66
Case#: 66, male, 16 years old, Chinese
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 11.8%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.2167G>A
LegacyVariant:
ClinVar: 10246
CAID: CA255138
gnomAD:
15
Case#: 15, male, 11 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.2275A>T
LegacyVariant:
ClinVar: No
CAID: CA414902563
gnomAD:
148
Case#: 148, male, 8 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.1282_1298delAGTCAATATTTGAACAA
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
154
Case#: 154, male, 27 years old, Chinese
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 4.6%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.3413delA
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
43
Case#: 43, male, 22 years old, Chinese
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.902G>A
LegacyVariant:
ClinVar: 10192
CAID: CA255079
gnomAD:
177
Case#: 177, male, 41 years old, Chinese
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%, Inhibitor present
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.del exons7_11
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
47
Case#: 47, male, 19 years old, Chinese
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.1241A>G
LegacyVariant:
ClinVar: No
CAID: CA414915839
gnomAD:
90
Case#: 90, male, 12 years old, Chinese
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.6406G>A
LegacyVariant:
ClinVar: No
CAID: CA414899430
gnomAD:
159
Case#: 159, male, 11 years old, Chinese
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 12%
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.3637delA
LegacyVariant:
ClinVar: No
CAID: CA255146
gnomAD:
85
Case#: 85, male, 31 years old, Chinese
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 9%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.6103G>A
LegacyVariant:
ClinVar: 381561
CAID: CA16609159
gnomAD:
49
Case#: 49, male, 56 years old, Chinese
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 5.1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.1660A>C
LegacyVariant:
ClinVar: No
CAID: CA414911810
gnomAD:
168
Case#: 168, male, 7 years old, Chinese
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 1.6%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.5480delA
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
105
Case#: 105, male, 8 years old, Chinese
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 49%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.6683G>A
LegacyVariant:
ClinVar: 10098
CAID: CA255016
gnomAD:
98
Case#: 98, male, 31 years old, Chinese
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 1.7%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.6544C>T
LegacyVariant:
ClinVar: 10321
CAID: CA255214
gnomAD:
172
Case#: 172, male, 32 years old, Chinese
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%, Inhibitor present
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.del exons1_25
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
163
Case#: 163, male, 30 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.3931_3932delinsTTT
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
58
Case#: 58, male, 8 years old, Chinese
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 1.1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.1909A>G
LegacyVariant:
ClinVar: No
CAID: CA414909856
gnomAD:
91
Case#: 91, male, 7 years old, Chinese
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 22%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.6437T>C
LegacyVariant:
ClinVar: 627110
CAID: CA414908033
gnomAD:
129
Case#: 129, male, 20 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.3637dupA
LegacyVariant:
ClinVar: No
CAID: CA10568191
gnomAD:
118
Case#: 118, male, 55 years old, Chinese
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 1.3%
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.5219+3A>G
LegacyVariant:
ClinVar: No
CAID: CA873340051
gnomAD:
Enhanced potency of recombinant factor VIIa with increased affinity to activated platelets
PMID: 31549480
Gene: F8
InsufficientEvidence: This article mentions variants and patient tissue being used separately; however, does not tie them in together, without a variant to tie the proband to, it’s insufficient evidence.
H (karachi
Case#: Nawaz_Proband_H (karachi) (Pakistan resident)14 y/o)
DiseaseAssertion: Hemophilia B (no severity assertion made)
FamilyInfo: None
ParentalTesting: None
CasePresentingHPOs: N/A
CaseNotHPOs: N/A
CasePreviousTesting: None
Gene: F9
Variant: NM_000133.4:c.127C>T (p.Arg43Trp)
ClinVar: 811505
CAID: CA414435537
gnomAD: Absent/Not Reported
PMID: 30160169
Gene: F8
HGNC: 3546
NoEvidence: This article does not mention probands with variants in Hemophilia A
c.6623A>G
Case#: 34
DiseaseAssertion: Hemophilia A
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FVIII:C 23%, Mild Phenotype, No inhibitors present
CasePreviousTesting: Screened for IVS-22 and IVS-1, sample was blinded for NGS and the sequencing component was validated by comparing results with Sanger Sequencing
Gene: F8
Variant: NM_000132.3(F8):c.6623A>G (p.Gln2208Arg)
ClinVar: 368117 https://www.ncbi.nlm.nih.gov/clinvar/variation/368117/
CAID: CA10567784
gnomAD: MAF for Gln2208Arg in the European (non-Finnish) population 0.00004320<br>https://gnomad.broadinstitute.org/variant/X-154090093-T-C?dataset=gnomad_r2_1
c.1345C>T
Case#: 43
DiseaseAssertion: Hemophilia B
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FIX:C 30% (Mild Phenotype)
CasePreviousTesting: Screened for IVS-22 and IVS-1, sample was blinded for NGS and the sequencing component was validated by comparing results with Sanger Sequencing
Gene: F9
Variant: NM_000133.3(F9):c.1345C>T (p.Arg449Trp)
ClinVar: 626990 https://www.ncbi.nlm.nih.gov/clinvar/variation/626990/
CAID: CA10529890
gnomAD: MAF for Arg449Trp in the European (non-Finnish) population 0.00006494<br>https://gnomad.broadinstitute.org/variant/X-138644189-C-T?dataset=gnomad_r2_1
c.575T>C
Case#: 5
DiseaseAssertion: Hemophilia A
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FVIII:C 26% (Mild Phenotype), No inhibitors present
CasePreviousTesting: Screened for IVS-22 and IVS-1, sample was blinded for NGS and the sequencing component was validated by comparing results with Sanger Sequencing
Gene: F8
Variant: NM_000132.3(F8):c.575T>C (p.Ile192Thr)
ClinVar: 618637 https://www.ncbi.nlm.nih.gov/clinvar/variation/618637/
CAID: CA414919417
gnomAD: Not reported
FIX mutation spectrum in haemophilia B patients from Jordan: identification of three novel mutations
PMID: 20695909
Gene: F9
HGNC: 3551
066–2002
Case#: 066-2002
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: 1% < FVIII:C < 5%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.5399G>A
LegacyVariant:
ClinVar: No
CAID: CA255162
gnomAD:
071–2025
Case#: 071-2025
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: 1% < FVIII:C < 5%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.2167G>A
LegacyVariant:
ClinVar: No
CAID: CA255138
gnomAD:
020–2070
Case#: 020-2070
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: 5% < FVIII:C < 40%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.558C>G
LegacyVariant:
ClinVar: No
CAID: CA414919454
gnomAD:
003–2002
Case#: 003-2002
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.3637delA
LegacyVariant:
ClinVar: No
CAID: CA255146
gnomAD:
020–1003
Case#: 020-1003
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:
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
035–2020
Case#: 035-2020
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: 1% < FVIII:C < 5%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.5275G>A
LegacyVariant:
ClinVar: No
CAID: CA414911087
gnomAD:
020–2021
Case#: 020-2021
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.1396T>C
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
071–2037
Case#: 071-2037
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:
LegacyVariant:
ClinVar: No
CAID:
gnomAD:
022–2003
Case#: 022-2003
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.278C>T
LegacyVariant:
ClinVar: No
CAID: CA414920106
gnomAD:
003–2025
Case#: 003-2025
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:
LegacyVariant:
ClinVar: No
CAID:
gnomAD:
001–1010
Case#: 001-1010
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.3274_3276delAACinsCC
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
035–2016
Case#: 035-2016
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.3637delA
LegacyVariant:
ClinVar: No
CAID: CA255146
gnomAD:
005–1002
Case#: 005-1002
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:
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
084–2003
Case#: 084-2003
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.209_212delTTGT
LegacyVariant:
ClinVar: No
CAID: CA255050
gnomAD:
020–2065
Case#: 020-2065
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: 5% < FVIII:C < 40%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.1834C>T
LegacyVariant:
ClinVar: No
CAID: CA255129
gnomAD:
004–2019
Case#: 004-2019
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.3637delA
LegacyVariant:
ClinVar: No
CAID: CA255146
gnomAD:
060–2006
Case#: 060-2006
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: 1% < FVIII:C < 5%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.1618C>A
LegacyVariant:
ClinVar: No
CAID: CA414911950
gnomAD:
001–2026
Case#: 001-2026
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.986G>A
LegacyVariant:
ClinVar: No
CAID: CA255089
gnomAD:
047–2002
Case#: 047-2002
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: 1% < FVIII:C < 5%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.6011C>A
LegacyVariant:
ClinVar: No
CAID: CA414905140
gnomAD:
Monitoring once-weekly recombinant factor IX prophylaxis in hemophilia B with thrombin generation assay and factor IX activity V. Nummi, V. Nummi orcid.org/0000-0002-5134-7288 Faculty of Medicine, University of Helsinki, Helsinki, Finland Coagulation Disorders Unit, Department of Hematology and Comprehensive Cancer Center, Laboratory Services, Helsinki University Hospital, Helsinki, FinlandSearch for more papers by this authorA. Jouppila, A. Jouppila Helsinki University Hospital Research Institute, Helsinki, FinlandSearch for more papers by this authorR. Lassila, Corresponding Author R. Lassila riitta.lassila@hus.fi Faculty of Medicine, University of Helsinki, Helsinki, Finland Coagulation Disorders Unit, Department of Hematology and Comprehensive Cancer Center, Laboratory Services, Helsinki University Hospital, Helsinki, Finland Correspondence: Riitta Lassila, Coagulation Disorders Unit, Department of Hematology and Comprehensive Cancer Center, Laboratory Services, Helsinki University Hospital, P.O. Box 372, 00029 HUS, Helsinki, Finland. Tel.: +358 40 517 5547; Fax: +358 9 471 74504; E-mail: riitta.lassila@hus.fiSearch for more papers by this author
PMID: 28406575
Gene: F9
HGNC: 3551
mutations
Case#: Ghanem_Caen (assumed male, from Caen)
DiseaseAssertion: Moderate Hemophilia B
FamilyInfo: N/A
ParentalTesting: None
CasePresentingHPOs: HP:0011858
CaseHPOsFreeText: reduced factor IX activity (FIX:C: 2 ; FIX:Ag: 52
CaseNotHPOs: None
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.128G>T (p.Arg43Leu)
ClinVar: 993549
CAID: CA414435545
gnomAD: Absent Not Reported
S10
Case#: S10, Iranian
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%, Mucosal bleeding
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The F8 gene was directly sequenced for all 26 exons using the Sanger sequencing method. PCR was performed and subsequently analyzed
Gene: F8
Variant: NM_000132.3:c.1931T>G
LegacyVariant:
ClinVar: No
CAID: CA414909677
gnomAD:
S6
Case#: S6, Iranian
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%, Mucosal bleeding, 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: NA
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
Mutation detection and inhibitor risk in Iranian patients with Hemophilia A: Six novel mutations
PMID: 33363863
Gene: F8
HGNCID: 3546
mutation
Case#: Cases 1464
DiseaseAssertion: Familial Severe Hemophilia B
FamilyInfo: In 16 cases, the family pedigree showed more than one affected individual (familial cases) and 12 cases were sporadic. In 17 cases, familial data was not available.
ParentalTesting: N/A
CasePresentingHPOs: HP:0011858
CaseHPOsFreeText: reduced factor IX activity (FIX:C: <1)
CaseNotHPOs: N/A
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.128G>A (p.Arg43Gln)
ClinVar: 810864
CAID: CA414435539
gnomAD: Absent/Not Reported
13.
Case#: 13
DiseaseAssertion: Hemophilia B, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0011858
CaseHPOFreeText: FIX:C = 6.6%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: All relevant sequences of F9 were PCR amplified and analyzed by DNA sequencing
Gene: F9
Variant: NM_000133.3:c.797C>T
LegacyVariant:
ClinVar: No
CAID: CA414443482
gnomAD:
34.
Case#: 34
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.223C>T
LegacyVariant:
ClinVar: No
CAID: CA340993
gnomAD:
19.
Case#: 19
DiseaseAssertion: Hemophilia B, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0011858
CaseHPOFreeText: FIX:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: All relevant sequences of F9 were PCR amplified and analyzed by DNA sequencing
Gene: F9
Variant: NM_000133.3:c.1129G>T
LegacyVariant:
ClinVar: No
CAID: CA414446072
gnomAD:
26.
Case#: 26
DiseaseAssertion: Hemophilia B, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0011858
CaseHPOFreeText: FIX:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: All relevant sequences of F9 were PCR amplified and analyzed by DNA sequencing
Gene: F9
Variant: NM_000133.3:c.1234G>T
LegacyVariant:
ClinVar: No
CAID: CA414446705
gnomAD:
42.
Case#: 42
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.252+2T>G
LegacyVariant:
ClinVar: No
CAID: CA414436440
gnomAD:
c.839G>A
Case#: 17, Spanish
DiseaseAssertion: Hemophilia A
FamilyInfo: Sporadic
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: Mild
CasePreviousTesting: All 26 exons and exon-intron boundaries of the F8 gene were amplified using primers and PCR, analyzed by direct forward and reverse sequencing using a DNA sequencing kit
Gene: F8
Variant: NM_000132.3:c.839G>A (p.Gly261Asp)
ClinVar: NA
CAID: CA414918260
gnomAD: Not reported
c.4155_4195dup
Case#: 6
DiseaseAssertion: Hemophilia A
FamilyInfo: Sporadic
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: Severe, Inhibitors present
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.4157_4197dup (p.Pro1400SerfsTer38)
ClinVar: NA
CAID: CA1139532048
gnomAD: Not reported
c.782T>C
Case#: 16, Spanish
DiseaseAssertion: Hemophilia A
FamilyInfo: Sporadic
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: Moderate
CasePreviousTesting: All 26 exons and exon-intron boundaries of the F8 gene were amplified using primers and PCR, analyzed by direct forward and reverse sequencing using a DNA sequencing kit
Gene: F8
Variant: NM_000132.3:c.782T>C (p.Leu242Pro)
ClinVar: NA
CAID: CA414918925
gnomAD: Not reported
Twenty-five novel mutations of the factor IX gene in haemophilia B
Case#: Wulff_Proband_2252 and Wulff_Proband_2270
DiseaseAssertion: Severe Hemophilia B
FamilyInfo: N/A
ParentalTesting: None
CasePresentingHPOs: HP:0011858
CaseHPOsFreeText: reduced factor IX activity
CaseNotHPOs: None
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.128G>T (p.Arg43Leu)
ClinVar: 993549
CAID: CA414435545
gnomAD: Absent/Not Reported
17
Case#: 17
DiseaseAssertion: Hemophilia B, moderate
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FIX:C = 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: All exons, UTRs, exon-intron junction regions, and the promotor of F9 were amplified by PCR and analyzed by direct DNA sequencing
Gene: F9
Variant: NM_000133.3:c.172G>C
LegacyVariant:
ClinVar: No
CAID: CA414435830
gnomAD:
A13
Case#: A13
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 10, FVIII:AG = 60, assay discrepancy present (OSA>CSA)
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: Coding region and intron/exon bound-aries of the F8 gene were amplified from all patient samples and directly sequenced using primers
Gene: F8
Variant: NM_000132.4:c.5303G>A
LegacyVariant:
ClinVar: No
CAID: CA10568007
gnomAD:
B14 – B16
Case#: B14 - B16
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C Chr = 10, FVIII:AG = 18, inverse assay discrepancy present (OSA<CSA)
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: Coding region and intron/exon bound-aries of the F8 gene were amplified from all patient samples and directly sequenced using primers
Gene: F8
Variant: NM_000132.4:c.1293G>C, NM_000132.4:c.1293G>T
LegacyVariant:
ClinVar: No
CAID: CA414915298, CA255100
gnomAD:
B32 – B44
Case#: B32 - B44
DiseaseAssertion: NA
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C Chr = 94, FVIII:AG = 88, inverse assay discrepancy present (OSA<CSA)
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: Coding region and intron/exon bound-aries of the F8 gene were amplified from all patient samples and directly sequenced using primers
Gene: F8
Variant: NM_000132.4:c.2215G>A
LegacyVariant:
ClinVar: No
CAID: CA255139
gnomAD:
A5 – A8
Case#: A5 - A8
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 26, FVIII:AG = 60, assay discrepancy present (OSA>CSA)
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: Coding region and intron/exon bound-aries of the F8 gene were amplified from all patient samples and directly sequenced using primers
Gene: F8
Variant: NM_000132.4:c.1649G>A
LegacyVariant:
ClinVar: No
CAID: CA255115
gnomAD:
mutation
Case#: Attali_LY23 (assumed male, from France)
DiseaseAssertion: Severe Hemophilia B
FamilyInfo: None
ParentalTesting: None
CasePresentingHPOs: HP:0011858
CasePresentingHPOsFreeText: reduced factor IX activity (FIX:C: <1 ; FIX:Ag: 44)
CaseNotHPOs: N/A
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.128G>A (p.Arg43Gln)
ClinVar: 810864
CAID: CA414435539
gnomAD: Absent/Not Reported
mutations
Case#: Wulff_Proband_031 & Wulff_Proband_048
DiseaseAssertion: Severe Hemophilia B
FamilyInfo: N/A
ParentalTesting: None
CasePresentingHPOs: HP:0011858
CaseHPOsFreeText: reduced factor IX activity (Proband_031: FIX:C: <1 FIX:Ag: 48 ; Proband_048 FIX:C <1 FIX:Ag: 52
CaseNotHPOs: None
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.128G>A (p.Arg43Gln)
ClinVar: 810864
CAID: CA414435539
gnomAD: Absent/Not Reported
Table I.
No evidence of NM_000133.4:c.84T>G (p.Cys28Trp) in this paper.
Clinical Problem Solving and Using New Paths in the Laboratory: Learning from Case Studies
PMID: 32820490
Gene: F9
HGNC: 3551
The proband, 12-year-old boy with moderate bleeding history, had manifest prolonged activated partial thromboplastin time (98.1 s) and markedly decreased FIX activity (1%).
Case#: 12 year old male
DiseaseAssertion: Hemophilia B, moderate
FamilyInfo: Uncle had mild Hemophilia B
ParentalTesting: No
CasePresentingHPOs: HP:0011858
CaseHPOFreeText: FIX:C = 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: exons and introns were amplified by PCR and subsequently analyzed by direct sequencing
Gene: F9
Variant:
LegacyVariant:
ClinVar:
CAID:
gnomAD:
Cysteine 19--arginine (in patient HB13O) alters thesignal peptide. The factor IX activity (20%) in thepatient record suggests mild disease
Case#: Family HB130
DiseaseAssertion: Mild Hemophilia B
FamilyInfo: N/A
ParentalTesting: N/A
CasePresentingHPOs: HP:0011858
CaseHPOsFreeText: reduced factor IX activity (FIX:C : 20%)
CaseNotHPOs: N/A
CasePreviousTesting:
Gene: F9
Variant: NM_000133.4:c.82T>C (p.Cys28Arg)
LegacyVariant: c.111T>C (p.Cys-19Arg)
ClinVar: 10657
CAID: CA255450
gnomAD: Absent/Not Reported
Table S3. F9 mutations.
Case#: Miller_Proband 1 (male)
DiseaseAssertion: Moderate Hemophilia B
FamilyInfo: N/A
ParentalTesting: N/A
CasePresentingHPOs: HP:0011858
CaseHPOsFreeText: reduced factor IX activity
CaseNotHPOs: N/A
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.82T>C (p.Cys28Arg)
ClinVar: 10657
CAID: CA255450
gnomAD: Absent/Not Reported
Factor IX mutations in Haemophilia B patients in Malaysia: a preliminary study
PMID: 22870602
Gene: F9
HGNC: 3551
Ala-10 residue (Ala[GCC) to Val[GCT]
Case#: Oldenburg_Patient_A and Oldenburg_Patient_C
DiseaseAssertion: Mild Hemophilia B (exacerbated due to phenprocoumon administration)
FamilyInfo: The parents of patients A and C emigrated from the same region in North-Eastern Europe (North Poland)
ParentalTesting: N/A
CasePresentingHPOs: HP:0011858
CaseHPOsFreeText: reduced factor IX activity, severe bleeding at each oral anticoagulation with phenprocoumon occurrence, bleeding in muscles of the upper leg
CaseNotHPOs: N/A
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.110C>T (p.Ala37Val)
ClinVar: Absent
CAID: CA414435437
gnomAD: Allele Frequency in European (non-Finnish) population: 0.00002186
Glucose hypometabolism in the visual cortex proportional to disease severity in patients with essential blepharospasm.
PMID: 31487599
Gene: F8
NoEvidence: No mention of blood disorders, F8 or Hemophilia A in this article.
Haemophilia A: the consequences of de novo mutations. Two case reports
PMID: 28488976
Gene: F8
HGNCID: 3546
Leu-23Pro
Case#: HB-KHF-04 (Male, Korean)
DiseaseAssertion: Severe Hemophilia B
FamilyInfo: Among the 33 patients, 13 had a family history (39%), while the rest of the patients did not (sporadic, 61%). 27 patients (82%) had the severe form of the disease, while 6 patients (18%) had the moderate form
ParentalTesting: N/A
CasePresentingHPOs: HP:0003645, HP:0011858
CaseHPOsFreeText: Prolonged partial thromboplastin time, reduced factor IX activity
CaseNotHPOs: None
CasePreviousTesting: aPTT and one-stage clotting assay at labs where patients were ascertained: FIX-deficient plasma (STA®-Deficient IX; Diagnostica Stago, Asnieres-sur-Seine, France; reference range, 60–150%) at Samsung Medical Center or HemosIL™ (Instrumentation Laboratory, Milan, Italy; reference range, 50–145%) at the Korea Hemophilia Foundation.
Gene: F9
Variant: NM_000133.4:c.68T>C (p.Leu23Pro)
ClinVar: Absent
CAID: CA414434403
gnomAD: Absent/Not Reported
p.Ala37Thr
Case#: Tamura_Case (male, 49 y/o)
DiseaseAssertion: Severe Hemophilia B
FamilyInfo: No family history of stroke, thrombosis or bleeding episodes
ParentalTesting: N/A
CasePresentingHPOs: HP:0012233, HP:0011858
CaseHPOsFreeText: cerebral infarction, prolonged APTT (58.4 s), elevated diluted Russell viper venom time ratio (2.68), and anti-β2 glycoprotein I antibody (9.7 U/mL) and anticardiolipin antibody IgG (39 U/mL), antiphospholipid antibody syndrome (APS), intramuscular hemorrhage, reduced factor IX activity (<0.5%)
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
6 months of age, the proband (male, born on 20 February 2008)
Case2: 6-month-old Male, China
DiseaseAssertion: Hemophilia B (Factor IX-deficient)
FamilyInfo: Mother and maternal grandmother are HB carriers due to a novel mutation in intron 3. Pedigree shown in Figure 1.
ParentalTesting: The F9 exons were amplified (RT-PCR) and exons 1 to 8 of the F9 gene were analyzed with the ABI 3130 Genetic Analyzer, Sequenced intron 3 of the F9 gene
CasePresentingHPOs: HP:0011858 (Reduced factor IX activity)
CaseHPOFreeRext: FIX:C 1%, Pelioma, Cyanotic bumps, Subcutaneous bleeding, knee swelling from crawling
CasePreviousTesting: Prenatal testing at 20 weeks
Gene: F9
Variant: NM_000133.3(F9):c.278-3A>G
ClinVar: 92225 https://www.ncbi.nlm.nih.gov/clinvar/variation/92225/#id_first
CAID: CA285284
gnomAD: Not Reported
Table 1
Case#: Cz32, Italy (Calabria)
DiseaseAssertion: Hemophilia A
FamilyInfo: Inherited
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FVII:C <1%
CasePreviousTesting: Polymerase chain reaction (PCR) analysis, Long PCR for detecting the intron 22 inversion was performed, Direct cycle sequence analysis using the Taq dye-deoxy terminator method
Gene: F8
Variant: F8, IVS22 INV
ClinVar: 10150 https://www.ncbi.nlm.nih.gov/clinvar/variation/10150/
CAID: NA
gnomAD: Not reported
Characterization of genetic defects of hemophilia B of Chinese origin
PMID: 1796396
Gene: F9
HGNC: 3551
An intronic mutation c.6430-3C>G in the F8 gene causes splicing efficiency and premature termination in hemophilia A
PMID: 29652675
Gene: F8
HGNC ID: HGNC:3546
The p.Pro521Leu substitution (patient P3)
Case#: P3 (female)
DiseaseAssertion: Carrier
FamilyInfo: N/A
ParentalTesting: Father was tested; has mild HA
CasePresentingHPOs: HP:0003125, HP:0001928
CaseHPOFreeText: Low FVIII levels (significant decrease in FVIII:C (48.4% ± 6.1, P < 0.01) and FVIII:Ag (36.6% ± 2.7, P < 0.01)), abnormal blood coagulation
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
CasePreviousTesting: Molecular Analysis included a southern blot assay, PCR, dHPLC and a multiplex ligation-dependent probe amplification analysis. Plasmid mutagenesis, plasmid transfection and in silico analysis were also performed.
Gene: F8
Variant: NM_000132.4:c.1562C>T
CAID: CA414912242
gnomAD: Absent/Not Reported
The CDC Hemophilia B mutation project mutation list: a new online resource
PMID: 24498619
Gene: F9
HGNC: 3551
Usual and unusual mutations in a cohort ofBelgian patients with hemophilia B
PMID: 27865967
Gene: F9
HGNC: 3551
Predictive Value of Slow and Fast EEG Oscillations for Methylphenidate Response in ADHD
PMID: 31304784
Gene: F8
NoEvidence: This article is not about Hemophilia A, blood disorders, or F8. This article is centered around ADHD.
Genotype-phenotype correlation in British families with X linked congenital stationary night blindness
PMID: 14609846
Gene: NYX
HGNC: 8082
Disease: Congenital stationary night blindness 1A
MONDO: 0010690
InheritancePattern: X-linked recessive
Prevalence: Congenital stationary night blindness has an estimated prevalence between 1 in 6,000 (PMID: 31427709) and 1 in 300,000 (PMID: 3487908). However, the prevalence of congenital stationary night blindness 1A specifically is unknown.
Penetrance: Penetrance is thought to be complete.
A novel GPR143 duplication mutation in a Chinese family with X-linked congenital nystagmus
PMID: 19390656
Gene: GPR143
HGNC: 20145
Disease: X-linked recessive ocular albinism
MONDO: 0021019
InheritancePattern: X-linked recessive
Prevalence: Ocular albinism has an estimated prevalence between 1 in 111,000 and 1 in 1,000,000 live births (PMID: 35495622)
Penetrance: Fully penetrant in males, with onset in infancy. Most female carriers appear to be unaffected.
Unique Variants in OPN1LW Cause Both Syndromic and Nonsyndromic X-Linked High Myopia Mapped to MYP1
PMID: 26114493
Gene: OPN1LW
HGNC: 9936
Disease: protan color blindness
MONDO: 0010565
InheritancePattern: X-linked
Prevalence: The overall prevalence of protan color blindness is approximately 1% in males, which is higher than that of blue cone monochromacy (~1 in 100,000, PMID: 35759666).
Penetrance: Known disease-causing alleles appear to be almost completely penetrant in males (PMID: 21167193).
Identification of Novel RPGR ORF15 Mutations in X-linked Progressive Cone-Rod Dystrophy (XLCORD) Families
PMID: 15914600
Gene: RPGR
HGNC: 10295
Disease: RPGR-related retinopathy
MONDO: MONDO:0100437
InheritancePattern: X-linked
Prevalence: The prevalence of RPGR-related retinopathy is calculated to be approximately 1 in 214,000, based on the known incidence of retinitis pigmentosa at 1 in 3,000, the proportion of retinitis pigmentposa that is X-linked at 20%, and the proportion of X-linked retinitis pigmentosa that is RPGR-associated at 70% (PMID: 34985506).
Penetrance: Penetrance is nearly 100% in hemizygous males but is incomplete and dependent upon the variant in heterozygous female carriers.
Heterozygous 'null allele' mutation in the human peripherin/RDS gene
PMID: 8111389
Gene: PRPH2
HGNC: 9942
Disease: retinitis pigmentosa 7
MONDO: 0011974
InheritancePattern: semi-dominant
Prevalence: The incidence of PRPH2-related cases among inherited retinal dystrophies is reported to range from 3.5% in North America to 10.3% in France (PMID: 36010202).
Penetrance: The penetrance among biallelic cases appears to be complete, while the monoallelic cases exhibit incomplete penetrance (PMID: 36609934).
Landscape of pathogenic variants in six pre-mRNA processing factor genes for retinitis pigmentosa based on large in-house data sets and database comparisons
PMID: 35138024
Gene: PRPF4
HGNC: 17349
Disease: retinitis pigmentosa 70
MONDO: 0014400
InheritancePattern: autosomal dominant
Prevalence: The overall prevalence of retinitis pigmentosa is between 1 in 3,000 and 1 in 4,000 individuals, while the proportion of retinitis pigmentosa with a dominant mode of inheritance is estimated to be 15-35% (between 1 in 8,500 and 1 in 27,000). The proportion of that incidence made up by the specific form caused by variants in PRPF4 is not clear.
Penetrance: Known disease-causing alleles appear to be incompletely penetrant (PMID: 25383878).
Mutations in the Genes for Interphotoreceptor Matrix Proteoglycans, IMPG1 and IMPG2, in Patients with Vitelliform Macular Lesions
PMID: 28644393
Gene: IMPG2
HGNC: 18362
Disease: retinitis pigmentosa 56
MONDO: 0013314
InheritancePattern: semi-dominant
Prevalence: Vitelliform macular dystrophy in general is estimated to have a prevalence of 1 in 5,500 (PMID: 27120116).
Penetrance: The penetrance of the phenotype among homozygous cases appears to be complete, while heterozygous carriers of deleterious variants show incomplete penetrance and variable expressivity.
Molecular cloning of a retina-specific membrane guanylyl cyclase
PMID: 1356371
Gene: GUCY2D
HGNC: 4689
Disease: Leber congenital amaurosis 1
MONDO: 0008764
InheritancePattern: Autosomal Recessive
Prevalence: The overall prevalence of Leber congenital amaurosis is between 1 in 33,000 and 1 in 100,000 newborns, while the proportion of Leber congenital amaurosis caused by GUCY2D variants is between 10% and 20% (PMID: 10951519). Thus, the prevalence of Leber congenital amaurosis 1 is between 1 in 165,000 and 1 in 1,000,000.
Penetrance: Fully penetrant, with onset in neonates or in infancy
Mutational screening of splicing factor genes in cases with autosomal dominant retinitis pigmentosa
PMID: 24959063
Gene: PRPF4
HGNC: 17349
Disease: retinitis pigmentosa 70
MONDO: 0014400
InheritancePattern: autosomal dominant
Prevalence: The overall prevalence of retinitis pigmentosa is between 1 in 3,000 and 1 in 4,000 individuals, while the proportion of retinitis pigmentosa with a dominant mode of inheritance is estimated to be 15-35% (between 1 in 8,500 and 1 in 27,000). The proportion of that incidence made up by the specific form caused by variants in PRPF4 is not clear.
Penetrance: Known disease-causing alleles appear to be incompletely penetrant (PMID: 25383878).
Improving the management of Inherited Retinal Dystrophies by targeted sequencing of a population-specific gene panel
PMID: 27032803
Gene: BBS1
HGNC: 966
Disease: Bardet-Biedl syndrome 1
MONDO: 0008854
InheritancePattern: autosomal recessive
Prevalence: The prevalence of BBS1 variants among Bardet-Biedl syndrome cohorts has been reported as at least 20% (PMID: 19402160), while the prevalence of Bardet-Biedl syndrome overall has been estimated between 1 in 13,500 and 1 in 160,000 live births, depending on the population (PMID: 22713813).
Penetrance: The penetrance of the phenotype among homozygous cases appears to be complete.
Lack of Interphotoreceptor Retinoid Binding Protein Caused by Homozygous Mutation of RBP3 Is Associated With High Myopia and Retinal Dystrophy
PMID: 25766589
Gene: RBP3
HGNC: 9921
Disease: retinitis pigmentosa 66
MONDO: 0014093
InheritancePattern: autosomal recessive
Prevalence: RBP3-related cases are believed to be very rare (possibly with estimated prevalence of less than 1 in 1,000,000), however, it is believed that there may be under-diagnosis (PMID: 37806543).
Penetrance: RBP3 disease-causing variants appear to have complete penetrance.
Germline Mutations in CTNNB1 Associated With Syndromic FEVR or Norrie Disease
PMID: 30640974
Gene: CTNNB1
HGNC: 2514
Disease: severe intellectual disability-progressive spastic diplegia syndrome
MONDO: 0014035
InheritancePattern: autosomal dominant
Prevalence: The incidence is unknown but estimated to be between 1 in 30,000 and 1 in 40,000 births (PMID: 32168371).
Penetrance: The penetrance of the cognitive impairment phenotype among cases appears to be near-complete, while the exudative vitreoretinopathy phenotype reportedly has a prevalence of ~39% among affected individuals with a syndromic diagnosis.
A core complex of BBS proteins cooperates with the GTPase Rab8 to promote ciliary membrane biogenesis
PMID: 17574030
Gene: BBS7
HGNC: 18758
Disease: Bardet-Biedl syndrome 7
MONDO: 0014435
InheritancePattern: autosomal recessive
Prevalence: The prevalence of BBS7 variants among Bardet-Biedl syndrome cohorts has been reported at 4.2% (PMID: 19402160), while the prevalence of Bardet-Biedl syndrome overall has been estimated between 1 in 13,500 and 1 in 160,000 live births, depending on the population (PMID: 22713813).
Penetrance: The penetrance of the phenotype among homozygous cases appears to be complete.
Identification of a novel RPGR mutation associated with X-linked cone-rod dystrophy in a Chinese family
PMID: 34800980
Gene: RPGR
HGNC: 10295
Disease: RPGR-related retinopathy
MONDO: MONDO:0100437
InheritancePattern: X-linked
Prevalence: The prevalence of RPGR-related retinopathy is calculated to be approximately 1 in 214,000, based on the known incidence of retinitis pigmentosa at 1 in 3,000, the proportion of retinitis pigmentposa that is X-linked at 20%, and the proportion of X-linked retinitis pigmentosa that is RPGR-associated at 70% (PMID: 34985506).
Penetrance: Penetrance is nearly 100% in hemizygous males but is incomplete and dependent upon the variant in heterozygous female carriers.
New mouse models for recessive retinitis pigmentosa caused by mutations in the Pde6a gene
PMID: 18849587
Gene: PDE6A
HGNC: 8785
Disease: retinitis pigmentosa 43
MONDO: MONDO:0013437
InheritancePattern: autosomal recessive
Prevalence: The overall prevalence of retinitis pigmentosa is between 1 in 3,000 and 1 in 4,000 individuals, while the proportion of retinitis pigmentosa with a recessive mode of inheritance is estimated to be 65-85% (between 1 in 3,500 and 1 in 6,200). Retinitis pigmentosa 43 is considered to be make up 2-5% of these cases, with an overall prevalence estimated between 1 in 70,000 and 1 in 310,000.
Penetrance: Known disease-causing alleles appear to be completely penetrant.
Next-Generation Sequencing and Novel Variant Determination in a Cohort of 92 Familial Exudative Vitreoretinopathy Patients
PMID: 25711638
Gene: LRP5
HGNC: 6697
Disease: osteoporosis-pseudoglioma syndrome
MONDO: 0009820
InheritancePattern: autosomal recessive
Prevalence: osteoporosis-pseudoglioma syndrome is estimated to occur in 1 out of every 2,000,000 live births.
Penetrance: The penetrance of the phenotype among homozygous or compound heterozygous cases appears to be complete, while heterozygous carriers of deleterious variants appear to be mildly affected.
Unusual OCT findings in a patient with CABP4-associated cone-rod synaptic disorder
PMID: 38206458
Gene: CABP4
HGNC: 1386
Disease: cone-rod synaptic disorder, congenital nonprogressive
MONDO: 0012490
InheritancePattern: autosomal recessive
Prevalence: The prevalence of the Åland eye disease or incomplete congenital stationary night blindness phenotype was estimated at 1 in 22,000 based on a Danish male cohort, with CABP4 variants specifically responsible for 1 out of 35 cases (PMID: 28002560).
Penetrance: Penetrance appears to be 100% among the reported individuals harboring biallelic disease-causing CABP4 variants.
The retinal degeneration slow (rds) gene product is a photoreceptor disc membrane-associated glycoprotein
PMID: 1986774
Gene: PRPH2
HGNC: 9942
Disease: retinitis pigmentosa 7
MONDO: 0011974
InheritancePattern: semi-dominant
Prevalence: The incidence of PRPH2-related cases among inherited retinal dystrophies is reported to range from 3.5% in North America to 10.3% in France (PMID: 36010202).
Penetrance: The penetrance among biallelic cases appears to be complete, while the monoallelic cases exhibit incomplete penetrance (PMID: 36609934).
Retinal Structure and Function in Achromatopsia: Implications for Gene Therapy
PMID: 24148654
GeneName: GNAT2
HGNC: 4394
Disease: achromatopsia 4
MonDO ID: MONDO_0013465
Inheritance: autosomal recessive
Identifying core biological processes distinguishing human eye tissues with precise systems-level gene expression analyses and weighted correlation networks
PMID: 30239781
Gene: GUCY2D
HGNC: 4689
Disease: Leber congenital amaurosis 1
MONDO: 0008764
InheritancePattern: Autosomal Recessive
Prevalence: The overall prevalence of Leber congenital amaurosis is between 1 in 33,000 and 1 in 100,000 newborns, while the proportion of Leber congenital amaurosis caused by GUCY2D variants is between 10% and 20% (PMID: 10951519). Thus, the prevalence of Leber congenital amaurosis 1 is between 1 in 165,000 and 1 in 1,000,000.
Penetrance: Fully penetrant, with onset in neonates or in infancy
Autozygome-guided exome sequencing in retinal dystrophy patients reveals pathogenetic mutations and novel candidate disease genes
PMID: 23105016
Gene: IMPG2
HGNC: 18362
Disease: retinitis pigmentosa 56
MONDO: 0013314
InheritancePattern: semi-dominant
Prevalence: Vitelliform macular dystrophy in general is estimated to have a prevalence of 1 in 5,500 (PMID: 27120116).
Penetrance: The penetrance of the phenotype among homozygous cases appears to be complete, while heterozygous carriers of deleterious variants show incomplete penetrance and variable expressivity.
Confirmation of FZD5 implication in a cohort of 50 patients with ocular coloboma
PMID: 32737437
autosomal dominant case
Lysosomal localization of the neuronal ceroid lipofuscinosis CLN5 protein
PMID: 11971870
Gene: CLN5
HGNC: 2076
Disease: Ceroid lipofuscinosis, neuronal, 5 (also known as Finnish variant late infantile neuronal ceroid lipofuscinosis, neuronal ceroid lipofuscinosis late infantile Finnish variant, or Finnish vLINCL)
MONDO: 0009745
InheritancePattern: Autosomal Recessive
Prevalence: Unknown, but part of a larger group of NCL disorders with a collective prevalence between 1 in 12,500 (PMID:9662406) and 1 in 100,000 (PMID:23374165)
Penetrance: Fully penetrant, with onset often in the late infantile period but in some cases during early adulthood or even as late as in the 6th decade of life
Human retinal organoids harboring IMPG2 mutations exhibit a photoreceptor outer segment phenotype that models advanced retinitis pigmentosa
PMID: 36206764
Gene: IMPG2
HGNC: 18362
Disease: retinitis pigmentosa 56
MONDO: 0013314
InheritancePattern: semi-dominant
Prevalence: Vitelliform macular dystrophy in general is estimated to have a prevalence of 1 in 5,500 (PMID: 27120116).
Penetrance: The penetrance of the phenotype among homozygous cases appears to be complete, while heterozygous carriers of deleterious variants show incomplete penetrance and variable expressivity.
Functional characterization of missense mutations at codon 838 in retinal guanylate cyclase correlates with disease severity in patients with autosomal dominant cone–rod dystrophy
PMID: 11115851
Gene: GUCY2D
HGNC: 4689
Disease: Cone-rod dystrophy 6
MONDO: 0011143
InheritancePattern: Autosomal Dominant
Prevalence: The overall prevalence of cone-rod dystrophy is between 1 in 30,000 and 1 in 40,000 (PMID: 17270046), while the proportion of cone-rod dystrophy caused by GUCY2D variants is between 19% and 23% (PMID: 22183351, PMID: 25515582). Thus, the prevalence of cone-rod dystrophy 6 is between 1 in 130,000 and 1 in 215,000.
Penetrance: Penetrance is age-dependent, with onset between the 1st and 6th decades of life.
Visual and ocular findings in a family with X-linked cone dysfunction and protanopia
PMID: 34287097
Gene: OPN1LW
HGNC: 9936
Disease: red color blindness
MONDO: MONDO:0010565
InheritancePattern: X-linked
Prevalence: Protanomaly and protanopia are common disorders with peak frequencies (among the males of certain populations) of 1.94% and 1.28%, respectively (PMID: 30258865).
Penetrance: The penetrance of the phenotype among hemizygous cases appears to be complete or near-complete.
Codon-Optimized RPGR Improves Stability and Efficacy of AAV8 Gene Therapy in Two Mouse Models of X-Linked Retinitis Pigmentosa
PMID: 28549772
Gene: RPGR
HGNC: 10295
Disease: RPGR-related retinopathy
MONDO: MONDO:0100437
InheritancePattern: X-linked
Prevalence: The prevalence of RPGR-related retinopathy is calculated to be approximately 1 in 214,000, based on the known incidence of retinitis pigmentosa at 1 in 3,000, the proportion of retinitis pigmentposa that is X-linked at 20%, and the proportion of X-linked retinitis pigmentosa that is RPGR-associated at 70% (PMID: 34985506).
Penetrance: Penetrance is nearly 100% in hemizygous males but is incomplete and dependent upon the variant in heterozygous female carriers.
A Tyr368His RPE65 founder mutation is associated with variable expression and progression of early onset retinal dystrophy in 10 families of a genetically isolated population
PMID: 12960219
Gene: RPE65
HGNC: 10294
Disease: Leber congenital amaurosis 2
MONDO: 0008765
InheritancePattern: Autosomal Recessive
Prevalence: The overall prevalence of Leber congenital amaurosis is between 1 in 33,000 and 1 in 100,000 newborns, while the proportion of Leber congenital amaurosis caused by RPE65 variants is between 1% and 16.7%. Thus, the prevalence of Leber congenital amaurosis 2 is between 1 in 200,000 and 1 in 10,000,000.
Penetrance: Fully penetrant, with onset typically by 1 year of age
LRP5 variants may contribute to ADPKD
PMID: 25920554
Gene: LRP5
HGNC: 6697
Disease: osteoporosis-pseudoglioma syndrome
MONDO: 0009820
InheritancePattern: autosomal recessive
Prevalence: osteoporosis-pseudoglioma syndrome is estimated to occur in 1 out of every 2,000,000 live births.
Penetrance: The penetrance of the phenotype among homozygous or compound heterozygous cases appears to be complete, while heterozygous carriers of deleterious variants appear to be mildly affected.
Patient-iPSC-Derived Kidney Organoids Show Functional Validation of a Ciliopathic Renal Phenotype and Reveal Underlying Pathogenetic Mechanisms
PMID: 29706353
Gene: IFT140
HGNC: 29077
Disease: Short-rib thoracic dysplasia 9 with or without polydactyly
MONDO: 0009964
InheritancePattern: autosomal recessive
Prevalence: Within the lumped disease entity for this curation, the most prevalent form may be retinitis pigmentosa. The prevalence of Saldino-Mainzer syndrome (one of the synonyms of Short-rib thoracic dysplasia 9) is less than 1 in 1,000,000. The prevalence of Leber congenital amaurosis cases caused by IFT140 variants (PMID: 26216056) is calculated to be less than 1 in 3,000,000. Although IFT140 variants are estimated to be responsible for less than 2% of RP, the prevalence of the overall disorder at 1 in 3,000 or 1 in 4,000 means the frequency of these cases could potentially be higher than 1 in 1,000,000.
Penetrance: Known variants for this lumped disease entity appear to be completely penetrant, with highly variable phenotypes and age of onset. On the other hand, the split disease entity caused by monoallelic IFT140 variants appears to have incomplete penetrance.
Cone Dystrophy Associated with a Novel Variant in the Terminal Codon of the RPGR-ORF15
PMID: 33805381
Gene: RPGR
HGNC: 10295
Disease: RPGR-related retinopathy
MONDO: MONDO:0100437
InheritancePattern: X-linked
Prevalence: The prevalence of RPGR-related retinopathy is calculated to be approximately 1 in 214,000, based on the known incidence of retinitis pigmentosa at 1 in 3,000, the proportion of retinitis pigmentposa that is X-linked at 20%, and the proportion of X-linked retinitis pigmentosa that is RPGR-associated at 70% (PMID: 34985506).
Penetrance: Penetrance is nearly 100% in hemizygous males but is incomplete and dependent upon the variant in heterozygous female carriers.
The mGluR6 ligand-binding domain, but not the C-terminal domain, is required for synaptic localization in retinal ON-bipolar cells
PMID: 34793838
Gene: TRPM1
HGNC: 7146
Disease: congenital stationary night blindness 1C
MONDO: MONDO:0013183
InheritancePattern: autosomal recessive
Prevalence: Congenital stationary night blindness has an estimated prevalence between 1 in 6,000 (PMID: 31427709) and 1 in 300,000 (PMID: 3487908). However, the prevalence of congenital stationary night blindness 1C specifically is unknown.
Penetrance: Penetrance is thought to be complete.
The Chlamydomonas reinhardtii BBSome is an IFT cargo required for export of specific signaling proteins from flagella
PMID: 20038682
Gene: BBS1
HGNC: 966
Disease: Bardet-Biedl syndrome 1
MONDO: 0008854
InheritancePattern: autosomal recessive
Prevalence: The prevalence of BBS1 variants among Bardet-Biedl syndrome cohorts has been reported as at least 20% (PMID: 19402160), while the prevalence of Bardet-Biedl syndrome overall has been estimated between 1 in 13,500 and 1 in 160,000 live births, depending on the population (PMID: 22713813).
Penetrance: The penetrance of the phenotype among homozygous cases appears to be complete.
In-frame deletion in a novel centrosomal/ciliary protein CEP290/NPHP6 perturbs its interaction with RPGR and results in early-onset retinal degeneration in the rd16 mouse
PMID: 16632484
Gene: RPGR
HGNC: 10295
Disease: RPGR-related retinopathy
MONDO: MONDO:0100437
InheritancePattern: X-linked
Prevalence: The prevalence of RPGR-related retinopathy is calculated to be approximately 1 in 214,000, based on the known incidence of retinitis pigmentosa at 1 in 3,000, the proportion of retinitis pigmentposa that is X-linked at 20%, and the proportion of X-linked retinitis pigmentosa that is RPGR-associated at 70% (PMID: 34985506).
Penetrance: Penetrance is nearly 100% in hemizygous males but is incomplete and dependent upon the variant in heterozygous female carriers.
Seven novel variants expand the spectrum of RPE65-related Leber congenital amaurosis in the Chinese population
PMID: 30996589
Gene: RPE65
HGNC: 10294
Disease: Leber congenital amaurosis 2
MONDO: 0008765
InheritancePattern: Autosomal Recessive
Prevalence: The overall prevalence of Leber congenital amaurosis is between 1 in 33,000 and 1 in 100,000 newborns, while the proportion of Leber congenital amaurosis caused by RPE65 variants is between 1% and 16.7%. Thus, the prevalence of Leber congenital amaurosis 2 is between 1 in 200,000 and 1 in 10,000,000.
Penetrance: Fully penetrant, with onset typically by 1 year of age
Retinitis Pigmentosa GTPase Regulator (RPGR)-interacting Protein Is Stably Associated with the Photoreceptor Ciliary Axoneme and Anchors RPGR to the Connecting Cilium
PMID: 11104772
Gene: RPGR
HGNC: 10295
Disease: RPGR-related retinopathy
MONDO: MONDO:0100437
InheritancePattern: X-linked
Prevalence: The prevalence of RPGR-related retinopathy is calculated to be approximately 1 in 214,000, based on the known incidence of retinitis pigmentosa at 1 in 3,000, the proportion of retinitis pigmentposa that is X-linked at 20%, and the proportion of X-linked retinitis pigmentosa that is RPGR-associated at 70% (PMID: 34985506).
Penetrance: Penetrance is nearly 100% in hemizygous males but is incomplete and dependent upon the variant in heterozygous female carriers.
Two novel CLN5 mutations in a Portuguese patient with vLINCL: Insights into molecular mechanisms of CLN5 deficiency
PMID: 16814585
Gene: CLN5
HGNC: 2076
Disease: Ceroid lipofuscinosis, neuronal, 5 (also known as Finnish variant late infantile neuronal ceroid lipofuscinosis, neuronal ceroid lipofuscinosis late infantile Finnish variant, or Finnish vLINCL)
MONDO: 0009745
InheritancePattern: Autosomal Recessive
Prevalence: Unknown, but part of a larger group of NCL disorders with a collective prevalence between 1 in 12,500 (PMID:9662406) and 1 in 100,000 (PMID:23374165)
Penetrance: Fully penetrant, with onset often in the late infantile period but in some cases during early adulthood or even as late as in the 6th decade of life
Neuronal Ceroid Lipofuscinoses Are Connected at Molecular Level: Interaction of CLN5 Protein with CLN2 and CLN3
PMID: 12134079
Gene: CLN5
HGNC: 2076
Disease: Ceroid lipofuscinosis, neuronal, 5 (also known as Finnish variant late infantile neuronal ceroid lipofuscinosis, neuronal ceroid lipofuscinosis late infantile Finnish variant, or Finnish vLINCL)
MONDO: 0009745
InheritancePattern: Autosomal Recessive
Prevalence: Unknown, but part of a larger group of NCL disorders with a collective prevalence between 1 in 12,500 (PMID:9662406) and 1 in 100,000 (PMID:23374165)
Penetrance: Fully penetrant, with onset often in the late infantile period but in some cases during early adulthood or even as late as in the 6th decade of life
In vitro stem cell modelling demonstrates a proof-of-concept for excess functional mutant TIMP3 as the cause of Sorsby fundus dystrophy
PMID: 32666594
Gene: TIMP3
HGNC: 11822
Disease: Sorsby fundus dystrophy (SFD), also known as Sorsby's fundus dystrophy, Sorsby pseudoinflammatory fundus dystrophy, or hemorrhagic macular dystrophy
MONDO: 0007640
InheritancePattern: Autosomal Dominant
Prevalence: Estimated at 1 in 220,000 (PMID: 28847738)
Penetrance: Fully penetrant, onset between the third and sixth decades of life
Thirty-year follow-up of a patient with leber congenital amaurosis and novel RPE65 mutations
PMID: 14962443
Gene: RPE65
HGNC: 10294
Disease: Leber congenital amaurosis 2
MONDO: 0008765
InheritancePattern: Autosomal Recessive
Prevalence: The overall prevalence of Leber congenital amaurosis is between 1 in 33,000 and 1 in 100,000 newborns, while the proportion of Leber congenital amaurosis caused by RPE65 variants is between 1% and 16.7%. Thus, the prevalence of Leber congenital amaurosis 2 is between 1 in 200,000 and 1 in 10,000,000.
Penetrance: Fully penetrant, with onset typically by 1 year of age
Overexpression of the gene product of ocular albinism 1 (GPR143/OA1) but not its mutant forms inhibits neurite outgrowth in PC12 cells
PMID: 31606330
Gene: GPR143
HGNC: 20145
Disease: X-linked recessive ocular albinism
MONDO: 0021019
InheritancePattern: X-linked recessive
Prevalence: Ocular albinism has an estimated prevalence between 1 in 111,000 and 1 in 1,000,000 live births (PMID: 35495622)
Penetrance: Fully penetrant in males, with onset in infancy. Most female carriers appear to be unaffected.
Retinal Phenotype in the rd9 Mutant Mouse, a Model of X-Linked RP
PMID: 31607844
Gene: RPGR
HGNC: 10295
Disease: RPGR-related retinopathy
MONDO: MONDO:0100437
InheritancePattern: X-linked
Prevalence: The prevalence of RPGR-related retinopathy is calculated to be approximately 1 in 214,000, based on the known incidence of retinitis pigmentosa at 1 in 3,000, the proportion of retinitis pigmentposa that is X-linked at 20%, and the proportion of X-linked retinitis pigmentosa that is RPGR-associated at 70% (PMID: 34985506).
Penetrance: Penetrance is nearly 100% in hemizygous males but is incomplete and dependent upon the variant in heterozygous female carriers.
Different RPGR exon ORF15 mutations in Canids provide insights into photoreceptor cell degeneration
PMID: 11978759
Gene: RPGR
HGNC: 10295
Disease: RPGR-related retinopathy
MONDO: MONDO:0100437
InheritancePattern: X-linked
Prevalence: The prevalence of RPGR-related retinopathy is calculated to be approximately 1 in 214,000, based on the known incidence of retinitis pigmentosa at 1 in 3,000, the proportion of retinitis pigmentposa that is X-linked at 20%, and the proportion of X-linked retinitis pigmentosa that is RPGR-associated at 70% (PMID: 34985506).
Penetrance: Penetrance is nearly 100% in hemizygous males but is incomplete and dependent upon the variant in heterozygous female carriers.
35 Q
Case: Patient 35, Family Q (Table 1.), F/42, Afro-Caribbean
DiseaseAssertion: VWD2A (IIE)
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs:
CaseHPOFreeRext: BAT = 4, FVIII:C (IU/dL) = 24, VWF:Ag (IU/dL) = 25, VWF:Act (IU/dL) = 14
CaseNOTHPOs:
CaseNOTHPOFreeText: Blood group O+
CasePreviousTesting:
GenotypingMethod: All samples were analyzed by captured-based high throughput sequencing which was performed with a custom-design of the VWF gene provided by Twist BioScience (San Francisco, USA). It comprised all 52 exons, intronic flanking regions, promoter and 3’UTR region of the VWF gene. Libraries were prepared by using the Twist NGS target enrichment solution (Twist BioScience) according to the manufacturer protocol. Samples were analyzed on a NovaSeq 6000 sequencer (Illumina) with a median read depth of 2500X by using the 300-cycle S1 NovaSeq 6000seq reagent kit with 150-bp paired-end reads. The raw data were analyzed with Mutect21 and Vardict2 tools. The inhouse NGSreport software (CHU Lille) was used for data visualization, sequences check and conservation of variants with high quality metrics. In some cases, patients genomic DNA was screened for sequence variations (large deletions, insertions and duplications) by Multiplex Ligation-dependent Probe Amplification (MCR Holland).
PreviouslyPublished: NA
Gene: VWF
Variant: c.1530G > A, p.(Val510 =) p.
HGVS: NM_000552.5:c.1530G>A (p.Val510=)
ClinVarID:
CAID: CA6403368
gnomAD: MAF of 0.00002198 (2/91004 alleles) in South Asian population https://gnomad.broadinstitute.org/variant/chr12-6062957-C-T?dataset=gnomad_r4
Variant: c.1892C > T, p.(Ala631Val)
HGVS: NM_000552.5:c.1892C>T (p.Ala631Val)
ClinVarID: 422844
CAID: CA6403245
gnomAD: MAF of 0.001908 (137/71810 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6056910-G-A?dataset=gnomad_r4
Variant: c.2220G > A, p.(Met740Ile)
HGVS: NM_000552.5:c.2220G>A (p.Met740Ile)
ClinVarID: 100206
CAID: CA201316
gnomAD: MAF of 0.1816 (13626/75022 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6046784-C-T?dataset=gnomad_r4
Variant: c.2451T > A, p.(His817Gln)
HGVS: NM_000552.5:c.2451T>A (p.His817Gln)
ClinVarID: 100224
CAID: CA228345
gnomAD: MAF of 0.1150 (8626/75016 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6036483-A-T?dataset=gnomad_r4
Variant: c.3445T > C, p.(Cys1149Arg)
HGVS: NM_000552.5:c.3445T>C (p.Cys1149Arg)
ClinVarID: 309
CAID: CA228410
gnomAD: MAF of 0.000003160 (1/316464 alleles) in European (non-Finnish) population https://gnomad.broadinstitute.org/variant/chr12-6022833-A-G?dataset=gnomad_r4
Variant: c.4414G > C p.(Asp1472His)
HGVS: NM_000552.5:c.4414G>C (p.Asp1472His)
ClinVarID: 256679
CAID: CA6402534
gnomAD: MAF of 0.5076 (38011/74882 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6019004-C-G?dataset=gnomad_r4
Variant: c.6554G > A, p.(Arg2185Gln)
HGVS: NM_000552.5:c.6554G>A (p.Arg2185Gln)
ClinVarID: 100443
CAID: CA228748
gnomAD: MAF of 0.1927 (14427/74878 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-5993906-C-T?dataset=gnomad_r4
Variant: c.8174A > G, p.(Asn2725Ser)
HGVS: NM_000552.5:c.8174A>G (p.Asn2725Ser)
ClinVarID:
CAID: CA232258860
gnomAD: MAF of 0.00004456 (2/44880 alleles) in East Asian population https://gnomad.broadinstitute.org/variant/chr12-5949865-T-C?dataset=gnomad_r4
44 U
Case: Patient 44, Family U (Table 1.), M/15, Afro-Caribbean
DiseaseAssertion: VWD2M
FamilyInfo: Patient 43 (M/10, Afro-Caribbean), Patient 46 (M/47, Afro-Caribbean, Patient 47(M/78, Afro-Caribbean) and Patient 48 (M/43, Afro Caribbean) also from Family U. (Table 1.)
ParentalGenotype(s): NA
CasePresentingHPOs:
CaseHPOFreeRext: BAT = 4, FVIII:C (IU/dL) = 48, VWF:Ag (IU/dL) = 25, VWF:Act (IU/dL) = 7
CaseNOTHPOs:
CaseNOTHPOFreeText: Blood group B+
CasePreviousTesting:
GenotypingMethod: All samples were analyzed by captured-based high throughput sequencing which was performed with a custom-design of the VWF gene provided by Twist BioScience (San Francisco, USA). It comprised all 52 exons, intronic flanking regions, promoter and 3’UTR region of the VWF gene. Libraries were prepared by using the Twist NGS target enrichment solution (Twist BioScience) according to the manufacturer protocol. Samples were analyzed on a NovaSeq 6000 sequencer (Illumina) with a median read depth of 2500X by using the 300-cycle S1 NovaSeq 6000seq reagent kit with 150-bp paired-end reads. The raw data were analyzed with Mutect21 and Vardict2 tools. The inhouse NGSreport software (CHU Lille) was used for data visualization, sequences check and conservation of variants with high quality metrics. In some cases, patients genomic DNA was screened for sequence variations (large deletions, insertions and duplications) by Multiplex Ligation-dependent Probe Amplification (MCR Holland).
PreviouslyPublished: NA
Gene: VWF
Variant: c.3943C > T p.(Arg1315Cys)
HGVS: NM_000552.5:c.3943C>T (p.Arg1315Cys)
ClinVarID: 100310
CAID: CA228502
gnomAD: MAF of 8.476e-7 (1/ 1179850 alleles) in European population https://gnomad.broadinstitute.org/variant/chr12-6019161-A-C?dataset=gnomad_r4
42 T
Case: Patient 42, Family T (Table 1.), F/60, Afro-Caribbean
DiseaseAssertion: VWD2A (IIA)
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs:
CaseHPOFreeRext: BAT = 8, FVIII:C (IU/dL) = 20, VWF:Ag (IU/dL) = 35, VWF:Act (IU/dL) = 6
CaseNOTHPOs:
CaseNOTHPOFreeText: Blood group O+
CasePreviousTesting:
GenotypingMethod: All samples were analyzed by captured-based high throughput sequencing which was performed with a custom-design of the VWF gene provided by Twist BioScience (San Francisco, USA). It comprised all 52 exons, intronic flanking regions, promoter and 3’UTR region of the VWF gene. Libraries were prepared by using the Twist NGS target enrichment solution (Twist BioScience) according to the manufacturer protocol. Samples were analyzed on a NovaSeq 6000 sequencer (Illumina) with a median read depth of 2500X by using the 300-cycle S1 NovaSeq 6000seq reagent kit with 150-bp paired-end reads. The raw data were analyzed with Mutect21 and Vardict2 tools. The inhouse NGSreport software (CHU Lille) was used for data visualization, sequences check and conservation of variants with high quality metrics. In some cases, patients genomic DNA was screened for sequence variations (large deletions, insertions and duplications) by Multiplex Ligation-dependent Probe Amplification (MCR Holland).
PreviouslyPublished: NA
Gene: VWF
Variant: c.4257T > G p.(His1419Gln)
HGVS: NM_000552.5:c.4257T>G (p.His1419Gln)
ClinVarID: 2691691
CAID: CA6402565
gnomAD: MAF of 0.0003166 (19/60010 alleles) in Admixed American population https://gnomad.broadinstitute.org/variant/chr12-6019161-A-C?dataset=gnomad_r4
Variant: c.4414G > C p.(Asp1472His)
HGVS: NM_000552.5:c.4414G>C (p.Asp1472His)
ClinVarID: 256679
CAID: CA6402534
gnomAD: MAF of 0.5076 (38011/74882 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6019004-C-G?dataset=gnomad_r4
Variant: c.4517C > T p.(Ser1506Leu)
HGVS: NM_000552.5:c.4517C>T (p.Ser1506Leu)
ClinVarID: 100369
CAID: CA228615
gnomAD: MAF of 0.0001735 (10/57628 alleles) in Admixed American population https://gnomad.broadinstitute.org/variant/chr12-6018901-G-A?dataset=gnomad_r4
51 Y
Case: Patient 51, Family Y (Table 1.), F/33, Afro-Caribbean
DiseaseAssertion: VWD1
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs:
CaseHPOFreeRext: BAT = 5, FVIII:C (IU/dL) = NA, VWF:Ag (IU/dL) = 30, VWF:Act (IU/dL) = 31
CaseNOTHPOs:
CaseNOTHPOFreeText: Blood group O+
CasePreviousTesting:
GenotypingMethod: All samples were analyzed by captured-based high throughput sequencing which was performed with a custom-design of the VWF gene provided by Twist BioScience (San Francisco, USA). It comprised all 52 exons, intronic flanking regions, promoter and 3’UTR region of the VWF gene. Libraries were prepared by using the Twist NGS target enrichment solution (Twist BioScience) according to the manufacturer protocol. Samples were analyzed on a NovaSeq 6000 sequencer (Illumina) with a median read depth of 2500X by using the 300-cycle S1 NovaSeq 6000seq reagent kit with 150-bp paired-end reads. The raw data were analyzed with Mutect21 and Vardict2 tools. The inhouse NGSreport software (CHU Lille) was used for data visualization, sequences check and conservation of variants with high quality metrics. In some cases, patients genomic DNA was screened for sequence variations (large deletions, insertions and duplications) by Multiplex Ligation-dependent Probe Amplification (MCR Holland).
PreviouslyPublished: NA
Gene: VWF
Variant: c.4751A > G, p.(Tyr1584Cys)
HGVS: NM_000552.5:c.4751A>G (p.Tyr1584Cys)
ClinVarID: 310
CAID: CA114162
gnomAD: MAF of 0.004105 (483/1179782 alleles) in European/Non-Finnish population https://gnomad.broadinstitute.org/variant/chr12-6018667-T-C?dataset=gnomad_r4
48 U
Case: Patient 48, Family U (Table 1.), M/43, Afro-Caribbean
DiseaseAssertion: VWD2M
FamilyInfo: Patient 43 (M/10, Afro-Caribbean), Patient 44 (M/15, Afro-Caribbean), Patient 46 (M/47, Afro-Caribbean) and Patient 47 (M/78, Afro Caribbean) also from Family U. (Table 1.)
ParentalGenotype(s): NA
CasePresentingHPOs:
CaseHPOFreeRext: BAT = 4, FVIII:C (IU/dL) = 32, VWF:Ag (IU/dL) = 25, VWF:Act (IU/dL) = 21
CaseNOTHPOs:
CaseNOTHPOFreeText: Blood group AB+
CasePreviousTesting:
GenotypingMethod: All samples were analyzed by captured-based high throughput sequencing which was performed with a custom-design of the VWF gene provided by Twist BioScience (San Francisco, USA). It comprised all 52 exons, intronic flanking regions, promoter and 3’UTR region of the VWF gene. Libraries were prepared by using the Twist NGS target enrichment solution (Twist BioScience) according to the manufacturer protocol. Samples were analyzed on a NovaSeq 6000 sequencer (Illumina) with a median read depth of 2500X by using the 300-cycle S1 NovaSeq 6000seq reagent kit with 150-bp paired-end reads. The raw data were analyzed with Mutect21 and Vardict2 tools. The inhouse NGSreport software (CHU Lille) was used for data visualization, sequences check and conservation of variants with high quality metrics. In some cases, patients genomic DNA was screened for sequence variations (large deletions, insertions and duplications) by Multiplex Ligation-dependent Probe Amplification (MCR Holland).
PreviouslyPublished: NA
Gene: VWF
Variant: c.3943C > T p.(Arg1315Cys)
HGVS: NM_000552.5:c.3943C>T (p.Arg1315Cys)
ClinVarID: 100310
CAID: CA228502
gnomAD: MAF of 8.476e-7 (1/ 1179850 alleles) in European population https://gnomad.broadinstitute.org/variant/chr12-6019161-A-C?dataset=gnomad_r4
47 U
Case: Patient 47, Family U (Table 1.), M/78, Afro-Caribbean
DiseaseAssertion: VWD2M
FamilyInfo: Patient 43 (M/10, Afro-Caribbean), Patient 44 (M/15, Afro-Caribbean), Patient 46 (M/47, Afro-Caribbean) and Patient 48 (M/43, Afro Caribbean) also from Family U. (Table 1.)
ParentalGenotype(s): NA
CasePresentingHPOs:
CaseHPOFreeRext: BAT = 4, FVIII:C (IU/dL) = 11, VWF:Ag (IU/dL) = 20, VWF:Act (IU/dL) = 12.6
CaseNOTHPOs:
CaseNOTHPOFreeText: Blood group B+
CasePreviousTesting:
GenotypingMethod: All samples were analyzed by captured-based high throughput sequencing which was performed with a custom-design of the VWF gene provided by Twist BioScience (San Francisco, USA). It comprised all 52 exons, intronic flanking regions, promoter and 3’UTR region of the VWF gene. Libraries were prepared by using the Twist NGS target enrichment solution (Twist BioScience) according to the manufacturer protocol. Samples were analyzed on a NovaSeq 6000 sequencer (Illumina) with a median read depth of 2500X by using the 300-cycle S1 NovaSeq 6000seq reagent kit with 150-bp paired-end reads. The raw data were analyzed with Mutect21 and Vardict2 tools. The inhouse NGSreport software (CHU Lille) was used for data visualization, sequences check and conservation of variants with high quality metrics. In some cases, patients genomic DNA was screened for sequence variations (large deletions, insertions and duplications) by Multiplex Ligation-dependent Probe Amplification (MCR Holland).
PreviouslyPublished: NA
Gene: VWF
Variant: c.3943C > T p.(Arg1315Cys)
HGVS: NM_000552.5:c.3943C>T (p.Arg1315Cys)
ClinVarID: 100310
CAID: CA228502
gnomAD: MAF of 8.476e-7 (1/ 1179850 alleles) in European population https://gnomad.broadinstitute.org/variant/chr12-6019161-A-C?dataset=gnomad_r4
Variant: c.4196G > A, p.(Arg1399His)
HGVS: NM_000552.5:c.4196G>A (p.Arg1399His)
ClinVarID: 293
CAID: CA114133
gnomAD: MAF of 0.01540 (456/29604 alleles) in Ashkenazi Jewish population https://gnomad.broadinstitute.org/variant/chr12-6019222-C-T?dataset=gnomad_r4
III-3,
Case: Patient III-3 (proband's granduncle; father of IV-2 and IV-3) DiseaseAssertion: Type 2A VWD, based on low plasma VWF:Ag and activity and lack of plasma HMW VWF multimers (diagnosis explicitly extended to this patient along with proband and IV-2, IV-3, IV-4). FamilyInfo: Granduncle of proband V-2; father of IV-2 and IV-3 (both also affected); part of 5-affected-member pedigree (Fig. 1). ParentalGenotype(s): NA — his own parents' (generation II) genotype status not reported. CasePresentingHPOs: HP:0012147 (Reduced quantity of VWF; VWF:Ag 21.6 U/dL), HP:0030129 (Impaired VWF:RCo; VWF:Rco 5.0 U/dL), HP:0030132 (Absence of large VWF multimers — plasma), HP:0003645 (Prolonged partial thromboplastin time; APTT 45.5 sec) CaseHPOFreeText: Described only generically as having "abnormal bleedings" / "similar clinical symptoms" to the proband — no itemized bleeding symptoms given for this individual specifically. FVIII:C 28.0 U/dL (nv 50-150). RIPA not tested (N/A). TT 16.7 sec and PT 14.0 sec both within normal range. CaseNOTHPOs: NA CaseNOTHPOFreeText: Platelet-associated VWF multimers normal (HMW multimers present) per the group finding covering this patient. CasePreviousTesting: Targeted confirmation of the familial VWF variant; not genome-wide. GenotypingMethod: Sanger sequencing/allele-specific analysis, same platform as proband. PreviouslyPublished: NA Gene: VWF Variant: Same novel heterozygous in-frame 6-bp deletion, exon 28, ΔD1529V1530 (VWF A2 domain) HGVS: c.4585_4590del (p.Asp1529_Val1530del) ClinVarID: NA CAID: NA gnomAD: NA
The proband was a 9-year-old boy, whose family pedigree is shown in Fig. 1. He suffered from frequent bruise, epistaxis, prolonged bleedings from small wounds, and delayed wound healing.
Case: Patient V-2, Male, 9 years old (proband) DiseaseAssertion: Type 2A VWD, based on history of abnormal bleeding, low plasma VWF:Ag and activity, low FVIII:C, and lack of plasma HMW VWF multimers. FamilyInfo: Proband of a pedigree (Fig. 1) with 5 affected individuals (V-2, III-3, IV-2, IV-3, IV-4) across multiple generations, all carrying the same variant; unaffected father (IV-5) does not carry it. ParentalGenotype(s): Mother (IV-4) heterozygous for the variant, affected. Father (IV-5) does not carry the variant, unaffected (normal VWF:Ag 95.2 IU/dL, normal multimer pattern). CasePresentingHPOs: HP:0000421 (Epistaxis), HP:0001934 (Persistent bleeding after trauma — "prolonged bleedings from small wounds"), HP:0012147 (Reduced quantity of VWF; VWF:Ag 20.5 U/dL), HP:0030129 (Impaired VWF:RCo; VWF:Rco 6.2 U/dL), HP:0030132 (Absence of large VWF multimers — plasma), HP:0011871 (Impaired RIPA; 28.5%), HP:0003645 (Prolonged partial thromboplastin time; APTT 58.1 sec) CaseHPOFreeText: Frequent bruising, delayed wound healing (no matching HPO code in the approved list); FVIII:C 25.0 U/dL (nv 50-150); TT 16.7 sec and PT 14.2 sec both within normal range. CaseNOTHPOs: NA CaseNOTHPOFreeText: Platelet-associated VWF multimers were normal (HMW multimers present, indistinguishable from controls) despite the plasma multimer defect — supports a secretion defect rather than a synthesis defect. CasePreviousTesting: Not genome-wide; targeted VWF gene analysis — Sanger sequencing of all 52 exons and intron-exon boundaries of VWF using published primers, followed by allele-specific cloning (pMD18-T vector) and sequencing to resolve the heterozygous deletion. GenotypingMethod: Direct Sanger sequencing (Applied Biosystems 310 DNA analyzer) of all VWF exons/boundaries; PCR amplification and cloning of individual alleles into pMD18-T vector to confirm and characterize the heterozygous deletion. PreviouslyPublished: NA — first report of this variant/family. Gene: VWF Variant: Novel heterozygous in-frame 6-bp deletion in exon 28, removing residues D1529 and V1530 (ΔD1529V1530) in the VWF A2 domain. Functional studies (HEK293 transfection) showed the mutant is expressed but its secretion is markedly impaired (42±4% of WT in conditioned medium, p<0.01) with intracellular retention (174±29% of WT in cell lysate, p<0.05) and ER colocalization (PDI co-staining); co-transfection with WT VWF reduced WT secretion (61±16% of WT alone, p<0.05), indicating a dominant-negative effect. Classified as a "Group I" type 2A mechanism (impaired intracellular transport/secretion). HGVS: c.4585_4590del (p.Asp1529_Val1530del) — confirmed against the authors' GenBank submission (JN625247) and cross-validated against a real ClinVar-confirmed exon 28 variant ClinVarID: NA CAID: NA gnomAD: NA
Identification and Functional Analysis of a Novel von Willebrand Factor Mutation in a Family with Type 2A von Willebrand Disease
PMID: 22479377 Gene: VWF HGNCID: HGNC:12726
homozygous c.2311A>G
Gene:VWF
HGNCID:12726
Case:11 yo female
DiseaseAssertion: Type 2N
FamilyInfo:Fig. 1, family 1, patient 4
ParentalGenotype(s):Unknown, obligate carriers
CasePresentingHPOs:HP:0000421, HP:0012147 HP:0030132, HP:0030130
CaseHPOFreeRext:Oral cavity and joint bleeding, Bleeding from small wounds and after tooth extraction, VWF:Ag 0.07 U/mL, VWF:Ac 0.08 U/mL, VWF:CB <0.05 U/mL, FVIII 0.01 U/mL, No VWF Multimers
GenotypingMethod: NGS
Gene:VWF
Variant:c.2311A>G
HGVS:NM_000552.5(VWF):c.2311A>G
ClinVarID:1065273
CAID:CA383522481
homozygous c.2311A>G
Gene:VWF
HGNCID:12726
Case:29 yo female
DiseaseAssertion: Type 2N
FamilyInfo:Fig. 1, family 1, patient 1
ParentalGenotype(s):Unknown, obligate carriers
CasePresentingHPOs:HP:0000421, HP:0000132, HP:0012147 HP:0030132, HP:0030130
CaseHPOFreeRext:Skin, GI, muscle, oral cavity, and joint bleeding, VWF: Ag 0.07 U/mL, VWF:Ac 0.08 U/mL, VWF:CB 0.05 U/mL, FVIII 0.02 U/mL, No VWF Multimers
GenotypingMethod: NGS
Gene:VWF
Variant:c.2311A>G
HGVS:NM_000552.5(VWF):c.2311A>G
ClinVarID:1065273
CAID:CA383522481
97 10 F 45 c.7604G.Ap.R2535Q Hmz 9 2.3 6 - -
Case: 97, F, 10 years, Indian
DiseaseAssertion: VWD type 3
FamilyInfo: no family history of disease, Consanguinity: no
ParentalGenotype: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: FVIII:C: (U/dl): 9, VWF:Ag (U/dl): 2.3, Bleeding Score: 6
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.7604G>A (p.Arg2535Gln), Exon 45
Homozygous
19 1.3 F 45 c.7725_7729delCTGTGp.R2575_E2577del Htz 3.6 1 4 + -
Case: 19, F, 1.3 years, Indian
DiseaseAssertion: VWD type 3
FamilyInfo:family history of disease, Consanguinity: no
ParentalGenotype: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: FVIII:C: (U/dl): 3.6, VWF:Ag (U/dl): 1, Bleeding Score: 4
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.7725_7729delCTGTG (p.Arg2575_Glu2577del), Exon 45, Heterozygous
10 42 M 20 c.2560C.T p.R854W Htz ,1 ,1 34 + -
Case: 10, M, 42 years, Indian
DiseaseAssertion: VWD type 3
FamilyInfo: family history of disease, Consanguinity: no
ParentalGenotype: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: FVIII:C: (U/dl): <1, VWF:Ag (U/dl): <1, Bleeding Score: 34
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.2560C>T (p.Arg854Trp), Exon 20
Heterozygous
38 Type2A(IIA)c.4589T>GN p.Val1530Gly 28 A2 htz Missense na 30 na na
Case: IP #38 (also in row 18 table 6)
DiseaseAssertion: type 2A (IIA) VWD
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs:
CaseHPOFreeRext:
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting:
GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.
PreviouslyPublished:
Gene: VWF
Variant: c.4589T>G p.Val1530Gly
HGVS:
ClinVarID: not found
CAID: CA383501045
gnomAD: absent
10-12Type2A (IIE)c.3296G>AN p.Cys1099Tyr 25 D3-C8-3htz Missense O/na/A131/na/26532/na/44 117OSCA/na
Case: IP #11 (also in row 6 table 6)
DiseaseAssertion: type 2A (IIE) VWD
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs:
CaseHPOFreeRext:
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting:
GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.
PreviouslyPublished:
Gene: VWF
Variant: c.3296G>A p.Cys1099Tyr
HGVS:
ClinVarID: not found
CAID: CA383512195
gnomAD: absent
51-54Type2A(IIA)c.4811T>AN p.Val1604Asp 28 A2 htz Missense O/A/O/O27/24/35/328/9/11/755CSA/57
Case: IP #52 (also in row 21 table 6)
DiseaseAssertion: type 2A (IIA) VWD
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs: HP:0032370 - blood group A
CaseHPOFreeRext: VWF:Ag [IU/dL] = 24; VWF:Ac [IU/dL] = 9; FVIII:C [IU/dL] = 57
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting:
GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.
PreviouslyPublished:
Gene: VWF
Variant: c.4811T>A p.Val1604Asp
HGVS:
ClinVarID: not found
CAID: CA383499144
gnomAD: absent
Case#: 23015, Age 74, Male, Blood Type A+ (Table S3)
Disease Assertion: VWD1
FamilyInfo: The patient is the only member of Family# 2310.
Parental Genotype: Not listed
CasePresentingHPOs: N/A
CaseHPOFreeText:VWF:Ag: 18, VWF:RCo:17.3, FVIII:C:19, VWF:CB:13
CaseNotHPOs: N/A
CaseNotHPOFreeText: Bleeding Score 3
Protein Expression: N/A
CasePreviousTesting: 48,48 Access-Array amplification. NGS Molecular analysis was performed. Sanger sequencing was used to validate selected mutations
Gene: VWF
Variant: NM_000552.4:c.2546+132G>A(p.=) and NM_000552.4:c.3614G>A (p.Arg1205His)
ClinVar: 308 ClinVar
CAID: CA232299449 and CA114160 CAID1 CAID2
gnomAD: MAF of 0.001179 ( 1/848 alleles) in the Latino population (CA232299449). gnomAD
Case#: 01010, Age 55, Male, Blood Type O+ (Table S3)
Disease Assertion:VWD1
FamilyInfo: Not listed
Parental Genotype:Not listed
CasePresentingHPOs:
CaseHPOFreeText: Bleeding score 5, VWF:Ag 27, VWF:RCo: 30, FVIII:C 51, VWF:CB: 32
CaseNotHPOs:
CaseNotHPOFreeText:
Protein Expression:
CasePreviousTesting: 48,48 Access-Array amplification. NGS Molecular analysis was performed. Sanger sequencing was used to validate selected mutations.
Gene: VWF
Variant:NM_000552.4(VWF):c.4751A>G (p.Tyr1584Cys)
ClinVar: 310
CAID: CA114162
gnomAD: MAF of 0.004024 (519/128972 alleles) in the European (non-Finnish) population.
Case#: 32005, Age 28, Female, Blood Type O- (Table S3)
Disease Assertion: VWD 1
FamilyInfo: The patient is the only member of Family# 3205.
Parental Genotype: Not listed
CasePresentingHPOs: N/A
CaseHPOFreeText: VWF:Ag: 30, VWF:RCo: 25, FVIII:C: 25, VWF:CB: 32
CaseNotHPOs: N/A
CaseNotHPOFreeText: Bleeding Score 4
Protein Expression: N/A
CasePreviousTesting: 48,48 Access-Array amplification. NGS Molecular analysis was performed. Sanger sequencing was used to validate selected mutations.
Gene: VWF
Variant: NM_000552.4:c.2546+132G>A (p.=) and NM_000552.4:c.4751A>G (p.Tyr1584Cys)
ClinVar: 310
CAID: CA232299449 and CA114162 CAID1 CAID2
gnomAD: MAF of 0.001179 (1/848 alleles) in the Latino population (CA232299449) gnomAD
MAF of 0.004024 (519/ 128972 alleles) in the European (non-Finnish) population. gnomAD
Case#: 02023, Age 28, Female, Blood type O+ (Table S3)
Disease Assertion: VWD 1
FamilyInfo: Family# 0206. 3 family members were included in the study. Everyone in the family have the same variant and all have type 1 VWD.
Parental Genotype: Not listed
CasePresentingHPOs:
CaseHPOFreeText: Bleeding score 18, VWF:Ag: 5.5, VWF:RCo: 8, FVIII:C: 11, VWF:CB: 4.2
CaseNotHPOs:
CaseNotHPOFreeText:
Protein Expression:
CasePreviousTesting: 48,48 Access-Array amplification. NGS Molecular analysis was performed. Sanger sequencing was used to validate selected mutations.
Gene: VWF
Variant: NM_000552.4:c.3614G>A (p.Arg1205His)
ClinVar: 308 ClinVar
CAID: CA114160 CAID
gnomAD: N/A
Case#: 27018, Age 31, Male, Blood Type O+ (Table S3)
Disease Assertion: VWD 1
FamilyInfo: The patient is one out of two members of Family#2709. Both patients variants were not determined.
Parental Genotype: Not listed
CasePresentingHPOs: N/A
CaseHPOFreeText: VWF:Ag:27, VWF:RCo:28.5, FVIII:C:59, VWF:CB:25
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: Not determined
ClinVar: N/A
CAID: N/A
gnomAD: N/A
Case: Patient E
DiseaseAssertion: VWD2N
FamilyInfo: Family 4
ParentalGenotype(s):
CasePresentingHPOs: HP:0012147, HP:0030129, HP:0030130, HP:0011871
CaseHPOFreeText: PTsec = 38.1, FVIII U/dL = 19.8, FVIII ratio = 0.42, VWF:Ag U/dL = 46.6, VWF:FVIIIB U/dL = 7.7, VWF:FVIIIB ratio = 0.16, VWF:CB U/dL = 44.8, VWF:RCo U/dL = 51.9, RIPA % = 64.8, PlatVWF:Ag U/dL = 60.6
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
Variant1: c.2561G>A (p.Arg854Gln)
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
Variant2:
I : 1
Case#: F7, I:1
DiseaseAssertion: Type 2 VWD
CaseHPOFreeText: partial loss of high molecular weight multimers, VWF:Ag = 88; VWF:RCo = 46; VWF:GPIbM = 81; 0.52; 0.93; 1.77
CasePreviousTesting: Not clearly described
Gene: VWF
Variant: p.[I1309V];[=]
HGVS: c.3925A>G (p.Ile1309Val)
CAID: CA228492
gnomAD: absent from gnomad v4.1.0
I : 1
Case#: F6, I:1
DiseaseAssertion: Type 2 VWD
CaseHPOFreeText: partial loss of high molecular weight multimers, VWF:Ag = 56; VWF:RCo = 29; VWF:GPIbM = 75; 0.51; 1.34; 2.63
CasePreviousTesting: Not clearly described
Gene: VWF
Variant: p.[H1268D];[=]
HGVS: c.3802C>G (p.His1268Asp)
CAID: CA228445
gnomAD: absent from gnomad v4.1.0
I : 1
Case#: F20, I:1
DiseaseAssertion: Type 2 VWD
CaseHPOFreeText: loss of high and intermediate MWMs, VWF:Ag = 34; VWF:RCo = 8; VWF:GPIbM = 23; 0.22; 0.68; 3.08
CasePreviousTesting: Not clearly described
Gene: VWF
Variant: p.[V1316M];[=]
HGVS: c.3946G>A (p.Val1316Met)
CAID: CA114127
gnomAD: absent from gnomad v4.1.0
II : 1
Case#: F5, II:1
DiseaseAssertion: Type 2 VWD
CaseHPOFreeText: all mutimers present, VWF:Ag = 56; VWF:RCo = 48; VWF:GPIbM = 49; 0.86; 0.87; 1.01
CasePreviousTesting: Not clearly described
Gene: VWF
Variant: p.[I1372S];[=]
HGVS: c.4115T>G (p.Ile1372Ser)
CAID: CA228535
gnomAD: https://gnomad.broadinstitute.org/variant/12-6019303-A-C?dataset=gnomad_r4
I : 1
Case#: F19, I:1
DiseaseAssertion: Type 2 VWD
CaseHPOFreeText: loss of high and intermediate MWMs, VWF:Ag = 35; VWF:RCo = 5; VWF:GPIbM = 28; 0.14; 0.81; 5.68
CasePreviousTesting: Not clearly described
Gene: VWF
Variant: p.[V1316M];[=]
HGVS: c.3946G>A (p.Val1316Met)
CAID: CA114127
gnomAD: absent from gnomad v4.1.0
I : 1
Case#: F5, I:1
DiseaseAssertion: Type 2 VWD
CaseHPOFreeText: all mutimers present, VWF:Ag = 105; VWF:RCo = 90; VWF:GPIbM = 87; 0.86; 0.82; 0.96
CasePreviousTesting: Not clearly described
Gene: VWF
Variant: p.[I1372S];[=]
HGVS: c.4115T>G (p.Ile1372Ser)
CAID: CA228535
gnomAD: https://gnomad.broadinstitute.org/variant/12-6019303-A-C?dataset=gnomad_r4
Safety of a pasteurized plasma‐derived Factor VIII and von Willebrand factor concentrate: analysis of 33 years of pharmacovigilance data
PMID: 28691218
Gene: VWF
HGNCID: 12726
von Willebrand disease
Gene: VWF
PMID: 9299039
22*IranF/361—YesSevere4975C→TR1659X28HomozygousDdeI (+)
Case: 22, F, 36, Iranian
DiseaseAssertion: VWD type 3
FamilyInfo: Consanguinity: Yes
ParentalGenotype: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: VWF:Ag (U/dl): 1, Bleeding symptoms: Severe
CaseNotHPOs: n/a
CaseNotHPOFreeText: Anti-VWF alloantibodies: no
CasePreviousTesting: n/a
Gene: VWF
Variant:
4975C→T (Arg1659X), Exon 28, Homozygous
14*IranF/262—YesSevere652C→TQ218X6HomozygousN.A.
Case: 14, F, 26, Iranian
DiseaseAssertion: VWD type 3
FamilyInfo: Consanguinity: Yes
ParentalGenotype: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: VWF:Ag (U/dl): 2, Bleeding symptoms: Severe
CaseNotHPOs: n/a
CaseNotHPOFreeText: Anti-VWF alloantibodies: no
CasePreviousTesting: n/a
Gene: VWF
Variant:
652C→T (Gln218X), Exon 6, Homozygous
33IndiaF/24<1—YesMild7137insTFS42HomozygousN.A.
Case: 33, F, 24, Indian
DiseaseAssertion: VWD type 3
FamilyInfo: Consanguinity: Yes
ParentalGenotype: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: VWF:Ag (U/dl): <1, Bleeding symptoms: Mild
CaseNotHPOs: n/a
CaseNotHPOFreeText: Anti-VWF alloantibodies: no
CasePreviousTesting: n/a
Gene: VWF
Variant:
7137insT (FS), Exon 42, Homozygous
38IndiaF/25<1—NoMild3379+1G→A/4414insCFS/FS25/28HeterozygousNlaIII (+)/N.A.
Case: 38, F, 25, Indian
DiseaseAssertion: VWD type 3
FamilyInfo: Consanguinity: No
ParentalGenotype: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: VWF:Ag (U/dl): <1, Bleeding symptoms: Mild
CaseNotHPOs: n/a
CaseNotHPOFreeText: Anti-VWF alloantibodies: no
CasePreviousTesting: n/a
Gene: VWF
Variant:
3379+1G→A (intronic), Exon 25
4414insC (FS), Exon 28
Compound Heterozygous
Note: The authors assume that 3379+1G→A causes a frameshift mutation. No potential splice site mutation was confirmed at the mRNA level; “Splice Site Prediction program” found all mutations likely to disrupt normal splicing. No possible splice site mutation could be identified on 100 chromosomes from a group of 50 normal subjects with same genetic background as patients, excluding the possibility that these mutations represent common polymorphisms.
Type IIB von Willebrand's disease: gene mutations and clinical presentation in nine families from Denmark, Germany and Sweden
PMID: 1419803
Gene: VWF
HGNC: 12726
Disease: von Willebrand disease type 2B
MONDO: 0015629
InheritancePattern: Autosomal Dominant
Prevalence: Overall VWD prevalence is estimated to be as high as 1 in 100 in the general population, with 1 in 10,000 pursuing tertiary care referral ((PMID: 28847738).
Penetrance: Fully penetrant / nearly fully penetrant for most pathogenic type 2 variants
Phenotypic and genotypic (exon 28) characterization of patients diagnosed with von Willebrand disease type 1 in Eastern Saudi Arabia
PMID: 37168293
Gene: VWF
HGNCID: 12726
PMID: 20409624
Gene: VWF
HGNC: 12726
Disease: von Willebrand disease type 2M
MONDO: 0015630
InheritancePattern: Autosomal Dominant
Prevalence: Overall VWD prevalence is estimated to be as high as 1 in 100 in the general population, with 1 in 10,000 pursuing tertiary care referral ((PMID: 28847738).
Penetrance: Fully penetrant / nearly fully penetrant for most pathogenic type 2 variants
Plasma levels of plasminogen activator inhibitor‐1 and bleeding phenotype in patients with von Willebrand disease
PMID: 28306198
Gene: VWF
HGNCID: 12726
6
Case: Patient 6 (Family B), male, 15yo
DiseaseAssertion: VWD2B
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0030132, HP:0030129, HP:0030130, HP:0011871, HP:0012147
(Absence of large von Willebrand factor multimers, impaired ristocetin cofactor assay activity, Impaired von Willebrand factor collagen binding activity, Impaired RIPA, Reduced quantity of VWF)
CaseHPOFreeText: blood group A, Platelet count x103/μl = 180, PFA 100 sec = >300, SPA % = 0, MADR mg/mL = 0.6, VWF:Ag U/dL = 30.9, VWF:CB U/dL = 12.5, VWF:CB ratio = 0.41, VWF:RCo U/dL = 11.4, VWF:RCo ratio = 0.37, Platelet VWF U/dL = 79.1, FVIII U/dL = 49.3, BAT F/M = 4
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: NA
GenotypingMethod: Sequencing of exon 28 of VWF
PreviouslyPublished: NA
Gene: VWF
Variant: c.3922C>T (p.Arg1308Cys)
HGVS: NM_000552.4(VWF):c.3922C>T (p.Arg1308Cys)
ClinVarID: 289; https://www.ncbi.nlm.nih.gov/clinvar/variation/289/
CAID: NA
gnomAD: absent
1
Case: Patient 1 (Family A), female, 48yo
DiseaseAssertion: VWD2B
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0030129, HP:0030130, HP:0011871, HP:0012147
(impaired ristocetin cofactor assay activity, Impaired von Willebrand factor collagen binding activity, Impaired RIPA, Reduced quantity of VWF)
CaseHPOFreeText: blood group A, Platelet count x103/μl = 232, PFA 100 sec = NA, SPA % = 12, MADR mg/mL = 0.45, VWF:Ag U/dL = 160.6, VWF:CB U/dL = 135.6, VWF:CB ratio = 0.84, VWF:RCo U/dL = 132.8, VWF:RCo ratio = 0.83, Platelet VWF U/dL = 92.0, FVIII U/dL = 78.0, BAT F/M = 6
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: NA
GenotypingMethod: Sequencing of exon 28 of VWF
PreviouslyPublished: NA
Gene: VWF
Variant: c.4115T>G (p.Ile1372Ser)
HGVS: NM_000552.4(VWF):c.4115T>G (p.Ile1372Ser)
ClinVarID: 100327; https://www.ncbi.nlm.nih.gov/clinvar/variation/100327/
gnomAD: MAF = 0.00006175 (7/113356 alleles) in the European (non-Finnish) population; https://gnomad.broadinstitute.org/variant/12-6128469-A-C?dataset=gnomad_r2_1
11
Case: Patient 11 (Family C), male, 80yo
DiseaseAssertion: VWD2B
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0030132, HP:0030129, HP:0030130, HP:0011871, HP:0012147
(Absence of large von Willebrand factor multimers, impaired ristocetin cofactor assay activity, Impaired von Willebrand factor collagen binding activity, Impaired RIPA, Reduced quantity of VWF)
CaseHPOFreeText: blood group O, Platelet count x103/μl = 182, PFA 100 sec = >300, SPA % = 0, MADR mg/mL = 0.45, VWF:Ag U/dL = 39.5, VWF:CB U/dL = 9.3, VWF:CB ratio = 0.24, VWF:RCo U/dL = 23.3, VWF:RCo ratio = 0.59, Platelet VWF U/dL = 113.90, FVIII U/dL = 52.1, BAT F/M = 14
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: NA
GenotypingMethod: Sequencing of exon 28 of VWF
PreviouslyPublished: NA
Gene: VWF
Variant: c.3922C>T (p.Arg1308Cys)
HGVS: NM_000552.4(VWF):c.3922C>T (p.Arg1308Cys)
ClinVarID: 289; https://www.ncbi.nlm.nih.gov/clinvar/variation/289/
CAID: NA
gnomAD: absent
heterozygous small deletion (p.Leu 757ValfsX22) together with a large deletion of exons 48–52
Case: IP-4
DiseaseAssertion: VWD3
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs:
CaseHPOFreeRext: VWF:Ag 3%
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: Direct sequencing of exons 2–52 including exon/intron boundaries of the VWF gene
GenotypingMethod: multiple ligation‐dependent probe amplification (MLPA; using kit P011 and P012; MRC Holland, Amsterdam, the Netherlands) according to the manufacturer’s instructions. The PCR products were run on an ABI PRISM 3130XL sequencer with the GeneScan 500 LIZ size standard and analyzed using GeneMapper Software 5.0 (Applied Biosystems, Darmstadt, Germany). Dosage analysis based on a comparison between deleted and reference wild‐type DNA samples was performed using the Excel‐based software Coffalyser V9.4 (MRC Holland).
PreviouslyPublished: NA
Gene: VWF
Variant: p.Leu757ValfsX22
HGVS:
ClinVarID:
CAID:
gnomAD:
MultipleGeneVariants:
GeneName: VWF
Variant: deletion of exons 48-52
ClinVarID or CAID:
gnomAD:
homozygous large deletion of exon 6
Case: IP-1
DiseaseAssertion: VWD3
FamilyInfo: 6 additional family members, 5 heterozygous and 1 homozygous. All meet criteria of mild VWD1.
ParentalGenotype(s): NA
CasePresentingHPOs:
CaseHPOFreeRext: VWF antigen (VWF:Ag) of <1%, VWF ristocetin‐cofactor activity (VWF:RCo) of <6% and factor VIII activity (FVIII:C) of 5%
CaseNOTHPOs: NA
CaseNOTHPOFreeText: NA
CasePreviousTesting: Direct sequencing of exons 2–52 including exon/intron boundaries of the VWF gene
GenotypingMethod: multiple ligation‐dependent probe amplification (MLPA; using kit P011 and P012; MRC Holland, Amsterdam, the Netherlands) according to the manufacturer’s instructions. The PCR products were run on an ABI PRISM 3130XL sequencer with the GeneScan 500 LIZ size standard and analyzed using GeneMapper Software 5.0 (Applied Biosystems, Darmstadt, Germany). Dosage analysis based on a comparison between deleted and reference wild‐type DNA samples was performed using the Excel‐based software Coffalyser V9.4 (MRC Holland).
PreviouslyPublished: NA
Gene: VWF
Variant: deletion of exon 6
HGVS:
ClinVarID:
CAID:
gnomAD:
Large deletions identified in patients with von Willebrand disease using multiple ligation-dependent probe amplification
PMID: 21410641
Gene: VWF
HGNCID: 12726
1
Case: 2A-9
DiseaseAssertion: VWD2A
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs: AcuStar RCo/Ag = 0.32; AcuStar CB/Ag = 0.34; ELISA CB/Ag = 0.40
CaseHPOFreeText:
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting:
GenotypingMethod: not described
PreviouslyPublished: PMID:20351307
Gene: VWF
Variant: c.3296G>A (p.Cys1099Tyr)
HGVS: NM_000552.5:c.3296G>A (p.Cys1099Tyr)
ClinVarID: n/a
CAID: CA383512195; https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA383512195
gnomAD: absent
1
Case: 2A-8
DiseaseAssertion: VWD2A
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs: AcuStar RCo/Ag = 0.43; AcuStar CB/Ag = 0.28; ELISA CB/Ag = 0.39
CaseHPOFreeText:
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting:
GenotypingMethod: not described
PreviouslyPublished: PMID:16985174
Gene: VWF
Variant: c.8313C>G (p.Cys2771Trp)
HGVS: NM_000552.5:c.8313C>G (p.Cys2771Trp)
ClinVarID: n/a
CAID: CA383486665; https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA383486665
gnomAD: absent
T001
Case: T001, M, 42
DiseaseAssertion: VWD type 3
FamilyInfo: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: Bleeding Score: 19 (Kruskal–Wallis followed by Mann–Whitney U post-hoc testing Post-hoc testing ), VWF:Ag (IU/ml): 0.01, VWF:RCo (IU/ml): 0.02, FVIII:C (IU/ml) : 0.02
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.221-977_532 + 7059del (p.Asp75_Gly178del), Exon 4-5, Homozygous
Note: ELISA-based assay for detecting alloantibodies, genomic analysis via sequencing of leukocytes for the VWF gene including exons 1-52 and about 1.5 km of VWF promoter, PCR amplification for variant confirmation, SALSA-MLPAVWF assay evaluation for partial/total gene deletions when sequencing did not reveal pathogenic explanation
T116F/2960.020.040.02c.8418_8419insTCCCp.Ser2807 fs52Homozygous
Case: T116, F, 29
DiseaseAssertion: VWD type 3
FamilyInfo: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: Bleeding Score: 6 (Kruskal–Wallis followed by Mann–Whitney U post-hoc testing Post-hoc testing ), VWF:Ag (IU/ml): 0.02, VWF:RCo (IU/ml): 0.04, FVIII:C (IU/ml): 0.02
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.8418_8419insTCCC (p.Ser2807 fs), Exon 52, Homozygous
Note: ELISA-based assay for detecting alloantibodies, genomic analysis via sequencing of leukocytes for the VWF gene including exons 1-52 and about 1.5 km of VWF promoter, PCR amplification for variant confirmation, SALSA-MLPAVWF assay evaluation for partial/total gene deletions when sequencing did not reveal pathogenic explanation
Case: P9, Chinese, male, 11yo
DiseaseAssertion: VWD1
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0012147
(Reduced quantity of VWF)
CaseHPOFreeText: type A blood, bleeding score = 2; VWF:Ag (%) = 5.3, VWF:RCo (%) = 4.7, FVIII:C (%) = 10.7, VWF:CB (%) = 4.5, VWFpp (%) = 4.1, VWF:RCo/VWF:Ag = 0.9, VWF:CB/VWF:Ag = 0.9, VWFpp/VWF:Ag = 0.8, FVIII:C/VWF:Ag = 2.0, RIPA (1.2 mg/ml, %) = 51.0
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: NA
GenotypingMethod: NGS
PreviouslyPublished: NA
Gene: VWF
Variant 1: c.4414G>C (p.Asp1472His)
HGVS: NM_000552.4(VWF):c.4414G>C (p.Asp1472His)
ClinVarID: 256679; https://www.ncbi.nlm.nih.gov/clinvar/variation/256679/
CAID: NA
gnomAD: MAF = 0.5077 (12039/23712 alleles; 3078 homozygotes) in the African/African-American population; https://gnomad.broadinstitute.org/variant/12-6128170-C-G?dataset=gnomad_r2_1
Variant 2: c.8079C>A (p.Cys2693Ter)
HGVS: NM_000552.5:c.8079C>A (p.Cys2693Ter)
ClinVarID: NA
CAID: CA383487414; http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA383487414
gnomAD: absent
Case: P78, Chinese, female, 23yo
DiseaseAssertion: VWD3
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0012147
(Reduced quantity of VWF)
CaseHPOFreeText: type O blood, bleeding score = 13; VWF:Ag (%) = <0.3, VWF:RCo (%) = <0.5, FVIII:C (%) = 4.3, VWF:CB (%) = <0.5, VWFpp (%) = <0.5, VWF:RCo/VWF:Ag = NA, VWF:CB/VWF:Ag = NA, VWFpp/VWF:Ag = NA, FVIII:C/VWF:Ag = NA
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: NA
GenotypingMethod: NGS
PreviouslyPublished: NA
Gene: VWF
Variant: c.5183_5186del - unregistered variant
HGVS: NA
ClinVarID: NA
CAID: NA
gnomAD: NA
Case: P75, Chinese, female, 25yo
DiseaseAssertion: VWD1
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0012147
(Reduced quantity of VWF)
CaseHPOFreeText: type O blood, bleeding score = 2; VWF:Ag (%) = 53.6, VWF:RCo (%) = 55.9, FVIII:C (%) = 74.0, VWF:CB (%) = 53.8, VWFpp (%) = 57.7, VWF:RCo/VWF:Ag = 1.0, VWF:CB/VWF:Ag = 1.0, VWFpp/VWF:Ag = 1.1, FVIII:C/VWF:Ag = 1.4
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: NA
GenotypingMethod: NGS
PreviouslyPublished: NA
Gene: VWF
Variant: c.6104G>A (p.Gly2035Asp)
HGVS: NM_000552.3:c.6104G>A (p.Gly2035Asp)
ClinVarID: NA
CAID: CA6402069; http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA6402069
gnomAD: MAF = 0.005613 (112/19954 alleles; 2 homozygotes) in the East Asian population; https://gnomad.broadinstitute.org/variant/12-6103733-C-T
The S1285F mutation alters the folding of A1 loop and avoids the exposure of the VWF protein to platelets. This substitution was detected in a 2M patient and her mother.
Efficacy and safety of a VWF/FVIII concentrate (wilate ® ) in inherited von Willebrand disease patients undergoing surgical procedures
PMID: 28026130
Gene: VWF
HGNCID: 12726
660
Case#: Ahmad_2014_660
DiseaseAssertion: VWD type 2A
FamilyInfo: heterozygous (probably affected according to multimer analysis) mother and sibling
ParentalGenotype: heterozygous mother and sibling, homozygous wt father
CasePresentingHPOs: none described
CaseHPOFreeText: none described
CaseNotHPOs:
CaseNotHPOFreeText:
CasePreviousTesting: not reported
GenotypingMethod: PCR, restriction digest
Gene: VWF
Variant: NM_000552.5(VWF):c.4883T>C (p.Ile1628Thr)
HGVS:
ClinVarID: 284
CAID:
gnomAD: not reported
MultipleGeneVariants:
Haemostatic patterns and bleeding scores of a genetically characterised Italian family with combined haemophilia A and type 1 von Willebrand disease
PMID: 27380589
Gene: VWF
HGNCID: 12726
Case 1
Case: Case 1, female, newborn
DiseaseAssertion: VWD2B
FamilyInfo: 2nd child of couple without family history of bleeding; 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 from both parents
CasePresentingHPOs: HP:0001873, HP:0000967, HP:0030129
(Thrombocytopenia, petechia, impaired ristocetin cofactor assay activity)
CaseHPOFreeText: born at 40wks, Detection of maternal alloantibodies against HPA antigens present on paternal platelets showed weak cross reactivity, VWF:RCo = 8 IU dL−1, VWF:RCo/VWF:Ag < 0.1, FVIII:C = 94 IU dL−1, RIPA could not be performed 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 (p.Leu1460Pro)
HGVS: NM_000552.3:c.4379T>C (p.Leu1460Pro)
ClinVarID:
CAID:
gnomAD:
Potential misdiagnosis of von Willebrand disease and haemophilia caused by ineffective mixing of thawed plasma
PMID: 28750474
Gene: VWF
HGNCID: 12726
AII:1
Proband: FA_II:1, male uknown age
FamilyDetails: heterozygous unaffected parents, parents were first cousins, VWF:Ag on low end of reference range
Labs: prolonged bleeding time (15min), reduced VWF:Ag (0.06 IU/mL), FVIII:Ag (0.18 IU/mL), FVIII:C (0.20 IU/mL), and VWF:RiCoF (0.06 IU/mL), absent multimers
Genotype: p.Arg273Trp reported as c.1067C>T (MANE transcript is 817C>T)
CAID: CA228829
His 30‐year‐old mother had epistaxis, easy bruising, gum bleeding, and abnormal menstrual score according to the Pictorial Bleeding Assessment Chart4 (PBAC = 192, nv < 185).
Case#: 2, Female, Age 30, blood type B, Mother of Proband
Disease Assertion: VWD1
FamilyInfo: Mother of proband, No family history
Parental Genotype: not listed
CasePresentingHPOs: HP:0000421, HP:0000978, HP:0000225
(Epistaxis, Bruising susceptibility, Gingival bleeding)
CaseHPOFreeText: abnormal menstrual score (PBAC= 192, nv<185), VWF:Ag: 45, VWF:RCo: 46, bleeding score 5
CaseNotHPOs:
CaseNotHPOFreeText:
Protein Expression:
CasePreviousTesting: Forward and reverse strands sequenced by automated sequencing technology, PCR techniques used to analyze exons 17, 26-31, and 52 of VWF gene
Gene: VWF
Variant:NM_000552.3:c.4276C>T (p.Arg1426Cys)
ClinVar:. N/A
CAID: CA6402561 CA6402561
gnomAD: MAF of 0.00006152 (1/16254 alleles) in the African population for CA6402561.
Case 12
Case: Case 12, ages 2-17, Croatian
DiseaseAssertion: VWD2A
FamilyInfo:
ParentalGenotypes(s):
CasePresentingHPOs:
CaseHPOFreeText:
CaseNOTHPOs:
CaseNOTHPOFreeText: bleeding score= 7, VWF:GPIbM (%)= 25.7, VWF:Ag (%)= 47.7, vWF:GPIbM/vWF:Ag ratio= 0.54, FVIII:C (%): 64, VWF: CBA (%)= 39.2
CasePreviousTesting:
Gene: VWF
Variant: c.4717G>A, p.Gly1573Ser
HGVS: NM_000552.5:c.4717G>A
ClinVar: 100384
gnomAD: https://gnomad.broadinstitute.org/variant/12-6127867-C-T?dataset=gnomad_r2_1
PT-VWD posing diagnostic and therapeutic challenges - small case series
PMID: 27819553
Gene: GP1BA
HGNCID: 4439
T3-1
Case: T3-1, female, 21yo
DiseaseAssertion: VWD3
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs:
CaseHPOFreeText: Blood type: O+, bleeding score = 24, VWF:Ag (IU/mL) = 0.01; VWF:RCo (IU/mL) = 0.00; FVIII:C (IU/mL) = 0.01
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting:
GenotypingMethod: qRT-PCR
PreviouslyPublished:
Gene: VWF
Variant 1: c.876delC (p.Pro293Glnfs*164)
HGVS: n/a
ClinVarID: n/a
CAID: n/a
gnomAD: n/a
Variant 2: c.1255C>T (p.Gln419Ter)
HGVS: NM_000552.5:c.1255C>T (p.Gln419Ter)
ClinVarID: n/a
CAID: CA232314778; https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA232314778
gnomAD: absent
Development of a novel flow cytometric immunobead array to quantify VWF: Ag and VWF: GPIbR and its application in acute myocardial infarction
PMID: 28523822
Gene: VWF
HGNCID: 12726
A 23-year-old female patient
Case: Patient from family A, a 23-year-old female consanguineous Chinese patient
DiseaseAssertion: Type 3 von Willebrand disease
FamilyInfo: Patient's parents were cousins, both heterozygous carriers, who had also had a son that died at 1 year old from heavy nose bleeding; no other details given
ParentalGenotype(s): Heterozygous carriers, no details given as far as specific genotypes
CasePresentingHPOs: HP:0000132
Menorrhagia
CaseHPOFreeRext:"When she was 2 years old, scalp hematoma was observed." and severely decreased FVIII:C, VWF:Ag (FVIII:C: 1.3%, VWF:Ag: 3.6%, VWF:RCo: <1.0%)
CaseNOTHPOs: N/A
CaseNOTHPOFreeText: "No mutation was found in the F8 or F9 gene"
CasePreviousTesting: N/A
GenotypingMethod: NGS was performed targeting all exons and intronic flanking regions of the F8 (OMIM: * 300841, NM_000132.3), F9 (OMIM: * 300746, NM_000133.3), and VWF (OMIM: * 613160, NM_000552.4) genes; Some exons of VWF gene could not be discriminated from its highly homologous pseudogene, and these exons were sequenced by Sanger sequencing
Gene: VWF
Variant: Homozygous VWF c.4696C>T (p.Arg1566Ter) nonsense mutation
HGVS: NM_000552.5:c.4696C>T
ClinVarID: 100382
CAID: CA228639
gnomAD: MAF of 0.00001333 (1/74998 alleles) in the African/African American population
Case presentation A 27-year-old woman
Case: Proband, female, 27 years old at report; ethnicity not reported.
DiseaseAssertion: VWD2A. The authors confirmed type 2A VWD based on VWF:Ac/VWF:Ag ratio <0.7 (excluding types 1C, 2N, and 3), RIPA negative for increased platelet affinity (excluding type 2B), and multimer analysis showing HMWM deletion with IMWM reduction (excluding type 2M).
FamilyInfo: The patient denied a family history of abnormal bleeding. The father carried VWF c.2281+1G>A and was not diagnosed with VWD (VWF:Ag 61%, VWF:Ac 60.6%, FVIII activity 82%, VWF:Ac/VWF:Ag ratio 0.9). The mother carried VWF c.4654T>A and was diagnosed by the authors as having low VWF per British Committee for Standards in Haematology criteria (VWF:Ag 40%, VWF:Ac 26.6%, FVIII activity 66%, VWF:Ac/VWF:Ag ratio 0.6). Neither parent had a history of abnormal bleeding. Parental laboratory results and genotypes are reported in Table 2.
ParentalGenotype: Both parents were genotyped. The father was heterozygous for c.2281+1G>A and the mother was heterozygous for c.4654T>A (Table 2). The authors report that the two variants were inherited separately from each parent, establishing compound heterozygosity. Note: Figure 2 shows Sanger sequencing validation for c.2281+1G>A only, confirming the variant in the patient and father and a normal genotype at that locus in the mother. No confirmatory sequencing trace is shown for the maternal c.4654T>A variant; that genotype is reported only in Table 2.
CasePresentingHPOs: HP:0000421, HP:0000132, HP:0004846, HP:0012147, HP:0030132, HP:0011871 (Epistaxis, Menorrhagia, Prolonged bleeding after surgery, Reduced quantity of VWF, Absence of large von Willebrand factor multimers, Impaired RIPA)
CaseHPOFreeText: Gingival bleeding persisted for two days after tooth extraction. History of frequent epistaxis and one episode of heavy menorrhagia in 2007 treated with plasma transfusion. ISTH-BAT bleeding score 7 (epistaxis score 1, bleeding after tooth extraction score 2, heavy menorrhagia with plasma transfusion score 4). VWF:Ag 26.2%, VWF:Ac 5.7%, FVIII activity 43%, VWF:Ac/VWF:Ag ratio 0.21. Low-concentration RIPA 23.7% (reference 30.0-70.0%). VWF multimer analysis demonstrated deletion of high-molecular-weight multimers and reduction of intermediate-molecular-weight multimers (Figure 1). Arachidonic acid-induced platelet aggregation was impaired, with a maximal aggregation rate of 14.3%.
CaseNotHPOs: HP:0003645, HP:0001873 (Prolonged partial thromboplastin time, Thrombocytopenia)
CaseNotHPOFreeText: APTT 39.2 s (reference 32.0-45.0), platelets 183x10^9/L (reference 125-350), PT 13.6 s (reference 11.0-15.0), and fibrinogen 2.71 g/L (reference 2.0-4.0) were all within reference ranges, as was thrombin time. High-concentration RIPA 52.9% (reference 40.0-80.0), normal. Systemic physical examination unremarkable with no active bleeding on admission. Prior laparoscopic surgery for luteal rupture without a remarkable increase in bleeding. Hemoglobin 125 g/L was marginally below the stated reference range (130-175), although the authors described the complete blood count as normal.
CasePreviousTesting: Whole-exome sequencing was performed, which is a genome-wide method. No genes other than VWF were reported as tested or implicated. No earlier molecular genetic testing was reported.
GenotypingMethod: Whole-exome sequencing followed by one-generation (Sanger) sequencing validation, performed on the proband and both parents.
Variant 1
Gene: VWF
Variant: c.2281+1G>A, heterozygous, inherited from the father. Intron 17 canonical splice donor site; the authors describe the affected region as lying between the D2 and D' domains. Classified as pathogenic by the authors per ACMG guidelines.
HGVS: NM_000552.5:c.2281+1G>A
ClinVar: NA
CAID: CA383523243
gnomAD: Absent (gnomAD v4.1.1; variant not found, region adequately covered)
Variant 2
Gene: VWF
Variant: c.4654T>A (p.Phe1552Ile), heterozygous, inherited from the mother. Exon 28, A2 domain; missense. Classified as a variant of uncertain significance by the authors per ACMG guidelines. Note: the article gives the protein consequence as p.Phe1152Ile in the Case Presentation and p.Phe1552Ile in the Discussion; these are internally inconsistent. p.Phe1552Ile is correct, as confirmed by HGVS validation and by the ClinGen Allele Registry record (NP_000543.3:p.Phe1552Ile), and is consistent with the stated exon 28 location.
HGVS: NM_000552.5:c.4654T>A (p.Phe1552Ile)
ClinVar: NA
CAID: CA383500446
gnomAD: Absent (gnomAD v4.1.1; variant not found, region adequately covered)
P4F/641Yes11384023260.9NormalNT270
Case: P4 Female, Korean, 64 years at report
DiseaseAssertion: VWD1
FamilyInfo: Positive family history, no details provided.
ParentalGenotype: NA
CasePresentingHPOs: HP:0030129, HP:0012147, HP:0030132, HP:0011871
(Impaired ristocetin cofactor assay activity, Reduced quantity of VWF, Absence of large von Willebrand factor multimers, Impaired RIPA)
CaseHPOFreeText: bleeding score 11, FVII:C 40%, VWF:Rco 23 IU/dL, VWF:Ag 26 IU/Dl, VWF:Rco/VWF:Ag 0.9, RIPA NT
CaseNotHPOs: HP:0003645, HP:0001873
(Prolonged partial thromboplastin time, Thrombocytopenia)
CaseNotHPOFreeText: aPTT 36s, platelets 270x10^9/L
CasePreviousTesting: NA
GenotypingMethod: Direct sequencing of all exons, flanking intronic sequences, and the promoter of VWF was performed.
Gene: VWF
Variant: c.3389G>A p.C1130Y
HGVS: NM_000552.4:c.2574C>G (p.Cys858Trp)
ClinVar: NA
CAID: CA232299278
gnomAD: MAF of 0.0001002 (2/19954 alleles) in the East Asian population
A Laboratory Phenotype/Genotype Correlation of 1167 French Patients From 670 Families With von Willebrand Disease A New Epidemiologic Picture
PMID: 26986123 Gene: von Willebrand factor HGNCID: 12726 Note: reported for group analysis with no associated probands/patient
PT-VWD posing diagnostic and therapeutic challenges – small case series.
PMID: 27819553
Gene: VWF
HGNCID: 12726
An infant with presumed maternal immune thrombocytopenic purpura had persistent thrombocytopenia with platelet clumping. The patient had no significant bleeding symptoms in the first year of life and von Willebrand antigen and ristocetin cofactor activity were normal. Absent high molecular weight multimers ultimately led to a genetically proven diagnosis of type 2B von Willebrand disease (3964G>A VWF exon 28), highlighting the challenges of establishing this diagnosis in infants.
Case: Rotz Proband, female, reported at birth
DiseaseAssertion: VWD2b
FamilyInfo: Mother was 30yo reported with new onset thrombocytopenia during labor, diagnosed with maternal ITP; mother also had history of menorrhagia and excessive bleeding with minor trauma; VWF profile revealed a Factor VIII activity=49 IU/dL, VWF antigen=32 IU/dL, and undetectable RCo
ParentalGenotype(s): mother also carried c.3964G>A unregistered variant
CasePresentingHPOs: HP:0001873, HP:0030132, HP:0000967, HP:0000421, HP:0001892, HP:0001903, HP:0001981
(thrombocytopenia, Absence of large von Willebrand factor multimers, Petechiae, epistaxis, abnormal bleeding, anemia, schistocyte)
CaseHPOFreeText: small hematoma at IV puncture site, platelet count was 9×109/L, ultrasound showed no hemorrhage, hemoglobin=7.6 g/dL
CaseNOTHPOs: HP:0012147, HP:0030129
(Reduced quantity of VWF, impaired ristocetin cofactor assay activity)
CaseNOTHPOFreeText: no unusual findings on physical exam
CasePreviousTesting: NA
GenotypingMethod: Sequencing of VWF exon 28
PreviouslyPublished: NA
Gene: VWF
Variant: c.3964G>A unregistered variant
HGVS: NA
ClinVarID: NA
CAID: NA
gnomAD: NA