UQU-HA33
Case#: UQU-HA33, Male, 2-months-old, Saudi Arabia
DiseaseAssertion: Hemophilia A
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: PTT 99.5, Disabled Right Knee, Severe
CasePreviousTesting: Screened for inversion 22 by inverse PCR, screened for inversion 1 by multiplexed PCR, capillary sequencing (Sanger method) was performed for factor VIII all 26 exons
Gene: F8
Variant: NM_000132.3:c.760A>G (p.Asn254Asp)
ClinVar: NA
CAID: CA414918977
gnomAD: Not reported
UQU-HB6
Case#: UQU-HB6, Male, 11-months-old, Saudi Arabia
DiseaseAssertion: Hemophilia B
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: Severe, Disabled right knee, PTT 52.2
CasePreviousTesting: Screened for all factor IX exons by capillary sequencing
Gene: F9
Variant: NM_000133.3(F9):c.880C>T (p.Arg294Ter)
ClinVar: 10587 https://www.ncbi.nlm.nih.gov/clinvar/variation/10587/
CAID: CA255344
gnomAD: Not reported
UQU-HA34
Case#: UQU-HA34, Male, 1-months-old, Saudi Arabia
DiseaseAssertion: Hemophilia A
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: PTT 94, Disabled Left elbow, Severe
CasePreviousTesting: Screened for inversion 22 by inverse PCR, screened for inversion 1 by multiplexed PCR, capillary sequencing (Sanger method) was performed for factor VIII all 26 exons
Gene: F8
Variant: NM_000132.3:c.1835G>C (p.Arg612Pro)
ClinVar: NA
CAID: CA414910775
gnomAD: Not reported
035–2019
Case#: 035-2019
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: 5% < FVIII:C < 40%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.923C>T
LegacyVariant:
ClinVar: No
CAID: CA255082
gnomAD:
035–2001
Case#: 035-2001
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.1963_1964insT
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
071–2027
Case#: 071-2027
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.4184_4186delGGAinsCCTC
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
020–1016
Case#: 020-1016
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:
015–2006
Case#: 015-2006
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.343G>T
LegacyVariant:
ClinVar: No
CAID: CA414919965
gnomAD:
060–2001
Case#: 060-2001
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:
066–2003
Case#: 066-2003
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: 5% < FVIII:C < 40%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.1649G>A
LegacyVariant:
ClinVar: No
CAID: CA255115
gnomAD:
010–1001
Case#: 010-1001
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.6742T>A
LegacyVariant:
ClinVar: No
CAID: CA414904758
gnomAD:
002–2002
Case#: 002-2002
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.2092T>C
LegacyVariant:
ClinVar: No
CAID: CA414908999
gnomAD:
038–2023
Case#: 038-2023
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.322_332þ8delGCTTCTGAGGGtgagtaaa
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
002–2006
Case#: 002-2006
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.4379delA
LegacyVariant:
ClinVar: No
CAID: CA255151
gnomAD:
001–2040
Case#: 001-2040
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.5630G>A
LegacyVariant:
ClinVar: No
CAID: CA414908131
gnomAD:
003–2001
Case#: 003-2001
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.493C>T
LegacyVariant:
ClinVar: No
CAID: CA255065
gnomAD:
mutation
Case#: Knobloch_Malmo_20 (assumed male, German)
DiseaseAssertion: Moderate Hemophilia B
FamilyInfo: N/A
ParentalTesting: None
CasePresentingHPOs: HP:0011858
CaseHPOsFreeText: reduced factor IX activity
CaseNotHPOs: N/A
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.127C>T (p.Arg43Trp)
LegacyVariant: c.6364C>T (p.Arg-4Trp)
ClinVar: 811505
CAID: CA414435537
gnomAD: Absent/Not Reported
mutation
No Case Level Evidence for NM_000133.4:c.128G>T (p.Arg43Leu)
1.
Case#: 1
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.88G>A
LegacyVariant:
ClinVar: No
CAID: CA414434500
gnomAD:
30.
Case#: 30
DiseaseAssertion: Hemophilia B, moderate
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0011858
CaseHPOFreeText: FIX:C = 3%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: All relevant sequences of F9 were PCR amplified and analyzed by DNA sequencing
Gene: F9
Variant: NM_000133.3:c.1291T>C
LegacyVariant:
ClinVar: No
CAID: CA414447130
gnomAD:
9.
Case#: 9
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.533G>A
LegacyVariant:
ClinVar: No
CAID: CA414440301
gnomAD:
37.
Case#: 37
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.655C>T
LegacyVariant:
ClinVar: No
CAID: CA255347
gnomAD:
8.
Case#: 8
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.422G>A
LegacyVariant:
ClinVar: No
CAID: CA414438897
gnomAD:
A1
Case#: A1
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 7, FVIII:AG = 25, 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.398A>G
LegacyVariant:
ClinVar: No
CAID: CA255061
gnomAD:
Usefulness of an in vitro cellular expression model for haemophilia A carrier diagnosis: illustration with five novel mutations in the F8 gene in women with isolated factor VIII:C deficiency
PMID: 25708597
Gene: F8
Disease: Hemophilia A
HGNC:3546
MONDO ID: MONDO:0010602
mutation
Case#: Cases 1157, 1125, 1382, and 1434
DiseaseAssertion: 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 (Case 1157 FIX:C: <1; FIX:Ag: 38) (Case 1125 FIX:C: <1; FIX:Ag: n/a (Case 1382 FIX:C: <1; FIX:Ag: 1) Case 1434 FIX:C <1; FIX:Ag: n/a)
CaseNotHPOs: N/A
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.127C>T (p.Arg43Trp)
LegacyVariant: c.6364C>T (p.Arg-4Trp)
ClinVar: 811505
CAID: CA414435537
gnomAD: Absent/Not Reported
Role of chromogenic assays in haemophilia A and B diagnosis
PMID: 29808946
Gene: F8
HGNC: 3546
NoEvidence: This article discusses the role of chromogenic assays in hemophilia A; no case reports in this article
Importance of diagnostic guidance in acquired hemophilia A
PMID: 31344171
Gene: F8
No Evidence: No variants or probands mentioned in this review of Hemophilia A
S12
Case#: S12, Iranian
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: Family history of HA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125, HP:0005261
CaseHPOFreeText: FVIII:C < 1%, Inhibitor present
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The F8 gene was directly sequenced for all 26 exons using the Sanger sequencing method. PCR was performed and subsequently analyzed
Gene: F8
Variant: NM_000132.3:c.del exons8_9
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
S19
Case#: S19, 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: NA
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
Table 1
Case#: N/A
DiseaseAssertion: Severe Hemophilia B
FamilyInfo: N/A
ParentalTesting: None
CasePresentingHPOs: HP:0001929
CaseHPOsFreeText: reduced factor IX activity
CaseNotHPOs: N/A
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.84T>G (p.Cys28Trp)
ClinVar: Absent
CAID: CA414434487
gnomAD: Absent/Not Reported
c.157G>A
Case#: 40
DiseaseAssertion: Hemophilia B
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FIX:C <1% (Severe Phenotype)
CasePreviousTesting: Screened for IVS-22 and IVS-1, sample was blinded for NGS and the sequencing component was validated by comparing results with Sanger Sequencing
Gene: F9
Variant: NM_000133.3:c.157G>A (p.Glu53Lys)
ClinVar: NA
CAID: CA414435726
gnomAD: Not reported
c.1025C>T
Case#: 48
DiseaseAssertion: Hemophilia B
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FIX:C 3% (Moderate Phenotype)
CasePreviousTesting: Screened for IVS-22 and IVS-1, sample was blinded for NGS and the sequencing component was validated by comparing results with Sanger Sequencing
Gene: F9
Variant: NM_000133.3(F9):c.1025C>T (p.Thr342Met)
ClinVar: 10607 https://www.ncbi.nlm.nih.gov/clinvar/variation/10607/
CAID: CA255381
gnomAD: Not reported
c.6506G>A
Case#: 31
DiseaseAssertion: Hemophilia A
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FVIII:C 17/25%, Mild Phenotype, 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.6506G>A (p.Arg2169His)
ClinVar: 10315 https://www.ncbi.nlm.nih.gov/clinvar/variation/10315/
CAID: CA255208
gnomAD: Not reported
c.1010–842G>A
Case#: 7
DiseaseAssertion: Hemophilia A
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FVIII:C 34/30/35% (Mild Phenotype), No inhibitors present
CasePreviousTesting: Screened for IVS-22 and IVS-1, sample was blinded for NGS and the sequencing component was validated by comparing results with Sanger Sequencing
Gene: F8
Variant: NM_000132.3:c.1010-842G>A
ClinVar: NA
CAID: CA337336857
gnomAD: MAF in Ashkenazi Jewish population 0.01105<br>https://gnomad.broadinstitute.org/variant/X-154195804-C-T
Missense mutations at ALA-10 in the factor IX propeptide:an insignificant variant in normal life but a decisive causeof bleeding during oral anticoagulant therapy
PMID: 9233593
Gene: F9
HGNC: 3551
Extensive serum cytokine analysis in patients with prostate cancer
PMID: 31430659
Gene: F8
No Evidence: This article does not mention F8, rather it discusses cytokine analysis.
Click here for additional data file.(2
NM_000133.4:c.128G>A (p.Arg43Gln) is mentioned in the paper, however, there is no case level data associated with the mentioned variant.
Thr37 mutation
Case#: Pezeshkpoor_Patient_P (male, 68 y/o, from Switzerland)
DiseaseAssertion: Moderate Hemophilia B
FamilyInfo: N/A
ParentalTesting: N/A
CasePresentingHPOs: HP:0011858
CaseHPOsFreeText: diffuse subcutaneous bleeding, low FIX:C levels (3%), international normalized ratio (INR) of 3.3, a prolonged aPTT of 88 s, reduced vitamin K-dependent coagulation factors
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
Val37 mutation.
Case#: Patient R (male, 83 y/o)
DiseaseAssertion: Severe Hemophilia B
FamilyInfo: N/A
ParentalTesting: N/A
CasePresentingHPOs: HP:0011858, HP:0012233
CaseHPOsFreeText: reduced factor IX activity (FIX:C: 2.4%), extensive subcutaneous bleeding
CaseNotHPOs: None
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.110C>T (p.Ala37Val)
ClinVar: Absent
CAID: CA414435437
gnomAD: Allele Frequency (European-non Finnish): 0.00002186
c.128G>T
Case#: Meireles_Proband_3 (assumed male)
DiseaseAssertion: Severe Hemophilia B
FamilyInfo: None
ParentalTesting: None
CasePresentingHPOs: HP:0011858
CaseHPOsFreeText: reduced factor IX activity
CaseNotHPOs: N/A
CasePreviousTesting: None
Gene: F9
Variant: NM_000133.4:c.128G>T (p.Arg43Leu)
ClinVar: 993549
CAID: CA414435545
gnomAD: Absent/Not Reported
variants
No mention of NM_000133.4:c.138G>T (p.Arg46Ser) in this publication.
9
Case#: 9, male, 19 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.1285C>T
LegacyVariant:
ClinVar: No
CAID: CA414915370
gnomAD:
114
Case#: 114, male, 16 years old, Chinese
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 3%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.601+1G>C
LegacyVariant:
ClinVar: No
CAID: CA414919361
gnomAD:
5
Case#: 5, male, 9 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.741G>A
LegacyVariant:
ClinVar: No
CAID: CA414919022
gnomAD:
64
Case#: 64, male, 6 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.2158G>C
LegacyVariant:
ClinVar: No
CAID: CA414903786
gnomAD:
23
Case#: 23, male, 21 years old, Chinese
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 2%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.6496C>T
LegacyVariant:
ClinVar: 10096
CAID: CA255013
gnomAD:
99
Case#: 99, male, 9 years old, Chinese
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.6544C>T
LegacyVariant:
ClinVar: 10321
CAID: CA255214
gnomAD:
92
Case#: 92, male, 61 years old, Chinese
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 4.2%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.6440G>T
LegacyVariant:
ClinVar: No
CAID: CA414908004
gnomAD:
106
Case#: 106, 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.6683G>A
LegacyVariant:
ClinVar: 10098
CAID: CA255016
gnomAD:
54
Case#: 54, male, 9 years old, Chinese
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 17%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.1834C>T
LegacyVariant:
ClinVar: 10236
CAID: CA255129
gnomAD:
Defective Propeptide Processing of BloodClotting Factor IX Caused by Mutation ofArginine to Glutamine at Position -
PMID: 3009023
Gene: F9
HGNC: 3551
mutations
Case#: Chan_Hong Kong 2 & Chan_Hong Kong 3 (Southern Chinese, assumed male)
DiseaseAssertion: Severe Hemophilia B
FamilyInfo: Carrier testing of at risk females in each family was completed by direct restriction enzyme analysis after determination of the specific FIX defect for the index patient
ParentalTesting: N/A
CasePresentingHPOs: HP:0011858
CaseHPOsFreeText: reduced factor IX activity (Chan_Hong Kong 2 FIX:Ag: 0.93; FIX:C: 0.04) (Chan_Hong Kong 3 FIXAg: 0.82; FIX:C: 0.01)
CaseNotHPOs: N/A
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.128G>A (p.Arg43Gln)
LegacyVariant: c.6365 G>A (p.Arg-4Gln)
ClinVar: 810864
CAID: CA414435539
gnomAD: Absent/Not Reported
7
Case#: 7
DiseaseAssertion: Hemophilia B, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FIX:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: All exons, UTRs, exon-intron junction regions, and the promotor of F9 were amplified by PCR and analyzed by direct DNA sequencing
Gene: F9
Variant: NM_000133.3:c.677G>A
LegacyVariant:
ClinVar: No
CAID: CA121128
gnomAD:
18
Case#: 18
DiseaseAssertion: Hemophilia B, moderate
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FIX:C = 3.9%
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.284A>G
LegacyVariant:
ClinVar: No
CAID: CA414437372
gnomAD:
A genetic analysis of 23 Chinese patients with hemophilia B
PMID: 27109384
Gene: F9
HGNCID: 3551
Enhanced potency of recombinant factor VIIa with increased
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
c.138GNT
A case of NM_000133.4:c.138G>T (p.Arg46Ser) is mentioned in this paper, but previously reported, and no case level evidence is given in this publication.
.A37D
Only mention of NM_000133.4:c.110C>A (p.Ala37Asp) in this publication.
mutations
Case#: VAN DE Water_NZ 2 (New Zealand, assumed male)
DiseaseAssertion: Moderate Hemophilia B
FamilyInfo: In 22 of the 32 families the mutation resulted in alteration of a restriction enzyme site. In these cases, researchers developed a rapid PCR based diagnosis assay, which eliminated the need for extensive family studies (enabled successful prenatal and carrier diagnostic studies to be undertaken in 22 subjects from five families)
ParentalTesting: N/A
CasePresentingHPOs: HP:0011858
CaseHPOsFreeText: reduced factor IX activity (2%)
CaseNotHPOs: N/A
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.128G>A (p.Arg43Gln)
LegacyVariant: c.6365 G>A (p.Arg-4Gln)
ClinVar: 810864
CAID: CA414435539
gnomAD: Absent/Not Reported
mutations
Case#: UK 130, Malmo 19, UK 134, Malmo 6, UK 129, Malmo 40, Malmo 20 (assumed male, from UK and Malmö, Sweden)
DiseaseAssertion: UK 130: Moderate Hemophilia B Malmo 19: Moderate Hemophilia B UK 134: Severe Hemophilia B Malmo 6: Severe Hemophilia B UK 129: Moderate Hemophilia B Malmo 40: Moderate Hemophilia B Malmo 20: Moderate Hemophilia B
FamilyInfo: None
ParentalTesting: N/A
CasePresentingHPOs: reduced factor IX activity
CaseHPOsFreeText: UK 130 FIX:C: 1.6 Malmo 19 FIX:C: 2.3 ; FIX:AG: 36 UK 134 FIX:C: <1 Malmo 6 FIX:C: <1 ; FIX:AG: 26-35 UK 129 FIX:C: 4 Malmo 40 FIX:C: 1 ; FIX:AG: 30 Malmo 20 FIX:C: 2 ; FIX:AG: 27
CaseNotHPOs: N/A
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.127C>T (p.Arg43Trp)
ClinVar: 811505
CAID: CA414435537
gnomAD: Absent/Not Reported
Prediction of factor VIII inhibitor development in the SIPPET cohort by mutational analysis and factor VIII antigen measurement
PMID: 29399993
Gene: F8
HGNC: 3546
InsufficientEvidence: This article mentions variants however there are no specific case reports mentioned therefore, insufficient evidence
p.Cys28Arg
Case#: N/A
DiseaseAssertion: Moderate/Mild Hemophilia B
FamilyInfo: Not provided
ParentalTesting: Not provided
CasePresentingHPOs: HP:0011858
CaseHPOsFreeText: reduced factor IX activity
CaseNotHPOs: N/A
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.82T>C (p.Cys28Arg)
ClinVar: 10657
CAID: CA255450
The final list of mutations is provided in Supplementary Table S1.
Case#: N/A
DiseaseAssertion: Mild Hemophilia B
FamilyInfo: N/A
ParentalTesting: N/A
CasePresentingHPOs: N/A
CaseHPOsFreeText: N/A
CaseNotHPOs: N/A
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.62G>T ((p.Gly21Val)
ClinVar: Absent
CAID: CA414434385
gnomAD: Absent/NotReported
Table 1
Case#: Cz37, 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: NM_000132.3:c.4379dup (p.Asn1460LysfsTer2)
ClinVar: NA
CAID: CA645292749
gnomAD: MAF for p.Asn1460LysfsTer2 in the European (non-Finnish) population 0.00001245<br>https://gnomad.broadinstitute.org/variant/X-154157685-A-AT
Homozygous and heterozygous retinal phenotypes in families harbouring IMPG2 mutations
PMID: 31264916
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.
Six Novel Missense Mutations in the LDL Receptor-Related Protein 5 (LRP5) Gene in Different Conditions with an Increased Bone Density
PMID: 12579474
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.
The human U4/U6 snRNP contains 60 and 90kD proteins that are structurally homologous to the yeast splicing factors Prp4p and Prp3p
PMID: 9257651
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).
Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease
PMID: 28041643
GeneName: GNAT2
HGNC: 4394
Disease: achromatopsia 4
MonDO ID: MONDO_0013465
Inheritance: autosomal recessive
Aberrant RNA splicing is the major pathogenic effect in a knock-in mouse model of the dominantly inherited c.1430A>G human RPE65 mutation
PMID: 30628748
Gene: RPE65
HGNC: 10294
Disease: Retinitis pigmentosa 87 with choroidal involvement
MONDO: 0032873
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 8,000 and 1 in 27,000). The prevalence of Retinitis pigmentosa 87 with choroidal involvement is considered to be much lower.
Penetrance: Incomplete penetrance, estimated at 80%
Oa1 knock-out: new insights on the pathogenesis of ocular albinism type 1
PMID: 11092754
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.
A mouse model for Finnish variant late infantile neuronal ceroid lipofuscinosis, CLN5, reveals neuropathology associated with early aging
PMID: 15459177
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
Proteoglycan IMPG2 Shapes the Interphotoreceptor Matrix and Modulates Vision
PMID: 32265257
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.
A Novel Tissue Inhibitor of Metalloproteinases-3 Mutation Reveals a Common Molecular Phenotype in Sorsby's Fundus Dystrophy
PMID: 10854443
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
A novel homozygous nonsense mutation in CABP4 causes congenital cone-rod synaptic disorder
PMID: 19074807
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.
Expression and characterization of the IPM 150 gene (IMPG1) product, a novel human photoreceptor cell-associated chondroitin-sulfate proteoglycan
PMID: 10601738
Gene: IMPG1
HGNC: 6055
Disease: vitelliform macular dystrophy 4
MONDO: 0014508
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.
ON pathway mutations increase susceptibility to form-deprivation myopia
PMID: 26072023
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.
Gene Therapy in Opn1mw−/−/Opn1sw−/− Mice and Implications for Blue Cone Monochromacy Patients with Deletion Mutations
PMID: 35272502
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).
A distinct vitreo-retinal dystrophy with early-onset cataract from recessive KCNJ13 mutations
PMID: 25475713
Gene: KCNJ13
HGNC: 6259
Disease: Leber congenital amaurosis 16
MONDO: 0013613
InheritancePattern: autosomal recessive
Prevalence: The overall prevalence of Leber congenital amaurosis is between 1 in 33,000 and 1 in 100,000 newborns (PMID: 10951519), while the proportion of Leber congenital amaurosis caused by KCNJ13 variants is unknown.
Penetrance: Known disease-causing alleles appear to be completely penetrant.
Essential role of Ca2+-binding protein 4, a Cav1.4 channel regulator, in photoreceptor synaptic function
PMID: 15452577
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.
Identification of a Novel Bardet-Biedl Syndrome Protein, BBS7, That Shares Structural Features with BBS1 and BBS2
PMID: 12567324
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.
Osteoporosis Pseudoglioma Syndrome
PMID: 33531964
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.
Identification of three novel OA1 gene mutations identified in three families misdiagnosed with congenital nystagmus and carrier status determination by real-time quantitative PCR assay
PMID: 12515581
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.
Phenotype in retinol deficiency due to a hereditary defect in retinol binding protein synthesis
PMID: 9888420
Gene: RBP4
HGNC: 9922
Disease: progressive retinal dystrophy due to retinol transport defect
MONDO: 0014060
InheritancePattern: autosomal recessive
Prevalence: RBP4-related cases have an estimated prevalence of less than 1 in 1,000,000 (https://www.orpha.net/en/disease/detail/352718?search=&mode=name)
Penetrance: RBP4 disease-causing variants appear to have complete penetrance in biallelic cases.
Abnormal Vessel Formation in the Choroid of Mice Lacking Tissue Inhibitor of Metalloprotease-3
PMID: 18408187
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
CSNB1 in Chinese families associated with novel mutations in NYX
PMID: 16670814
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.
Two-year progression analysis of RPE65 autosomal dominant retinitis pigmentosa
PMID: 29947567
Gene: RPE65
HGNC: 10294
Disease: Retinitis pigmentosa 87 with choroidal involvement
MONDO: 0032873
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 8,000 and 1 in 27,000). The prevalence of Retinitis pigmentosa 87 with choroidal involvement is considered to be much lower.
Penetrance: Incomplete penetrance, estimated at 80%
Functional photoreceptor loss revealed with adaptive optics: An alternate cause of color blindness
PMID: 15148406
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).
Deletion in the OA1 gene in a family with congenital X linked nystagmus
PMID: 11520764
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.
Interphotoreceptor matrix proteoglycans IMPG1 and IMPG2 proteolyze in the SEA domain and reveal localization mutual dependency
PMID: 36109576
Gene: IMPG1
HGNC: 6055
Disease: vitelliform macular dystrophy 4
MONDO: 0014508
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.
Deletion of the Impg2 gene causes the degeneration of rod and cone cells in mice
PMID: 32242237
Gene: IMPG1
HGNC: 6055
Disease: vitelliform macular dystrophy 4
MONDO: 0014508
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.
A Novel Protein LZTFL1 Regulates Ciliary Trafficking of the BBSome and Smoothened
PMID: 22072986
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.
CORD9 a New Locus for arCRD: Mapping to 8p11, Estimation of Frequency, Evaluation of a Candidate Gene
PMID: 11581183
Gene: ADAM9
HGNC: 216
Disease: cone-rod dystrophy 9
MONDO: MONDO:0013002
InheritancePattern: autosomal recessive
Prevalence: The prevalence of cone-rod dystrophy in general is estimated to be 1 in 40,000 (PMID: 17270046), however, the specific prevalence of cone-rod dystrophy 9 is unknown.
Penetrance: Penetrance appears to be complete in reported families, but it is possible that incomplete penetrance may be associated with some variants.
Identification of 11 Novel Mutations in 8 BBS Genes by High-Resolution Homozygosity Mapping
PMID: 19797195
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.
Monoallelic IFT140 pathogenic variants are an important cause of the autosomal dominant polycystic kidney-spectrum phenotype
PMID: 26216056
Gene: IFT140
HGNC: 29077
Disease: polycystic kidney disease
MONDO: 0020642
InheritancePattern: autosomal dominant
Prevalence: The overall prevalence of polycystic kidney disease is between 1 in 400 and 1 in 1,000 individuals (PMID: 30523303).
Penetrance: Disease caused by monoallelic IFT140 variants is incompletely penetrant.
A CLN5 mutation causing an atypical neuronal ceroid lipofuscinosis of juvenile onset
PMID: 15728307
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
Pineal Photoreceptor Cells Are Required for Maintainingthe Circadian Rhythms of Behavioral Visual Sensitivity inZebrafish
PMID: 22815753
GeneName: GNAT2
HGNC: 4394
Disease: achromatopsia 4
MonDO ID: MONDO_0013465
Inheritance: autosomal recessive
RPGR Isoforms in Photoreceptor Connecting Cilia and the Transitional Zone of Motile Cilia
PMID: 12766038
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.
Mutations in the human retinal degeneration slow gene in autosomal dominant retinitis pigmentosa
PMID: 1684223
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).
De novo and inherited dominant variants in U4 and U6 snRNA genes cause retinitis pigmentosa
PMID: 41513982
Gene: RNU4-2
HGNC: 10193
Disease: inherited retinal dystrophy
MONDO: 0019118
InheritancePattern: autosomal dominant
Prevalence: The prevelance of retinitis pigmentosa in general is between 1 in 750 and 1 in 9,000 individuals (PMID: 37108642). The proportion of those cases caused by RNU4-2 variants is not well known.
Penetrance: Penetrance appears to be incomplete, with family pedigrees including apparently unaffected carriers.
A retinitis pigmentosa GTPase regulator (RPGR)- deficient mouse model for X-linked retinitis pigmentosa (RP3)
PMID: 10725384
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.
Sorsby's fundus dystrophy mutations impair turnover of TIMP-3 by retinal pigment epithelial cells
PMID: 16223891
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
Mutations in the Genes for Interphotoreceptor Matrix Proteoglycans, IMPG1 and IMPG2, in Patients with Vitelliform Macular Lesions
PMID: 28644393
Gene: IMPG1
HGNC: 6055
Disease: vitelliform macular dystrophy 4
MONDO: 0014508
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.
The 21-kDa protein is a transformation-sensitive metalloproteinase inhibitor of chicken fibroblasts
PMID: 1845973
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
Mutations in NYX, encoding the leucine-rich proteoglycan nyctalopin, cause X-linked complete congenital stationary night blindness
PMID: 11062471
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.
Mutations in the X-Linked Retinitis Pigmentosa Genes RPGR and RP2 Found in 8.5% of Families with a Provisional Diagnosis of Autosomal Dominant Retinitis Pigmentosa
PMID: 23372056
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.
Tissue inhibitor of metalloproteinases-3 is a component of Bruch's membrane of the eye.
PMID: 9006347
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
Factors that Determine Ca2+ Sensitivity of Photoreceptor Guanylyl Cyclase. Kinetic Analysis of the Interaction between the Ca2+-Bound and the Ca2+-Free Guanylyl Cyclase Activating Proteins (GCAPs) and Recombinant Photoreceptor Guanylyl Cyclase 1 (RetGC-1)
PMID: 15504042
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.
Insights into the pathogenesis of dominant retinitis pigmentosa associated with a D477G mutation in RPE65
PMID: 29659842
Gene: RPE65
HGNC: 10294
Disease: Retinitis pigmentosa 87 with choroidal involvement
MONDO: 0032873
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 8,000 and 1 in 27,000). The prevalence of Retinitis pigmentosa 87 with choroidal involvement is considered to be much lower.
Penetrance: Incomplete penetrance, estimated at 80%
Codons 837 and 838 in the retinal guanylate cyclase gene on chromosome 17p: hot spots for mutations in autosomal dominant cone-rod dystrophy?
PMID: 10676808
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.
Loss of C. elegans BBS-7 and BBS-8 protein function results in cilia defects and compromised intraflagellar transport
PMID: 15231740
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.
Genotype-Dependent Variability in Residual Cone Structure in Achromatopsia: Toward Developing Metrics for Assessing Cone Health
PMID: 25277229
GeneName: GNAT2
HGNC: 4394
Disease: achromatopsia 4
MonDO ID: MONDO_0013465
Inheritance: autosomal recessive
prpf4 is essential for cell survival and posterior lateral line primordium migration in zebrafish
PMID: 30174136
GUCY2D Cone–Rod Dystrophy-6 Is a “Phototransduction Disease” Triggered by Abnormal Calcium Feedback on Retinal Membrane Guanylyl Cyclase 1
PMID: 29440533
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.
Whole exome sequencing identifies a novel splice-site mutation in IMPG2 gene causing Stargardt-like juvenile macular dystrophy in a north Indian family
PMID: 34990796
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.
Splice-site mutations identified in PDE6A responsible for retinitis pigmentosa in consanguineous Pakistani families
PMID: 26321862
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.
A dominant mutation in RPE65 identified by whole-exome sequencing causes retinitis pigmentosa with choroidal involvement
PMID: 21654732
Gene: RPE65
HGNC: 10294
Disease: Retinitis pigmentosa 87 with choroidal involvement
MONDO: 0032873
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 8,000 and 1 in 27,000). The prevalence of Retinitis pigmentosa 87 with choroidal involvement is considered to be much lower.
Penetrance: Incomplete penetrance, estimated at 80%
cGMP phosphodiesterase-alpha mutation causes progressive retinal atrophy in the Cardigan Welsh corgi dog
PMID: 10393029
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.
Functional exploration of the IFT-A complex in intraflagellar transport and ciliogenesis
PMID: 28207750
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.
The genetic landscape of inherited eye disorders in 74 consecutive families from the United Arab Emirates
PMID: 32783370
Gene: KCNJ13
HGNC: 6259
Disease: Leber congenital amaurosis 16
MONDO: 0013613
InheritancePattern: autosomal recessive
Prevalence: The overall prevalence of Leber congenital amaurosis is between 1 in 33,000 and 1 in 100,000 newborns (PMID: 10951519), while the proportion of Leber congenital amaurosis caused by KCNJ13 variants is unknown.
Penetrance: Known disease-causing alleles appear to be completely penetrant.
A BBS1 SVA F retrotransposon insertion is a frequent cause of Bardet-Biedl syndrome
PMID: 33169370
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.
Long-Range PCR-Based NGS Applications to Diagnose Mendelian Retinal Diseases
PMID: 33546218
Gene: PROM1
HGNC: 9454
Disease: retinitis pigmentosa 41
MONDO: 0012796
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). The proportion of that incidence made up by the specific form caused by biallelic variants in PROM1 is not clear.
Penetrance: Known disease-causing alleles appear to be completely penetrant in the homozygous state, and for at least some heterozygous variants associated with other disease entities.
Transgenic zebrafish expressing mutant human RETGC-1 exhibit aberrant cone and rod morphology
PMID: 23328348
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.
Identification of novel PROM1 mutations responsible for autosomal recessive maculopathy with rod-cone dystrophy
PMID: 30588538
Gene: PROM1
HGNC: 9454
Disease: retinitis pigmentosa 41
MONDO: 0012796
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). The proportion of that incidence made up by the specific form caused by biallelic variants in PROM1 is not clear.
Penetrance: Known disease-causing alleles appear to be completely penetrant in the homozygous state, and for at least some heterozygous variants associated with other disease entities.
A homologous genetic basis of the murine cpfl1 mutant and human achromatopsia linked to mutations in the PDE6C gene
PMID: 19887631
Gene: PDE6C
HGNC: 8787
Disease: cone dystrophy 4
MONDO: 0013129
InheritancePattern: recessive
Prevalence: cone dystrophy in general is estimated to have a prevalence of 1 in 40,000 (PMID: 30578485).
Penetrance: The penetrance of the phenotype among homozygous cases appears to be complete.
Two point mutations of RPE65 from patients with retinal dystrophies decrease the stability of RPE65 protein and abolish its isomerohydrolase activity
PMID: 16754667
Gene: RPE65
HGNC: 10294
Disease: Retinitis pigmentosa 20
MONDO: 0013425
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 recessive Retinitis pigmentosa caused by RPE65 variants is ~2%. (PMID: 9501220) Thus, the prevalence of Retinitis pigmentosa 20 is between 1 in 150,000 and 1 in 200,000.
Penetrance: Fully penetrant, with onset typically in childhood
ADAM9 Is Involved in Pathological Retinal Neovascularization
PMID: 19273593
Gene: ADAM9
HGNC: 216
Disease: cone-rod dystrophy 9
MONDO: MONDO:0013002
InheritancePattern: autosomal recessive
Prevalence: The prevalence of cone-rod dystrophy in general is estimated to be 1 in 40,000 (PMID: 17270046), however, the specific prevalence of cone-rod dystrophy 9 is unknown.
Penetrance: Penetrance appears to be complete in reported families, but it is possible that incomplete penetrance may be associated with some variants.
Exome Sequencing of 47 Chinese Families with Cone-Rod Dystrophy: Mutations in 25 Known Causative Genes
PMID: 23776498
Gene: PDE6C
HGNC: 8787
Disease: cone dystrophy 4
MONDO: 0013129
InheritancePattern: recessive
Prevalence: cone dystrophy in general is estimated to have a prevalence of 1 in 40,000 (PMID: 30578485).
Penetrance: The penetrance of the phenotype among homozygous cases appears to be complete.
A common NYX mutation in Flemish patients with X linked CSNB
PMID: 18617546
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.
Sorsby's fundus dystrophy tissue inhibitor of metalloproteinases-3 (TIMP-3) mutants have unimpaired matrix metalloproteinase inhibitory activities, but affect cell adhesion to the extracellular matrix
PMID: 11827795
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
BBS1 branchpoint variant is associated with non-syndromic retinitis pigmentosa
PMID: 33910932
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.
Mutations in the gene encoding the alpha-subunit of rod phosphodiesterase in consanguineous Pakistani families
PMID: 17110911
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.
PRPF4 mutations cause autosomal dominant retinitis pigmentosa
PMID: 24419317
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).
Molecular genetic analysis using targeted NGS analysis of 677 individuals with retinal dystrophy
PMID: 30718709
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.
Novel mutation in CTNNB1 causes familial exudative vitreoretinopathy (FEVR) and microcephaly: case report and review of the literature
PMID: 32039639
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.
RPE65 Is Essential for the Function of Cone Photoreceptors in NRL-Deficient Mice
PMID: 17251447
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
UNUSUAL EARLY-ONSET VITELLIFORM DYSTROPHY POSSIBLY LINKED TO THE INTERPHOTORECEPTOR MATRIX PROTEOGLYCAN-1 P.LEU154PRO MUTATION
PMID: 30688845
Gene: IMPG1
HGNC: 6055
Disease: vitelliform macular dystrophy 4
MONDO: 0014508
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.
Mutations in the tissue inhibitor of metalloproteinases-3 (TIMP3) in patients with Sorsby's fundus dystrophy
PMID: 7894485
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
Evaluation of Complex Inheritance Involving the Most Common Bardet-Biedl Syndrome Locus (BBS1)
PMID: 12524598
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.
Clinical and Molecular Findings in Osteoporosis-Pseudoglioma Syndrome
PMID: 16252235
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.
Defects in the Cell Signaling Mediator β-Catenin Cause the Retinal Vascular Condition FEVR
PMID: 28575650
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 second independent Tyr168Cys mutation in the tissue inhibitor of metalloproteinases-3 (TIMP3) in Sorsby's fundus dystrophy.
PMID: 8728699
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
Tissue Inhibitor of Metalloproteinases-3 Peptides Inhibit Angiogenesis and Choroidal Neovascularization in Mice
PMID: 23469166
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
A Novel TIMP3 Mutation Associated With Sorsby Fundus Dystrophy
PMID: 15824229
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
S-opsin knockout mice with the endogenous M opsin gene replaced by an L opsin variant
PMID: 24801621
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).
In vivo imaging of a cone mosaic in a patient with achromatopsia associated with a GNAT2 variant
PMID: 27718025
GeneName: GNAT2
HGNC: 4394
Disease: achromatopsia 4
MonDO ID: MONDO_0013465
Inheritance: autosomal recessive
Prevalence of RPGR-Mediated Retinal Dystrophy in an Unselected Cohort of Over 5000 Patients
PMID: 34985506
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 rod photoreceptor ATP-binding cassette transporter gene, ABCR, and retinal disease: from monogenic to multifactorial
PMID: 10396622
Gene: ABCA4
HGNC: 34
Disease: age related macular degeneration 2
MONDO: 0007932
InheritancePattern: autosomal dominant
Prevalence: The overall prevalence of age-related macular degeneration is estimated to be 9.9-19.5% (early-stage) or 1.1-3.9% (late-stage) among all people over age 50 years (PMID: 31712255).
Penetrance: The penetrance of proposed disease-causing alleles is not clear but is expected to be incomplete and age-dependent.
Optimization of Retinal Gene Therapy for X-Linked Retinitis Pigmentosa Due to RPGR Mutations
PMID: 28566226
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.
9614228
PMID: 9614228
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.
50 12 M 19 c.2443-1G.C Hmz 2 1 6 - -
Case: 50, M, 12 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): 2, VWF:Ag (U/dl): 1, Bleeding Score: 6
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.2443-1G>C, Exon 19
Homozygous
48 2.5 M 18 c.2303G.A p.R768Q Hmz 2.5 ,1 6 - -
Case: 48, M, 2.5 years, Indian
DiseaseAssertion: VWD type 3
FamilyInfo: no family history of disease, Consanguinity: no
ParentalGenotype: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: FVIII:C: (U/dl): 2.5, VWF:Ag (U/dl): <1, Bleeding Score: 6
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.2303G>A (p.Arg768Gln), Exon 18
Homozygous
13 3 M 31 c.5335C.T p.R1779* Hmz 5.4 ,1 3 - -
Case: 13, M, 3 years, Indian
DiseaseAssertion: VWD type 3
FamilyInfo: Consanguinity: no, no family history of disease
ParentalGenotype: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: FVIII:C: (U/dl): 5.4, VWF:Ag (U/dl): <1, Bleeding Score: 3
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.5335C>T (p.Arg1779*), Exon 31, Homozygous
29 0.8 F 28 c.3835G.A p.V1279I Hmz 1.6 1.8 3 + +
Case: 29, F, 0.8 years, Indian
DiseaseAssertion: VWD type 3
FamilyInfo: family history of disease, Consanguinity: yes
ParentalGenotype: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: FVIII:C: (U/dl): 1.6, VWF:Ag (U/dl): 1.8, Bleeding Score: 3
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.3835G>A (p.Val1279Ile), Exon 28
Homozygous
9 2.5 M 28 c.4975C.T p.R1659* Hmz 7 1.5 9 - -
Case: 9, M, 2.5 years, Indian
DiseaseAssertion: VWD type 3
FamilyInfo: Consanguinity: no, no family history of disease
ParentalGenotype: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: FVIII:C: (U/dl): 7, VWF:Ag (U/dl): 1.5, Bleeding Score: 9
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.4975C>T (p.Arg1659*), Exon 28, Homozygous
3 22 F 8 c.970C.T p.R324* Hmz ,1 ,1 4 - -
Case: 3, F, 22 years, Indian
DiseaseAssertion: VWD type 3
FamilyInfo: Consanguinity: no, no family history of disease
ParentalGenotype: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: FVIII:C: (U/dl): <1, VWF:Ag (U/dl): <1, Bleeding Score: 4
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.970C>T (p.Arg324*), Exon 8, Homozygous
Case: P57, Chinese, male, 28yo
DiseaseAssertion: VWD2B
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0012147
(Reduced quantity of VWF)
CaseHPOFreeText: type AB blood, bleeding score = 5; VWF:Ag (%) = 33.4, VWF:RCo (%) = 3.2, FVIII:C (%) = 49.2, VWF:CB (%) = 4.8, VWFpp (%) = 67.3, VWF:RCo/VWF:Ag = 0.1, VWF:CB/VWF:Ag = 0.1, VWFpp/VWF:Ag = 2.0, FVIII:C/VWF:Ag = 1.5, RIPA (0.5 mg/ml, %) = 18.2, PLT(×109/l) = 146
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: NA
GenotypingMethod: NGS
PreviouslyPublished: NA
Gene: VWF
Variant 1: c.2089G>C (p.Glu697Gln)
HGVS: NM_000552.5:c.2089G>C (p.Glu697Gln)
ClinVarID: NA
CAID: CA383494704; http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA383494704
gnomAD: absent
Variant 2: 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
Variant 3: c.8113G>A (p.Gly2705Arg)
HGVS: NM_000552.4(VWF):c.8113G>A (p.Gly2705Arg)
ClinVarID: 256702; https://www.ncbi.nlm.nih.gov/clinvar/variation/256702/
CAID: NA
gnomAD: MAF = 0.1254 (3839/30614 alleles; 279 homozygotes)
Case: P39,Chinese, female, 21yo
DiseaseAssertion: VWD1
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0012147
(Reduced quantity of VWF)
CaseHPOFreeText: type O blood, bleeding score = 10; VWF:Ag (%) = 13.0, VWF:RCo (%) = 14.3, FVIII:C (%) = 32.1, VWF:CB (%) = 12.9, VWFpp (%) = 12.1, VWF:RCo/VWF:Ag = 1.1, VWF:CB/VWF:Ag = 1.0, VWFpp/VWF:Ag = 0.9, FVIII:C/VWF:Ag = 2.5
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: NA
GenotypingMethod: NGS
PreviouslyPublished: NA
Gene: VWF
Variant: c.8116-2delA
HGVS: NA
ClinVarID: NA
CAID: NA
gnomAD: NA
Case: P50, Chinese, male, 51yo
DiseaseAssertion: VWD1
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0012147
(Reduced quantity of VWF)
CaseHPOFreeText: type AB blood, bleeding score = 6; VWF:Ag (%) = 4.1, VWF:RCo (%) = 3.0, FVIII:C (%) = 7.8, VWF:CB (%) = 1.9, VWFpp (%) = 51.0, VWF:RCo/VWF:Ag = 0.7, VWF:CB/VWF:Ag = 0.5, VWFpp/VWF:Ag = 12.4, FVIII:C/VWF:Ag = 1.9, RIPA (1.2 mg/ml, %) = 97.1
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: NA
GenotypingMethod: NGS
PreviouslyPublished: NA
Gene: VWF
Variant: c.971G>C (p.Arg324Pro)
HGVS: NM_000552.5:c.971G>C (p.Arg324Pro)
ClinVarID: NA
CAID: CA383506405; http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA383506405
gnomAD: absent
Case: P20, Chinese, female, 15yo
DiseaseAssertion: VWD3
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0012147
(Reduced quantity of VWF)
CaseHPOFreeText: type A blood, bleeding score = 12; VWF:Ag (%) = 0.7, VWF:RCo (%) = 0.6, FVIII:C (%) = 3.9, VWF:CB (%) = 0.5, VWFpp (%) = 0.6, VWF:RCo/VWF:Ag = 0.9, VWF:CB/VWF:Ag = 0.7, VWFpp/VWF:Ag = 0.9, FVIII:C/VWF:Ag = 5.6
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: NA
GenotypingMethod: NGS
PreviouslyPublished: NA
Gene: VWF
Variant: c.2217_2220dup - Unregistered Variant
HGVS: NA
ClinVarID: NA
CAID: NA
gnomAD: NA
Case: P88, Chinese, female, 4yo
DiseaseAssertion: VWD3
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0012147
(Reduced quantity of VWF)
CaseHPOFreeText: type O blood, bleeding score = 11; VWF:Ag (%) = 0.5, VWF:RCo (%) = <0.5, FVIII:C (%) = 3.0, 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 = 6.0
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: NA
GenotypingMethod: NGS
PreviouslyPublished: NA
Gene: VWF
Variant: 1 c.1591C>T (p.Gln531Ter)
HGVS: NM_000552.5:c.1591C>T (p.Gln531Ter)
ClinVarID: NA
CAID: CA383498290; http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA383498290
gnomAD: absent
Variant 2: c.6678dupC - Unregistered Variant
HGVS: NA
ClinVarID: NA
CAID: NA
gnomAD: NA
4 C
Case: Patient 4, Family C (Table 1.), F/38, Afro-Caribbean
DiseaseAssertion: VWD1
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs:
CaseHPOFreeRext: BAT = 16, FVIII:C (IU/dL) = NA, VWF:Ag (IU/dL) = 40, VWF:Act (IU/dL) = 36
CaseNOTHPOs:
CaseNOTHPOFreeText: Blood group A
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.2365A > G p.(Thr789Ala)
HGVS: NM_000552.5:c.2365A>G (p.Thr789Ala)
ClinVarID: 256659
CAID: CA6403090
gnomAD: MAF of 0.5793 (43409/74928 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/12-6044368-T-C?dataset=gnomad_r4
Variant: c.2385T > C p.(Tyr795 =)
HGVS: NM_000552.5:c.2385T>C (p.Tyr795=)
ClinVarID: 256660
CAID: CA6403087
gnomAD: MAF of 0.5788 (43385/74952 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/12-6044348-A-G?dataset=gnomad_r4
Variant: c.4019T > C p.(Leu1340Arg)
the paper incorrectly lists the amino acid change as Leu1340Arg but it should be Leu1340Pro
HGVS: NM_000552.5:c.4019T>C
ClinVarID: 3061402
CAID: CA383505745
gnomAD:
Variant: c.4457C > T p.(Ser1486Leu)
HGVS: NM_000552.5:c.4457C>T (p.Ser1486Leu)
ClinVarID: 560630
CAID: CA6402527
gnomAD: MAF of 0.009120 (684/74998 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/12-6018961-G-A?dataset=gnomad_r4
Variant: c.6187C > T p.(Pro2063Ser)
HGVS: NM_000552.5:c.6187C>T (p.Pro2063Ser)
ClinVarID: 100436
CAID: CA202650
gnomAD: MAF of 0.04780 (4353/91066 alleles) in Africa/African American population https://gnomad.broadinstitute.org/variant/12-5994484-G-A?dataset=gnomad_r4
Variant: c.7059G > C p.(Glu2353Ser)
paper incorrectly lists amino acid change as Glu2353Ser but it should be Glu2353Asp
HGVS: NM_000552.5:c.7059G>C
ClinVarID: 993253
CAID: CA6401794
gnomAD: MAF of 0.006101 (458/75068 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-5983172-C-G?dataset=gnomad_r4
1 A
Case: Patient 1, Family A (Table 1.), F/49, Afro-Caribbean
DiseaseAssertion: VWD2B
FamilyInfo: Patient 2 (F/15, Afro-Caribbean) from same family A (Table 1.)
ParentalGenotype(s): NA
CasePresentingHPOs:
CaseHPOFreeRext: BAT = 7, FVIII:C (IU/dL) = 28, VWF:Ag (IU/dL) = 35, VWF:Act (IU/dL) = 10
CaseNOTHPOs:
CaseNOTHPOFreeText:
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.3946G > A p.(Val1316Met)
HGVS: NM_000552.5:c.3946G>A (p.Val1316Met)
ClinVarID: 290
CAID: CA114127
gnomAD:
26 N
Case: Patient 26, Family N (Table 1.), F/58, Afro-Caribbean
DiseaseAssertion: VWD2A (IIE)
FamilyInfo: Patient 27 (M/20, Afro-Caribbean) also in Family N. (Table 1.)
ParentalGenotype(s): NA
CasePresentingHPOs:
CaseHPOFreeRext: BAT =12, FVIII:C (IU/dL) = NA, VWF:Ag (IU/dL) = 15, VWF:Act (IU/dL) = 10
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.1530G > A, p.(Val510 =)
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
17 G
Case: Patient 17, Family G (Table 1.), F/79, Afro-Caribbean
DiseaseAssertion: VWD2A (IIE)
FamilyInfo: Patient 10 (M/22, Afro-Caribbean) and Patient 17 (F/58, Afro-Caribbean) also from Family G. (Table 1.)
ParentalGenotype(s): NA
CasePresentingHPOs:
CaseHPOFreeRext: BAT =4, FVIII:C (IU/dL) = 29, VWF:Ag (IU/dL) = 17, VWF:Act (IU/dL) = 5
CaseNOTHPOs:
CaseNOTHPOFreeText: Blood group A+
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
16 G
Case: Patient 16, Family G (Table 1.), F/58, Afro-Caribbean
DiseaseAssertion: VWD2A (IIE)
FamilyInfo: Patient 10 (M/22, Afro-Caribbean) and Patient 17 (F/79, Afro-Caribbean) also from Family G. (Table 1.)
ParentalGenotype(s): NA
CasePresentingHPOs:
CaseHPOFreeRext: BAT =23, FVIII:C (IU/dL) = 44, VWF:Ag (IU/dL) = 20, VWF:Act (IU/dL) = 14
CaseNOTHPOs:
CaseNOTHPOFreeText: Blood group A+
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
Case#: 37006, Age 45, Female, Blood Type B+ (Table S3)
Disease Assertion: VWD 1
FamilyInfo: The patient is the only member of Family#3706.
Parental Genotype: Not listed
CasePresentingHPOs: N/A
CaseHPOFreeText: VWF:Ag:7.6, VWF:RCo:5, FVIII:C: 8.9, VWF:CB: 6.9
CaseNotHPOs: N/A
CaseNotHPOFreeText: Bleeding Score 5
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.3426T>C (p.Cys1142=), NM_000552.4:c.3614G>A (p.Arg1205His), NM_000552.4:c.7771-49G>A , NM_000552.4:c.3485_3486delinsTG (pPro1162Leu)
ClinVar: 256668 , 308, 619934 ClinVar1 ClinVar2 ClinVar3
CAID: CA6402757, CA114160, CA1139532197, and CA658683073 CAID1 CAID2 CAID3 CAID4
gnomAD: MAF of 0.2228 (2240/ 10052 alleles) in the African population (CA6402757). gnomAD
Case#: 35004, Age 16, Male, Blood Type A+ (Table S3)
Disease Assertion: VWD 1
FamilyInfo: The patient is one of 4 members of Family# 3501. All members have the same variants, and patient 35001 has an additional variant.
Parental Genotype: Not listed
CasePresentingHPOs: N/A
CaseHPOFreeText: Bleeding Score 6, VWF:Ag: 5.6, VWF:RCo: 7.9, FVIII:C: 19, VWF:CB: 7.8
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
Protein Expression: N/A
CasePreviousTesting: 48,48 Access-Array amplification. NGS Molecular analysis was performed. Sanger sequencing was used to validate selected mutations.
Gene: VWF
Variant: NM_000552.3:c.5198T>C (p.Leu1733Pro) and NM_000552.4:c.6187C>T (p.Pro2063Ser)
ClinVar: 100436 ClinVar
CAID: CA383496267 and CA202650 CAID1 CAID2
gnomAD: MAF of 0.04854 (1486/ 30616 alleles) in the South Asian population (CA202650). gnomAD
Case#: 21011, Age 54, Male, Blood Type A+ (Table S3)
Disease Assertion: VWD 1
FamilyInfo: The patient is the only member of Family#2111.
Parental Genotype: Not listed
CasePresentingHPOs: N/A
CaseHPOFreeText: Bleeding Score 5, VWF:Ag: 12, VWF:RCo:20.3, FVIII:C 33, VWF:CB:16
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
Protein Expression: N/A
CasePreviousTesting: 48,48 Access-Array amplification. NGS Molecular analysis was performed. Sanger sequencing was used to validate selected mutations
Gene: VWF
Variant: NP_000543.2:p.Ser83Ter (c.246_247insT)
ClinVar: N/A
CAID: PA1139532036 CAID
gnomAD: N/A
Case#: 02068, Age 58, Female, Blood Type O+ (Table S3)
Disease Assertion: VWD 1
FamilyInfo: Patient is the only member of family #0225
Parental Genotype: Not listed
CasePresentingHPOs: N/A
CaseHPOFreeText: Bleeding Score 13,VWF:Ag: 11, VWF:RCo: 9.2, FVIII:C: 46, VWF:CB:14
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
Protein Expression: N/A
CasePreviousTesting: 48,48 Access-Array amplification. NGS Molecular analysis was performed. Sanger sequencing was used to validate selected mutations
Gene: VWF
Variant:NM_000552.4:c.6352C>T (p.Arg2118Trp) and NM_000552.4:c.8155+3G>C
ClinVar: 100490
CAID: CA6402006 and CA228825
gnomAD: MAF of 0.0001504 (3/19950 alleles) in the East Asian population (CA6402006).
Case#: 32004, Age 65, Female, Blood Type A-
Disease Assertion: VWD 1
FamilyInfo: The patient is the only member of Family#3204.
Parental Genotype: Not listed
CasePresentingHPOs: N/A
CaseHPOFreeText: Bleeding Score 19, VWF:Ag: 9.8, VWF:RCo:4, FVIII:C: 6.3, VWF:CB: 5
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
Protein Expression: N/A
CasePreviousTesting: 48,48 Access-Array amplification. NGS Molecular analysis was performed. Sanger sequencing was used to validate selected mutations.
Gene: VWF
Variant: NM_000552.4:c.2821-123A>C (p.=)
ClinVar: N/A
CAID: CA1139532189 CAID
gnomAD: N/A
P16
Case: P16, F/20
DiseaseAssertion: VWD1
FamilyInfo: No family history
ParentalGenotype: NA
CaseHPOFreeText: The bleeding score was 10, aPTT was 35 seconds, FVIII:C was 58%, VWF:RCo was 71 IU/dL, and VWF:Ag was 73 IU/dL, with a VWF:RCo/VWF:Ag ratio of 1.0. The VWF multimer pattern was normal, RIPA was not tested, and the platelet count was 250 × 10⁹/L.
CasePreviousTesting: NA
GenotypingMethod: Direct sequencing of all exons, flanking intronic sequences, and the promoter of VWF was performed.
Gene: VWF
Variant: no mutation detected
HGVS:
ClinVar:
CAID:
gnomAD:
P15
Case: P15, M/45
DiseaseAssertion: VWD1
FamilyInfo: Positive family history, no details provided.
ParentalGenotype: NA
CaseHPOFreeText: The bleeding score was 11, aPTT was 59 seconds, FVIII:C was 3%, VWF:RCo was 11 IU/dL, and VWF:Ag was 6 IU/dL, with a VWF:RCo/VWF:Ag ratio of 1.8. The VWF multimer pattern was normal, RIPA was 2 ohms, and the platelet count was 378 × 10⁹/L.
CasePreviousTesting: NA
GenotypingMethod: Direct sequencing of all exons, flanking intronic sequences, and the promoter of VWF was performed.
Gene: VWF
Variant: c.2574C>G, p.C858W — heterozygous
HGVS: NM_000552.5(VWF):c.2574C>G (p.Cys858Trp)
ClinVar:
CAID: CA232299278
gnomAD: https://gnomad.broadinstitute.org/variant/chr12-6034799-G-C?dataset=gnomad_r4
Whole blood ristocetin-activated platelet impedance aggregometry (Multiplate) for the rapid detection of Von Willebrand disease
PMID: 28692107
Gene: VWF
HGNCID: 12726
von Willebrand factor propeptide missense variants affect anterograde transport to Golgi resulting in ER retention
Case: VWD cohort index patients (IPs)
DiseaseAssertion: congenital bleeding disorder
FamilyInfo: Six index patients (IPs), from VWD cohort of patients of Germany and Pakistan
ParentalGenotype(s):
CasePresentingHPOs: HP:0000006
CaseHPOFreeText: IP1 (VWF:Ag (IU/dl)=12), IP2 (WF:Ag (IU/dl)=1), IP3 (VWF:Ag (IU/dl)=29), IP4 (VWF:Ag (IU/dl)= 1), IP5 (VWF:Ag (IU/dl)=35), IP6 (VWF:Ag (IU/dl)= 1)
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting:
GenotypingMethod: Not provided
PreviouslyPublished:
Gene: VWF
Variant: IP1 c.164G>A (p.Gly55Glu), IP2 c.4019T>G, c.257T>A (p.Leu1340Arg , p.Val86Glu), IP3 c.571T>C (p.Trp191Arg), IP4 c.3797C>T, c.631A>G (p.Pro1266Leu, p.Asn211Asp) , IP5 c.3931C>T, c.1001G>A (p.Gln1311X,p.Gly334Glu) , IP6 c.2561G>A, c.1824C>G (p.Arg854Gln , p.Cys608Trp)
HGVS: NM_000552.4 and NP_000543.2
ClinVarID:https://www.ncbi.nlm.nih.gov/clinvar/?term=VWF%5Bgene%5D&redir=gene
CAID: 00311186–00311190
gnomAD:n/a
20
Case: Patient 20 (Family G), male, 58yo
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 B, Platelet count x103/μl = 213, PFA 100 sec = >300, SPA % = 12.6, MADR mg/mL = 0.3, VWF:Ag U/dL = 48.4, VWF:CB U/dL = 4.6, VWF:CB ratio = 0.10, VWF:RCo U/dL = 13.5, VWF:RCo ratio = 0.28, Platelet VWF U/dL = 175, FVIII U/dL = 56.4, BAT F/M = 17
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: NA
GenotypingMethod: Sequencing of exon 28 of VWF
PreviouslyPublished: NA
Gene: VWF
Variant: c.3922C>T (p.Arg1308Cys)
HGVS: NM_000552.4(VWF):c.3922C>T (p.Arg1308Cys)
ClinVarID: 289; https://www.ncbi.nlm.nih.gov/clinvar/variation/289/
CAID: NA
gnomAD: absent
1
Case: Patient 1 (Family A), female, 3yo
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 B, Platelet count x103/μl = 290, PFA 100 sec = >264, SPA % = NA, MADR mg/mL = NA, VWF:Ag U/dL = 41.0, VWF:CB U/dL = 4.4, VWF:CB ratio = 0.11, VWF:RCo U/dL = 13.2, VWF:RCo ratio = 0.33, Platelet VWF U/dL = 76.4, FVIII U/dL = 36.1, BAT F/M = NA
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: NA
GenotypingMethod: Sequencing of exon 28 of VWF
PreviouslyPublished: NA
Gene: VWF
Variant: c.3922C>T (p.Arg1308Cys)
HGVS: NM_000552.4(VWF):c.3922C>T (p.Arg1308Cys)
ClinVarID: 289; https://www.ncbi.nlm.nih.gov/clinvar/variation/289/
CAID: NA
gnomAD: absent
von Willebrand Factor (VWF) Inhibitors in Two Brothers with von Willebrand Disease: A Case Report
PMID: 40673043
Gene: VWF
HGNCID: HGNC:12726
T154M/16240.010.030.01c.1656_1657insT, c.8418_8419insTCCCp.Trp552 fs, p.Ser2807 fs14/52Compound heterozygous
Case: T154, M, 16
DiseaseAssertion: VWD type 3
FamilyInfo: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: Bleeding Score: 24 (Kruskal–Wallis followed by Mann–Whitney U post-hoc testing Post-hoc testing ), VWF:Ag (IU/ml): 0.01, VWF:RCo (IU/ml): 0.03, FVIII:C (IU/ml): 0.01
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.1656_1657insT (p.Trp552 fs), Exon 14
c.8418_8419insTCCC (p.Ser2807 fs), Exon 52
Compound heterozygous
Note: ELISA-based assay for detecting alloantibodies, genomic analysis via sequencing of leukocytes for the VWF gene including exons 1-52 and about 1.5 km of VWF promoter, PCR amplification for variant confirmation, SALSA-MLPAVWF assay evaluation for partial/total gene deletions when sequencing did not reveal pathogenic explanation
T065M/15220.010.020.01c.3303C>Ap.Cys1101*25Homozygous
Case: T065, M, 15
DiseaseAssertion: VWD type 3
FamilyInfo: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: Bleeding Score: 22 (Kruskal–Wallis followed by Mann–Whitney U post-hoc testing Post-hoc testing ), VWF:Ag (IU/ml): 0.01, VWF:RCo (IU/ml): 0.02, FVIII:C (IU/ml): 0.01
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.3303C>A (p.Cys1101*), Exon 25, 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
Criteria for low von Willebrand factor diagnosis and risk score to predict future bleeding
PMID: 33370487
Gene: VWF
A Novel Case of Compound Heterozygous Type 3Von Willebrand Disease
PMID: unknown
Gene: VWF
HGNCID: 12726
Case: 2 year old female
DiseaseAssertion: type 3 VWD
FamilyInfo: 27 year old parents with no history of abnormal bleeding, non-consanguineous. Older brother (4 years old) with symptoms, younger brother asymptomatic.
ParentalGenotype(s): Mother is heterozygous for c.2345del variant. Father is heterozygous for exon 6 deletion.
CasePresentingHPOs: HP:0001934, HP:0000978, HP:0000225, HP:0001058, HP:0001058, HP:0012147, HP:0030132
CaseHPOFreeRext: reduced VWF activity
CaseNOTHPOs: HP:0001873, HP:0008151
CaseNOTHPOFreeText: reduced factor VIII
CasePreviousTesting: n/a
GenotypingMethod: unknown
PreviouslyPublished: n/a
Gene: VWF
Variant: compound heterozygous c2345delC in exon 18 and deletion in exon 6
HGVS: NM_000552.5:c.2435del p. (Pro812ArgfsTer31)
ClinVarID: 303
CAID:
gnomAD: 0.00007187 (11/1613916 alleles) https://gnomad.broadinstitute.org/variant/12-6044297-CG-C?dataset=gnomad_r4
proband (II-4 in Fig. 1) had melena at 50 years of age,
Case II-4: Male, Japan, Japanese, part of Family<br /> DiseaseAssertion: VWD2M<br /> FamilyInfo: Japanese; Fig.1; epistaxis and bleeding described and highlighted in text<br /> ParentalGenotype: Consanguineous <br /> CasePresentingHPOs: HP:0002249 (melena), HP:0000421 (epistaxis), HP:0004846 (prolonged bleeding after surgery)<br /> CaseHPOFreeText: Melena at 50 years of age, Left putinamal hemorrhaging at 58 years of age, bleeding time was 30 min<br /> CaseNotHPOs:<br /> NotHPOsFreeText: platelet count, prothrombin time were normal<br /> CasePreviousTesting: Proband's VWF gene was analyzed using an enzyme-linked immunosorbent assay kit and PCR was done. Clinical bleeding expression was estimated.<br /> Gene: VWF<br /> Variant: p.Leu1733Pro mutation <br /> ClinVar:<br /> CAID:<br /> gnomAD:
Role of red blood cells in the anemia‐associated bleeding under high shear conditions
PMID: 28470853
Gene: VWF
HGNCID: 12726
A 30‐year‐old male patient
Case#: Patient B, Male, Age 30, Chinese
Disease Assertion: VWD3
FamilyInfo: Consanguineous marriage between parents. Parents had 2 daughters and a son. One daughter died (1 year old) due to bleeding disorder. Mother's VWF:Ag 58% and VWF:RCo 36%. Family pedigree in Figure 2 (a). Both parents were heterozygous carriers of the variant.
Parental Genotype: Both Heterozygous
CasePresentingHPOs: HP:0003645
(Prolonged partial thromboplastin time)
CaseHPOFreeText: Hematoma in the lower extremity, VWF:Ag: 0.5%, VWF:RCo: 0.1%, FVIII:C 1.2%, APTT: 72.0 s
CaseNotHPOs:
CaseNotHPOFreeText: PT: 13.6 s, TT: 14.9s
Protein Expression: N/A
CasePreviousTesting: NGS targeting all exons and covered F8, F9, and VWF genes; and Sanger Sequencing
Gene: VWF
Variant: NM_000552.4:c.6450C>A
ClinVar: N/A
CAID: CA383491381 CAID
gnomAD:N/A
Case: Case 2, male, hispanic, symptom onset at birth
DiseaseAssertion: Platelet-type VWD (PT-VWD)
FamilyInfo: Parents were tested for platelet antigen 5a (HPA5a): mother was negative and father was positive, parents had normal VWD panels including VWF multimer and RIPA test
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0004846, HP:0000978, HP:0001873, HP:0012541, HP:0030132
(Prolonged bleeding after surgery, easy bruising, thrombocytopenia, Cephalohematoma, Absence of large von Willebrand factor multimers)
CaseHPOFreeText: peripheral blood smear showed platelet clumping and large granular platelets, Platelet (×109/L) = 61, Factor VIII (IU/mL) = 0.94, VWF:Ag (IU/mL) = 0.88, VWF:RCo (IU/mL) = 0.34, VWF:CB (IU/mL) = ND, RCo/Ag ratio = 0.39, CB/Ag ratio = NA, VWF: HMW Multimers = absent
CaseNOTHPOs: NA
CaseNOTHPOFreeText: umbilical cord bleeding, bleeding after heel stick
CasePreviousTesting: no mutations in exon 28 of VWF gene
GenotypingMethod: NA
PreviouslyPublished: NA
Gene: GP1BA
Variant: c.763A>G (p.Met255Val)
HGVS: NM_000173.7(GP1BA):c.763A>G (p.Met255Val)
ClinVarID: 4155; https://www.ncbi.nlm.nih.gov/clinvar/variation/4155/
CAID:
gnomAD: absent
Case: Case 3, female
DiseaseAssertion: Platelet-type VWD (PT-VWD)
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0000978, HP:0000421, HP:0000132, HP:0004846, HP:0001873, HP:0030129, HP:0030132
(easy bruising, epistaxis, Menorrhagia, Prolonged bleeding after surgery, thrombocytopenia, Impaired ristocetin cofactor assay activity, Absence of large von Willebrand factor multimers)
CaseHPOFreeText: pregnancy complicated by progressive thrombocytopenia; Platelet (×109/L) = 135, Factor VIII (IU/mL) = 0.78, VWF:Ag (IU/mL) = 0.69, VWF:RCo (IU/mL) = 0.22, VWF:CB (IU/mL) = ND, RCo/Ag ratio = 0.32, CB/Ag ratio = ND, VWF: HMW Multimers = absent
CaseNOTHPOs: NA
CaseNOTHPOFreeText: NA
CasePreviousTesting: NA
GenotypingMethod: NA
PreviouslyPublished: NA
Gene: GP1BA
Variant: c.746G>T (p.Gly249Val)
HGVS: NM_000173.7(GP1BA):c.746G>T (p.Gly249Val)
ClinVarID: 4153; https://www.ncbi.nlm.nih.gov/clinvar/variation/4153/
CAID:
gnomAD: absent
10 Type 2A c.3610C > T Nc.3839T > C Np.Arg1204Trpp.Phe1280Ser2728D3-E3A1htzhtzMissenseMissensena 26 14 34
Case: 10 (also in (also in row 10 table 6)
DiseaseAssertion: type 2A VWD
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs:
CaseHPOFreeRext: VWF:Ag [IU/dL] = 26; VWF:Ac [IU/dL] = 14; FVIII:C [IU/dL] = 34
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting:
GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.
PreviouslyPublished:
Gene: VWF
Variant: c.3610C>T p.Arg1204Trp
HGVS:
ClinVarID: 2682106
CAID:
gnomAD: absent
MultipleGeneVariants:
Gene: VWF
Variant: c.3839T>C p.Phe1280Ser
CAID: CA383506874
gonmAD: absent
8 Type2A (IIC)c.1915C>TN p.Arg639Cys 15 D2-C8-2htz Missense O 68 49 76
Case: IP #8 (also in row 5 table 6)
DiseaseAssertion: type 2A (IIC) VWD
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs: HP:0032442 - blood group O
CaseHPOFreeRext: VWF:Ag [IU/dL] = 68; VWF:Ac [IU/dL] = 49; FVIII:C [IU/dL] = 76
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.1915C>T p.Arg639Cys
HGVS:
ClinVarID: not found
CAID: CA232310080
gnomAD: 0.00001592 (24 in 1508000) no homozygotes https://gnomad.broadinstitute.org/variant/12-6056887-G-A?dataset=gnomad_r4
31
Case: IP #31
DiseaseAssertion: type 2A VWD
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs:
CaseHPOFreeRext: VWF:Ag [IU/dL] = 14; VWF:Ac [IU/dL] = 6; FVIII:C [IU/dL] = n/a
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting:
GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.
PreviouslyPublished:
Gene: VWF
Variant: c.4151T>G p.Leu1384Arg
HGVS:
ClinVarID: not found
CAID: CA383504381
gnomAD: absent
6 Type2A (IIC)c.1835T>GN p.Val612Gly 15 D2-C8-2hmz Missense O 63 39RCo 88
Case: IP #6 (also in row 3 table 6)
DiseaseAssertion: type 2A (IIC) VWD
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs: HP:0032442 - blood group O
CaseHPOFreeRext: VWF:Ag [IU/dL] = 63; VWF:Ac [IU/dL] = 39; FVIII:C [IU/dL] = 88
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.1835T>G p.Val612Gly
HGVS:
ClinVarID: not found
CAID: CA383497104
gnomAD: 0.000001298 (2 in 1541314) no homozygotes https://gnomad.broadinstitute.org/variant/12-6056967-A-C?dataset=gnomad_r4
Revascularization Operation for Moyamoya Disease with Concurrent von Willebrand Disease
PMID: 28866059
Gene: VWF
HGNCID: 12726
Common and rare von Willebrand factor (VWF) coding variants, VWF levels, and factor VIII levels in African Americans: the NHLBI Exome Sequencing Project
PMID: 23690449
Gene: VWF
HGNC: 12726
Disease: von Willebrand Disease Type 2N
MONDO: 0015631
InheritancePattern: Autosomal Recessive
Prevalence: Various sources (PMID: 28847738, PMID:19809303, PMID:29115006) can be combined to estimate the prevalence of VWD Type 2N between 1:15,000 and 1:80,000.
Penetrance: VWD type 2 is fully penetrant / nearly fully penetrant for most pathogenic variants.
Case#: Iannuzzi_1991_IV-1, M, age unknown, origin unknown
DiseaseAssertion: VWD type 2A
FamilyInfo: Affected mother, aunt, grandfather, and many other relatives. LOD score 3.61 reported (12 affected and genotype positive, 4 unaffected genotype positive. 4 affected also have HTT with vWD.
ParentalGenotype:
CasePresentingHPOs: As reported elsewhere (Hanna etal1984), the diagnosis of typeII AvWD was based on the following: bleedingtime, FVIII procoagulant activity, vFW:Ag, ristocetincofactoractivity, platelet aggregation studies, and vWF multimer analysis
CaseHPOFreeText:
CaseNotHPOs:
CaseNotHPOFreeText:
CasePreviousTesting:
GenotypingMethod: PCR-RFLP of exon 28 of VWF
Gene: VWF
Variant:
HGVS: NM_000552.5(VWF):c.4883T>C (p.Ile1628Thr)
ClinVarID: 284
CAID:
gnomAD: not reported
MultipleGeneVariants:
III : 3
Case#: F10, III:3
DiseaseAssertion: Type 2 VWD
CaseHPOFreeText: complete loss of high MWM, VWF:Ag = 25; VWF:RCo = 6; VWF:GPIbM = 17; 0.23; 0.67; 2.95
CasePreviousTesting: Not clearly described
Gene: VWF
Variant: p.[R1306W];[=]
HGVS: c.3916C>T (p.Arg1306Trp)
CAID: CA114123
gnomAD: absent from gnomad v4.1.0
183< 1< 13−−20Mc.1992insC/c.5557C>Tp.C665LfsX13/p.R1853X16/3215/16N/PD
Case: Patient 18, M, Hungarian
DiseaseAssertion: VWD type 3
FamilyInfo: compatible with recessive inheritance
ParentalGenotype(s): n/a
CasePresentingHPOs: n/a
CaseHPOFreeRext: Bleeding score: 20, VWF:Ag (IU dL−1): < 1, VWF:CB (IU dL−1): < 1, FVIII:C (IU dL−1): 3, VWF:RCo below detection limit (<10 IU dL−1), not detectable VWF on multimer gels
CaseNOTHPOs: n/a
CaseNOTHPOFreeText: no inhibitor detected, did not become refractory to factor replacement therapy
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.1992insC (p.Cys665LeufsX13), Exon 16
c.5557C>T (p.Arg1853X), Exon 32
Intron 40 VNTR 15/16
Note: multimer electrophoresis, Recombinant VWF antigen concentrations and Collagen binding activity (VWF:CB) measured by ELISA, direct sequencing of the 51 exons and the exon‐intron boundaries, Breakpoint analysis and breakpoint‐specific PCR
Prevalence and Risk Factors Associated With Hypertension in von Willebrand Disease
PMID: 27655998
Gene: VWF
HGNCID: 12726
Blood volume–based von Willebrand factor to prevent postpartum hemorrhage in von Willebrand disease
PMID: 29296713
Gene: VWF
HGNCID: 12726
60.862.80.977141.9NormalExon 13c.1531A>C‡p.Lys511GlnD2Missense
Case:Croatian adult patient
DiseaseAssertion: VWD1
ParentalGenotype(s): Not specified
CasePresentingHPOs: HP:0001892, HP:0011890, HP:0000132, HP:0002239, HP:0000790, HP:0001342
CaseHPOFreeText: Normal VWF:Ag of 62.8%, VWF:GPIbM of 60.8%, FVIII:C of 71% and VWF:CBA of 41.9%. Normal multimer distribution.
CaseNOTHPOs: Not specified
CaseNOTHPOFreeText: Normal multimer size distribution (tested in Agarose gel).
CasePreviousTesting: Not reported
GenotypingMethod: Illumina NGS, custom designed panel covering all 52 exons as well as intronic flanking regions and promoter region of VWF gene.
PreviouslyPublished: None
Gene: VWF
Variant: c.1531A>C
HGVS: NM_000552.4:c.1531A>C (p.Lys511Gln)
ClinVarID: Not available
CAID: CA383500354
gnomAD: Not available
VWD2-3†10.917.20.632110.1↓HMWM,↓IMWM28c.3829G>T§p.Asp1277TyrA1Missense2A
Case: Croatian adult patient
DiseaseAssertion: VWD2A
FamilyInfo: No variant detected in a family member with VWD2
ParentalGenotype(s): Not specified
CasePresentingHPOs: HP:0001892, HP:0011890, HP:0000132, HP:0002239, HP:0000790, HP:0001342
CaseHPOFreeText: Reduced VWF:Ag of 17.2%, VWF:GPIbM of 10.9%, FVIII:C of 21% and VWF:CBA of 10.1%. Reduced levels of HMWM and IMWM in multimer distribution.
CaseNOTHPOs: Not specified
CaseNOTHPOFreeText: Not reported.
CasePreviousTesting: Not reported
GenotypingMethod: Illumina NGS, custom designed panel covering all 52 exons as well as intronic flanking regions and promoter region of VWF gene.
PreviouslyPublished: None
Gene: VWF
Variant: c.3829G>T
HGVS: NM_000552.4:c.3829G>T (p.Asp1277Tyr)
ClinVarID: Not available
CAID: CA383506920
gnomAD: Not available