.3:c.2159T>C (p.Leu720Pro)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA115834 (p.Arg584Ter) and CA399798955 (p.Leu720Pro)
gnomAD: N/A
11CabGT-11
Case11: (Proband CabGT-11) Female, age not specified, Caucasian
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
ProteinExpression: Flow cytometry showed <5% GPIIb and 20% GPIIIa surface expression
Platelet Aggregation: N/A
CasePreviousTesting: Promoter and exon sequences of aIIb and b3 genes were amplified and directly sequence
Gene: ITGA2B
Variant: NM_000419.3:c.1787T>C (p.Ile596Thr)
LegacyVariant: N/A
ClinVar: 2900
CAiD: CA115846
gnomAD MAF in the European (non-Finnish) population is 0.0001325 https://gnomad.broadinstitute.org/variant/17-42457148-A-G
23CabGT-23
Case23: (Proband CabGT-23) Female, age not specified, Caucasian
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
ProteinExpression: Flow cytometry showed 10% GPIIb and 14% GPIIIa surface expression
Platelet Aggregation: N/A
CasePreviousTesting: Promoter and exon sequences of aIIb and b3 genes were amplified and directly sequence
Gene: ITGB3
Variant: NM_000212.2:c.665T>C (p.Leu222Pro)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA291224887
gnomAD MAF in the European (non-Finnish) population is 0.00006482 https://gnomad.broadinstitute.org/variant/17-45363676-T-C
patient (GT-2)
Case2: GT-2, gender, age, ethnicity not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: HP:0000979
(Purpura)
CaseHPOFreeText: Severe bleeding syndrome, frequent hematomas, has a history of blood transfusion with platelet concentrates
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometry showed that this patient lacked integrin αIIbβ3 expression
PlateletAggregation: Platelets failed to aggregate with physical agonists
CasePreviousTesting: N/A
Gene: ITGB3
Variant:NM_000212.2:c.940G>T (p.Asp314Tyr)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA400025612
gnomAD: N/A
CM
Case9: Patient CM, gender, age and ethnicity not specified
DiseaseAssertion: Glanzmann thrombasthenia type I
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Bleeding symptoms were evaluated by examining available hospital records. Mild bleeders were defined as those who had minor symptoms, such as epistaxis or gum bleeds, and moderate bleeders suffered, in addition, from bleeding complications after surgery and trauma. Severe bleeders were defined as those with a history of spontaneous or life-threatening hemorrhages, such as gastrointestinal bleeding, or who had repeated episodes requiring platelet transfusion. See Table 1.
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: See Table 6
PlateletAggregation: See Table 6
CasePreviousTesting: To ascertain the mutations, we sequenced the coding regions of the αIIb and β3 subunits including the exon/intron boundaries
Gene: ITGA2B
Variant: NM_000419.3:c.2051T>G (p.Leu684Arg)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA399799849
gnomAD: N/A
GT16
Case16: GT-16, Kosovo, gender or age not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: Mother: c.1594T>C heterozygous and Father: 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.842C>T and c.2602–2A>G/c.2602–3C>A het do not show up in the clin gen registry (Unregistered Variant?)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA399805055
gnomAD: N/A
GT9
Case9: GT-9, Caucasian, gender or age not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: Mother: c.1186G>A heterozygous and Father: c.3060_2T>C heterozygous
CasePresentingHPOs: N/A
CaseHPOFreeText: Bleeding symptoms are severe (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.1186G>A and NM_000419.3:c.3060+2T>C
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA399804315 and CA290944108
gnomAD: MAF in the South Asian population is 0.00006622 http://gnomad.broadinstitute.org/variant/17-42460885-C-T and MAF in the European non-Finnish population is 0.00003876 http://gnomad.broadinstitute.org/variant/17-42451720-A-G
GT11
Case11: GT-11, Arab, gender or age not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: Mother: c.3092delT heterozygous and Father: deceased
CasePresentingHPOs: N/A
CaseHPOFreeText: Bleeding symptoms are severe (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.641T>C and NM_000419.3:c.3092delT
LegacyVariant: N/A
ClinVar: 2901
CAiD: CA115848 and CA915940323
gnomAD: N/A
GT7
Case7: (GT-7) Female, 57 years old, French
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Mucocutaneous bleeding
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.565C>T (p.Pro189Ser)
LegacyVariant: (p.Pro163Ser) (The paper gives legacy and current nomenclature)
ClinVar: N/A
CAiD: CA291224669
gnomAD MAF in the European (non-Finnish) population is 0.00002638 https://gnomad.broadinstitute.org/variant/17-45362012-C-T
Case 2
Case#: Case 2, 20 yo Female
DiseaseAssertion: Glanzman thrombasthenia
ParentalGenotype: Not provided
CasePresentingHPOs: (HP:0000978, Bruising susceptibility) (HP:0000421, Epistaxis)
PlateletAggregation: Strong reduction of platelet aggregation with all agonists, except ristocetin. Normal platelet count.
CaseHPOFreeText:
CaseNotHPOs:
CaseNotHPOFreeText:
ProteinExpression: Flow cytometry, platelets with 18% to 24% residual αIIbβ3
CasePreviousTesting: Not provided
PreviouslyPublished: Not provided
Gene: ITGB3
HGVS: NM_000212.3:c.187C>T
ClinVar: 631774 https://www.ncbi.nlm.nih.gov/clinvar/variation/631774/
CAID: CA8622892
gnomAD: PopMax = 0.00002555 https://gnomad.broadinstitute.org/variant/17-47283375-C-T?dataset=gnomad_r4
Gene: ITGB3
HGVS: NM_000212.3:c.505C>T
ClinVar: 953061 https://www.ncbi.nlm.nih.gov/clinvar/variation/953061/
CAID: CA291224658
gnomAD: PopMax = 2.800e-7 https://gnomad.broadinstitute.org/variant/17-47284586-C-T?dataset=gnomad_r4
GT 64
Case37: GT64, Female, India, age of onset is 16 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 48
Case31: GT48, Male, India, age of onset is 5 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)
L
Case12: Patient ID L, Female, 10 years old, ethnicity not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Patient L is related to patient M (See Table 1; very minimal information)
ParentalGenotype: N/A
CasePresentingHPOs: HP:0000978, HP:0000225
(Easy bruising, gingival bleeding)
CaseHPOFreeText: N/A
CaseNotHPOs: HP:0000967, HP:0000979, HP:0004406, HP:0002239, HP:0002239, HP:0000790, HP:0005261, HP:0002248
(Petechiae, purpura, recurrent epistaxis, GI bleeding, intracranial hemorrhage, hematuria, hemarthrosis, hematemesis)
CaseNotHPOsFreeText: Hemorrhage after dental, hemorrhage after trauma, ear bleeding, hematoma
ProteinExpression: N/A
PlateletAggregation: Defective response to ADP, adrenaline, collagen, arachidonic acid, and normal response to ristocetin
CasePreviousTesting: Exon PCR was used to amplify coding regions of the ITGA2B and ITGB3 genes. PCR products were purified and Sanger sequenced. Segregation using parental samples was undertaken when available.
Gene: ITGB3
Variant: NC_000017.11:g.47284509T>G (p.Leu143Trp)
LegacyVariant: N/A
ClinVar: 13567
CAiD: CA123252
gnomAD: MAF in Other population 0.0001629 http://gnomad.broadinstitute.org/variant/17-45361875-T-G
PreviouslyPublished: PMID: 9376589
K
Case11: Patient ID K, Male, 5 years old, ethnicity not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Related to Patient's I and J (See Table 1)
ParentalGenotype: N/A (Parents are consangenous)
CasePresentingHPOs: HP:0000978, HP:0004406, HP:0000225, HP:0002239, HP:0000790
(Easy bruising, recurrent epistaxis, gingival bleeding, GI bleeding, hematuria)
CaseHPOFreeText: Hemorrhage after trauma, hematoma, ear bleeding
CaseNotHPOs: HP:0000967, HP:0000979, HP:0002239, HP:0000790, HP:0005261, HP:0002248
(Petechiae, purpura, intracranial hemorrhage, hemarthrosis, hematemesis)
CaseNotHPOsFreeText: Hemorrhage after dental, ear bleeding
ProteinExpression: N/A
PlateletAggregation: Defective response to ADP, adrenaline, collagen, arachidonic acid, and normal response to ristocetin
CasePreviousTesting: Exon PCR was used to amplify coding regions of the ITGA2B and ITGB3 genes. PCR products were purified and Sanger sequenced. Segregation using parental samples was undertaken when available.
Gene: ITGA2B
Variant: NM_000419.3:c.1652G>A
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA8602986
gnomAD: MAF in South Asian population is 0.00006536 http://gnomad.broadinstitute.org/variant/17-42457470-C-T
PreviouslyPublished: PMID: 19172520
Supplementary Table S1 & S2 Proband and Variant Information:
Case8: GT9, Male, 86, French
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: HP:0000421
(Epistaxis)
CaseHPOFreeText: Moderate mucocutaneous bleeding
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometry showed 10-20% 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.665T>C (p.Leu222Pro) and NM_000212.2:c.1871G>A (p.Cys624Tyr)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA291224887 and CA400032726
gnomAD: MAF in the European (non-Finnish) population 0.00006482 http://gnomad.broadinstitute.org/variant/17-45363676-T-C
Supplementary Table S1 & S2 Proband and Variant Information:
Case33: GT36a, Female, 49 years old, Spanish
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Affected brother who is proband 36b and affected sister who is proband 36c in this study
ParentalGenotype: N/A
CasePresentingHPOs: HP:0000421, HP:0000225
(Epistaxis, gingival bleeding)
CaseHPOFreeText: Bleeding at the onset of menses
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.131G>T (p.Gly44Val) and NM_000419.3:c.1440-13_1440-1de (p.Arg480Serfs*106)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA399806881 and CA913184940
gnomAD: N/A
Supplementary Table S1 & S2 Proband and Variant Information:
Case55: GT55, Female, 28, Argentinian/Brazilian
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Has an affected sister (this is all the information we are provided with)
ParentalGenotype: N/A
CasePresentingHPOs: HP:0000225, HP:0000421
(Gingival bleeding, epistaxis)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometry showed 11-22% 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.647C>T (p.Ala216Val)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA399805506
gnomAD: N/A
Supplementary Table S1 & S2 Proband and Variant Information:
Case35: GT36c, Female, 47 years old, Spanish
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Affected sister who is proband 36 a and affected brother proband 36b
ParentalGenotype: N/A
CasePresentingHPOs: HP:0000132, HP:0011891
(Menorrhagia, post-partum hemorrhage)
CaseHPOFreeText: Intra-abdominal hemorrhage and bleeding after trauma
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.131G>T (p.Gly44Val) and NM_000419.3:c.1440-13_1440-1de (p.Arg480Serfs*106)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA399806881 and CA913184940
gnomAD: N/A
Patient'sCase.
Case1: (Patient P), age and ethnicity not specified (cannot access previously published article where patient information is detailed: (Caen, J. P., Rosa, J.-P., Soria, C. & Boizard, B. (1983) C. R. Acad. Sci. Ser. 2 29, 479-481)
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: See pedigree in Fig. 5
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Exhibited lifelong bleeding tendency
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
ProteinExpression: See Table 1
PlateletAggregation: Failure of platelets to aggregate and to bind fibrinogen in response to agonists such as ADP, collagen or thrombin
CasePreviousTesting: Sequenced the cytoplasmic domain of ITGB3 following PCR on the platelet RNA
Gene: ITGB3
Variant: NM_000212.2:c.2332T>C (p.Ser778Pro)
LegacyVariant: (p.Ser752Pro)
ClinVar: 13556
CAiD: CA123230
gnomAD: N/A
PreviouslyPublished: PMID: 6223690 (this article is not available on through UNC Libraries and there is no option to request the text either)
The patient was a 35‐year‐old female
Case1: Female, 35 years old, Japanese
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Pedigree found in Fig 4
ParentalGenotype: Mother: heterozygote for (p.Ile330Asn) and Father: heterozygote for (p.His306Pro)
CasePresentingHPOs: N/A
CaseHPOFreeText: Profuse bleeding at times
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
ProteinExpression: The surface expression of αIIbβ3 complex on the patient's platelets was not observed in the flow cytometric analysis used to detect the αIIbβ3 complex (Fig. 1A).
PlateletAggregation: No aggregation of patient's platelets in response to ADP and collagen but normal aggregation occurred in response to ristocetin
CasePreviousTesting: Nucleotide sequences of beta3 cDNA and beta3 genomic DNA were analyzed by the dye terminator cycle sequencing method, in addition the nucleotide sequences of alphaIIbeta cDNA were anlso analyzed based on the published sequence of alphaIIbeta
Gene: ITGB3
Variant: NM_000212.2:c.989T>A (p.Ile330Asn) and NM_000212.2:c.917A>C (p.His306Pro)
LegacyVariant: (p.Ile304Asn) and (p.His280Pro)
ClinVar: N/A
CAiD: CA400025722 and CA291224999
gnomAD: MAF in the East Asian population is 0.00005437 https://gnomad.broadinstitute.org/variant/17-45364575-A-C
Type I thrombasthenic patient, FLD
Case3: Patient FLD
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs:
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: N/A
PlateletAggregation: N/A
CasePreviousTesting: N/A
Gene: ITGA2B
Variant: NM_000419.3:c.818G>A (p.Gly273Asp)
LegacyVariant: (G242D)
ClinVar: 2894
CAiD: CA115837
gnomAD: N/A
GT-71c
Case52: (GT-71) 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: ITGA2B
Variant: NM_000419.3:c.1142C>T (p.Thr381Ile)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA399804396
gnomAD: N/A
GT-74
Case55: (GT-74) 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
3.Adult woman/Algeria
Case2: (Patient 3) Female (adult), age not specified, Algeria
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Severe bleeding when she was a child
CaseNotHPOs: N/A
ProteinExpression: Absent surface expression of alphaIIbbeta3
Platelet Aggregation: Absent platelet aggregation (this is all they mentioned)
CasePreviousTesting: N/A
Gene: ITGA2B
Variant: NM_000419.3:c.1063G>A (p.Glu355Lys)
LegacyVariant: (p.Glu324Lys)
ClinVar: 2899
CAiD: CA115844
gnomAD MAF in the European (non-Finnish) population is 0.00001978 https://gnomad.broadinstitute.org/variant/17-42461008-C-T
PreviouslyPublished: PMID: 12362239 and 23346430
1.Adult woman/France
Case1: (Patient 1) Woman (adult), age not specific, France
DiseaseAssertion: Glanzmann thrombasthenia (also have undergone deep vein thrombosis)
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Moderate bleeding according to Table 1
CaseNotHPOs: N/A
ProteinExpression: Trace amounts of residual alphaIIbbeta3 (this is all that was mentioned)
Platelet Aggregation: Absent platelet aggregation (this is all that was mentioned)
CasePreviousTesting: N/A
Gene: ITGB3
Variant: NM_000212.2:c.1448G>A (p.Cys483Tyr)
LegacyVariant: (p.Cys457Tyr)
ClinVar: N/A
CAiD: CA400029324
gnomAD N/A
PreviouslyPublished: 12152649 and 21848888
Case3: Patient MR, 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 and ITGB3
Variant: NM_000419.3:c.526C>G (p.Pro176Ala) and NM_000212.2:c.224del ,
LegacyVariant: (p.Pro145Ala)
ClinVar: N/A
CAiD: CA399805793 and CA8622899
gnomAD: MAF in the European non Fin pop is 0.000008795 for the ITGB3 variant
A 52-year-old male patient
Case1: Male, 52 years old, ethnicity not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: One of the patient’s daughters carried the c.2437C>A mutation. The other daughter carried the c.1771_1772insG along with c.339C>G mutation, indicating that these mutations are on the same allele.
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Recurrent hemorrhagic symptoms, bleeding time >20 minutes and PFA-100 closure times were > 300 seconds
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
ProteinExpression: Flow cytometric analysis showed a clearly detectable but strongly reduced amount of surface expressed GPIIb and GPIIIa
PlateletAggregation: Platelets failed to aggregate in response to ADP, arachidonic acid, epinephrine, and collagen.
CasePreviousTesting: Sequencing of exons of GPIIb gene was performed
Gene: ITGA2B
Variant: NM_000419.3:c.1771dup (p.Asp560GlyfsX16), NM_000419.3:c.2437C>A (p.His782Asn)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA915940334, CA399795907, CA500624465
gnomAD: N/A
GT24
Case15: (GT24) 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: ITGB3
Variant: NM_000212.2:c.953T>C (p.Leu318Ser)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA400025639
gnomAD MAF in the European Finnish population is 0.00004620 https://gnomad.broadinstitute.org/variant/17-45367060-T-C
A 9-year old female
Case1: Female, 9 years old, Indian
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: Article mentions parents have the variant (at end of article); however, no details are provided
CasePresentingHPOs: HP:0000225, HP:0000421
(Gingival bleeding, recurrent epistaxis)
CaseHPOFreeText: Prolonged bleeding from cuts
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometry showed the presence of normal levels of GPIIb, GPIIIa, GPIIb-IIIa and GPIb-IX on the patients platelet surface
PlateletAggregation: In spite of the normal levels of GPIIb-IIIa and normal fibrinogen binding the platelets showed complete absence of aggregation in response to ADP (6 mM) and collagen (4 mg/mL).
CasePreviousTesting: Denaturing gradient gel electrophoresis analysis and DNA sequencing were done to detect abnormalities. DNA sequencing of exon 3 o ITGB3 was performed
Gene: ITGB3
Variant: M_000212.2:c.445T>C (p.Ser149Pro)
LegacyVariant: (p.Ser123Pro)
ClinVar: N/A
CAiD: CA400021997
gnomAD: N/A
9LMIHomozygote1346G
Case9: Patient LM (can be found in the GT database) gender and age are not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A Not reported for this proband
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Undetectable for this patient
PlateletAggregation: N/A
CasePreviousTesting: N/A
Gene: ITGA2B
Variant: NM_000419.3:c.1346G>A (p.Gly449Asp)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA399803552
gnomAD: N/A
PreviouslyPublished: Reference number 20 in this article
AP
Case22: Patient AP, gender and age are not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: HP:0000421, HP:0000225, HP:0006298
(Epistaxis, gingival bleeding, prolonged bleeding after tooth extraction)
CaseHPOFreeText: Hematoma
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: 12-20% GPIIIa and GPIIb surface expression
PlateletAggregation: N/A
CasePreviousTesting: N/A
Gene: ITGA2B
Variant: NM_000419.3:c.3077G>A (p.Arg1026Gln) other mutation was not found
LegacyVariant: N/A
ClinVar: 50232
CAiD: CA10575572
gnomAD: MAF in the European (non-Finnish) population is 0.000008801 https://gnomad.broadinstitute.org/variant/17-42449775-C-T
PreviouslyPublished: References 37 and 38
F4P1
Case4: Patient F4P1, Male, 43 years old, Tunisian
DiseaseAssertion: Glanzmann thrombasthenia type I
FamilyInfo: Table 1 states there is a family history of bleeding (we have minimal to no specific info on this)
ParentalGenotype: N/A
CasePresentingHPOs: HP:0004406 (Recurrent epsitaxis)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: N/A
PlateletAggregation: GT diagnosis was based on absent platelet aggregation induced by ADP, collagen, and TRAP and subnormal or cyclical ristocetin induced agglutination
CasePreviousTesting: Using PCR they successfully amplified 20 DNA fragments for the ITGA2B gene (covering more than 48% of the ITGA2B gene constituting 30 exons) and15 DNA fragments of theITGB3gene (covering 15 exons)
Gene: ITGA2B and ITGB3
Variant: ITGA2B variants: g.13378A>C, g.14856C>A, g.19021C>T (I am denoting this as Unknown Variants as I need guidance with these-- biocurator curating this paper can also look them up- but I am noting them here) and ITGB3 variants: NM_000212.2:c.176T>C (p.Leu59Pro) and NM_000212.2:c.1143A>C (p.Val381Val) and NM_000212.2:c.1545G>A (p.Arg515Arg)
LegacyVariant: N/A
ClinVar: 13558 (p.Leu59Pro), 255535 (p.Val381Val), 255537 (p.Arg515Arg)
CAiD: CA123235 (p.Leu59Pro), CA8623175 (p.Val381Val), CA8623284 (p.Arg515Arg)
gnomAD: MAF in the Ashkenazi Jewish population is 0.1565 https://gnomad.broadinstitute.org/variant/17-45360730-T-C for (p.Leu59Pro) and MAF in the East Asian population is 0.5857 https://gnomad.broadinstitute.org/variant/17-45368337-A-C for (p.Val381Val) and MAF in the East Asian population for (p.Arg515Arg) is 0.3455 https://gnomad.broadinstitute.org/variant/17-45369789-G-A
Patient 2
Case2: Patient 2, diagnosed at 5 years, gender and ethnicity not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: HP:0000421, HP:0000225, HP:0000790
(Epistaxis, gingival bleeding, hematuria)
CaseHPOFreeText: Reduced clot retraction
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Immunoblot analysis of platelet lysates showed no detectable pro-αIIb or mature αIIb in any of the patient samples. Trace amounts of Beta3 were detected in samples from this patient
PlateletAggregation: Absent in vitro platelet aggregation in response to ADP, epinephrine and collagen but a normal initial phase response to ristocetin
CasePreviousTesting: Polymerase chain reaction (PCR), single strand conformation polymorphism (SSCP) analysis, and DNA sequencing was performed for ITGA2B
Gene: ITGA2B
Variant: NM_000419.3:c.953C>G (p.Ser318Leu)
LegacyVariant: p.Ser287Leu
ClinVar: N/A
CAiD: CA399804788
gnomAD: N/A
Supplemental Table S1:
Cases38and39: Females, Italy, age not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Moderate bleeding
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: <5% αIIbβ3 expression
PlateletAggregation: Absent platelet aggregation (all the information that is provided in Supp. Table S1)
CasePreviousTesting: Sanger sequencing of exons, splice sites and untranslated regions of the ITGA2B and ITGB3 genes was performed
Gene: ITGA2B
Variant: NM_000419.3:c.2254C>G (p.Leu752Val) and NM_000419.3:c.2264G>C (p.Arg755Pro)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA8602773 and CA8602772
gnomAD: MAF in the European non Finnish population is 0.00001032 https://gnomad.broadinstitute.org/variant/17-42454390-G-C and MAF in the European non Finnish population is 0.00001060 https://gnomad.broadinstitute.org/variant/17-42454380-C-G
PreviouslyPublished: PMID: 12083483
female infant
Case#: Female, at birth
DiseaseAssertion: Glanzmann Thrombasthenia
FamilyInfo: Figure 1 Consanguinity Mother: 27 yo. Positive for mutation. Epistaxis, hypochromic microcytic anemia, cesarean postoperative vaginal bleeding. Maternal aunt present with GT, Positive for mutation. Maternal cousin present with GT, Positive for mutation. Paternal cousins present with GT, Positive for mutation.
ParentalGenotype: Both parents heterozygous carriers.
CasePresentingHPOs: HP:0000978, Bruising susceptibility. HP:0000225, Gingival bleeding. HP:0003265, Neonatal hyperbilirubinemia. HP:0011869, Abnormal platelet function. HP:0004887, Respiratory failure requiring assisted ventilation. HP:0000967, Petechiae.
PlateletAggregation: Normal coagulation. Reduced platelet function.
CaseHPOFreeText: APGAR score 9. Spontaneous skin bruising. Started on feeds second day of life.
ProteinExpression: Platelet function assays showed severely reduced activity.
Gene: ITGB3
Variant: p.Asp145Asn
HGVS: NP_000203.2:p.Asp145Asn
ClinVar: 627066
CAID: CA400021939
gnomAD: Absent
F/16
Case11: Female, 16 years old, Tamil Nadu India
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: HP:0000225, HP:0006298, HP:0031364
(Gingival bleeding, prolonged bleeding after dental extraction, ecchymosis)
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: ITGB3
Variant: NM_000212.2:c.1801T>G (p.Cys601Gly)
LegacyVariant: (p.Cys575Gly)
ClinVar: N/A
CAiD: CA400032570
gnomAD: N/A
mutation
Case#: Attali_LY04 (assumed male, from France)
DiseaseAssertion: Moderate Hemophilia B
FamilyInfo: None
ParentalTesting: None
CasePresentingHPOs: HP:0011858
CasePresentingHPOsFreeText: reduced factor IX activity (FIX:C: 3 ; FIX:Ag: 41)
CaseNotHPOs: N/A
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.127C>T (p.Arg43Trp)
ClinVar: 811505
CAID: CA414435537
gnomAD: Absent/Not Reported
genetic defects
Case#: Taipei_1 & Taipei_2 (assumed male; Chinese)
DiseaseAssertion: Severe Hemophilia B
FamilyInfo: Mothers of both families were found to be carriers as well as several other females in the family
ParentalTesting: Mothers were carriers
CasePresentingHPOs: HP:0011858
CaseHPOsFreeText: reduced factor IX activity (Patient 1: FIX:C: <1% FIX:Ag: 38 ; Patient 2: FIX:C: <1% ; FIX:Ag: 55)
CaseNotHPOs: None
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.128G>A (p.Arg43Gln)
ClinVar: 810864
CAID: CA414435539
gnomAD: Absent/Not Reported
p.Cys28Gly
Case#: N/A
DiseaseAssertion: Severe Hemophilia B
FamilyInfo: Not provided
ParentalTesting: Not provided
CasePresentingHPOs: HP:0011858
CaseHPOsFreeText: reduced factor IX activity
CaseNotHPOs: N/A
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.82T>G (p.Cys28Gly)
ClinVar: Absent
CAID: CA414434482