mutation
Case#: Green_Malmo_6 (assumed male)
DiseaseAssertion: Severe Hemophillia B
FamilyInfo: N/A
ParentalTesting: N/A
CasePresentingHPOs: HP:0011858
CaseHPOsFreeText: reduced factor IX activity (FIX:C <1%, FIX:Ag: 26-34)
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
S3
Case#: S3, Iranian
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
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.95delC
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
S13
Case#: S13, Iranian
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: Family history of HA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125, HP:0005261
CaseHPOFreeText: FVIII:C < 1%
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:
S30
Case#: S30, Iranian
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: 5% < FVIII:C < 30%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The F8 gene was directly sequenced for all 26 exons using the Sanger sequencing method. PCR was performed and subsequently analyzed
Gene: F8
Variant: NM_000132.3:c.2090T>C
LegacyVariant:
ClinVar: No
CAID: CA414909005
gnomAD:
S17
Case#: S17, Iranian
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%, Mucosal bleeding
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The F8 gene was directly sequenced for all 26 exons using the Sanger sequencing method. PCR was performed and subsequently analyzed
Gene: F8
Variant: NM_000132.3:c.1063C>T
LegacyVariant:
ClinVar: No
CAID: CA255031
gnomAD:
S1
Case#: S1, Iranian
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125, HP:0005261
CaseHPOFreeText: FVIII:C < 1%
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.209_212del
LegacyVariant:
ClinVar: No
CAID: CA255050
gnomAD:
S22
Case#: S22, 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:
S9
Case#: S9, Iranian
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125, HP:0005261
CaseHPOFreeText: FVIII:C < 1%
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.2945dupA
LegacyVariant:
ClinVar: No
CAID: CA255142
gnomAD:
S2
Case#: S2, Iranian
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
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: NA
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
S21
Case#: S21, Iranian
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: Family history of HA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125, HP:0005261
CaseHPOFreeText: FVIII:C < 1%, Inhibitor present
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The F8 gene was directly sequenced for all 26 exons using the Sanger sequencing method. PCR was performed and subsequently analyzed
Gene: F8
Variant: NM_000132.3:c.6213A>T
LegacyVariant:
ClinVar: No
CAID: CA414903164
gnomAD:
S24
Case#: S24, Iranian
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%, Mucosal bleeding, Inhibitor present
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The F8 gene was directly sequenced for all 26 exons using the Sanger sequencing method. PCR was performed and subsequently analyzed
Gene: F8
Variant: NM_000132.3:c.5509A>T
LegacyVariant:
ClinVar: No
CAID: CA414908661
gnomAD:
009–1005
Case#: 009-1005
DiseaseAssertion: Hemophilia A,
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C ..., 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:
001–2046
Case#: 001-2046
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.822G>T
LegacyVariant:
ClinVar: No
CAID: CA337337669
gnomAD:
004–2003
Case#: 004-2003
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.5589delG
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
004–2015
Case#: 004-2015
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.2152_2153delAA
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
084–2004
Case#: 084-2004
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: 5% < FVIII:C < 40%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.1910A>G
LegacyVariant:
ClinVar: No
CAID: CA414909849
gnomAD:
071–2024
Case#: 071-2024
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: 1% < FVIII:C < 5%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.2167G>A
LegacyVariant:
ClinVar: No
CAID: CA255138
gnomAD:
066–2001
Case#: 066-2001
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.6098T>C
LegacyVariant:
ClinVar: No
CAID: CA414904604
gnomAD:
006–1001
Case#: 006-1001
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:
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
072–2009
Case#: 072-2009
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.1332A>T
LegacyVariant:
ClinVar: No
CAID: CA414914974
gnomAD:
005–2001
Case#: 005-2001
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.3277delAT
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
003–2014
Case#: 003-2014
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant:
LegacyVariant:
ClinVar: No
CAID:
gnomAD:
015–2002
Case#: 015-2002
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.6876_6877delCT
LegacyVariant:
ClinVar: No
CAID: CA873368227
gnomAD:
071–2036
Case#: 071-2036
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:
038–1010
Case#: 038-1010
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant:
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
071–2001
Case#: 071-2001
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.901C>T
LegacyVariant:
ClinVar: No
CAID: CA414917990
gnomAD:
035–2013
Case#: 035-2013
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: 1% < FVIII:C < 5%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.5275G>A
LegacyVariant:
ClinVar: No
CAID: CA414911087
gnomAD:
091–2010
Case#: 091-2010
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: 5% < FVIII:C < 40%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.1475A>G
LegacyVariant:
ClinVar: No
CAID: CA337334224
gnomAD:
071–2023
Case#: 071-2023
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: 1% < FVIII:C < 5%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.2167G>A
LegacyVariant:
ClinVar: No
CAID: CA255138
gnomAD:
047–2001
Case#: 047-2001
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.3637delA
LegacyVariant:
ClinVar: No
CAID: CA255146
gnomAD:
084–2001
Case#: 084-2001
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.100delG
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
091–2005
Case#: 091-2005
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: 1% < FVIII:C < 5%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.5393C>A
LegacyVariant:
ClinVar: No
CAID: CA414909064
gnomAD:
020–2054
Case#: 020-2054
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: 5% < FVIII:C < 40%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.1899G>T
LegacyVariant:
ClinVar: No
CAID: CA414910251
gnomAD:
001–2050
Case#: 001-2050
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.4011insA
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
060–2004
Case#: 060-2004
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.272T>C
LegacyVariant:
ClinVar: No
CAID: CA414920117
gnomAD:
004–2012
Case#: 004-2012
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.3637delA
LegacyVariant:
ClinVar: No
CAID: CA255146
gnomAD:
020–2063
Case#: 020-2063
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: 5% < FVIII:C < 40%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.558C>G
LegacyVariant:
ClinVar: No
CAID: CA414919454
gnomAD:
002–1002
Case#: 002-1002
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%, Inhibitor present
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant:
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
072–2007
Case#: 072-2007
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.5686_5687insA
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
071–2035
Case#: 071-2035
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:
020–2020
Case#: 020-2020
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.3637delA
LegacyVariant:
ClinVar: No
CAID: CA255146
gnomAD:
001–2025
Case#: 001-2025
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.986G>A
LegacyVariant:
ClinVar: No
CAID: CA255089
gnomAD:
010–1002
Case#: 010-1002
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%, Inhibitor present
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant:
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
020–2038
Case#: 020-2038
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: 5% < FVIII:C < 40%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.1834C>T
LegacyVariant:
ClinVar: No
CAID: CA255129
gnomAD:
015–2011
Case#: 015-2011
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: 1% < FVIII:C < 5%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.1241A>G
LegacyVariant:
ClinVar: No
CAID: CA414915839
gnomAD:
086–2006
Case#: 086-2006
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%, Inhibitor present
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.1537G>C
LegacyVariant:
ClinVar: No
CAID: CA414912560
gnomAD:
020–2013
Case#: 020-2013
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.5368_5370delATC
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
001–2041
Case#: 001-2041
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: 5% < FVIII:C < 40%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.2167G>A
LegacyVariant:
ClinVar: No
CAID: CA255138
gnomAD:
Today, the Danish family consists of 275 known persons, all of whom are the offspring of six original proband siblings born in the middle of the nineteenth century ( Fig 1); at present, 28 living cases of mild haemophilia are known in the family. A cousin-to-cousin marriage of an affected male haemophiliac and an obligate carrier resulted in four sisters homozygous for the haemophilic mutation.
Case#: 8, male
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: Proband's mother and sister are confirmed carriers of hemophilia
ParentalTesting: Mother was tested and found to be a carrier of hemophilia
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: 5% < FVIII:C < 40%, FVIII:Ag = 25%, assay discrepancy present (OSA>CSA)
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: For exons 1–13 and 15–26, PCR primers were designed for denaturing gradient gel electrophoresis (DGGE) and exon 14 was amplified in four overlapping fragments and subsequently sequenced. VWF:Ag was tested and found to be within normal ranges.
Gene: F8
Variant: NM_000132.3:c.694A>T
LegacyVariant:
ClinVar: No
CAID: CA414919124
gnomAD:
Cys-19Tyr
Case#: 52HBT167 (Turkish; assumed male)
DiseaseAssertion: Moderate Hemophilia B
FamilyInfo: N/A
ParentalTesting: Not provided
CasePresentingHPOs: HP:0011858
CaseHPOsFreeText: Reduced factor IX activity (FIX:C:3.9)
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.83G>A (p.Cys28Tyr)
LegacyVariant: c.112G>A (p.Cys-19Tyr)
ClinVar: Absent/Not Reported
CAID: CA414434483
gnomAD: Absent/Not Reported
HB_132
Case#: HB_132 (assumed male)
DiseaseAssertion: Mild-Moderate Hemophilia B
FamilyInfo: Not provided
ParentalTesting: Not provided
CasePresentingHPOs: N/A
CasePresentingHPOsFreeText: Mild-Moderate Hemophilia B, Quality parameters given as read depth and strand bias for the mutated positions: 3098/0.51
CaseNotHPOs: N/A
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.82T>C (p.Cys28Arg)
ClinVar: 10657
CAID: CA255450
gnomAD: Absent/Not Reported
71
Case#: 71, male, 6 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.5398C>T
LegacyVariant:
ClinVar: 10275
CAID: CA255163
gnomAD:
112
Case#: 112, male, 31 years old, Chinese
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: NA
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 1.8%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.265_265+1dup
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
134
Case#: 134, male, 6 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.5152_5153insACACTAT
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
124
Case#: 124, male, 17 years old, Chinese
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%, Inhibitor present
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.14dupT
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
102
Case#: 102, male, 17 years old, Chinese
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 65.7%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.6617A>T
LegacyVariant:
ClinVar: No
CAID: CA414906010
gnomAD:
32
Case#: 32, male, 18 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.362G>A
LegacyVariant:
ClinVar: No
CAID: CA414919924
gnomAD:
37
Case#: 37, male, 53 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.397T>C
LegacyVariant:
ClinVar: No
CAID: CA414919824
gnomAD:
143
Case#: 143, male, 19 years old, Chinese
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 3.1%
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.3144_3145delinsAG
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
25
Case#: 25, male, 13 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.6976C>T
LegacyVariant:
ClinVar: 10085
CAID: CA255007
gnomAD:
184
Case#: 184, male, 6 years old, Chinese
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 5.1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.del exon26
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
109
Case#: 109, male, 29 years old, Chinese
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%, Inhibitor present
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.6967C>T
LegacyVariant:
ClinVar: 10333
CAID: CA255225
gnomAD:
11
Case#: 11, male, 32 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.1765A>T
LegacyVariant:
ClinVar: No
CAID: CA414911223
gnomAD:
14
Case#: 14, male, 10 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.1990C>T
LegacyVariant:
ClinVar: No
CAID: CA414909465
gnomAD:
76
Case#: 76, male, 30 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.5551T>C
LegacyVariant:
ClinVar: No
CAID: CA414908519
gnomAD:
8
Case#: 8, male, 11 years old, Chinese
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%, Inhibitor present
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.1063C>T
LegacyVariant:
ClinVar: 10139
CAID: CA255031
gnomAD:
65
Case#: 65, male, 13 years old, Chinese
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 2.1%
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.2167G>A
LegacyVariant:
ClinVar: 10246
CAID: CA255138
gnomAD:
181
Case#: 181, male, 42 years old, Chinese
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%, Inhibitor present
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.del exons14_26
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
17
Case#: 17, male, 10 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.2404C>T
LegacyVariant:
ClinVar: No
CAID: CA414901774
gnomAD:
140
Case#: 140, 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.dup exons1_22
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
153
Case#: 153, male, 52 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.3409_3410delCT
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
176
Case#: 176, male, 18 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.del exon6
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
89
Case#: 89, male, 36 years old, Chinese
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.6406G>A
LegacyVariant:
ClinVar: No
CAID: CA414899430
gnomAD:
136
Case#: 136, male, 20 years old, Chinese
DiseaseAssertion: Hemophilia A, moderate
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.dup exon14
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
162
Case#: 162, male, 27 years old, Chinese
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%, Inhibitor present
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.3637delA
LegacyVariant:
ClinVar: No
CAID: CA255146
gnomAD:
30
Case#: 30, male, 27 years old, Chinese
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: NA
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 4.1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.361G>A
LegacyVariant:
ClinVar: No
CAID: CA414919926
gnomAD:
81
Case#: 81, male, 19 years old, Chinese
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 7.1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.5707G>A
LegacyVariant:
ClinVar: No
CAID: CA414907751
gnomAD:
128
Case#: 128, male, 10 years old, Chinese
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.3637dupA
LegacyVariant:
ClinVar: No
CAID: CA10568191
gnomAD:
62
Case#: 62, male, 50 years old, Chinese
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 38.5%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.2111C>T
LegacyVariant:
ClinVar: No
CAID: CA414908864
gnomAD:
147
Case#: 147, male, 22 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.1126delG
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
158
Case#: 158, male, 7 years old, Chinese
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 14.3%
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.3637delA
LegacyVariant:
ClinVar: No
CAID: CA255146
gnomAD:
180
Case#: 180, male, 13 years old, Chinese
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%, Inhibitor present
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.del exon14
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
46
Case#: 46, male, 21 years old, Chinese
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 2.3%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.1172G>A
LegacyVariant:
ClinVar: 10111
CAID: CA120918
gnomAD:
167
Case#: 167, male, 18 years old, Chinese
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: Noted Family History
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.5046delC
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
53
Case#: 53, male, 21 years old, Chinese
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 15.9%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.1834C>T
LegacyVariant:
ClinVar: 10236
CAID: CA255129
gnomAD:
70
Case#: 70, male, 16 years old, Chinese
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: NA
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 3%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.5398C>T
LegacyVariant:
ClinVar: 10275
CAID: CA255163
gnomAD:
31
Case#: 31, male, 41 years old, Chinese
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.361G>A
LegacyVariant:
ClinVar: No
CAID: CA414919926
gnomAD:
133
Case#: 133, male, 59 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.4599_4600dup
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
171
Case#: 171, male, 7 years old, Chinese
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%, Inhibitor present
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.del exons1_14
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
21
Case#: 21, male, 16 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.6403C>T
LegacyVariant:
ClinVar: 10088
CAID: CA255011
gnomAD:
94
Case#: 94, male, 8 years old, Chinese
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 8.5%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.6448G>A
LegacyVariant:
ClinVar: No
CAID: CA414907951
gnomAD:
3
Case#: 3, male, 39 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.616G>T
LegacyVariant:
ClinVar: No
CAID: CA414919319
gnomAD:
27
Case#: 27, male, 30 years old, Chinese
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.266G>C
LegacyVariant:
ClinVar: No
CAID: CA414920127
gnomAD:
c.59T>C p.Leu20Ser
Case#: Guo_Proband_2 (assumed male; Chinese)
DiseaseAssertion: Moderate Hemophilia B
FamilyInfo: N/A
ParentalTesting: None
CasePresentingHPOs: HP:0011858
CaseHPOsFreeText: reduced factor IX activity FIX:C:2.1%; FIX:Ag:1.6
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.59T>C (p.Leu20Ser)
ClinVar: Absent
CAID: CA414434363
gnomAD: Absent/Not Reported
c.83G>A p.Cys28Tyr
Case#: Guo_Proband_3 (assumed male; Chinese)
DiseaseAssertion: Moderate Hemophilia B
FamilyInfo: N/A
ParentalTesting: None
CasePresentingHPOs:
CaseHPOsFreeText: reduced factor IX activity FIX:C: 2.9%; FIX:Ag: 3.0)
CaseNotHPOs: N/A
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.83G>A (p.Cys28Tyr)
ClinVar: Absent
CAID: CA414434483
gnomAD: Absent/Not Reported
Table 1
Case#: Cz22, 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(F8):c.1336C>T (p.Arg446Ter)
ClinVar: 10145 https://www.ncbi.nlm.nih.gov/clinvar/variation/10145/
CAID: CA255038
gnomAD: Not reported
Table 2
Case#: Cz19, Italy (Calabria)
DiseaseAssertion: Hemophilia A
FamilyInfo: Inherited
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FVII:C 3%
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.1538-18G>A
ClinVar: 811357 https://www.ncbi.nlm.nih.gov/clinvar/variation/811357/
CAID: CA873354114
gnomAD: Not reported
Table 2
Case#: Cz2, Italy (Calabria)
DiseaseAssertion: Hemophilia A
FamilyInfo: Inherited
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FVII:C 4%
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.1538-18G>A
ClinVar: 811357 https://www.ncbi.nlm.nih.gov/clinvar/variation/811357/
CAID: CA873354114
gnomAD: Not reported
Table 2
Case#: Cz34, Italy (Calabria)
DiseaseAssertion: Hemophilia A
FamilyInfo: Inherited
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FVII:C 4%
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.1538-18G>A
ClinVar: 811357 https://www.ncbi.nlm.nih.gov/clinvar/variation/811357/
CAID: CA873354114
gnomAD: Not reported
Table 1
Case#: Cz21, Italy (Calabria)
DiseaseAssertion: Hemophilia A
FamilyInfo: Inherited
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FVII:C <1%
CasePreviousTesting: Polymerase chain reaction (PCR) analysis, Long PCR for detecting the intron 22 inversion was performed, Direct cycle sequence analysis using the Taq dye-deoxy terminator method
Gene: F8
Variant: F8, IVS22 INV
ClinVar: 10150 https://www.ncbi.nlm.nih.gov/clinvar/variation/10150/
CAID: NA
gnomAD: Not reported
Table 1
Case#: Cz14, 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(F8):c.5953C>T (p.Arg1985Ter)
ClinVar: 10300 https://www.ncbi.nlm.nih.gov/clinvar/variation/10300/
CAID: CA255191
gnomAD: Not reported
c.1307A>C
Case#: 10
DiseaseAssertion: Hemophilia A
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FVIII:C 22% (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.1307A>C (p.Gln436Pro)
ClinVar: NA
CAID: CA414915176
gnomAD: Not reported
c.1274T>A
Case#: 42
DiseaseAssertion: Hemophilia B
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FIX:C 10% (Mild Phenotype)
CasePreviousTesting: Screened for IVS-22 and IVS-1, sample was blinded for NGS and the sequencing component was validated by comparing results with Sanger Sequencing
Gene: F9
Variant: NM_000133.3:c.1274T>A (p.Leu425Ter )
ClinVar: NA
CAID: CA414446997
gnomAD: Not reported
c.689G>A
Case#: 45
DiseaseAssertion: Hemophilia B
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FIX:C 5% (Moderate Phenotype)
CasePreviousTesting: Screened for IVS-22 and IVS-1, sample was blinded for NGS and the sequencing component was validated by comparing results with Sanger Sequencing
Gene: F9
Variant: NM_000133.3:c.689G>A (p.Gly230Glu)
ClinVar: NA
CAID: CA414441179
gnomAD: Not reported
c.5123G>A
Case#: 20
DiseaseAssertion: Hemophilia A
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FVIII:C 18%, Mild Phenotype, No inhibitors present
CasePreviousTesting: Screened for IVS-22 and IVS-1, sample was blinded for NGS and the sequencing component was validated by comparing results with Sanger Sequencing
Gene: F8
Variant: NM_000132.3(F8):c.5123G>A (p.Arg1708His)
ClinVar: 10266 https://www.ncbi.nlm.nih.gov/clinvar/variation/10266/
CAID: CA255154
gnomAD: MAF for Arg1708His in the South Asian population 0.00005507<br> https://gnomad.broadinstitute.org/variant/X-154156942-C-T?dataset=gnomad_r2_1
c.6845C>G
Case#: 36
DiseaseAssertion: Hemophilia A
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FVIII:C 33/30%, Mild Phenotype, No inhibitors present
CasePreviousTesting: Screened for IVS-22 and IVS-1, sample was blinded for NGS and the sequencing component was validated by comparing results with Sanger Sequencing
Gene: F8
Variant: NM_000132.3:c.6845C>G (p.Ser2282Cys)
ClinVar: NA
CAID: CA414903435
gnomAD: Not reported
c.396A>C
Case#: 3
DiseaseAssertion: Hemophilia A
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FVIII:C 18% (Mild Phenotype), No inhibitors present
CasePreviousTesting: Screened for IVS-22 and IVS-1, sample was blinded for NGS and the sequencing component was validated by comparing results with Sanger Sequencing
Gene: F8
Variant: NM_000132.3(F8):c.396A>C (p.Glu132Asp)
ClinVar: 10171 https://www.ncbi.nlm.nih.gov/clinvar/variation/10171/
CAID: CA255060
gnomAD: MAF for Glu132Asp in Other population 0.0003762<br> https://gnomad.broadinstitute.org/variant/X-154221416-T-G?dataset=gnomad_r2_1
c.1291T>G
Case#: 41
DiseaseAssertion: Hemophilia B
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FIX:C 2/2% (Moderate Phenotype)
CasePreviousTesting: Screened for IVS-22 and IVS-1, sample was blinded for NGS and the sequencing component was validated by comparing results with Sanger Sequencing
Gene: F9
Variant: NM_000133.3:c.1291T>G (p.Trp431Gly)
ClinVar: NA
CAID: CA414447127
gnomAD: Not reported
c.580G>A
Case#: 44
DiseaseAssertion: Hemophilia B
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FIX:C 23% (Mild Phenotype)
CasePreviousTesting: Screened for IVS-22 and IVS-1, sample was blinded for NGS and the sequencing component was validated by comparing results with Sanger Sequencing
Gene: F9
Variant: NM_001313913.1:c.580G>A (p.Asp194Asn)
ClinVar: NA
CAID: CA414441211
gnomAD: Not reported
c.2043G>A
Case#: 16
DiseaseAssertion: Hemophilia A
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FVIII:C 31% (Mild Phenotype), No inhibitors present
CasePreviousTesting: Screened for IVS-22 and IVS-1, sample was blinded for NGS and the sequencing component was validated by comparing results with Sanger Sequencing
Gene: F8
Variant: NM_000132.3:c.2043G>A (p.Met681Ile)
ClinVar: NA
CAID: CA414909257
gnomAD: Not reported
Val37 mutation.
Case#: Patient Q (male, 83 y/o, born in South Germany)
DiseaseAssertion: Severe Hemophilia B
FamilyInfo: Brother died from a life threatening bleeding complication under phenprocoumon therapy
ParentalTesting: N/A
CasePresentingHPOs: HP:0011858, HP:0012233
CaseHPOsFreeText: reduced factor IX activity (FIX:C: 2%), muscle hematoma of the extremities, subcutaneous bleed of the body and lower extremities.
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
Thr37 mutation
Case#: Pezeshkpoor_Patient_O (male, 36 y/o, from Switzerland)
DiseaseAssertion: Severe Hemophilia B
FamilyInfo: N/A
ParentalTesting: N/A
CasePresentingHPOs: HP:0002625, HP:0011858
CaseHPOsFreeText: deep vein thrombosis, low FIX:C levels (<1%), prolonged aPTT of 90 seconds, diffuse muscle bleeding
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
AdditionalCaseInfo: Sequencing of SERPINC1 revealed a splice site mutation located at c.1154-14G>A
Thr37 mutation
Case#: Pezeshkpoor_Patient_M (male, 58 y/o, from Switzerland)
DiseaseAssertion: Hemophilia B
FamilyInfo: N/A
ParentalTesting: N/A
CasePresentingHPOs: HP:0011858
CaseHPOsFreeText: spontaneous bleeding symptoms from the blood, the mouth, the tongue, and epiglottis, low FIX:C levels
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.109G>A (p.Ala37Thr)
ClinVar: 804089
CAID: CA10529736
gnomAD: Allele Frequency in population where variant was found in the highest (South Asian population): 0.0001128
18.
Case#: 18
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.1068G>T
LegacyVariant:
ClinVar: No
CAID: CA414445683
gnomAD:
33.
Case#: 33
DiseaseAssertion: Hemophilia B, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0011858
CaseHPOFreeText: FIX:C < 1%, Inhibitor present
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.103G>T
LegacyVariant:
ClinVar: No
CAID: CA414435383
gnomAD:
25.
Case#: 25
DiseaseAssertion: Hemophilia B, moderate
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0011858
CaseHPOFreeText: FIX:C = 2%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: All relevant sequences of F9 were PCR amplified and analyzed by DNA sequencing
Gene: F9
Variant: NM_000133.3:c.1204G>A
LegacyVariant:
ClinVar: No
CAID: CA414446446
gnomAD:
12.
Case#: 12
DiseaseAssertion: Hemophilia B, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0011858
CaseHPOFreeText: FIX:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: All relevant sequences of F9 were PCR amplified and analyzed by DNA sequencing
Gene: F9
Variant: NM_000133.3:c.761G>A
LegacyVariant:
ClinVar: No
CAID: CA414443235
gnomAD:
5
Case#: 5
DiseaseAssertion: Hemophilia B, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0011858
CaseHPOFreeText: FIX:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: All relevant sequences of F9 were PCR amplified and analyzed by DNA sequencing
Gene: F9
Variant: NM_000133.3:c.305G>T
LegacyVariant:
ClinVar: No
CAID: CA414437422
gnomAD:
41.
Case#: 41
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.1135C>T
LegacyVariant:
ClinVar: No
CAID: CA255391
gnomAD:
17.
Case#: 17
DiseaseAssertion: Hemophilia B, moderate
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0011858
CaseHPOFreeText: FIX:C = 3%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: All relevant sequences of F9 were PCR amplified and analyzed by DNA sequencing
Gene: F9
Variant: NM_000133.3:c.1025C>T
LegacyVariant:
ClinVar: No
CAID: CA255381
gnomAD:
c.128G>A
Case#: Meireles_Proband_2 (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>A (p.Arg43Trp)
ClinVar: 810864
CAID: CA414435539
gnomAD: Absent/Not Reported
c.127C>T
Case#: Meireles_Proband_4 (assumed male)
DiseaseAssertion: Severe Hemophilia B
FamilyInfo: None
ParentalTesting: None
CasePresentingHPOs: HP:0011858
CaseHPOsFreeText: reduced factor IX activity
CaseNotHPOs: N/A
CasePreviousTesting: None
Gene: F9
Variant: NM_000133.4:c.127C>T (p.Arg43Trp)
ClinVar: 811505
CAID: CA414435537
gnomAD: Absent/Not Reported
HB55
Case#: Family HB55
DiseaseAssertion: Severe Hemophilia B
FamilyInfo: N/A
ParentalTesting: None
CasePresentingHPOs: HP:0011858
CaseHPOsFreeText: reduced factor IX activity (FIX:C: <1)
CaseNotHPOs: None
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.128G>T (p.Arg43Leu)
ClinVar: 993549
CAID: CA414435545
gnomAD: Absent/Not Reported
A2. A3
Case#: A2, A3
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 4, FVIII:AG = 35, 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.881C>T
LegacyVariant:
ClinVar: No
CAID: CA255077
gnomAD:
B75
Case#: B75
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C Chr = 9, FVIII:AG = 10, inverse assay discrepancy present (OSA<CSA)
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: Coding region and intron/exon bound-aries of the F8 gene were amplified from all patient samples and directly sequenced using primers
Gene: F8
Variant: NM_000132.4:c.5323T>G
LegacyVariant:
ClinVar: No
CAID: CA255159
gnomAD:
B76
Case#: B76
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C Chr = 7, FVIII:AG = 10, inverse assay discrepancy present (OSA<CSA)
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: Coding region and intron/exon bound-aries of the F8 gene were amplified from all patient samples and directly sequenced using primers
Gene: F8
Variant: NM_000132.4:c.5398C>G
LegacyVariant:
ClinVar: No
CAID: CA255164
gnomAD:
B45 – B72
Case#: B45 - B72
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C Chr = 9, FVIII:AG = 16, inverse assay discrepancy present (OSA<CSA)
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: Coding region and intron/exon bound-aries of the F8 gene were amplified from all patient samples and directly sequenced using primers
Gene: F8
Variant: NM_000132.4:c.5096A>T
LegacyVariant:
ClinVar: No
CAID: CA255022
gnomAD:
c.3557delT
Case#: 5
DiseaseAssertion: Hemophilia A
FamilyInfo: Sporadic
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: Severe
CasePreviousTesting: All 26 exons and exon-intron boundaries of the F8 gene were amplified using primers and PCR, analyzed by direct forward and reverse sequencing using a DNA sequencing kit
Gene: F8
Variant: NM_000132.3:c.3561del
ClinVar: NA
CAID: CA873342537
gnomAD: Not reported
c.762A>G
Case#: 15, Spanish
DiseaseAssertion: Hemophilia A
FamilyInfo: Sporadic
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: Severe
CasePreviousTesting: All 26 exons and exon-intron boundaries of the F8 gene were amplified using primers and PCR, analyzed by direct forward and reverse sequencing using a DNA sequencing kit
Gene: F8
Variant: NA
ClinVar: NA
gnomAD: NA
C.6317A>C
Case#: 27
DiseaseAssertion: Hemophilia A
FamilyInfo: Positive
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: Severe
CasePreviousTesting: All 26 exons and exon-intron boundaries of the F8 gene were amplified using primers and PCR, analyzed by direct forward and reverse sequencing using a DNA sequencing kit
Gene: F8
Variant: NM_000132.3:c.6317A>C (p.Gln2087Pro)
ClinVar: NA
CAID: CA414900070
gnomAD: Not reported
c.1706C>G
Case#: 22
DiseaseAssertion: Hemophilia A
FamilyInfo: Sporadic
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: Severe
CasePreviousTesting: All 26 exons and exon-intron boundaries of the F8 gene were amplified using primers and PCR, analyzed by direct forward and reverse sequencing using a DNA sequencing kit
Gene: F8
Variant: NM_000132.3:c.1706C>G (p.Pro550Arg)
ClinVar: NA
CAID: CA414911701
gnomAD: Not reported
c.6135G>T
Case#: 9
DiseaseAssertion: Hemophilia A
FamilyInfo: Sporadic
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: Severe
CasePreviousTesting: All 26 exons and exon-intron boundaries of the F8 gene were amplified using primers and PCR, analyzed by direct forward and reverse sequencing using a DNA sequencing kit
Gene: F8
Variant: NA
ClinVar: NA
CAID: NA
gnomAD: NA
c.3093delAAGA
Case#: 4
DiseaseAssertion: Hemophilia A
FamilyInfo: Positive
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: Severe, Inhibitors present
CasePreviousTesting: All 26 exons and exon-intron boundaries of the F8 gene were amplified using primers and PCR, analyzed by direct forward and reverse sequencing using a DNA sequencing kit
Gene: F8
Variant: NM_000132.3(F8):c.3091_3094del (p.Lys1031fs)
ClinVar: 369689 https://www.ncbi.nlm.nih.gov/clinvar/variation/369689/
CAID: CA645509240
gnomAD: Not reported
C.6301C>G
Case#: 26
DiseaseAssertion: Hemophilia A
FamilyInfo: Positive
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: Mild
CasePreviousTesting: All 26 exons and exon-intron boundaries of the F8 gene were amplified using primers and PCR, analyzed by direct forward and reverse sequencing using a DNA sequencing kit
Gene: F8
Variant: NM_000132.3(F8):c.6301C>G (p.His2101Asp)
ClinVar: 804137 https://www.ncbi.nlm.nih.gov/clinvar/variation/804137/
CAID: CA414900220
gnomAD: Not reported
c.584T>C
Case#: 14, Spanish
DiseaseAssertion: Hemophilia A
FamilyInfo: Sporadic
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: Severe
CasePreviousTesting: All 26 exons and exon-intron boundaries of the F8 gene were amplified using primers and PCR, analyzed by direct forward and reverse sequencing using a DNA sequencing kit
Gene: F8
Variant: NM_000132.3:c.584T>C (p.Leu195Pro)
ClinVar: NA
CAID: CA414919399
gnomAD: Not reported
c.5286T>A
Case#: 25
DiseaseAssertion: Hemophilia A
FamilyInfo: Sporadic
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: Moderate
CasePreviousTesting: All 26 exons and exon-intron boundaries of the F8 gene were amplified using primers and PCR, analyzed by direct forward and reverse sequencing using a DNA sequencing kit
Gene: F8
Variant: NM_000132.3:c.5286T>A (p.Phe1743Leu)
ClinVar: NA
CAID: CA414910973
gnomAD: Not reported
c.2766delC
Case#: 3
DiseaseAssertion: Hemophilia A
FamilyInfo: Positive
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: Moderate
CasePreviousTesting: All 26 exons and exon-intron boundaries of the F8 gene were amplified using primers and PCR, analyzed by direct forward and reverse sequencing using a DNA sequencing kit
Gene: F8
Variant: NM_000132.3:c.2766del (p.Leu923Ter)
ClinVar: NA
CAID: CA923726358
gnomAD: Not reported
mutations in the factor IX gene resulting in hemophilia B
Case#: Gostout_Proband_189 (assumed male, Asian (from India))
DiseaseAssertion: Severe Hemophilia B
FamilyInfo: N/A
ParentalTesting: None
CasePresentingHPOs: HP:0011858
CaseHPOsFreeText: reduced factor IX activity (FIX:C: 3%)
CaseNotHPOs: None
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.127C>T (p.Arg43Trp)
LegacyVariant: c.6364C>T (p.Arg-4Trp)
ClinVar: 811505
CAID: CA414435537
gnomAD: Absent/Not Reported
mutations in the factor IX gene resulting in hemophilia B.
Case#: Gostout_Proband_280 (assumed male, Asian (from Japan))
DiseaseAssertion: Severe Hemophilia B
FamilyInfo: N/A
ParentalTesting: None
CasePresentingHPOs: HP:0011858
CaseHPOsFreeText: reduced factor IX activity (FIX:C: 1.8%)
CaseNotHPOs: None
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.128G>A (p.Arg43Gln)
ClinVar: 810864
CAID: CA414435539
gnomAD: Absent/Not Reported
UQU-HB4
Case#: UQU-HB4, Male, 6-months-old, Saudi Arabia
DiseaseAssertion: Hemophilia B
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: Severe, PTT 60.1
CasePreviousTesting: Screened for all factor IX exons by capillary sequencing
Gene: F9
Variant: NM_000133.3(F9):c.1025C>T (p.Thr342Met)
ClinVar: 10607 https://www.ncbi.nlm.nih.gov/clinvar/variation/10607/
CAID: CA255381
gnomAD: Not reported
UQU-HB2
Case#: UQU-HB2, Male, 2-months-old, Saudi Arabia
DiseaseAssertion: Hemophilia B
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: Severe, PTT 74.5, Disabled right knee
CasePreviousTesting: Screened for all factor IX exons by capillary sequencing
Gene: F9
Variant: NM_001313913.1:c.580G>A (p.Asp194Asn)
ClinVar: NA
CAID: CA414441211
gnomAD: Not reported
UQU-HA38
Case#: UQU-HA36, Male, 1-months-old, Saudi Arabia
DiseaseAssertion: Hemophilia A
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0001892 (Abnormal bleeding)
CaseHPOFreeText: Mild, FVIII: 1 to <5% (moderate HA) based on text
CasePreviousTesting: Screened for inversion 22 by inverse PCR, screened for inversion 1 by multiplexed PCR, capillary sequencing (Sanger method) was performed for factor VIII all 26 exons
Gene: F8
Variant: NM_000132.3:c.99G>T (p.Trp33Cys)
ClinVar: NA
CAID: CA414920529
gnomAD: Not reported
8
Case#: 8
DiseaseAssertion: Hemophilia B, moderate
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FIX:C = 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: All exons, UTRs, exon-intron junction regions, and the promotor of F9 were amplified by PCR and analyzed by direct DNA sequencing
Gene: F9
Variant: NM_000133.3:c.349T>C
LegacyVariant:
ClinVar: No
CAID: CA414437669
gnomAD:
16
Case#: 16
DiseaseAssertion: Hemophilia B, moderate
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FIX:C = 1.5%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: All exons, UTRs, exon-intron junction regions, and the promotor of F9 were amplified by PCR and analyzed by direct DNA sequencing
Gene: F9
Variant: NM_000133.3:c.427C>G
LegacyVariant:
ClinVar: No
CAID: CA414438921
gnomAD:
11
Case#: 11
DiseaseAssertion: Hemophilia B, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FIX:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: All exons, UTRs, exon-intron junction regions, and the promotor of F9 were amplified by PCR and analyzed by direct DNA sequencing
Gene: F9
Variant: NM_000133.3:c.676C>T
LegacyVariant:
ClinVar: No
CAID: CA255350
gnomAD:
Hb15
Case#: HB15 (assumed male, Tunisian)
DiseaseAssertion: Severe Hemophilia B
FamilyInfo: None
ParentalTesting: None
CasePresentingHPOs: HP:0011858
CaseHPOsFreeText: reduced factor IX activity (FIX: <1)
CaseNotHPOs: None
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.128G>A (p.Arg43Gln)
ClinVar: 810864
CAID: CA414435539
gnomAD: Absent/Not Reported
6365
Case#: Patient B (assumed male)
DiseaseAssertion: Moderate, Sporadic Hemophilia B
FamilyInfo: Patient B is deceased and only a DNA sample was available; his two sisters and mother are carriers
ParentalTesting: Mother was heterozygous for the variant
CasePresentingHPOs: None
CaseNotHPOs: N/A
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.128G>A (p.Arg43Gln)
LegacyVariant: c.6365 G>A (p.Arg-4Gln)
ClinVar: 810864
CAID: CA414435539
gnomAD: Absent/Not Reported
6364 C→T
Case#: Ivaskevicius_Proband_LT65 (assumed male, Lithuanian)
DiseaseAssertion: Severe Hemophilia B
FamilyInfo: N/A
ParentalTesting: N/A
CasePresentingHPOs: HP:0011858
CaseHPOsFreeText: reduced factor IX activity (FIX:C: 0)
CaseNotHPOs: N/A
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.127C>T (p.Arg43Trp)
LegacyVariant: c.6364C>T (p.Arg-4Trp)
ClinVar: 811505
CAID: CA414435537
gnomAD: Absent/Not Reported
The final list of mutations is provided in Supplementary Table S1.
Case#: N/A
DiseaseAssertion: Severe Hemophilia B
FamilyInfo: N/A
ParentalTesting: N/A
CasePresentingHPOs: N/A
CaseHPOsFreeText: N/A
CaseNotHPOs: N/A
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.71T>C (p.Leu24Pro)
ClinVar: Absent
CAID: CA414434410
gnomAD: Absent/NotReported
The final list of mutations is provided in Supplementary Table S1.
Case#: N/A
DiseaseAssertion: Severe Hemophilia B
FamilyInfo: N/A
ParentalTesting: N/A
CasePresentingHPOs: N/A
CaseHPOsFreeText: N/A
CaseNotHPOs: N/A
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.59T>C (p.Leu20Ser)
ClinVar: Absent
CAID: CA414434363
gnomAD: Absent/NotReported
Table S1
Case#: Li_Proband_1 (male)
DiseaseAssertion: Moderate Hemophilia B
FamilyInfo: Not provided
ParentalTesting: Not provided
CasePresentingHPOs: N/A
CaseNotHPOs: N/A
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.82T>C (p.Cys28Arg)
ClinVar: 10657
CAID: CA255450
gnomAD: Absent/Not Reported
Case#: Patient A (assumed male)
DiseaseAssertion: Severe (sporadic) Hemophilia B
FamilyInfo: Variant also localized in affected brother, mother (Native American descent) is deceased but maternal grandmother and two maternal aunts screened negative, researchers believe this de novo mutation originated during either grandparent’s gametogenesis.
ParentalTesting: Mother deceased, no mention of father
CasePresentingHPOs: HP:0011858
CaseHPOsFreeText: FIX Clotting Activity (U/dl): < 1, Antigen Level (U/dl): < 1
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.50T>A (p.Ile17Asn)
LegacyVariant: c.79T>A (p.Ile-30Asn)
ClinVar: Absent
CAID: CA414434315
gnomAD: Absent/Not Reported
Case#: Liu_Proband_56/439/440/486/830 (assumed male; Chinese)
DiseaseAssertion: Severe Hemophilia B
FamilyInfo: N/A
ParentalTesting: N/A
CasePresentingHPOs: HP:0011858
CaseHPOsFreeText: reduced factor IX activity
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.128G>A (p.Arg43Gln)
ClinVar: Absent
CAID: CA414435539
gnomAD: Absent/Not Reported
Case#: Liu_Proband_438 (assumed male; Chinese)
DiseaseAssertion: Severe Hemophilia B
FamilyInfo: N/A
ParentalTesting: N/A
CasePresentingHPOs: HP:0011858
CaseHPOsFreeText: reduced factor IX activity
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.127C>T (p.Arg43Trp)
ClinVar: Absent
CAID: CA414435537
gnomAD: Absent/Not Reported
c.83G>A
Case#: Salviato_Proband_2164 (male, Chinese)
DiseaseAssertion: Hemophilia B
FamilyInfo: N/A
ParentalTesting: N/A
CasePresentingHPOs: HP:0011858
CaseHPOsFreeText: reduced factor IX activity
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.83G>A (p.Cys28Tyr)
ClinVar: Absent
CAID: CA414434483
gnomAD: Absent/Not Reported
mutant factor IX
Case#: Salle_Proband_J-C L (male, 23 y/o, white)
DiseaseAssertion: Severe Hemophilia B
FamilyInfo: family history is negative for any haemostatic disorder
ParentalTesting: family history is negative for any haemostatic disorder
CasePresentingHPOs: HP:0011858, HP:0012233, HP:0000421
CaseHPOsFreeText: reduced factor IX activity (FIX:C: <0.01 % FIX:Ag: 0.46), muscular haematoma, haemarthrosis, nose bleeding
CaseNotHPOs: N/A
CasePreviousTesting: None
Gene: F9
Variant: NM_000133.4:c.128G>A (p.Arg43Gln)
ClinVar: 810864
CAID: CA414435539
gnomAD: Absent/Not Reported
c.83G>A/p.Cys28Tyr
Case#: Nummi_Proband_6 (assumed male)
DiseaseAssertion: Moderate Hemophilia B
FamilyInfo: N/A
ParentalTesting: None
CasePresentingHPOs: HP:0001929 (FIX baseline clotting activity: 1
CaseHPOsFreeText: reduced factor IX activity
CaseNotHPOs: N/A
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.83G>A (p.Cys28Tyr)
ClinVar: Absent
CAID: CA414434483
gnomAD: Absent/Not Reported
Case#: Oldenburg Cases A, B and C (A: 66 y/o, B: 38 y/o, C: 30 y/o (all in Germany))
DiseaseAssertion: Mild Hemophilia B
FamilyInfo: No bleeding tendency noted in any of these patients family history
ParentalTesting: N/A
CasePresentingHPOs: HP:0011858
CaseHPOsFreeText: severe bleeding at each occasion of oral anticoagulation with phenoprocoumon, bleeding was located in the muscles of the upper leg (patients A and C) and scrotum, left calf and thigh musles (patient B), reduced factor IX levels
CaseNotHPOs: N/A
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.109G>A (p.Ala37Thr)
LegacyVariant: p.Ala-10Thr
ClinVar: 804089
CAID: CA10529736
gnomAD: Allele Frequency in population where variant was found in the highest (South Asian population): 0.0001128
AdditionalCaseInfo: all patients were unrelated up to the third generation. However, the parents of patients A and C emigrated from the same region in North-Eastern Europe (North Poland)
p.Ala315dup (patient P2)
CaseInfo: P2 (female)
DiseaseAssertion: Carrier
FamilyInfo: N/A
ParentalTesting: N/A
CasePresentingHPOs: HP:0003125, HP:0004846, HP:0001892
CaseHPOFreeText: Low FVIII levels (undetectable FVIII:C levels and significant decrease in FVIII:Ag levels: 1.7% ± 1.1), prolonged bleeding after surgery, mild bleeding tendency
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
CasePreviousTesting: Molecular Analysis included a southern blot assay, PCR, dHPLC and a multiplex ligation-dependent probe amplification analysis. Plasmid mutagenesis, plasmid transfection were also performed.
Gene: F8
Variant: NM_000132.3:c.943del
CAID: CAID:CA255085
gnomAD: Absent/Not Reported
p.Cys28Trp
Case#: N/A
DiseaseAssertion: Severe Hemophilia B
FamilyInfo: None
ParentalTesting: N/A
CasePresentingHPOs: HP:0001929
CasePresentingHPOsFreeText: reduced factor IX activity
CaseNotHPOs: None
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.84T>G (p.Cys28Trp)
ClinVar: Absent
CAID: CA414434487
gnomAD: Absent/Not Reported
Mutations
Case#: Weinmann_Family 9248
DiseaseAssertion: Severe Hemophilia B
FamilyInfo: 16 of the families were from the Pacific Northwest, 4 from Colorado, and 6 were referred from elsewhere in the United States
ParentalTesting: N/A
CasePresentingHPOs: HP:0011858
CaseHPOsFreeText: reduced factor IX activity (FIX:C: <1%, FIX:Ag: 37)
CaseNotHPOs: N/A
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.127C>T (p.Arg43Trp)
LegacyVariant: c.6364C>T
ClinVar: 811505
CAID: CA414435537
gnomAD: Absent/Not Reported
identify the causative mutation
Case#: Belvini_Proband_15 (male, Italian)
DiseaseAssertion: Severe Hemophilia B
FamilyInfo: N/A
ParentalTesting: N/A
CasePresentingHPOs: HP:0011858
CaseHPOsFreeText: reduced factor IX activity
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.128G>A (p.Arg43Gln)
ClinVar: 810864
CAID: CA414435539
gnomAD: Absent/Not Reported
37, G-IA
Case#: Riegelsberg (male)
DiseaseAssertion: Severe Hemophilia B
FamilyInfo: Mother carries only the G-to-A transition (age at conception: 30 y/o). Origin of variant cannot be proved, since maternal grandparents were deceased at time of report.
ParentalTesting: Mother carries only the G-to-A transition, father shows to not be affected (figure 1)
CasePresentingHPOs: HP:0011858
CaseHPOsFreeText: FIX Coagulant %: < 1, FIX Antigen %: < 1
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.8G>A (p.Arg3His)
LegacyVariant: c.37G>A
ClinVar: 695909
CAID: CA10529706
gnomAD: Filtering AF: 0.0002304 (no homozygotes)
two
Case#: Meindl_1996_Family_RP07_Proband, male, age not specified, family origin either German or British
CasePresentingHPOs: HP:0000510 (Rod-cone dystrophy)
CaseHPOFreeText: The proband has been diagnosed with retinitis pigmentosa. Disease onset was reported as early.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: The family members previously underwent linkage analysis to map the underlying genetic cause to the region on chromosome Xp21.1 between the CYBB and OTC genes.
CaseMethod1: Hybridization analysis of amplified cDNA fragments from the RPGR locus to look for deletions, and SSCP analysis to look for point mutations
CaseMethod2: Sanger sequencing of the RPGR locus
CaseGenotypingMethod: The family members previously underwent linkage analysis to map the underlying genetic cause to the region on chromosome Xp21.1 between the CYBB and OTC genes. Amplified cDNA fragments from the RPGR locus were then screened by hybridization analysis to look for deletions and SSCP analysis to look for point mutations. The presence of the variant was confirmed by Sanger sequencing of the RPGR locus.
Variant: The affected family members harbor the NM_001034853.2(RPGR):c.154G>T (p.Gly52Ter) variant in the hemizygous state.
ClinVar: 98747
gnomAD: The variant was not found in gnomAD v.2.1.1.
VariantEvidence: NM_001034853.2(RPGR):c.154G>T (p.Gly52Ter) is a nonsense variant predicted to trigger nonsense-mediated decay or to at least disrupt the C-terminal 94% of the protein product.
CaseAddInfo: The proband is a member of Family RP07.
CasePMIDs: N/A
retrospective study
Case#: Olivier_2021_Family_D_Proband_II:2, male, age 58 years at the time of report, national origin reported as Spanish
CasePresentingHPOs: HP:0007737 (Bone spicule pigmentation of the retina), HP:0007843 (Attenuation of retinal blood vessels), HP:0030629 (Perifoveal ring of hyperautofluorescence)
CaseHPOFreeText: The proband and his sibling have been diagnosed with autosomal recessive retinitis pigmentosa, with clinical signs in the fundus reportedly consistent with this diagnosis.
CaseNotHPOs: HP:0040049 (Macular edema), HP:0030500 (Yellow/white lesions of the macula)
CaseNotHPOFreeText: N/A
CasePreviousTesting: It is not clear whether previous testing methods included systematic genotyping of loci associated with VMD or RP.
CaseMethod1: Screening of IMPG1 using either gene panel testing or exome sequencing
CaseMethod2: Sanger sequencing-based confirmation
CaseGenotypingMethod: Genotyping is not entirely clear but has at least included panel-based analysis of the IMPG1 locus and Sanger sequencing-based confirmation.
Variant: The proband harbors the NM_001563.4(IMPG1):c.1875A>G (p.Ile625Met) variant in the homozygous state.
CAID: CA364775681
gnomAD: This variant is not found in gnomAD v2.1.1.
VariantEvidence: NM_001563.4(IMPG1):c.1875A>G (p.Ile625Met) is a missense variant that lacks evidence of a functional impact on the protein product.
CaseAddInfo: The patient's sister is similarly affected with the same homozygous genotype, while an unaffected sister harbored the variant in the heterozygous state. Parental consanguinity is not reported but family origin is from a small village.
CasePMIDs: N/A
variant
Case#: Holmberg_Patient_2, male, age 3 at onset and age 12 at time of study, Finnish origin
CasePresentingHPOs: HP:0003208 (Fingerprint intracellular accumulation of autofluorescent lipopigment storage material), HP:0011463 (Childhood onset), HP:0001268 (Mental deterioration), HP:0000572 (Visual loss), HP:0001251 (Ataxia), HP:0002540 (Inability to walk), HP:0001250 (Seizure), HP:0000550 (Undetectable electroretinogram), HP:0012018 (EEG with temporal focal spikes), HP:0100952 (Enlarged sylvian cistern), HP:0006855 (Cerebellar vermis atrophy), HP:0002198 (Dilated fourth ventricle), HP:0033725 (Thin corpus callosum), HP:0030891 (Periventricular white matter hyperdensities), HP:0012690 (T2 hypointense thalamus), HP:0001312 (Giant somatosensory evoked potentials)
CaseHPOFreeText: Age of onset was 3, while mental decline was present at age 3 and both visual deterioration and giant flash visual evoked potentials at age 6. Abolished ERG was found at age 7, and ataxia at age 8. Seizures and Loss of independent walking occurred at age 9. Posterior EEG spikes in response to low-frequency photic stimuli were observed. T2-weighted images showed increased signal intensity of the periventricular white matter and posterior limb of the capsula interna. The thalamus had abnormally low signal intensity compared to the putamen, caudate nuclei, and white matter.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: Other than clinical phenotype characterization, it is not clear what genotype tests preceded CLN5 sequencing.
CaseMethod1: N/A
CaseMethod2: N/A
CaseGenotypingMethod: Each exon of CLN5 was PCR-amplified and Sanger sequenced in both directions.
Variant: The patient is homozygous for the NM_006493.4(CLN5):c.1028_1029del (p.Thr342_Tyr343insTer) variant.
ClinVar: 2564 (homozygous)
gnomAD: The maximum allele frequency of the NM_006493.4(CLN5):c.1028_1029del (p.Thr342_Tyr343insTer) variant is 0.0008137 (within the European Finnish population, with no homozygous occurrences). https://gnomad.broadinstitute.org/variant/13-77575052-CAT-C
VariantEvidence: NM_006493.4(CLN5):c.1028_1029del (p.Thr342_Tyr343insTer) is a recurring frameshift variant that is predicted to disrupt approximately 5% of CLN5 at the C-terminus and has been shown to disturb its localization to the lysosome (PMID:20052765).
CaseAddInfo: N/A
CasePMIDs: N/A
known
Case#: Holmberg_Patient_5, female, age 4 at onset and age 7 at time of study, Finnish origin
CasePresentingHPOs: HP:0003208 (Fingerprint intracellular accumulation of autofluorescent lipopigment storage material), HP:0011463 (Childhood onset), HP:0001268 (Mental deterioration), HP:0000572 (Visual loss), HP:0012018 (EEG with temporal focal spikes), HP:0100952 (Enlarged sylvian cistern), HP:0006855 (Cerebellar vermis atrophy), HP:0002198 (Dilated fourth ventricle), HP:0033725 (Thin corpus callosum), HP:0030891 (Periventricular white matter hyperdensities), HP:0012690 (T2 hypointense thalamus)
CaseHPOFreeText: Age of onset was 4, while visual deterioration was found at age 6. Mental decline was found at age 7. Posterior EEG spikes in response to low-frequency photic stimuli were observed. T2-weighted images showed increased signal intensity of the periventricular white matter and posterior limb of the capsula interna. The thalamus had abnormally low signal intensity compared to the putamen, caudate nuclei, and white matter.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: Other than clinical phenotype characterization, it is not clear what genotype tests preceded CLN5 sequencing.
CaseMethod1: N/A
CaseMethod2: N/A
CaseGenotypingMethod: Each exon of CLN5 was PCR-amplified and Sanger sequenced in both directions.
Variant: The patient is homozygous for the NM_006493.4(CLN5):c.78G>A (p.Trp26Ter) variant.
ClinVar: 2565 (homozygous)
gnomAD: The maximum allele frequency of the NM_006493.4(CLN5):c.78G>A (p.Trp26Ter) variant is 0.00005132 (within the European non-Finnish population, with no homozygous occurrences). https://gnomad.broadinstitute.org/variant/13-77566311-G-A
VariantEvidence: NM_006493.4(CLN5):c.78G>A (p.Trp26Ter) is a recurring nonsense variant that is predicted to trigger nonsense-mediated decay of CLN5.
CaseAddInfo: N/A
CasePMIDs: N/A
family 1002, direct genomic sequencing was performed on the amplified exon 4 fragment from the proband
Case#: Family 1002, Greek, 26 years, now living in USA.
CaseHPOs:
CaseHPOsFreeText: Difficulty adapting to the dark from early childhood. Fundus exam (see Fig 2A) at age 26 years showed yellow-white dots, sharply demarcated, sparing the macula and radiating from the perimacular region; well-defined foveal reflex, absent pigmentary changes, normal vascular caliber.
CaseNotHPOsFreeText: No other associated ocular or systemic disorders.
CasePreviousTesting: RBP3 excluded by heteroduplex analysis and sequencing (this study). Affected siblings had non-concordant pattern for an intragenic RFLP analyzed by Southern blot.
CaseMethod1: SSCP
CaseMethod2: Sanger sequencing
Variant: c.712G>T (p.Gly238Trp) (homozygous)
ClinVar: 8003
CAID: CA119196
gnomAD: The highest population MAF in gnomAD v2.1.1 is 0.0004532 (Latino/Admixed American); no homozygotes in any population.
CaseAddInfo: Parents are seventh cousins
Not scoring because another patients with this genotype has already been included.
In MOL0277, a homozygous intronic change (c.411-8A→G) was the only potentially pathogenic change identified. Sequence of cDNA derived from patients' peripheral blood lymphocyte mRNA demonstrated that this mutation activated a cryptic splice acceptor site giving rise only to an aberrant transcript (Figure 2B). The mutant transcript has seven additional base pairs of sequence added to the beginning of exon 6 and is predicted to introduce a frameshift resulting in premature termination (R137SfsX16).
Case#: Parry_2009_Family_MOL0277_patient_IV:2, male, age not specified, family origin reported to be Arab Muslim
CasePresentingHPOs: HP:0410280 (Pediatric onset), HP:0007663 (Reduced visual acuity), HP:0007401 (Macular atrophy), HP:0000580 (Pigmentary retinopathy), HP:0007769 (Peripheral retinal degeneration), HP:0008323 (Abnormal light- and dark-adapted electroretinogram)
CaseHPOFreeText: The proband was diagnosed with cone-rod dystrophy, with family showing autosomal recessive mode of inheritance. Most affected members of the proband's family had white patches around the optic disc and in the posterior pole.
CaseNotHPOs: HP:0000639 (Nystagmus), HP:0000613 (Photophobia)
CaseNotHPOFreeText: N/A
CasePreviousTesting: The proband and his family have been initially genotyped by autozygosity mapping with both 10k and 250k Affymetrix SNP arrays and microsatellite markers.
CaseMethod1: Autozygosity mapping
CaseMethod2: Sanger sequencing
CaseGenotypingMethod: The proband and his family have been initially genotyped by autozygosity mapping with both 10k and 250k Affymetrix SNP arrays and microsatellite markers. Sanger sequencing of the ADAM9 locus then identified the variants.
Variant: The proband harbors the NM_003816.3(ADAM9):c.411-8A>G variant in the homozygous state.
ClinVar: 6879
gnomAD: This variant was not found in gnomAD v2.1.1.
VariantEvidence: NM_003816.3(ADAM9):c.411-8A>G is a variant in intron 5 that has been shown to trigger aberrant splicing and abolish normal splicing by activating use of a cryptic splice acceptor site (Figure 2B). The predicted result is to add 7 bp to the 5' end of exon 6 and introduce a frameshift causing premature termination. Since this affects exon 6 of 21, the predicted result is nonsense-mediated decay or truncation of the C-terminal 83% of the protein product (p.Arg137SerfsX16).
CaseAddInfo: The proband's family is known to be consanguineous, with the parents being first cousins (pedigree shown in Figure 2).
CasePMIDs: N/A
65 + 5G-->A
Case#: Gu_1997_Patient_arRP181-II-1, female, 45, German ethnicity
CasePresentingHPOs: HP:0000662 (Nyctalopia), HP:0000572 (Visual loss), HP:0410280 (Pediatric onset), HP:0000546 (Retinal degeneration), HP:0000618 (Blindness)
CaseHPOFreeText: Visual loss had onset in childhood. Retinal degeneration was diagnosed at age 10. Legal blindness was found at age 18.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: Previous testing was limited to clinical diagnosis of arRP.
CaseMethod1: PCR amplification and Sanger sequencing
CaseMethod2: N/A
CaseGenotypingMethod: RPE65 was subjected to PCR amplification and Sanger sequencing.
Variant: The patient is homozygous for the NM_000329.3(RPE65):c.11+5G>A variant.
ClinVar: 98825 (homozygous)
gnomAD: The maximum allele frequency of the NM_000329.3(RPE65):c.11+5G>A variant is 0.0001626 (in the European non-Finnish population, with no homozygotes): https://gnomad.broadinstitute.org/variant/1-68915573-C-T
VariantEvidence: The variant is located within intron 1 of the RPE65 transcript and affects part of the splice donor consensus sequence. SpliceAI calculates a delta score of 0.06 for loss of splice donor site.
CaseAddInfo: Consanguinity of the parents is not proven but considered possible due to their origin from the same village. One of the patient's three siblings is affected (similarly or more severely), but none have been genotyped.
CasePMIDs: N/A
Affected individuals of the nonconsanguineous simplex FII
Case#: Perrault_2012_Patient_FII1, male, 18 years of age at time of study, ethnicity not specified
CasePresentingHPOs: HP:0003577 (Congenital onset), HP:0000639 (Nystagmus), HP:0025573 (Mild myopia), HP:0007994 (Peripheral visual field loss), HP:0007663 (Reduced visual acuity), HP:0007814 (Retinal pigment epithelial mottling), HP:0000608 (Macular degeneration), HP:0000550 (Undetectable electroretinogram), HP:0010164 (Cone-shaped epiphyses of the toes), HP:0003774 (Stage 5 chronic kidney disease), HP:0002153 (Hyperkalemia), HP:0000113 (Polycystic kidney dysplasia), HP:0000556 (Retinal dystrophy), HP:0001396 (Cholestasis), HP:0010230 (Cone-shaped epiphyses of the phalanges of the hand)
CaseHPOFreeText: Photoattraction was listed as a phenotype. Acetylated alpha-tubulin staining in cultured fibroblasts showed an absence of primary cilia in a high number of cells from this patient.
CaseNotHPOs: HP:0004322 (Short stature), HP:0000773 (Short ribs), HP:0000900 (Thickened ribs), HP:0000929 (Abnormal skull morphology), HP:0040064 (Abnormality of limbs), HP:0001263 (Global developmental delay), HP:0004979 (Metaphyseal sclerosis)
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
CaseMethod1: Ciliome resequencing of a customized target enrichment library (consisting of 1,666 genes)
CaseMethod2: Sanger sequencing of the 29 coding exons of IFT140
CaseGenotypingMethod: The patient was genotyped by ciliome resequencing of a customized target enrichment library (consisting of 1,666 genes), confirmed by Sanger sequencing of the 29 coding exons of IFT140
Variant: The patient is a compound heterozygote harboring the NM_014714.4(IFT140):c.932A>G (p.Tyr311Cys) and NM_014714.4(IFT140):c.857_860del (p.Ile286LysfsTer6) variants in IFT140.
ClinVar: 31681
CAID: CA129888
gnomAD: Neither variant was found in gnomAD.
VariantEvidence: Exogenous expression of the FLAG-tagged p.Tyr311Cys variant in the RPE1 (retinal pigment epithelial) cell line revealed an inability to co-localize with gamma-tubulin, indicating a defect in localization to the basal body in most cells, although milder than another suspected pathogenic missense variant (Figure 3A). The p.Ile286LysfsTer6) variant is a frameshift variant in exon 8 of 31, introducing a premature stop codon predicted to trigger nonsense-mediated decay or at least disrupt the C-terminal 81% of the protein product.
CaseAddInfo: The proband's parents are reportedly non-consanguineous.
CasePMIDs: N/A
novel mutation
Case#: Corton_2010_Family_RP-72_patient_IV:2, male, age 35 years at time of study, age 6 at onset, Spanish family origin from Galicia
CasePresentingHPOs: HP:0000662 (Nyctalopia), HP:0000540 (Hypermetropia), HP:0007663 (Reduced visual acuity), HP:0030526 (Severe constriction of peripheral visual field), HP:0000550 (Undetectable electroretinogram), HP:0007737 (Bone spicule pigmentation of the retina), HP:0007401 (Macular atrophy), HP:0007843 (Attenuation of retinal blood vessels), HP:0000543 (Optic disc pallor)
CaseHPOFreeText: The proband and his affected family members have been diagnosed with autosomal recessive retinitis pigmentosa.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: Haplotype analysis was initially performed in the patient and his affected family members.
CaseMethod1: Haplotype analysis
CaseMethod2: Sanger sequencing of PDE6A, PDE6B, and RHO
CaseGenotypingMethod: Haplotype analysis was initially performed in the patient and his affected family members, showing shared regions of homozygosity in the PDE6A, PDE6B, and RHO genes. Sanger sequencing was then performed on PCR products of exons and flanking regions from these three loci.
Variant: The proband harbors the NM_000440.3(PDE6A):c.2053G>A (p.Val685Met) variant in the homozygous state.
ClinVar: 29874
gnomAD: In gnomAD v2.1.1, NM_000440.3(PDE6A):c.2053G>A (p.Val685Met) has a frequency of 0.00008531 (11/128938) in the European non-Finnish population, with 0 homozygotes https://gnomad.broadinstitute.org/variant/5-149263074-C-T
VariantEvidence: A mutation equivalent to this variant in the homozygous nmf28/nmf28 mouse model caused grainy abnormalities in fundus pigmentation associated with loss of most photoreceptor cells shortly after birth, as well as loss of cGMP-PDE6 activity resulting in increased intracellular cGMP levels (PMID: 18849587).
CaseAddInfo: The proband is from a family with multiple consanguineous unions and three affected paternal aunts.
CasePMIDs: N/A
Sequence of a patient carrying the CLN5 Fin major mutation, (AT)2467 deletion.
Case#: Savukoski_Fin_Major_Patient_1, no demographic details, Finnish origin
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: Previous testing relied on linkage analysis using PCR-amplifiable polymorphisms, including microsatellite markers. The marker D13S160 was found to co-segregate with disease with a LOD score of 4.78 across 14 Finnish pedigrees, mapping the disease locus to chromosome 13q21.1-q32 (PMID:7942847). A follow-up study used two additional microsatellite markers to map the locus to a 200-kb region (PMID:8661106), which was then analyzed in the present study and found to contain a single coding gene.
CaseMethod1: Linkage analysis using PCR-amplifiable polymorphisms, including microsatellite markers, followed by more detailed linkage analysis using two additional microsatellite markers to map the locus to a smaller 200-kb region (PMID:8661106).
CaseMethod2: N/A
CaseGenotypingMethod: PCR products from the four exons of CLN5 were generated from the affected individual and a control individual and subjected to Sanger sequencing. Genome-wide analysis methods were not used.
Variant: Patient is homozygous for NM_006493.4(CLN5):c.1028_1029del (p.Thr342_Tyr343insTer), although this variant is referred to in the article as (AT)2467del.
ClinVar: 2564
gnomAD: The variant is reported to have a maximum allele frequency of 0.0008137 (in the European Finnish population, with no homozygous individuals). https://gnomad.broadinstitute.org/variant/13-77575052-CAT-C
VariantEvidence: This frameshift variant is expected to truncate 16 amino acids from the C-terminus of CLN5 (between 4-5% of the total polypeptide), without triggering NMD. However, it abolishes an N-glycosylation site (PMID:24058541). This may explain why it fails to localize to large endosomes but rather is retained within the ER, possibly indicating improper folding (PMID:24058541). It also exhibits reduced stability relative to other variants (PMID:24058541).
CaseAddInfo: N/A
CasePMIDs: PMID:7942847, PMID:8661106
Sequence of a Dutch patient with the CLN5 European mutation, a G2127→A transversion.
Case#: Savukoski_European_Patient_1, no demographic details, Dutch origin
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
CaseMethod1: N/A
CaseMethod2: N/A
CaseGenotypingMethod: PCR products from the four exons of CLN5 were generated from the affected individual and a control individual and subjected to Sanger sequencing. Genome-wide analysis methods were not used.
Variant: Patient is homozygous for NM_006493.4(CLN5):c.688G>A (p.Asp230Asn), although this variant is referred to in the article as c.G2127A or p.Asp279Asn.
ClinVar: 2566
gnomAD: The variant is reported to have a maximum allele frequency of 0.00005437 (in the East Asian population, with no homozygous individuals). https://gnomad.broadinstitute.org/variant/13-77574715-G-A
VariantEvidence: This missense variant in the fourth / final exon is predicted to introduce an additional N-glycosylation site within the C-terminal region of CLN5. Slower electrophoretic migration of the exogenously expressed protein indicates that the abnormal N-glycosylation site is functional (PMID:20052765). The variant also disturbs lysosomal trafficking (PMID:20052765).
CaseAddInfo: N/A
CasePMIDs: N/A
488
Case#: Bravo-Gil_2016_Proband_488, sex not specified, onset at birth, family origin reported as Spanish
CasePresentingHPOs: HP:0000618 (Blindness), HP:0001133 (Constriction of peripheral visual field), and HP:0000662 (Nyctalopia), HP:0003577 (Congenital onset), HP:0000639 (Nystagmus), HP:0010442 (Polydactyly). HP:0001249 (Intellectual disability), HP:0001513 (Obesity)
CaseHPOFreeText: The proband is part of an inherited retinal disease cohort and received an initial diagnosis of Bardet-Biedl syndrome. Reduced visual acuity was the first visual symptom. The patient is now described as having total blindness.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: The proband was genotyped by a capture-based next-generation sequencing panel that included 64 known retinal genes.
CaseMethod1: next-generation sequencing panel
CaseMethod2: Sanger sequencing of BBS1 to validate the presence of the variants
CaseGenotypingMethod: The proband was genotyped by a capture-based next-generation sequencing panel that included 64 known retinal genes, followed by Sanger sequencing of BBS1 to validate the presence of the variants.
Variant: The proband harbors the NM_024649.5(BBS1):c.1169T>G (p.Met390Arg) and NM_024649.5(BBS1):c.118del (p.Cys40fs) variants in the compound heterozygous state.
ClinVar ID: 12143, 802688
gnomAD: The NM_024649.5(BBS1):c.1169T>G (p.Met390Arg) variant is found in gnomAD v2.1.1 at a frequency of 0.002773 in the European (non-Finnish) population, with 358 alleles / 129114 total alleles (0 homozygotes) https://gnomad.broadinstitute.org/variant/11-66293652-T-G?dataset=gnomad_r2_1 The NM_024649.5(BBS1):c.118del (p.Cys40fs) variant is found in gnomAD v2.1.1 at a frequency of 0.00005782 (2 alleles / 34592 total alleles, with 0 homozygotes) in the Admixed American population https://gnomad.broadinstitute.org/variant/11-66278553-CT-C?dataset=gnomad_r2_1
VariantEvidence: NM_024649.5(BBS1):c.1169T>G (p.Met390Arg) is a missense variant with mouse knock-in evidence of a similar disease-causing effect in the homozygous state (PMID: 18032602). This has not been taken into account in scoring, as the mouse model has been scored separately. However, it has provided a rationale not to down-score for the relatively high gnomAD frequency of this variant. NM_024649.5(BBS1):c.118del (p.Cys40fs) is a frameshift variant in exon 2 of 17 that is predicted to trigger nonsense-mediated decay or to at least truncate the C-terminal 93% of the protein product.
CaseAddInfo: The proband's family has not been described as consanguineous.
CasePMIDs: N/A
95
Case#: Bravo-Gil_2016_Proband_95, sex not specified, age 7 years at onset, family origin reported as Spanish
CasePresentingHPOs: HP:0007663 (Reduced visual acuity), HP:0001133 (Constriction of peripheral visual field), and HP:0000662 (Nyctalopia), HP:0000550 (Undetectable electroretinogram), HP:0410280 (Pediatric onset)
CaseHPOFreeText: The proband is part of an inherited retinal disease cohort and received an initial diagnosis of simplex retinitis pigmentosa. Night blindness was the first visual symptom.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: The proband was genotyped by a capture-based next-generation sequencing panel that included 64 known retinal genes.
CaseMethod1: next-generation sequencing panel
CaseMethod2: Sanger sequencing of BBS1 to validate the presence of the variants
CaseGenotypingMethod: The proband was genotyped by a capture-based next-generation sequencing panel that included 64 known retinal genes, followed by Sanger sequencing of BBS1 to validate the presence of the variants.
Variant: The proband harbors the NM_024649.5(BBS1):c.1169T>G (p.Met390Arg) and NM_024649.5(BBS1):c.1474-2A>G variants in the compound heterozygous state.
ClinVar ID: 12143
CAID: CA381424925
gnomAD: The NM_024649.5(BBS1):c.1169T>G (p.Met390Arg) variant is found in gnomAD v2.1.1 at a frequency of 0.002773 in the European (non-Finnish) population, with 358 alleles / 129114 total alleles (0 homozygotes) https://gnomad.broadinstitute.org/variant/11-66293652-T-G?dataset=gnomad_r2_1 The NM_024649.5(BBS1):c.1474-2A>G variant was not found in gnomAD v2.1.1.
VariantEvidence: NM_024649.5(BBS1):c.1169T>G (p.Met390Arg) is a missense variant with mouse knock-in evidence of a similar disease-causing effect in the homozygous state (PMID: 18032602). This has not been taken into account in scoring, as the mouse model has been scored separately. However, it has provided a rationale not to down-score for the relatively high gnomAD frequency of this variant. NM_024649.5(BBS1):c.1474-2A>G is a canonical splice site variant in intron 14 that is predicted but not confirmed to disrupt BBS1 splicing.
CaseAddInfo: The proband's family has not been described as consanguineous.
CasePMIDs: N/A
BBS7
Case#: Solmaz_2015_Proband_9, male, age 19 years at time of report, part of cohort from Turkey
CasePresentingHPOs: HP:0031418 (Increased body mass index), HP:0000510 (Rod-cone dystrophy), HP:0000750 (Delayed speech and language development), HP:0000218 (High palate), HP:0000678 IDental crowding), HP:0010442 (Polydactyly), HP:0001159 (Syndactyly), HP:0001156 (Brachydactyly), HP:0000026 (Male hypogonadism), HP:0001256 (Intellectual disability, mild)
CaseHPOFreeText: The patient has been diagnosed with Bardet-Biedl syndrome.
CaseNotHPOs: HP:0000365 (Hearing impairment), HP:0000077 (Abnormality of the kidney)
CaseNotHPOFreeText: N/A
CasePreviousTesting: Previous genotyping consisted of an NGS-based panel focusing on the BBS1, BBS2, ARL6, BBS4, BBS5, MKKS, BBS7, TTC8, BBS9, BBS10, TRIM32, BBS12, MKS1, CEP290, WDPCP, SDCCAG8, NPHP1 loci.
CaseMethod1: NGS-based panel focusing on the BBS1, BBS2, ARL6, BBS4, BBS5, MKKS, BBS7, TTC8, BBS9, BBS10, TRIM32, BBS12, MKS1, CEP290, WDPCP, SDCCAG8, NPHP1 loci.
CaseMethod2: Sanger sequencing of the BBS7 locus
CaseGenotypingMethod: Genotyping consisted of an NGS-based panel focusing on the BBS1, BBS2, ARL6, BBS4, BBS5, MKKS, BBS7, TTC8, BBS9, BBS10, TRIM32, BBS12, MKS1, CEP290, WDPCP, SDCCAG8, NPHP1 loci, followed by Sanger sequencing of the BBS7 locus.
Variant: The patient harbors the NM_018190.4:c.712_715del (p.Arg238GlufsTer59) variant in the homozygous state.
CAID: CA3064432
gnomAD: The NM_018190.4:c.712_715del (p.Arg238GlufsTer59) variant is found in gnomAD v2.1.1 at a maximum allele frequency of 0.0001146 (13/113390) in the European non-Finnish population, with 0 homozygotes https://gnomad.broadinstitute.org/variant/4-122775861-CCTCT-C
VariantEvidence: NM_018190.4:c.712_715del (p.Arg238GlufsTer59) is an out-of-frame deletion variant in exon 7 of 18 and is predicted to trigger nonsense-mediated decay or to at least truncate the C-terminal 65% of the protein product.
CaseAddInfo: Consanguinity of this specific patient's family is unknown, but the cohort was reported to have a high rate of consanguineous probands.
CasePMIDs: N/A
V.1
Case: Gliem_2000_Family_2_patient_V.1, male, country of origin Germany, onset at 51 years of age
DiseaseAssertion: Sorsby fundus dystrophy
FamilyInfo: The variant was inherited by the proband rather than acquired de novo.
CasePresentingHPOs: HP:0007663 (Reduced visual acuity), HP:0011510 (Drusen), HP:0000533 (Chorioretinal atrophy), HP:0012508, (Metamorphopsia), HP:0000662 (Nyctalopia)
CaseHPOFreeText: Presentation at age 51 with visual loss. Evaluation at age 71 found widespread central and midperipheral chorioretinal atrophy, thinning of the choroid in areas of atrophy, central focal subretinal fibrosis at the posterior pole, metamorphopsia (with onset in the sixth decade of life), and nyctalopia that was only developed late in disease progression.
CaseNOTHPOs: N/A
CaseNOTHPOFreeText: N/A
CasePreviousTesting: Phenotypic characterization only
GenotypingMethod: Sanger sequencing of PCR products from all 5 exons and flanking splice junctions of the TIMP3 gene.
PreviouslyPublished: Some of the family members were previously identified by genotyping as having Sorsby fundus dystrophy (PMID:25390527), and are more extensively phenotypically described in this study.
SupplementalData: N/A
Variant: Patients harbor the NM_000362.5(TIMP3):c.545A>G (p.Tyr182Cys) missense variant.
CAID: CA411540365
gnomAD: Variant is absent from gnomAD.
VariantEvidence: This missense variant within exon 5 of TIMP3 results in an unpaired Cys residue.
F5-P9,10,11PRSS56: c.[1066dupC];[1066dupC],p.[Gln356ProfsX152];[Gln356ProfsX152
Case#: Gal_2011_Family_5_Proband_P9, female, age 21 years at time of report, family national origin described as Saudi
CasePresentingHPOs: Hypermetropia HP:0000540, Microphthalmia HP:0000568
CaseHPOFreeText: The proband received a diagnosis of posterior microphthalmos, with one feature being a moderate papillomacular fold.
CaseNotHPOs: Ocular hypertension HP:0007906
CaseNotHPOFreeText: N/A
CasePreviousTesting: The proband's family may have been previously subjected to linkage mapping, and was also previously genotyped by Sanger sequencing of the MFRP locus.
CaseMethod1: Sanger sequencing of MFRP
CaseMethod2: Sanger sequencing of PRSS56
CaseGenotypingMethod: The proband's family may have been previously subjected to linkage mapping, and was also previously genotyped by Sanger sequencing of the MFRP locus, followed by Sanger sequencing of PRSS56.
Variant: The individual harbors the NM_001195129.2(PRSS56):c.1066dup (p.Gln356fs) variant in the homozygous state.
ClinVar: 31077
gnomAD: This variant is found in gnomAD v4.1.0 at a frequency of 0.0008496 in the Middle Eastern population https://gnomad.broadinstitute.org/variant/2-232523817-A-AC?dataset=gnomad_r4
VariantEvidence: NM_001195129.2(PRSS56):c.1066dup (p.Gln356fs) is a frameshift variant in exon 9 of 13 and is predicted to trigger nonsense-mediated decay.
CaseAddInfo: The proband is from a cohort where more than half of the families had known consanguinity.
CasePMIDs: N/A
The JATD1 patient was notable for having had severe kidney involvement requiring kidney transplant during childhood, as well as retinal disease, as detailed in Table 1. In addition, typical skeletal features of JATD were present in this patient (Fig. 1A, F, and L). We proceeded to screen additional patients using a diagnostic NGS panel developed for ciliopathies encompassing all exons and adjacent intronic boundaries of 131 known ciliopathy genes. This totaled 2,412 coding exons of genes selected from cilia proteome and ciliary trafficking studies (Frank et al., 2012).
Case#: Schmidts_2013_Patient_JATD1, male, 12 years of age at time of study, of Serbian ethnicity
CasePresentingHPOs: HP:0003593 (Infantile onset), HP:0002093 (Respiratory insufficiency), HP:0000556 (Retinal dystrophy), HP:0009370 (Type A brachydactyly), HP:0004322 (Short stature), HP:0005257 (Thoracic hypoplasia), HP:0010579 (Cone-shaped epiphysis), HP:0000369 (Low-set ears), HP:0003774 (Stage 5 chronic kidney disease), HP:0007703 (Abnormality of retinal pigmentation), HP:0000803 (Renal cortical cysts), HP:0033130 (Abnormal renal echogenicity), HP:0000822 (Hypertension), HP:0000773 (Short ribs), HP:0000900 (Thickened ribs), HP:0000774 (Narrow chest)
CaseHPOFreeText: This proband was diagnosed with Jeune's asphyxiating thoracic dystrophy (JATD).
CaseNotHPOs: HP:0010442 (Polydactyly), HP:0001737 (Pancreatic cysts), HP:0001392 (Abnormality of the liver), HP:0001263 (Global developmental delay)
CaseNotHPOFreeText: N/A
CasePreviousTesting: Previous testing appears to have been limited to a clinical diagnosis of Jeune's asphyxiating thoracic dystrophy.
CaseMethod1: Whole exome sequencing, focusing on variants consistent with autosomal recessive inheritance and homologous to genes present in the ciliary proteome.
CaseMethod2: Sanger sequencing of IFT140 in the patient and available family members
CaseGenotypingMethod: The patient and family members were genotyped by whole exome sequencing and confirmed by Sanger sequencing of IFT140.
Variant: The patient is a compound heterozygote harboring the paternal NM_014714.4(IFT140):c.874G>A (p.Val292Met) and maternal NM_014714.4(IFT140):c.1380del (p.Asn460fs) variants in IFT140.
ClinVar ID: 97053, 97055
gnomAD: The NM_014714.4(IFT140):c.874G>A (p.Val292Met) variant is present in gnomAD at a frequency of 0.000008852 in the European non-Finnish population (1/112966, with no homozygotes). https://gnomad.broadinstitute.org/variant/16-1637962-C-T The NM_014714.4(IFT140):c.1380del (p.Asn460fs) variant is present in gnomAD at a frequency of 0.000008804 in the European non-Finnish population (1/113590, with no homozygotes). https://gnomad.broadinstitute.org/variant/16-1633366-CG-C
VariantEvidence: NM_014714.4(IFT140):c.874G>A (p.Val292Met) is a missense variant that does not have functional evidence of gene impact. NM_014714.4(IFT140):c.1380del (p.Asn460fs) is a frameshift variant that introduces a premature stop codon in exon 12/31 and is predicted to trigger NMD or at least to truncate ~69% of the protein product.
CaseAddInfo: The proband's parents are each heterozygous for one variant.
CasePMIDs: N/A
i
Case#: Haider_2000_Proband_6, sex, age, and origin not reported
CasePresentingHPOs: N/A
CaseHPOFreeText: The proband is part of a cohort in which all patients had a diagnosis of enhanced S-cone syndrome, based on electroretinogram and/or psychophysics, as well as optical coherence tomography. Other phenotypes within the cohort members (but not tracked individually) included increased sensitivity to blue light; visual loss, night blindness occurring from early in life, varying degrees of L-cone and M-cone vision, and retinal degeneration.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: Previous genotyping was limited to Sanger sequencing of NR2E3, followed by SSCP to screen other family members for the variant.
CaseMethod1: Sanger sequencing of NR2E3
CaseMethod2: SSCP analysis of PCR products from NR2E3
CaseGenotypingMethod: Genotyping was performed by Sanger sequencing of NR2E3, followed by SSCP to screen other family members for the variant.
Variant: The individual harbors the NM_014249.4(NR2E3):c.310C>T (p.Arg104Trp) variant in the homozygous state.
ClinVarID: 846973
gnomAD: The variant is found in gnomAD version 4.1.0 at a frequency of 0.00002739 (2 alleles / 73,032 total alleles) in the African / African-American population, with no homozygous occurrences. https://gnomad.broadinstitute.org/variant/chr15-71811830-C-T?dataset=gnomad_r4
VariantEvidence: NM_014249.4(NR2E3):c.310C>T (p.Arg104Trp) is a missense variant within the zinc finger / DNA-binding domain of NR2E3,.
CaseAddInfo: It is not clear whether or not the proband comes from a consanguineous family.
CasePMIDs: N/A
m
Case#: Haider_2000_Proband_1, male, age and origin not reported
CasePresentingHPOs: N/A
CaseHPOFreeText: The proband is part of a cohort in which all patients had a diagnosis of enhanced S-cone syndrome, based on electroretinogram and/or psychophysics, as well as optical coherence tomography. Other phenotypes within the cohort members (but not tracked individually) included increased sensitivity to blue light; visual loss, night blindness occurring from early in life, varying degrees of L-cone and M-cone vision, and retinal degeneration.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: Previous genotyping was limited to Sanger sequencing of NR2E3, followed by SSCP to screen other family members for the variant.
CaseMethod1: Sanger sequencing of NR2E3
CaseMethod2: SSCP analysis of PCR products from NR2E3
CaseGenotypingMethod: Genotyping was performed by Sanger sequencing of NR2E3, followed by SSCP to screen other family members for the variant.
Variant: The individual harbors the NM_014249.4(NR2E3):c.119-2A>C variant in the homozygous state.
ClinVarID: 191059
gnomAD: The variant is found in gnomAD version 4.1.0 at a frequency of 0.001359 in the Ashkenazi Jewish population and 0.0007992 in the European (non-Finnish) population (919 / 1,149,942), with no homozygotes observed. https://gnomad.broadinstitute.org/variant/chr15-71811481-A-C?dataset=gnomad_r4
VariantEvidence: NM_014249.4(NR2E3):c.119-2A>C is a canonical splice acceptor site variant adjacent to exon 2 of 6, which is an out-of-frame exon that could potentially trigger nonsense-mediated decay if skipped.
CaseAddInfo: The proband is the offspring of 3rd cousins and has an affected sibling and an affected second cousin once removed harboring the variant in the same homozygous genotype (Figure 3c).
CasePMIDs: N/A
non-syndromic
Case#: Jespersgaard_2019_Patient_163, gender and age not specified, origin likely to be Danish based on cohort
CasePresentingHPOs: N/A
CaseHPOFreeText: The proband has been diagnosed with retinitis pigmentosa, as part of a larger group of generalized non-syndromic retinal dystrophies. Detailed phenotypes are not described.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: Next-generation sequencing was performed focusing on a targeted panel of 125 genes known to be linked to inherited retinal disease.
CaseMethod1: NGS panel
CaseMethod2: N/A
CaseGenotypingMethod: Next-generation sequencing was performed focusing on a targeted panel of 125 genes known to be linked to inherited retinal disease. It is not clear whether Sanger sequencing was used to validate the genotyping of this particular case.
Variant: The proband harbors the NM_000440.3(PDE6A):c.612del (p.Lys205fs) variant in the homozygous state.
ClinVar: 636056
gnomAD: The NM_000440.3(PDE6A):c.612del (p.Lys205fs) variant is not found in gnomAD v2.1.1.
VariantEvidence: NM_000440.3(PDE6A):c.612del (p.Lys205fs) is a frameshift variant in exon 2 that is predicted to result in nonsense-mediated decay or at least to truncate the C-terminal ~76% of the protein product.
CaseAddInfo: N/A
CasePMIDs: N/A
4
Case#: Xin_Patient_8, sex not mentioned, age 5.5 at onset, U.S. nationality, Indian ethnicity
CasePresentingHPOs: HP:0004302 (Functional motor deficit), HP:0000512 (Abnormal electroretinogram), HP:0001250 (Seizure), HP:0001268 (Mental deterioration), HP:0011463 (Childhood onset)
CaseHPOFreeText: Motor difficulty was the phenotype at presentation (age 5.5). Cognitive regression (age 6), and visual findings (abnormal ERG) had later onset.
CaseNotHPOs: HP:0003205 (Curvilinear intracellular accumulation of autofluorescent lipopigment storage material), HP:0003208 (Fingerprint intracellular accumulation of autofluorescent lipopigment storage material)
CaseNotHPOFreeText: The electron microscopy findings referred to above (from conjunctiva biopsy) were normal.
CasePreviousTesting: Previous testing for mutations in the CLN1, CLN2, CLN3, CLN6, and CLN8 had already occurred, using PCR amplification and Sanger sequencing to exclude the possibility of variants in the exons and surrounding noncoding regions. Genome-wide analysis methods were not used, as NCL had already been diagnosed based on clinical phenotypes.
CaseMethod1: PCR amplification of the coding and surrounding non-coding regions of each gene, followed by bidirectional Sanger sequencing
CaseMethod2: as mentioned
CaseGenotypingMethod: CLN5 genotyping was performed by PCR amplification of the four exons and surrounding non-coding regions was performed, followed by bi-directional Sanger sequencing. Synthetic multiplex ligation-dependent probe amplification (MLPA) was then used to calculate average gene dosage ratio for each ratio, in order to detect large deletions.
Variant: The patient is believed to be homozygous for the NM_006493.4(CLN5):c.428A>G p.Asn143Ser variant.
ClinVar: 56539 (homozygous)
gnomAD: The NM_006493.4(CLN5):c.428A>G p.Asn143Ser variant is absent from gnomAD.
VariantEvidence: NM_006493.4(CLN5):c.428A>G p.Asn143Ser is a missense variant at a highly conserved residue, and is speculated by the authors to function as an exonic splicing enhancer. SpliceAI finds some evidence of a possible donor loss (change score of 0.02) or acceptor gain (change score of 0.09).
CaseAddInfo: Parents have not been subjected to genotyping, so homozygosity of variants is assumed. This conclusion was supported by failure to detect a deletion. Family history of non-consanguinity or consanguinity was not mentioned, but both parents share the same local area of origin within India.
CasePMIDs: N/A
insertion
Case#: Xin_Patient_10, sex not mentioned, age 5 at onset, U.S. nationality, Pakistani ethnicity
CasePresentingHPOs: HP:0004302 (Functional motor deficit), HP:0000572 (Visual loss), HP:0001250 (Seizure), HP:0001268 (Mental deterioration), HP:0011463 (Childhood onset), HP:0003205 (Curvilinear intracellular accumulation of autofluorescent lipopigment storage material), HP:0003208 (Fingerprint intracellular accumulation of autofluorescent lipopigment storage material)
CaseHPOFreeText: Motor difficulty was the phenotype at presentation (age 5). Cognitive regression and Seizures had onset at age 5, while Visual loss had onset at age 24.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: Previous testing for mutations in the CLN1, CLN2, CLN3, CLN6, and CLN8 had already occurred, using PCR amplification and Sanger sequencing to exclude the possibility of variants in the exons and surrounding noncoding regions. Genome-wide analysis methods were not used, as NCL had already been diagnosed based on clinical phenotypes.
CaseMethod1: PCR amplification of the coding and surrounding non-coding regions of each gene, followed by bidirectional Sanger sequencing
CaseMethod2: as mentioned
CaseGenotypingMethod: CLN5 genotyping was performed by PCR amplification of the four exons and surrounding non-coding regions was performed, followed by bi-directional Sanger sequencing. Synthetic multiplex ligation-dependent probe amplification (MLPA) was then used to calculate average gene dosage ratio for each ratio, in order to detect large deletions.
Variant: The patient is believed to be homozygous for the NM_006493.4(CLN5):c.379dup p.Thr127AsnfsTer11 variant.
CAID: CA611398060 (homozygous)
gnomAD: The maximum allele frequency for the NM_006493.4(CLN5):c.379dup p.Thr127AsnfsTer11 variant is 0.00003266 (jn the South Asian population, with no homozygotes).
VariantEvidence: NM_006493.4(CLN5):c.379dup p.Thr127AsnfsTer11 is a frameshift variant that disrupts ~65% of the protein product and is likely to trigger nonsense mediated decay.
CaseAddInfo: Parents have not been subjected to genotyping, so homozygosity of variants is assumed. This conclusion was supported by failure to detect a deletion, and by family history of consanguinity.
CasePMIDs: N/A
An additional IMPG1 variant was found in a simplex case of the French family NAX1. This female individual had a small vitelliform disk and was heterozygous for the splice-site mutation c.1824+1G>A in intron 13; this mutation was absent from the human SNP databases (Figure 4A). No other mutation was found in this proband. Her two unaffected sisters and her mother were also heterozygous for the mutation. However, the two unaffected sisters shared a paternal allele different from the paternal allele of the affected sister (Figure 4A), suggesting that the proband could harbor an unidentified paternal mutation located in the noncoding regions of IMPG1. An incomplete penetrance or a mutation in a different gene could also be considered.
Case#: Manes_2013_Family_NAX1_Proband_II:2, female, age unreported, national origin reported as French
CasePresentingHPOs: HP:0007677 (Vitelliform-like macular lesions), HP:0032037 (Mildly reduced visual acuity), HP:0030469 (Abnormal dark-adapted electroretinogram, specifically reduced)
CaseHPOFreeText: The patient has been diagnosed with vitelliform macular dystrophy.
CaseNotHPOs: HP:0008179 (Decreased Arden ratio of electrooculogram), HP:0008275 (Abnormal light-adapted electroretinogram)
CaseNotHPOFreeText: N/A
CasePreviousTesting: Previous testing appears to have been limited to Sanger sequencing-based screening of exon 7 of IMPG1.
CaseMethod1: Sanger sequencing of the 17 exons and flanking intronic sequences
CaseMethod2: N/A
CaseGenotypingMethod: Genotyping appears to have included Sanger-based sequencing of the 17 exons and intronic flanking sequences of the IMPG1 locus.
Variant: The proband harbors the NM_001563.4(IMPG1):c.1824+1G>A variant in the heterozygous state.
ClinVar: 1240018
gnomAD: The NM_001563.4(IMPG1):c.1824+1G>A variant was found in gnomAD v2.1.1 at a frequency of 0.00002980 (1/33554) in the Latino / Admixed American population, with 0 homozygotes https://gnomad.broadinstitute.org/variant/6-76660278-C-T?dataset=gnomad_r2_1
VariantEvidence: NM_001563.4(IMPG1):c.1824+1G>A is a canonical splice site variant in intron 13 that does not have evidence confirming an impact on the gene product, however, it has been reported by the same researchers in a proband with retinitis pigmentosa (PMID: 32817297).
CaseAddInfo: The proband has two unaffected sisters and an unaffected mother who share the same genotype. Consanguinity is not reported in this family. It is possible that the proband harbors a second unidentified variant in trans, inherited from the father.
CasePMIDs: N/A
7775
Case#: Morimura_1998_Family_7775_Patient_II-1, female, age and family origin not specified
CasePresentingHPOs: HP:0000546 (Retinal degeneration)
CaseHPOFreeText: While specific phenotypes are not provided, the initial diagnosis of Leber congenital amaurosis indicates that the proband was either born blind or lost vision within a period of months after birth.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: All 14 RPE65 exons and flanking sequences were PCR-amplified and subjected to single-strand conformation polymorphism analysis (SSCA).
CaseMethod1: Screening of PCR-amplified RPE65 exons using SSCA
CaseMethod2: Sanger sequencing of all 14 exons of RPE65
CaseGenotypingMethod: PCR-amplified exons identified by SSCA as candidates to harbor variants were subjected to Sanger sequencing.
Variant: The proband is a homozygote within the RPE65 locus, harboring the NM_000329.3(RPE65):c.271C>T (p.Arg91Trp) variant.
ClinVar: 13115 (homozygous)
gnomAD: The NM_000329.3(RPE65):c.271C>T (p.Arg91Trp) variant has a maximum allele frequency of 0.0002406 (within the African / African-American population, with no homozygotes): https://gnomad.broadinstitute.org/variant/1-68910541-G-A
VariantEvidence: The NM_000329.3(RPE65):c.271C>T (p.Arg91Trp) variant was also detected in this publication in a heterozygous state within two apparently unrelated probands with Retinitis pigmentosa (Figure 2A) and Leber congenital amaurosis (Figure 2B), respectively. A separate publication (PMID: 16754667) expressed this missense variant in non-patient cells and showed that it abolished the isomerohydrolase activity of the protein product, reduced its stability, and shifted the subcellular localization from predominantly membrane-associated to predominantly cytosolic.
CaseAddInfo: Genotyping of the proband's mother revealed NM_000329.3(RPE65):c.271C>T (p.Arg91Trp) in a heterozygous state. The father was not genotyped. Potential consanguinity between the parents was not reported.
CasePMIDs: N/A
Gly40Ser (GGC to AGC)
Case#: Morimura_1998_Family_9148_Patient_II-1, male, age and family origin not specified
CasePresentingHPOs: HP:0000546 (Retinal degeneration)
CaseHPOFreeText: While specific phenotypes are not provided, the initial diagnosis of Leber congenital amaurosis indicates that the proband was either born blind or lost vision within a period of months after birth.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: All 14 RPE65 exons and flanking sequences were PCR-amplified and subjected to single-strand conformation polymorphism analysis (SSCA).
CaseMethod1: Screening of PCR-amplified RPE65 exons using SSCA
CaseMethod2: Sanger sequencing of all 14 exons of RPE65
CaseGenotypingMethod: PCR-amplified exons identified by SSCA as candidates to harbor variants were subjected to Sanger sequencing.
Variant: The proband is a compound heterozygote within the RPE65 locus, harboring the NM_000329.3(RPE65):c.118G>A (p.Gly40Ser) and NM_000329.3(RPE65):c.544C>T (p.His182Tyr) variants.
ClinVar: 98830, 98875
gnomAD: The NM_000329.3(RPE65):c.2T>C (p.Met1Thr) variant has a maximum allele frequency of 0.00009643 (within the Ashkenazi Jewish population, with no homozygotes): https://gnomad.broadinstitute.org/variant/1-68912520-C-T The NM_000329.3(RPE65):c.544C>T (p.His182Tyr) variant has a maximum allele frequency of 0.00009925 (within the Ashkenazi Jewish population, with no homozygotes): https://gnomad.broadinstitute.org/variant/1-68906635-G-A
VariantEvidence: The paternal NM_000329.3(RPE65):c.118G>A (p.Gly40Ser) and maternal NM_000329.3(RPE65):c.544C>T (p.His182Tyr) variants are missense variants that do not have evidence of gene impact.
CaseAddInfo: Genotyping of family members revealed the two variants to be in trans. The brother of the proband shares the same genotype and diagnosis of Leber congenital amaurosis.
CasePMIDs: N/A
Glu102Lys (GAA to AAA)
Case#: Morimura_1998_Family_3867_Patient_II-1, female, age and family origin not specified
CasePresentingHPOs: HP:0000546 (Retinal degeneration)
CaseHPOFreeText: While specific phenotypes are not provided, the initial diagnosis of Leber congenital amaurosis indicates that the proband was either born blind or lost vision within a period of months after birth.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: All 14 RPE65 exons and flanking sequences were PCR-amplified and subjected to single-strand conformation polymorphism analysis (SSCA).
CaseMethod1: Screening of PCR-amplified RPE65 exons using SSCA
CaseMethod2: Sanger sequencing of all 14 exons of RPE65
CaseGenotypingMethod: PCR-amplified exons identified by SSCA as candidates to harbor variants were subjected to Sanger sequencing.
Variant: The proband is a compound heterozygote within the RPE65 locus, harboring the NM_000329.3(RPE65):c.271C>T (p.Arg91Trp) and NM_000329.3(RPE65):c.304G>A (p.Glu102Lys) variants.
ClinVar: 13115, 98862
gnomAD: The NM_000329.3(RPE65):c.271C>T (p.Arg91Trp) variant has a maximum allele frequency of 0.0002406 (within the African / African-American population, with no homozygotes): https://gnomad.broadinstitute.org/variant/1-68910541-G-A The NM_000329.3(RPE65):c.304G>A (p.Glu102Lys) variant is not found within gnomAD.
VariantEvidence: NM_000329.3(RPE65):c.304G>A (p.Glu102Lys) is a missense variant that does not have evidence of gene impact. The NM_000329.3(RPE65):c.271C>T (p.Arg91Trp) variant was also detected in this publication in a heterozygous state within two apparently unrelated probands with Retinitis pigmentosa (Figure 2A) and Leber congenital amaurosis (Figure 2B), respectively. A separate publication (PMID: 16754667) expressed this missense variant in non-patient cells and showed that it abolished the isomerohydrolase activity of the protein product, reduced its stability, and shifted the subcellular localization from predominantly membrane-associated to predominantly cytosolic.
CaseAddInfo: Genotyping of the proband's parents revealed NM_000329.3(RPE65):c.271C>T (p.Arg91Trp) as the paternal variant and NM_000329.3(RPE65):c.304G>A (p.Glu102Lys) as a de novo variant.
CasePMIDs: N/A
The two affected individuals in Family B had initial symptoms of decreased night vision with onset of disease in the first few years of life (Table 2). The fundus showed features of an atypical retinal dystrophy with white flecks in the periphery and gliotic scars in the posterior pole (Figure 2C). ERGs were of the rod-cone type. The condition of the ERG and clinical features were highly suggestive of an enhanced S-cone syndrome (ESCS) phenotype [11]. However, ESCS could not be confirmed as the patient did not undergo optical coherence tomography for macula schisis. In addition, the gliotic scars observed were unusual.
Case#: Kannabiran _2012_Proband_B-2, male, age 10 years at time of report, national origin from India
CasePresentingHPOs: Nyctalopia HP:0000662, Childhood onset HP:0011463, Retinal flecks HP:0012045, Decreased light- and dark-adapted electroretinogram amplitude (rod-cone pattern) HP:0000654, Retinal pigment epithelial atrophy HP:0007722
CaseHPOFreeText: The proband has a diagnosis of autosomal recessive retinitis pigmentosa, with phenotypes highly suggestive of enhanced S-cone syndrome. The proband had gliotic scars in the posterior pole. No OCT was performed, so it is unknown whether macula schisis was present.
CaseNotHPOs: Abnormal optic disc morphology HP:0012795, Abnormal retinal artery morphology HP:0000630, Bone spicule pigmentation of the retina HP:0007737
CaseNotHPOFreeText: N/A
CasePreviousTesting: Previous genotyping consisted of homozygosity mapping, which established linkage to a 41Mb region of chromosome 15, identifying NR2E3 and RLBP1 as the likely candidate loci.
CaseMethod1: Homozygosity mapping within the family of the proband
CaseMethod2: Sanger sequencing of NR2E3 and RLBP1
CaseGenotypingMethod: Genotyping was performed by homozygosity mapping within the family of the proband, followed by Sanger sequencing of NR2E3 and RLBP1.
Variant: The individual harbors the NM_014249.4(NR2E3):c.143_144delinsAGTGTGCCTCCAGTGCCTCGCTCCA (p.Arg48fs) variant in the homozygous state.
ClinVarID: 183143
gnomAD: The variant was not found in gnomAD version 4.1.0.
VariantEvidence: NM_014249.4(NR2E3):c.143_144delinsAGTGTGCCTCCAGTGCCTCGCTCCA (p.Arg48fs) is a frameshift variant in exon 2 of 8 that is predicted to introduce a premature stop codon and trigger nonsense-mediated decay.
CaseAddInfo: The proband has two unaffected heterozygous parents and an affected sister who shares the same homozygous genotype.
CasePMIDs: N/A
335 bp deletion in exon 3c−d in two families (X05 and X09)
Case#: Allen_2003_Familly_X05_Proband, male, age not mentioned, British national origin
CasePresentingHPOs: HP:0007642 (Congenital stationary night blindness), HP:0007663 (Reduced visual acuity), HP:0031624 (Moderate myopia), HP:0007984 (Electronegative electroretinogram)
CaseHPOFreeText: ERG with absent scotopic oscillatory potential, subnormal ON response
CaseNotHPOs: N/A
CaseNotHPOFreeText: Normal OFF response
CasePreviousTesting: N/A
CaseMethod1: Sanger sequencing of PCR-amplified exons from NYX and CACNA1F
CaseMethod2: Haplotype analysis using microsatellite markers surrounding the NYX locus
CaseGenotypingMethod: The proband and family members were subjected to Sanger sequencing of NYX to identify the variant, followed by microsatellite-based haplotype analysis of families sharing the same variant.
Variant: The proband harbors the NM_022567.2(NYX):c.1122_*11del (p.Ser374ArgfsTer10) variant on the X chromosome.
CAID: CA2573050969
gnomAD: NM_022567.2(NYX):c.1122_*11del (p.Ser374ArgfsTer10) was not found in gnomAD.
VariantEvidence: NM_022567.2(NYX):c.1122_*11del (p.Ser374ArgfsTer10) is a frameshift variant in exon 3/3 that is not predicted to trigger NMD but disrupts the C-terminal 22% of the protein product. A separate publication (PMID: 14507859) indicates that variants (such as this one) that remove the C-terminal GPI anchor disrupt NYX function by triggering its mislocalization to and accumulation in the ER and Golgi and its absence from its normal destination at the cell surface. This is a recurrent variant reported here in multiple apparently unrelated British families (X05 and X09).
CaseAddInfo: N/A
CasePMIDs: N/A
c.481–12T>A and c.1483–2A>G in family CHRO 9
Case#: Chang_2009_Family_CHRO9_Proband_II:3, female, age 26 years at time of report, family origin not described
CasePresentingHPOs: HP:0000613 (Photophobia), HP:0003593 (Infantile onset), HP:0001141 (Severely reduced visual acuity), HP:0011003 (High myopia), HP:0000551 (Color vision defect, described as complete lack of color discrimination), HP:0000603 (Central scotoma), HP:0030465 (Undetectable light-adapted electroretinogram), HP:0030479 (Abnormal amplitude of light-adapted flicker electroretinogram, described as extinguished), HP:0007401 (Macular atrophy)
CaseHPOFreeText: The proband and an affected family member were previously diagnosed with achromatopsia.
CaseNotHPOs: HP:0030469 (Abnormal dark-adapted electroretinogram)
CaseNotHPOFreeText: N/A
CasePreviousTesting: Affected and unaffected family members were initially subjected to genotyping of the CNGA3, GNGB3, and GNAT2 loci, confirming absence of causal variants in these known achromatopsia-related genes.
CaseMethod1: Sanger sequencing of CNGA3, GNGB3, and GNAT2
CaseMethod2: Sanger sequencing of the 22 exons and flanking regions of PDE6C
CaseGenotypingMethod: CNGA3, GNGB3, and GNAT2 were previously screened / known not to harbor causal variants for achromatopsia. The family members were then subjected to Sanger sequencing of the 22 exons and flanking regions of PDE6C.
Variant: The proband harbors the NM_006204.4(PDE6C):c.481-12T>A and NM_006204.4(PDE6C):c.1483-2A>G variants in the compound heterozygous state.
ClinVar ID: 8770, 8771
gnomAD: The NM_006204.4(PDE6C):c.481-12T>A variant was not found in gnomAD v2.1.1. The NM_006204.4(PDE6C):c.1483-2A>G variant was not found in gnomAD v2.1.1.
VariantEvidence: NM_006204.4(PDE6C):c.481-12T>A is an intronic variant that has been subjected to a mini-gene assay in COS7 cells and triggers a fully penetrant splicing defect (use of a cryptic splice site 10 nucleotides upstream, resulting in a frameshift encoding p.Asn161fsX169, Figure S5A). NM_006204.4(PDE6C):c.1483-2A>G is a canonical splice site variant that has been subjected to a mini-gene assay in COS7 cells and triggers a fully penetrant splicing defect (exon 12 skipping, resulting in an in-frame deletion encoding p.495_543del49, Figure S5B).
CaseAddInfo: The patient has an affected sister who shares the same compound heterozygous genotype, while the parents and one other sibling are each unaffected carriers.
CasePMIDs: N/A
TCD-G proband
Case#: Bowne_2011_Family_TCD-G_Patient_53, male, unspecified age, family origin in Ireland
CasePresentingHPOs: N/A
CaseHPOFreeText: The patient was initially diagnosed with retinitis pigmentosa prior to genotyping. Detailed phenotypes are not specified for individual patients.
CaseNotHPOs: HP:0003593 (Infantile onset), HP:0011463 (Childhood onset)
CaseNotHPOFreeText: N/A
CasePreviousTesting: Candidate gene sequencing for variants in other known retinitis pigmentosa genes. SNP-based linkage analysis mapped the phenotype of autosomal dominant retinitis pigmentosa to an 8.8-Mb genomic region located at chr1 p31. It is not clear whether the patient was one of 3 affected individuals subjected to whole exome sequencing.
CaseMethod1: SNP-based linkage analysis and whole exome sequencing
CaseMethod2: Candidate gene sequencing
CaseGenotypingMethod: Sanger sequencing of 11 candidate genes among the 50 known genes from the mapped region, including RPE65 and PDE4B.
Variant: The patient harbors the NM_000329.3(RPE65):c.1430A>G (p.Asp477Gly) variant in one allele of RPE65.
ClinVar: 750796
gnomAD: The NM_000329.3(RPE65):c.1430A>G (p.Asp477Gly) variant was not found in gnomAD.
VariantEvidence: Exogenous expression of the variant reveals protein expression levels, cellular localization and retinoid isomerase activity comparable to the wild-type (PMID: 29659842). However, knock-in mouse models exhibit retinyl ester accumulation (PMID: 29659842), abnormally slow regeneration of 11-cis-retinal after light exposure, and ERG results indicative of delayed dark adaptation (PMID: 28041994). Mice with CRISPR-mediated knock-in of the variant also exhibit a splicing defect in RPE65 due to the introduction of a cryptic splice site, which likely triggers a frameshift, exclusion of exons 13 and 14 from the transcript, and premature truncation of the protein product (PMID: 30628748).
CaseAddInfo: N/A
CasePMIDs: PMID: 20861475, PMID: 16799052, PMID: 17982421, PMID: 17924349, PMID: 19520207, PMID: 17003455
had truncation
Case#: Family_11850_Proband_II-2, onset before age 7 years, male, seen at a medical center in Guangzhou
CasePresentingHPOs: High myopia HP:0011003, Blurred vision HP:0000622, Childhood onset HP:0011463, Protanopia HP:0011522
CaseHPOFreeText: The proband is part of a cohort in which all patients had a diagnosis of early onset high myopia, with onset in early childhood and either high myopia or axial length >25 mm before age 7, or refractive errors <-10 as an adult.
CaseNotHPOs: Nystagmus HP:0000639, Photophobia HP:0000613, Nyctalopia HP:0000662
CaseNotHPOFreeText: N/A
CasePreviousTesting: Genotyping of the proband was performed by either targeted exome sequencing or whole exome sequencing.
CaseMethod1: targeted exome or whole exome sequencing
CaseMethod2: Sanger sequencing of OPN1LW
CaseGenotypingMethod: Genotyping of the proband was performed by either targeted exome sequencing or whole exome sequencing, followed by Sanger sequencing of OPN1LW.
Variant: The individual harbors the NM_020061.6(OPN1LW):c.518_519insC (p.Ala174CysfsTer?) variant in the hemizygous state.
CAID: CA3071606830
gnomAD: The variant was not found in gnomAD version 4.1.0.
VariantEvidence: NM_020061.6(OPN1LW):c.518_519insC (p.Ala174CysfsTer?) is a nonsense variant in exon 3 of 6 that is predicted to undergo nonsense-mediated decay.
CaseAddInfo: The proband was seen at a medical center in Guangzhou. The variant was inherited from the proband's unaffected mother.
CasePMIDs: N/A
preserved functional vision until later life with essentially uninvolved peripheral retina
Case: Tabata_1998_Family_Ue_patient_1, female, 73 years of age at onset of visual symptoms, country of origin Japan
DiseaseAssertion: Sorsby's fundus dystrophy
FamilyInfo: The proband has two affected siblings. All three were subjected to genotyping.
CasePresentingHPOs: HP:0007663 (Reduced visual acuity), HP:0025094 (Disciform macular scar), HP:0000603 (Central scotoma), HP:0030496 (Macular exudate), HP:0030506 (Yellow/white lesions of the retina), HP:0025243 (Subretinal hemorrhage), HP:0000580 (Pigmentary retinopathy), HP:0030491(Choriocapillaris atrophy)
CaseHPOFreeText: Onset of decreased central vision was seen in the 8th decade of life (both eyes between the ages of 73 and 77).
CaseNOTHPOs: HP:0007994 (Peripheral visual field loss), HP:0000512 (Abnormal electroretinogram), HP:0000662 (Nyctalopia)
CaseNOTHPOFreeText: Although central vision was decreased, peripheral fundi remained uninvolved. Patient had no difficulties with daily activities.
CasePreviousTesting: PCR-based heteroduplex analysis using gel electophoresis
CaseGenotypingMethod: Sanger sequencing
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: NM_000362.5:c.439-2dup (TIMP3) is predicted to disrupt a splice acceptor site at the junction of intron 4 and exon 5.
CAID: CA1139771334
gnomAD: Variant is absent from gnomAD.
VariantEvidence: Variant introduces an extra base within a splice acceptor site within intron 4, two bases upstream of exon 5.
The 55-year-old proband (III-6 in Fig. 1a) was a woman who presented with gait instability, dysarthria, and a mild cognitive deficit. Her past medical history had been unremarkable until she first sought neurological expert consultation after age 50 years because of unsteady gait.
Case#: Mancini_2015_Patient_III-6, female, age 52 at onset of visual symptoms, North-West Italian origin
CasePresentingHPOs: HP:0003596 (Middle age onset), HP:0002355 (Difficulty walking), HP:0001260 (Dysarthria), HP:0001268 (Mental deterioration), HP:0000572 (Visual loss), HP:0001272 (Cerebellar atrophy), HP:0006855 (Cerebellar vermis atrophy), HP:0008278 (Cerebellar cortical atrophy), HP:0001251 (Ataxia), HP:0002317 (Unsteady gait), HP:0000639 (Nystagmus), HP:0001310 (Dysmetria), HP:0007350 (Hyperreflexia in upper limbs), HP:0002395 (Lower limb hyperreflexia), HP:0000736 (Short attention span), HP:0002075 (Dysdiadochokinesis), HP:0001123 (Visual field defect), HP:0030528 (Paracentral scotoma), HP:0000543 (Optic disc pallor), HP:0002346 (Head tremor)
CaseHPOFreeText: Presentation was at age 52, with visual loss (attributed to glaucoma) as the first phenotype manifested. Pale and excavated optic disc (bilateral) was consistent with severe glaucoma or previous lesion of optic nerve. Neurological symptoms were recognized at age 55 (gait instability, dysarthria, and mild cognitive deficit). Onset of slight attention deficit, nystagmus with vertical component, dysarthric slurred speech, mild head tremor, truncal ataxia, mild dysmetria and dysdiadochokinesia, ataxic gait / posture, brisk deep reflexes in all four limbs, marked cerebellar atrophy (particularly in the vermis), severe bilateral cortical atrophy (especially parietal and temporal), limited visual field (bilateral, with paracentral scotoma in the left eye only), and pale and excavated optic discs (bilateral) were found at age 58. Dysarthria worsened at age 61, when patient also exhibited an inability to walk unassisted, severe intentional tremor in the limbs, and severe cognitive impairment.
CaseNotHPOs: HP:0410280 (Pediatric onset), HP:0003474 (Somatic sensory dysfunction), HP:0002353 (EEG abnormality), HP:0040129 (Abnormal nerve conduction velocity),
CaseNotHPOFreeText: N/A
CasePreviousTesting: Previous testing was limited to molecular tests ruling out Friedreich Ataxia and Spinocerebellar Ataxia types 1 and 2.
CaseMethod1: N/A
CaseMethod2: N/A
CaseGenotypingMethod: Whole exome sequencing of the proband and the affected sibling. Homozygosity was assumed due to the consanguinity of the family, contributing to the decision to focus on the variant in CLN5. This variant was confirmed by Sanger sequencing of PCR products from exon 4 of the CLN5 gene in both affected family members and an additional unaffected sibling. Parents were not subjected to genotyping.
Variant: The proband is homozygous for the NM_006493.4(CLN5):c.788G>A (p.Ser263Asn) variant.
ClinVar: 183049 (homozygous)
gnomAD: The maximum allele frequency for the NM_006493.4(CLN5):c.788G>A (p.Ser263Asn) variant is 0.000008805 (in the European non-Finnish population, with no homozygotes). https://gnomad.broadinstitute.org/variant/13-77574815-G-A
VariantEvidence: The variant encodes a missense substitution that results in aberrant retention in the ER compartment rather than proper localization to lysosomal vesicles (Figs. 1E-1J).
CaseAddInfo: Family is consanguineous (parents were first cousins).
CasePMIDs: N/A
nonsense
Case#: Gong_2001_Proband_2, no reported gender, age or national origin
CasePresentingHPOs: HP:0004349 (Reduced bone mineral density)
CaseHPOFreeText: The proband has been diagnosed with osteoporosis-pseudoglioma syndrome segregating with an autosomal recessive mode of inheritance. This implies a combination of ophthalmologic and radiographic features, but these have not been described in detail.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: Genome-wide linkage mapping with 160 SSRP markers was performed on three different consanguineous kindreds (from Finland, South Africa, and Italy) (fig. 1), but it is not clear whether this proband was a member of one of these kindreds.
CaseMethod1: Linkage analysis with additional markers around a strong candidate marker
CaseMethod2: Sanger sequencing of PCR-amplified exons and flanking regions of the LRP5 locus
CaseGenotypingMethod: Genotyping appears to have been limited to Sanger sequencing of PCR-amplified exons and flanking regions of the LRP5 locus.
Variant: The patient harbors the NM_002335.4(LRP5):c.1282C>T (p.Arg428Ter) variant in the homozygous state.
ClinVar: 6269
gnomAD: The NM_002335.4(LRP5):c.1282C>T (p.Arg428Ter) variant was not found in gnomAD v2.1.1.
VariantEvidence: NM_002335.4(LRP5):c.1282C>T (p.Arg428Ter) is a nonsense variant in exon 6 out of 23 that is predicted to trigger nonsense-mediated decay or at least to truncate the C-terminal ~74% of the protein product.
CaseAddInfo: The family is reportedly consanguineous.
CasePMIDs: PMID: 8659519
Homozygosity mapping was performed in a consanguineous family with four affected members originally referred as cases of LCA. Detailed electroretinographic recordings were obtained. Results: A novel homozygous single base-pair insertion was identified in all four siblings. The patients had an LCA-like phenotype, including either flat or greatly diminished electroretinographic activity. Conclusions: This report significantly expands on the phenotype associated with calcium binding protein 4 mutations, which has so far been limited to congenital stationary night blindness, and further demonstrates how molecular data often blur the boundaries between what are believed to be clinically distinct retinal disorders.
Case#: Aldahmesh_2010_Family_Proband_II-1, male, onset in early childhood, age 12 years at time of report, family ancestry reported as Dutch
CasePresentingHPOs: HP:0011463 (Childhood onset), HP:0000639 (Nystagmus), HP:0007663 (Reduced visual acuity), HP:0000613 (Photophobia), HP:0000551 (Color vision defect)
CaseHPOFreeText: The proband and his sibling have a diagnosis of cone-rod dysfunction, including color vision described as severely abnormal and electroretinogram responses that showed absent cone a-wave but normal-to-subnormal rod function.
CaseNotHPOs: HP:0000662 (Nyctalopia)
CaseNotHPOFreeText: N/A
CasePreviousTesting: Previous genotyping was limited to homozygosity mapping of the sibling and his affected sister that identified a shared region of homozygosity on chromosome 13.
CaseMethod1: Homozygosity mapping
CaseMethod2: Sanger sequencing of CABP4
CaseGenotypingMethod: Genotyping began with homozygosity mapping of the sibling and his affected sister that identified a shared region of homozygosity on chromosome 13, followed by Sanger sequencing of PCR products from the CABP4 gene.
Variant: The individual harbors the NM_145200.5(CABP4):c.646C>T (p.Arg216Ter) variant in the homozygous state.
ClinVar ID: 190959
gnomAD: The variant is found in gnomAD version 4.1.1 at a frequency of 0.0001418 in the European (non-Finnish) population, with 0 homozygotes https://gnomad.broadinstitute.org/variant/chr11-67457677-C-T?dataset=gnomad_r4
VariantEvidence: NM_145200.5(CABP4):c.646C>T (p.Arg216Ter) is a nonsense variant within exon 4 of 6 that is predicted to trigger nonsense-mediated decay.
CaseAddInfo: The proband's family includes a similarly affected sister harboring the variant in the homozygous state, and unaffected parents who each carry the variant in the heterozygous state. Consanguinity has not been commented upon.
CasePMIDs: N/A
The point mutation present in patients from two large pedigrees of Hispanic origin (from Costa Rica) changes a tryptophan codon to the stop codon TAG (W350X; Fig. 5a). This is predicted to eliminate the portion of nyctalopin required for establishing the GPI anchor, and potentially results in the protein being soluble rather than membrane-tethered.
Case#: Bech-Hansen_2000_Patient_610-1, male, age and race not mentioned, national origin in Costa Rica
CasePresentingHPOs: HP:0030640 (Complete congenital stationary night blindness)
CaseHPOFreeText: Patients in this study have a diagnosis of complete congenital stationary night blindness. Although this implies nyctalopia and photopic vision loss, specific phenotypic details are absent.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: Linkage analysis was performed using 17 X-chromosomal restriction fragment length polymorphism markers.
CaseMethod1: FokI restriction enzyme digestion of the relevant PCR product to monitor segregation in the proband and family members
CaseMethod2: Sanger sequencing of PCR amplified exons from NYX
CaseGenotypingMethod: Linkage analysis was initially performed using 17 X-chromosomal restriction endonuclease-based markers. The proband and family members were then subjected to restriction enzyme analysis of PCR products and Sanger sequencing to identify the variant.
Variant: The proband harbors the NM_001378477.3(NYX):c.1034G>A (p.Trp345Ter) variant on the X chromosome.
ClinVar: 11421
gnomAD: NM_001378477.3(NYX):c.1034G>A (p.Trp345Ter) has a maximum allele frequency of 0.00007388 (2/27070, with no males or homozygous females) in the Latino / Admixed American population. https://gnomad.broadinstitute.org/variant/X-41333755-G-A
VariantEvidence: This nonsense variant is located in the final exon and is not predicted to trigger NMD, but introduces a premature stop codon that truncates 28% of the protein product. The disrupted region is part of the predicted GPI anchor responsible for tethering the protein to the membrane.
CaseAddInfo: N/A
CasePMIDs: N/A
All affected individuals displayed an early cone dysfunction characterized by decreased vision acuity, with severe color dyschromatopsia and photophobia, during the 1st decade of life. At this stage, ophthalmoscopical examinations were not specific. By contrast, electrophysiological testing revealed marked loss of photopic function, with scotopic function relatively well preserved, and the visual field showed a consistent central scotoma. During the 2d and 3d decades, visual acuity decreased dramatically, and the color-vision defect was confined to achromatopsia, hampering normal schooling and professional insertion. After 40 years, peripheral visual field loss and progressive night blindness were observed, and the ERG became unrecordable (individual I-1; fig. 1).
Case#: Perrault_1998_Patient_I-1, male, age and ethnicity not described
CasePresentingHPOs: HP:0410280 (Pediatric onset), HP:0007663 (Reduced visual acuity), HP:0007641 (Dyschromatopsia), HP:0000613 (Photophobia), HP:0000603 (Central scotoma), HP:0011516 (Achromatopsia), HP:0007994 (Peripheral visual field loss), HP:0007675 (Progressive night blindness), HP:0000550 (Undetectable electroretinogram)
CaseHPOFreeText: Onset was during the 1st decade of life. Diagnosis was autosomal dominant cone-rod dystrophy.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: Previous testing established linkage to the D17S1796 and D17S1881 microsatellite markers.
CaseMethod1: Sanger sequencing of PCR products from each of the 18 exons of the GUCY2D locus
CaseMethod2: N/A
CaseGenotypingMethod: The proband and his family members were subjected to linkage analysis using the D17S1796 and D17S1881 microsatellite markers, as well as sequencing of PCR products from each of the 18 exons of the GUCY2D locus.
Variant: The proband harbors the NM_000180.3(GUCY2D):c.[2511G>C;2512C>T;2516C>T] variant in the heterozygous state.
ClinVar: 453244
gnomAD: The variant was not found in gnomAD.
VariantEvidence: NM_000180.3(GUCY2D):c.[2511G>C;2512C>T;2516C>T] is a missense variant that causes three adjacent substitutions at the protein level (p.Glu837Asp;Arg838Cys;Thr839Met), located within the coiled-coil domain that mediates dimerization. Codon 838 has proven to be a hot spot disrupted in other families similarly affected with autosomal dominant cone-rod dystrophy (PMID: 9618177, PMID: 12552567, PMID: 26298565). The p.Arg838Cys substitution has been shown to disrupt the calcium sensitivity of GUCY2D and to trigger the inability to inactivate cyclase activity at high physiological calcium ion concentrations (PMID: 11115851).
CaseAddInfo: The patient is a member of a three-generation family with affected children and grandchildren.
CasePMIDs: N/A