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:
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:
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:
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
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
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
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:
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
Identification and Genetic Analysis of a Factor IX Gene Intron 3 Mutation in a Hemophilia B Pedigree in China
PMID: 25330515
Gene: F9
HGNCID: 3551
Phase 1, single‐dose escalating study of marzeptacog alfa (activated), a recombinant factor VIIa variant, in patients with severe hemophilia
PMID: 30151972
Gene: F8
HGNC: 3546
NoEvidence: This article does not mention specific case reports with variants
Fig. 1
Case#: 12 year old male
DiseaseAssertion: Hemophilia B, moderate
FamilyInfo: Mother was a carrier. Maternal uncle has the same hemizygous mutation
ParentalTesting: Family Pedigree reveals that the mother was a carrier of the variant identified in the proband
CasePresentingHPOs: HP:0011858, HP:0030839
CaseHPOFreeText: FIX:C = 1%, proband had a history of soft tissue hemorrhages since 7 years of age
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: Direct nucleotide sequencing was completed
Gene: F9
Variant: NM_000133.3:c.157G>C
LegacyVariant:
ClinVar: No
CAID: CA414435729
gnomAD:
New technologies in gene therapy for inducing immune tolerance in hemophilia A
PMID: 30345839
Gene: F8
HGNC: 3546
NoEvidence: This article discusses new technologies in gene therapy for inducing immune tolerance in hemophilia A, there are no case reports with variants mentioned in this article
Night blindness in Sorsby's fundus dystrophy reversed by vitamin A
PMID: 7550309
Gene: TIMP3
HGNC: 11822
Disease: Sorsby fundus dystrophy (SFD), also known as Sorsby's fundus dystrophy, Sorsby pseudoinflammatory fundus dystrophy, or hemorrhagic macular dystrophy
MONDO: 0007640
InheritancePattern: Autosomal Dominant
Prevalence: Estimated at 1 in 220,000 (PMID: 28847738)
Penetrance: Fully penetrant, onset between the third and sixth decades of life
FIV3
FamilyLabel: Perrault_2012_Family_FIV
Family#PresentingHPOs: HP:0003593 (Infantile onset), HP:0000639 (Nystagmus), HP:0007663 (Reduced visual acuity)
Family#PresentingHPOFreeText: Staining of ciliary axonemes for acetylated alpha-tubulin detected an absence of cilia in a high percentage of cultured fibroblast cells, relative to control patients. Affected family members have been diagnosed with Mainzer-Saldino syndrome.
FamilyNotHPOs: HP:0001410 (Decreased liver function), HP:0012211 (Abnormal renal physiology)
FamilyNotHPOFreeText: IFT140 protein localization along the ciliary axoneme was unaffected in patient FIV3, however, two components of the anterograde transport IFT-B complex, IFT88 and IFT46, were aberrantly localized. They were evenly distributed along the cilium instead of primarily localized at the base and the tip of the cilium, suggesting an alteration in retrograde ciliary transport.
CountryOrigin: Saudi Arabia
Ethnicity: Not described.
Race: Not described.
Family#PreviousTesting: N/A
FamilyMethod1: Ciliome resequencing of a customized target enrichment library (consisting of 1,666 genes)
Family#Method2: Sanger sequencing of the 29 coding exons of IFT140.
Family#GenotypingMethod: The family 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
Affected: 3
Unaffected: 3
Segregations: 2 segregation were reported. The pedigree can be found in Figure S1. The family was described as consanguineous.
PublishedLOD: N/A
eLOD: 1.50
AddSegregationInfo: N/A
ProbandLabel: Perrault_2012_patient_FIV3
Variant: Affected individuals harbor the NM_014714.4(IFT140):c.1990G>A (p.Glu664Lys) variant in a homozygous state.
ClinVar: 31679
gnomAD: The NM_014714.4(IFT140):c.1990G>A (p.Glu664Lys) variant is present in gnomAD at a frequency of 0.00004031 in the African / African-American population (1/24806, with no homozygotes) https://gnomad.broadinstitute.org/variant/16-1614075-C-T
FamilyAddInfo: The parents of the affected family members are reportedly consanguineous (first cousins).
FamilyPMIDs: 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
Mainzer-Saldino Syndrome Is a Ciliopathy Caused by IFT140 Mutations
PMID: 22503633
Gene: IFT140
HGNC: 29077
Disease: Short-rib thoracic dysplasia 9 with or without polydactyly
MONDO: 0009964
InheritancePattern: autosomal recessive
Prevalence: Within the lumped disease entity for this curation, the most prevalent form may be retinitis pigmentosa. The prevalence of Saldino-Mainzer syndrome (one of the synonyms of Short-rib thoracic dysplasia 9) is less than 1 in 1,000,000. The prevalence of Leber congenital amaurosis cases caused by IFT140 variants (PMID: 26216056) is calculated to be less than 1 in 3,000,000. Although IFT140 variants are estimated to be responsible for less than 2% of RP, the prevalence of the overall disorder at 1 in 3,000 or 1 in 4,000 means the frequency of these cases could potentially be higher than 1 in 1,000,000.
Penetrance: Known variants for this lumped disease entity appear to be completely penetrant, with highly variable phenotypes and age of onset. On the other hand, the split disease entity caused by monoallelic IFT140 variants appears to have incomplete penetrance.
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
SFD pedigrees
FamilyLabel: Weber_1994_Family_M
Family#PresentingHPOs: HP:0011506 (Choroidal neovascularization), HP:0025094 (Disciform macular scar), HP:0007663 (Reduced visual acuity)
FamilyHPOFreeText: Choroidal neovascular invasion of the macula was bilateral. This occurred early in the presentation and led to the disciform scar and loss of central vision.
FamilyNotHPOs: N/A
CountryOrigin:
Family#PreviousTesting:
Family#GenotypingMethod: Sanger sequencing of Weber_1994_Family_M_patient_IV-2
Affected: 1
Unaffected: 1
Segregations: N/A
PublishedLOD:
eLOD: Insufficient information available
AddSegregationInfo: Absence of segregation info from the family is due to the fact that genotyping was limited to only the proband and one unaffected control.
ProbandLabel: Weber_1994_Family_M_patient_IV-2
Variant: NM_003490.4:c.711+5602T>C, p.Tyr191Cys
ClinVar: 12677
gnomAD: Variant is absent from gnomAD.
FamilyAddInfo: Variant was first referred to in PMID:7894485 as "Tyr168Cys" but encodes Tyr191Cys in the updated polypeptide sequence.
FamilyPMIDs: PMID:2000899
We report two Italian siblings presenting in their mid-50s with difficulty in walking, dysarthria and progressive cognitive decline. Visual loss, ascribed to glaucoma, manifested a few years before the other symptoms. Brain MRI showed severe cerebellar atrophy, prevalent in the vermis, with marked cortical atrophy of both hemispheres. Exome sequencing identified a novel homozygous mutation (c.935G > A;p.Ser312Asn) in the ceroid neuronal lipofuscinosis type 5 gene (CLN5).
FamilyLabel: Mancini_2015_Family_ATA-7-TO
FamilyPresentingHPOs: 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)
FamilyPresentingHPOFreeText: Presentation was in the middle of the 6th decade of life.
FamilyNotHPOs: HP:0410280 (Pediatric onset), HP:0003474 (Somatic sensory dysfunction)
FamilyNotHPOFreeText: N/A
CountryOrigin: Italy (North-West)
Ethnicity: Italian
Race: Not mentioned
Family#PreviousTesting: Previous testing was limited to molecular tests ruling out Friedreich Ataxia and Spinocerebellar Ataxia types 1 and 2.
Family#Method1: N/A
Family#Method2: N/A
Family#GenotypingMethod: 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.
Affected: 2
Unaffected: 1
Segregations: 1 segregation was reported, with none inconsistent (see pedigree in Figure 1A). The patient's family is consanguineous, with the parents being first cousins.
PublishedLOD: N/A
eLOD: N/A
AddSegregationInfo: N/A
ProbandLabel: Mancini_2015_Patient_III-5
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
FamilyAddInfo: N/A
FamilyPMIDs: N/A
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
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
Impg2
ExperimentName: Morpholino-based disruption of Impg2 in medaka fish
NonHumanModel: Oryzias latipes
GeneAlteration: Model animals were subjected to targeted disruption of Impg2 by morpholino-based silencing.
ModelPhenotype: HP:0030610 (Photoreceptor outer segment loss on macular OCT).
HumanPhenotype: HP:0000529 (Progressive visual loss), HP:0000662 (Nyctalopia), HP:0000551 (Color vision defect), HP:0008002 (Abnormality of macular pigmentation), HP:0000543 (Optic disc pallor), HP:0007843 (Attenuation of retinal blood vessels), HP:0000533 (Chorioretinal atrophy), HP:0000518 (Cataract), HP:0008323 (Abnormal light- and dark-adapted electroretinogram), HP:0007737 (Bone spicule pigmentation of the retina), HP:0007994 (Peripheral visual field loss), HP:0000603 (Central scotoma)
ModelEvidence: Morpholino-injected animals exhibit decreased photoreceptor outer segment length, especially for cones (Figures 4I, 4J).
ModelVariant: The model does not introduce a variant previously observed in human patients, but rather disrupts the expression of the Impg2 ortholog using a morpholino.
Isolation and characterization of cGMP phosphodiesterase from bovine rod outer segments
PMID: 227876
Gene: PDE6A
HGNC: 8785
Disease: retinitis pigmentosa 43
MONDO: MONDO:0013437
InheritancePattern: autosomal recessive
Prevalence: The overall prevalence of retinitis pigmentosa is between 1 in 3,000 and 1 in 4,000 individuals, while the proportion of retinitis pigmentosa with a recessive mode of inheritance is estimated to be 65-85% (between 1 in 3,500 and 1 in 6,200). Retinitis pigmentosa 43 is considered to be make up 2-5% of these cases, with an overall prevalence estimated between 1 in 70,000 and 1 in 310,000.
Penetrance: Known disease-causing alleles appear to be completely penetrant.
phosphodiesterase
ExperimentName: PDE6A forms a complex with PDE6B and PDE6G
InteractingGene: HGNC:8786 (PDE6B, implicated in retinitis pigmentosa 40) and HGNC:8789 (PDE6G, implicated in retinitis pigmentosa 57)
InteractionType: physical
InteractionMethod: size exclusion chromatography
InteractionEvidence: Purification of the cGMP phosphodiesterase complex from bovine rod outer segments yields a subunit of 88 kDa (PDE6A), a subunit of 84 kDa (PDE6B), and a subunit of 13 kDa (PDE6G), (Figure 2). This article shows that PDE6A interacts with and co-purifies with PDE6B and PDE6G in a single complex isolated from bovine retina. A subsequent article by Pittler et al. later established the position of PDE6A on chromosome 5 (PMID: 2155175).
In this study, we reinvestigated a large, highly consanguineous Finnish family previously diagnosed as having early-onset autosomal recessive SFD.
FamilyLabel: Felbor_1997_Family_1
Family#PresentingHPOs: HP:0007663 (Reduced visual acuity), HP:0001089 (Iris atrophy), HP:0007703 (Abnormality of retinal pigmentation), HP:0000501 (Glaucoma)
FamilyHPOFreeText: Early onset of visual loss between the second and fourth decade of life, with the first sign in young family members being uneven or absent pigmentation in the extreme fundus periphery. Affected individuals experienced progressive vision loss, iris atrophy, and glaucoma in some cases.
FamilyNotHPOs: N/A
FamilyNotHPOFreeText: N/A
CountryOrigin: Finland
Family#PreviousTesting: Single-stranded conformational analysis (SSCA) of the coding and promoter regions of TIMP3, detecting a mobility shift in exon 5 that was specific to affected individuals. Sanger sequencing of PCR products from exon 5 of the TIMP3 gene, in samples from the proband and a control individual.
Family#GenotypingMethod: Enzymatic digestion of TIMP3 exon 5 PCR products with the HaeIII restriction endonuclease.
Affected: 9
Unaffected: 9
Segregations: 8
PublishedLOD: Maximum LOD score, Zmax, was reported as 3.03 (at theta = .001, for the D22S281 marker, previously linked to the TIMP3 locus in PMID:8919688)
eLOD: 2.4
AddSegregationInfo: N/A
ProbandLabel: Felbor_1997_Family_1_patient_III-4
Variant: Affected patients harbor the NM_000362.5(TIMP3):c.565G>T (p.Gly189Cys) missense variant.
ClinVar: 12679
gnomAD: Variant is absent from gnomAD.
FamilyAddInfo: This highly consanguineous family was previously proposed to show an autosomal recessive pattern of inheritance (not previously observed for Sorsby fundus dystrophy). The family has been genotyped for the first time in this study, revealing segregation of disease phenotypes with a heterozygous variant in TIMP3, with autosomal dominant inheritance.
FamilyPMIDs: PMID:7148944, PMID:2387082
Autosomal recessive Sorsby fundus dystrophy revisited: molecular evidence for dominant inheritance.
PMID: 8981947
Gene: TIMP3
HGNC: 11822
Disease: Sorsby fundus dystrophy (SFD), also known as Sorsby's fundus dystrophy, Sorsby pseudoinflammatory fundus dystrophy, or hemorrhagic macular dystrophy
MONDO: 0007640
InheritancePattern: Autosomal Dominant
Prevalence: Estimated at 1 in 220,000 (PMID: 28847738)
Penetrance: Fully penetrant, onset between the third and sixth decades of life
A null mutation in the photoreceptor guanylate cyclase gene causes the retinal degeneration chicken phenotype
PMID: 9448321
Gene: GUCY2D
HGNC: 4689
Disease: Leber congenital amaurosis 1
MONDO: 0008764
InheritancePattern: Autosomal Recessive
Prevalence: The overall prevalence of Leber congenital amaurosis is between 1 in 33,000 and 1 in 100,000 newborns, while the proportion of Leber congenital amaurosis caused by GUCY2D variants is between 10% and 20% (PMID: 10951519). Thus, the prevalence of Leber congenital amaurosis 1 is between 1 in 165,000 and 1 in 1,000,000.
Penetrance: Fully penetrant, with onset in neonates or in infancy
Nyctalopin Expression in Retinal Bipolar Cells Restores Visual Function in a Mouse Model of Complete X-Linked Congenital Stationary Night Blindness
PMID: 17881478
Gene: NYX
HGNC: 8082
Disease: Congenital stationary night blindness 1A
MONDO: 0010690
InheritancePattern: X-linked recessive
Prevalence: Congenital stationary night blindness has an estimated prevalence between 1 in 6,000 (PMID: 31427709) and 1 in 300,000 (PMID: 3487908). However, the prevalence of congenital stationary night blindness 1A specifically is unknown.
Penetrance: Penetrance is thought to be complete.
The mouse ortholog of the neuronal ceroid lipofuscinosis CLN5 gene encodes a soluble lysosomal glycoprotein expressed in the developing brain
PMID: 15207259
Gene: CLN5
HGNC: 2076
Disease: Ceroid lipofuscinosis, neuronal, 5 (also known as Finnish variant late infantile neuronal ceroid lipofuscinosis, neuronal ceroid lipofuscinosis late infantile Finnish variant, or Finnish vLINCL)
MONDO: 0009745
InheritancePattern: Autosomal Recessive
Prevalence: Unknown, but part of a larger group of NCL disorders with a collective prevalence between 1 in 12,500 (PMID:9662406) and 1 in 100,000 (PMID:23374165)
Penetrance: Fully penetrant, with onset often in the late infantile period but in some cases during early adulthood or even as late as in the 6th decade of life
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
novel
Case#: Holmberg_Patient_7, female, age 4 at onset and age 9 at time of study, Finnish origin with some ancestors traced to Sweden
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 4, while mental decline, visual deterioration and abolished ERG were found at age 7. Ataxia and Seizures developed at age 8, while Loss of independent walking and Giant flash visual evoked potentials 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: HP:0007082 (Dilated third ventricle)
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 a compound heterozygote harboring the NM_006493.4(CLN5):c.1028_1029del (p.Thr342_Tyr343insTer) and NM_006493.4(CLN5):c.522dup (p.Trp175LeufsTer30) variants.
ClinVar: 2564, 56543
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 The maximum allele frequency of the NM_006493.4(CLN5):c.522dup (p.Trp175LeufsTer30) variant is 0.00007033 (within the European non-Finnish population, with no homozygotes) https://gnomad.broadinstitute.org/variant/13-77570218-A-AC
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). NM_006493.4(CLN5):c.522dup (p.Trp175LeufsTer30) is also a frameshift variant, is predicted to disrupt ~51% of the protein product, and exhibits defective localization to the ER rather than the lysosome (PMID:20052765).
CaseAddInfo: N/A
CasePMIDs: N/A
In mice, however, a null mutation in the GC1 gene produces a cone dystrophy; the GC1–/– rods remain viable and responsive to light (18Yang R.B. Robinson S.W. Xiong W.H. Yau K.W. Birch D.G. Garbers D.L. J. Neurosci. 1999; 19: 5889-5897Crossref PubMed Google Scholar, 19Coleman J.E. Zhang Y. Brown G.A. Semple-Rowland S.L. Investig. Ophthalmol. Vis. Sci. 2004; 45: 3397-3403Crossref PubMed Scopus (39) Google Scholar).
ExperimentName: Updated phenotypes from homozygous Gucy2e mouse knockout model
NonHumanModel: Mus musculus
GeneAlteration: The mouse Gucy2e gene was disrupted by the introduction of a neomycin-resistance gene cassette into exon 5, resulting in a truncated protein lacking its transmembrane domain (PMID: 10407028). The effects of this knockout were studied in both heterozygous and homozygous states.
ModelPhenotype: HP:0030465 (Undetectable light-adapted electroretinogram), HP:0030483 (Reduced amplitude of dark-adapted bright flash electroretinogram a-wave), HP:0030469 (Abnormal dark-adapted electroretinogram), HP:0000479 (Abnormal retinal morphology)
HumanPhenotype: HP:0007663 (Reduced visual acuity), HP:0007688 (Undetectable light- and dark-adapted electroretinogram), HP:0007703 (Abnormality of retinal pigmentation)
ModelEvidence: This publication confirms previously-reported ERG abnormalities of rod and especially cone photoreceptors. The abnormal retinal morphology HPO term refers to abnormalities in the ultrastructure of the photoreceptor outer segment, which exhibited disorganization (Figures S2B, S2F, 8C, and 8E) and low GCAP1 and GCAP2 expression levels (Figures 5J and 5N), providing early signs of instability and degeneration.
ModelVariant: The mouse model disrupts the expression of the endogenous GC1 protein product but does not feature knock-in of a variant from a human patient.
Disruption of RPGR protein interaction network is the common feature of RPGR missense variations that cause XLRP
PMID: 30622176
Gene: RPGR
HGNC: 10295
Disease: RPGR-related retinopathy
MONDO: MONDO:0100437
InheritancePattern: X-linked
Prevalence: The prevalence of RPGR-related retinopathy is calculated to be approximately 1 in 214,000, based on the known incidence of retinitis pigmentosa at 1 in 3,000, the proportion of retinitis pigmentposa that is X-linked at 20%, and the proportion of X-linked retinitis pigmentosa that is RPGR-associated at 70% (PMID: 34985506).
Penetrance: Penetrance is nearly 100% in hemizygous males but is incomplete and dependent upon the variant in heterozygous female carriers.
Four-point linkage analysis gave a maximum lod score of approximately 7.6 at both D8S1769 and GATA101H09 in the large consanguineous family. Recombination events defined an interval of 8.7 cM between D8S1820 and D8S532 within which the gene must lie. This 8p11 locus (CORD9) is immediately distal to but distinct from the RP1 autosomal dominant RP (adRP) locus.
FamilyLabel: Danciger_2001_Family
Family#PresentingHPOs: HP:0011463 (Childhood onset), HP:0007663 (Reduced visual acuity), HP:0001141 (Severely reduced visual acuity), HP:0007994 (Peripheral visual field loss), HP:0000545 (Myopia), HP:0000483 (Astigmatism), HP:0000523 (Subcapsular cataract)
FamilyPresentingHPOFreeText: The affected family members have been diagnosed with severe cone-rod dystrophy segregating with an autosomal recessive mode of inheritance.
FamilyNotHPOs: N/A
FamilyNotHPOFreeText: N/A
CountryOrigin: Brazil
Ethnicity: Brazilian
Race: Not described
Family#PreviousTesting: Linkage mapping has been performed in affected and unaffected family members using short tandem repeat markers across the genome.
Family#Method1: Linkage mapping using short tandem repeat markers
Family#Method2: Haplotype analysis with markers within an 8-cM region of chromosome 8p11.
Family#GenotypingMethod: Linkage mapping has been performed in affected and unaffected family members using short tandem repeat markers across the genome, followed by haplotype analysis within the linkage region. A subsequent publication sequenced 10 out of 34 genes within the linkage region and found homozygous variants in ADAM9 in particular (PMID: 19409519).
Affected: 5
Unaffected: 7
Segregations: 7 segregations are shown by the pedigree in Figure 1.
PublishedLOD: 7.6 (associated with the D8S1769 and GATA101H09 short tandem repeat markers on chromosome 8p11)
eLOD: N/A
AddSegregationInfo: N/A
ProbandLabel: Danciger_2001_Family_Patient_A
Variant: The affected family members harbor the NM_003816.3(ADAM9):c.1130+1G>A variant in the homozygous state.
ClinVar: 6876
gnomAD: This variant was not found in gnomAD v2.1.1.
VariantEvidence: The NM_003816.3(ADAM9):c.1130+1G>A variant is predicted to disrupt a canonical splice site in intron 11.
FamilyAddInfo: The family is known to be consanguineous, with the parents of affected individuals being second cousins.
FamilyPMIDs: PMID: 19409519
Combining a prioritization strategy and functional studies nominates 5'UTR variants underlying inherited retinal disease
PMID: 38184646
Gene: PRPF4
HGNC: 17349
Disease: retinitis pigmentosa 70
MONDO: 0014400
InheritancePattern: autosomal dominant
Prevalence: The overall prevalence of retinitis pigmentosa is between 1 in 3,000 and 1 in 4,000 individuals, while the proportion of retinitis pigmentosa with a dominant mode of inheritance is estimated to be 15-35% (between 1 in 8,500 and 1 in 27,000). The proportion of that incidence made up by the specific form caused by variants in PRPF4 is not clear.
Penetrance: Known disease-causing alleles appear to be incompletely penetrant (PMID: 25383878).
Visually impaired rhesus macaques show signs of achromatopsia.
ExperimentName: This macaque model harbors a homozygous loss-of-function variant in PDE6C.
NonHumanModel: Macaca mulatta
GeneAlteration: The model animals are homozygous for a missense variant, p.Arg565Gln, which is shown to cause a decrease in enzymatic activity.
ModelPhenotype: HP:0007663 (Reduced visual acuity, particularly in well illuminated settings where unaffected animals led them by the hand), HP:0001483 (Eye poking), HP:0030465 (Undetectable light-adapted electroretinogram), normal dark-adapted ERG, HP:0007401 (Macular atrophy), HP:0011504 (Bull's eye maculopathy), HP:0030619 (Reduced OCT-measured foveal thickness), HP:0030610 (Photoreceptor outer segment loss on macular OCT), HP:0030609 (Photoreceptor layer loss on macular OCT)
HumanPhenotype: HP:0030465 (Undetectable light-adapted electroretinogram), HP:0030534 (Abnormal best corrected visual acuity test), HP:0000551 (Color vision defect), HP:0000613 (Photophobia), HP:0000639 (Nystagmus), HP:0007401 (Macular atrophy), HP:0000545 (Myopia)
ModelEvidence: This is a naturally occurring macaque model that matches the autosomal recessive mode of inheritance from the human patients (Figure 7) and exhibits reduced visual acuity (Supplemental Video 1), lack of light-adapted ERG responses and normal dark-adapted ERG responses (Figures 1A-1E, Figure 2). The affected animals also exhibit progressive macular atrophy consistent with achromatopsia (Figure 3). Reduced foveal thickness was also observed (Figures 4A, 4B), as well as thinning of the outer nuclear layer and photoreceptor outer segments (Figures 5A, 5B).
ModelVariant: This model did not introduce a disease-associated variant known from an affected human patient, but rather studied a naturally occurring variant disrupting the PDE6C locus.
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
The retinal pigment epithelium in Sorsby Fundus Dystrophy shows increased sensitivity to oxidative stress-induced degeneration
PMID: 32828705
Gene: TIMP3
HGNC: 11822
Disease: Sorsby fundus dystrophy (SFD), also known as Sorsby's fundus dystrophy, Sorsby pseudoinflammatory fundus dystrophy, or hemorrhagic macular dystrophy
MONDO: 0007640
InheritancePattern: Autosomal Dominant
Prevalence: Estimated at 1 in 220,000 (PMID: 28847738)
Penetrance: Fully penetrant, onset between the third and sixth decades of life
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
Mutations in RPE65 cause autosomal recessive childhood-onset severe retinal dystrophy
PMID: 9326941
Gene: RPE65
HGNC: 10294
Disease: Retinitis pigmentosa 20
MONDO: 0013425
InheritancePattern: Autosomal Recessive
Prevalence: The overall prevalence of Retinitis pigmentosa is between 1 in 3,000 and 1 in 4,000 individuals, while the proportion of recessive Retinitis pigmentosa caused by RPE65 variants is ~2%. (PMID: 9501220) Thus, the prevalence of Retinitis pigmentosa 20 is between 1 in 150,000 and 1 in 200,000.
Penetrance: Fully penetrant, with onset typically in childhood
912 + 1G-->T
FamilyLabel: Gu_1997_Family_PMK18
FamilyPresentingHPOs: HP:0410280 (Pediatric onset), HP:0007663 (Reduced visual acuity), HP:0001098 (Abnormal fundus morphology)
FamilyPresentingHPOFreeText: Onset is early and course of disease is severe. The appearance of the fundus in adulthood is considered characteristic of retinitis pigmentosa.
FamilyNotHPOs: N/A
CountryOrigin: India
Ethnicity: Not mentioned
Race: Not mentioned
Family#PreviousTesting: Previous testing consisted of linkage analysis using microsatellite repeat markers (D152803, DJS1665, D1S438 and DJS1728) associated with the RPE65 locus.
Family#Method1: Linkage analysis
Family#GenotypingMethod: PCR products from affected and control family members were screened by restriction digest analysis using the Msel endonuclease.
Affected: 5
Unaffected: 4
Segregations: 7 segregations were reported, with one inconsistent (patient V-8 is heterozygous while the other affected patients are all homozygous). The pedigree (Figure 1) shows consanguinity between the parents of each affected individual.
PublishedLOD: N/A
eLOD: 2.91
AddSegregationInfo: N/A
ProbandLabel: Gu_1997_Family_PMK18_Patient_V-1
Variant: 4 out of 5 affected individuals are homozygous for the variant.
ClinVar: 98893
gnomAD: The NM_000329.3(RPE65):c.858+1G>T variant is not shown in gnomAD.
FamilyAddInfo: The family pedigree shows consanguinity in the parents of all affected individuals.
FamilyPMIDs: N/A
Cloning of the gene for ocular albinism type 1 from the distal short arm of the X chromosome
PMID: 7647783
Gene: GPR143
HGNC: 20145
Disease: X-linked recessive ocular albinism
MONDO: 0021019
InheritancePattern: X-linked recessive
Prevalence: Ocular albinism has an estimated prevalence between 1 in 111,000 and 1 in 1,000,000 live births (PMID: 35495622)
Penetrance: Fully penetrant in males, with onset in infancy. Most female carriers appear to be unaffected.
RP1L1 variants are associated with a spectrum of inherited retinal diseases including retinitis pigmentosa and occult macular dystrophy
PMID: 23281133
Gene: RP1L1
HGNC: 15946
Disease: occult macular dystrophy
MONDO: 0013316
InheritancePattern: autosomal dominant
Prevalence: The prevalence of occult macular dystrophy is "significantly less than one in 10,000 or 100,000 (https://www.reviewofoptometry.com/article/the-best-is-yet-to-come-feb).
Penetrance: The disease is known to be incompletely penetrant in family members carrying the heterozygous p.Arg45Trp variant (PMID: 20826268).
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
autosomal recessive
FamilyLabel: Corton_2010_Family_RP-72
Family#PresentingHPOs: HP:0410280 (Pediatric onset), HP:0000662 (Nyctalopia), HP:0000540 (Hypermetropia), HP:0007663 (Reduced visual acuity), HP:0001133 (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)
FamilyPresentingHPOFreeText: The affected family members have been diagnosed with retinitis pigmentosa segregating with an autosomal recessive mode of inheritance.
FamilyNotHPOs: N/A
FamilyNotHPOFreeText: N/A
CountryOrigin: Spain / Galicia
Ethnicity: Spanish
Race: Not specifically described
Family#PreviousTesting: N/A
Family#Method1: Haplotype analysis
Family#Method2: Sanger sequencing of 3 candidate genes; PDE6A, PDE6B, and RHO
Family#GenotypingMethod: Haplotype analysis was performed in affected and unaffected family members to identify candidate regions of homozygosity in all affected individuals. Sanger sequencing was then performed on PCR products of exons and flanking regions from the PDE6A, PDE6B, and RHO loci.
Affected: 4
Unaffected: 5 fully genotyped
Segregations: 4 segregations are shown by the pedigree in Figure 1a.
PublishedLOD: N/A
eLOD: 2.43
AddSegregationInfo: N/A
ProbandLabel: Corton_2010_Family_RP-72_patient_IV:2
Variant: The affected family members harbor 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).
FamilyAddInfo: The family includes multiple consanguineous unions, including the proband's parents, and three affected paternal aunts.
FamilyPMIDs: N/A
Next-Generation Sequencing–Based Molecular Diagnosis of a Chinese Patient Cohort With Autosomal Recessive Retinitis Pigmentosa
PMID: 23661369
Gene: ADAM9
HGNC: 216
Disease: cone-rod dystrophy 9
MONDO: MONDO:0013002
InheritancePattern: autosomal recessive
Prevalence: The prevalence of cone-rod dystrophy in general is estimated to be 1 in 40,000 (PMID: 17270046), however, the specific prevalence of cone-rod dystrophy 9 is unknown.
Penetrance: Penetrance appears to be complete in reported families, but it is possible that incomplete penetrance may be associated with some variants.
In the IMPG2 mutant, a 7 nt deletion in exon 3 led to a premature termination on the same exon. In both cases, we expected nonsense-mediated decay and consequent loss of IMPG1 and IMPG2 proteins (Fig. 2A). The IHC analysis confirmed the absence of IMPG1 or IMPG2 proteoglycans in IMPG1 and IMPG2 KO mice, respectively.
ExperimentName: CRISPR/Cas9-based disruption of mouse Impg2
NonHumanModel: Mus musculus
GeneAlteration: Model animals were subjected to CRISPR/Cas9-based deletion of 7bp from exon 3 of Impg2, and analyzed in the homozygous state. Absence of Impg2 signal was confirmed by immunofluorescent staining. Mice were studied at ages 5 months and 8 months.
ModelPhenotype: HP:0030612 (Abnormal retinal morphology, specifically mislocalization / scattering of IMPG1 throughout the outer segment and at the boundary with the RPE), HP:0030643 (Vitelliform-like subretinal lesions), HP:0000654 (Decreased light- and dark-adapted electroretinogram amplitude)
HumanPhenotype: HP:0000529 (Progressive visual loss), HP:0000662 (Nyctalopia), HP:0000551 (Color vision defect), HP:0008002 (Abnormality of macular pigmentation), HP:0000543 (Optic disc pallor), HP:0007843 (Attenuation of retinal blood vessels), HP:0000533 (Chorioretinal atrophy), HP:0000518 (Cataract), HP:0008323 (Abnormal light- and dark-adapted electroretinogram), HP:0007737 (Bone spicule pigmentation of the retina), HP:0007994 (Peripheral visual field loss), HP:0000603 (Central scotoma)
ModelEvidence: This is the first mouse model of Impg2 disruption, with confirmed absence of Impg2 in the homozygous animals. Abnormalities included mislocalization of Impg1 and the cone-specific marker Pna (Figure 2), accumulation of anomalous material between the photoreceptor outer segment and RPE (Figure 3), development of subretinal hyper-reflective vitelliform lesions (Figure 4), and reduction in the amplitudes of ERG responses from both rods (Figure 5A) and cones (Figure 5B).
ModelVariant: The model does not introduce a variant previously observed in human patients, but rather disrupts the expression of the Impg2 ortholog.
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
The Benign Concentric Annular Macular Dystrophy Locus Maps to 6p12.3-q16
PMID: 14691150
Gene: IMPG1
HGNC: 6055
Disease: vitelliform macular dystrophy 4
MONDO: 0014508
InheritancePattern: semi-dominant
Prevalence: Vitelliform macular dystrophy in general is estimated to have a prevalence of 1 in 5,500 (PMID: 27120116).
Penetrance: The penetrance of the phenotype among homozygous cases appears to be complete, while heterozygous carriers of deleterious variants show incomplete penetrance and variable expressivity.
Eyes shut homolog (EYS) interacts with matriglycan of O-mannosyl glycans whose deficiency results in EYS mislocalization and degeneration of photoreceptors
PMID: 32385361
Gene: EYS
HGNC: 21555
Disease: Retinitis pigmentosa 25
MONDO: MONDO:0011272
InheritancePattern: autosomal recessive
Prevalence: The overall prevalence of retinitis pigmentosa is between 1 in 3,000 and 1 in 4,000 individuals, while the proportion of retinitis pigmentosa caused by homozygous or compound heterozygous EYS variants is estimated to be 12% in the French population (PMID: 20333770), implying in an overall prevalence between 1 in 25,000 and 1 in 33,000.
Penetrance: The disease appears to be completely penetrant among published families.
Photoreceptor peripherin is the normal product of the gene responsible for retinal degeneration in the rds mouse
PMID: 1992463
Gene: PRPH2
HGNC: 9942
Disease: retinitis pigmentosa 7
MONDO: 0011974
InheritancePattern: semi-dominant
Prevalence: The incidence of PRPH2-related cases among inherited retinal dystrophies is reported to range from 3.5% in North America to 10.3% in France (PMID: 36010202).
Penetrance: The penetrance among biallelic cases appears to be complete, while the monoallelic cases exhibit incomplete penetrance (PMID: 36609934).
Systemic splicing factor deficiency causes tissue-specific defects: a zebrafish model for retinitis pigmentosa
PMID: 21051334
Gene: PRPF4
HGNC: 17349
Disease: retinitis pigmentosa 70
MONDO: 0014400
InheritancePattern: autosomal dominant
Prevalence: The overall prevalence of retinitis pigmentosa is between 1 in 3,000 and 1 in 4,000 individuals, while the proportion of retinitis pigmentosa with a dominant mode of inheritance is estimated to be 15-35% (between 1 in 8,500 and 1 in 27,000). The proportion of that incidence made up by the specific form caused by variants in PRPF4 is not clear.
Penetrance: Known disease-causing alleles appear to be incompletely penetrant (PMID: 25383878).
Interactions within the Coiled-coil Domain of RetGC-1 Guanylyl Cyclase Are Optimized for Regulation Rather than for High Affinity
PMID: 11306565
Gene: GUCY2D
HGNC: 4689
Disease: Cone-rod dystrophy 6
MONDO: 0011143
InheritancePattern: Autosomal Dominant
Prevalence: The overall prevalence of cone-rod dystrophy is between 1 in 30,000 and 1 in 40,000 (PMID: 17270046), while the proportion of cone-rod dystrophy caused by GUCY2D variants is between 19% and 23% (PMID: 22183351, PMID: 25515582). Thus, the prevalence of cone-rod dystrophy 6 is between 1 in 130,000 and 1 in 215,000.
Penetrance: Penetrance is age-dependent, with onset between the 1st and 6th decades of life.
Haplotype reconstruction in three SFD families revealed that the identified c.113C>G, p.(Ser38Cys) mutation is a founder in Belgian and northern French families with a late-onset SFD phenotype.
GroupName: Naessens_2019_Group
GroupPresentingHPOs: HP:0011510 (Drusen)
GroupHPOFreeText: Relatively late onset of phenotypes between ages 49 and 74. Drusen / deposits were universal except for 3 individuals between the ages of 37 and 47.
GroupNotHPOs: N/A
GroupNotHPOFreeText: pulmonary involvement
GroupDemographics
NumberMales: 13
NumberFemales: 9
CountryOrigin: Belgium (Families 1 and 3) or northern France (Family 2)
Ethnicity: Not mentioned
Race: Not mentioned
AgeRange: The individuals mentioned range in age from 51 to 74 years, although other unmentioned individuals may be older or younger.
TotalNumber: 22
FamilyInfo: 21
NoFamily: 1
VariantCount: 22
NonVariant: 0
OtherVariant: N/A
GroupPreviousTesting: N/A
GroupGenotypingMethod: PCR amplification of all 5 coding exons of TIMP3, followed by Sanger sequencing
SPACR Encoded by IMPG1 Is Essential for Photoreceptor Survival by Interplaying between the Interphotoreceptor Matrix and the Retinal Pigment Epithelium
PMID: 36140676
Gene: IMPG1
HGNC: 6055
Disease: vitelliform macular dystrophy 4
MONDO: 0014508
InheritancePattern: semi-dominant
Prevalence: Vitelliform macular dystrophy in general is estimated to have a prevalence of 1 in 5,500 (PMID: 27120116).
Penetrance: The penetrance of the phenotype among homozygous cases appears to be complete, while heterozygous carriers of deleterious variants show incomplete penetrance and variable expressivity.
Peripherin mutations cause a distinct form of recessive Leber congenital amaurosis and dominant phenotypes in asymptomatic parents heterozygous for the mutation
PMID: 26061163
Gene: PRPH2
HGNC: 9942
Disease: retinitis pigmentosa 7
MONDO: 0011974
InheritancePattern: semi-dominant
Prevalence: The incidence of PRPH2-related cases among inherited retinal dystrophies is reported to range from 3.5% in North America to 10.3% in France (PMID: 36010202).
Penetrance: The penetrance among biallelic cases appears to be complete, while the monoallelic cases exhibit incomplete penetrance (PMID: 36609934).
(https://eyeintegration.nei.nih.gov/)
Selection A - Gene is expressed in tissues relevant to disease:
ExperimentName: High GUCY2D mRNA expression in human retina relative to other tissue types
TissueExpression: Retina (UBERON:0000966)
ExpressionEvidence: Evidence can be accessed on the publication-associated website (https://eyeintegration.nei.nih.gov/) through the Pan-Tissue Plots feature.
CLN5 and CLN8 protein association with ceramide synthase: biochemical and proteomic approaches
PMID: 23160995
Gene: CLN5
HGNC: 2076
Disease: Ceroid lipofuscinosis, neuronal, 5 (also known as Finnish variant late infantile neuronal ceroid lipofuscinosis, neuronal ceroid lipofuscinosis late infantile Finnish variant, or Finnish vLINCL)
MONDO: 0009745
InheritancePattern: Autosomal Recessive
Prevalence: Unknown, but part of a larger group of NCL disorders with a collective prevalence between 1 in 12,500 (PMID:9662406) and 1 in 100,000 (PMID:23374165)
Penetrance: Fully penetrant, with onset often in the late infantile period but in some cases during early adulthood or even as late as in the 6th decade of life
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
Targeted multi-gene panel testing for the diagnosis of Bardet Biedl syndrome: Identification of nine novel mutations across BBS1, BBS2, BBS4, BBS7, BBS9, BBS10 genes
PMID: 26518167
Gene: BBS7
HGNC: 18758
Disease: Bardet-Biedl syndrome 7
MONDO: 0014435
InheritancePattern: autosomal recessive
Prevalence: The prevalence of BBS7 variants among Bardet-Biedl syndrome cohorts has been reported at 4.2% (PMID: 19402160), while the prevalence of Bardet-Biedl syndrome overall has been estimated between 1 in 13,500 and 1 in 160,000 live births, depending on the population (PMID: 22713813).
Penetrance: The penetrance of the phenotype among homozygous cases appears to be complete.
Gene therapy was performed on adult squirrel monkeys (Saimiri sciureus) that were missing the L opsin gene. In this species, some females have trichromatic colour vision while males are red-green colour blind2.
ExperimentName: Colorblind squirrel monkeys were rescued by human OPN1LW.
NonHumanModel: Saimiri sciureus
GeneAlteration: Male squirrel monkeys were missing OPN1LW gene. Controls with the intact gene were not part of the study.
RescueVariant: Rescue was performed by subretinal injection of recombinant adeno-associated virus containing human OPN1LW under control of the appropriate enhancer and promoter and featured the wild-type gene rather than a variant.
RescuePhenotype: The rescued phenotypes are inability to discriminate between blue and green wavelengths to obtain a food reward and defects in performance on a computer-administered Cambridge colour test.
RescueMethod: This rescue model has injection of recombinant adeno-associated virus containing human wild-type OPN1LW under control of the appropriate enhancer and promoter.
RescueEvidence: Squirrel monkeys gained the ability to discriminate between blue and green wavelengths to obtain a food reward (data not shown), as well as significant improvement in ability to distinguish colors occurring at ~20 weeks post-injection (Figure 3A). Gaps in the ability to detect certain wavelengths pre-injection (solid lines) were filled in post-injection (dotted lines) in monkey 1 (Panel 3B) and monkey 2 (Panel 3C). These confirmed that monkeys had become trichomatic and matched the new ability to access food rewards.
ModelVariant: The model does not include any human OPN1LW variant, only the wild-type gene.
We demonstrate that the 60 and 90kD tri-snRNP proteins specifically associate with the U4/U6 snRNP at salt concentrations where the tri-snRNP complex has dissociated. The primary structures of the 60kD and 90kD proteins were determined by cloning and sequencing their respective cDNAs. The U4/U6-60kD protein possesses a C-terminal WD domain that contains seven WD repeats and thus belongs to the WD-protein family, whose best-characterized members include the Gbeta subunits of heterotrimeric G proteins. A database homology search revealed a significant degree of overall homology (57.8% similarity, 33.9% identity) between the human 60kD protein and the Saccharomyces cerevisiae U4/U6 snRNP protein Prp4p. Two additional, previously undetected WD repeats (with seven in total) were also identified in Prp4p, consistent with the possibility that 60kD/Prp4p, like beta-transducin, may adopt a propeller-like structure. The U4/U6-90kD protein was shown to exhibit significant homology, particularly in its C-terminal half, with the S. cerevisiae splicing factor Prp3p, which also associates with the yeast U4/U6 snRNP. Interestingly, U4/U6-90kD shares short regions of homology with E. coli RNase III, including a region encompassing its double-stranded RNA binding domain. Based on their structural similarity with essential splicing factors in yeast, the human U4/U6-60kD and 90kD proteins are likely also to play important roles in the mammalian splicing process.
Selection A- Gene with same function implicated in disease
ExperimentName: PRPF4 is a U4/U6 small nuclear ribonucleoprotein component that functions in mRNA splicing.
GOterm: GO:0000398 (mRNA splicing, via spliceosome)
FunctionalEvidence: PRPF4, PRPF3, PRPF31, and PRPF8 are all splicing factors involved in mRNA processing and are encoded by genes that harbor variants associated with retinitis pigmentosa.
HGNC: HGNC:17348 (PRPF3, retinitis pigmentosa 18), HGNC:15446 (PRPF31, retinitis pigmentosa 11), HGNC:17340 (PRPF8, retinitis pigmentosa 13)
GeneEvidence: PRPF3 harbors variants that cause retinitis pigmentosa 18 (PMID: 11773002), PRPF31 harbors variants that cause retinitis pigmentosa 11 (PMID: 12444105), and PRPF8 harbors variants that cause retinitis pigmentosa 13 (PMID: 7951236).
SharedGeneImplication: PRPF4, PRPF3, PRPF31, and PRPF8 are encode splicing factors involved in mRNA processing.
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
RPE65 is the isomerohydrolase in the retinoid visual cycle
PMID: 16116091
Gene: RPE65
HGNC: 10294
Disease: Leber congenital amaurosis 2
MONDO: 0008765
InheritancePattern: Autosomal Recessive
Prevalence: The overall prevalence of Leber congenital amaurosis is between 1 in 33,000 and 1 in 100,000 newborns, while the proportion of Leber congenital amaurosis caused by RPE65 variants is between 1% and 16.7%. Thus, the prevalence of Leber congenital amaurosis 2 is between 1 in 200,000 and 1 in 10,000,000.
Penetrance: Fully penetrant, with onset typically by 1 year of age
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
Impacts of two point mutations of RPE65 from Leber's congenital amaurosis on the stability, subcellular localization and isomerohydrolase activity of RPE65
PMID: 16828753
Gene: RPE65
HGNC: 10294
Disease: Retinitis pigmentosa 20
MONDO: 0013425
InheritancePattern: Autosomal Recessive
Prevalence: The overall prevalence of Retinitis pigmentosa is between 1 in 3,000 and 1 in 4,000 individuals, while the proportion of recessive Retinitis pigmentosa caused by RPE65 variants is ~2%. (PMID: 9501220) Thus, the prevalence of Retinitis pigmentosa 20 is between 1 in 150,000 and 1 in 200,000.
Penetrance: Fully penetrant, with onset typically in childhood
Analysis of the OA1 gene reveals mutations in only one-third of patients with X-linked ocular albinism
PMID: 8634705
Gene: GPR143
HGNC: 20145
Disease: X-linked recessive ocular albinism
MONDO: 0021019
InheritancePattern: X-linked recessive
Prevalence: Ocular albinism has an estimated prevalence between 1 in 111,000 and 1 in 1,000,000 live births (PMID: 35495622)
Penetrance: Fully penetrant in males, with onset in infancy. Most female carriers appear to be unaffected.
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
Our results revealed that the PRPF31 deficiency causes mis-splicing of genes involved in RNA processing (PRPF3, PRPF8, PRPF4, and PRPF19) and phototransduction (RHO, ROM1, FSCN2, GNAT2, and GNAT1) in the retina in the PRPF31 reduced samples. Mis-splicing of genes implicated in phototransduction was associated with photoreceptor degeneration observed in RP patients.
PRPF4, PRPF3, PRPF31, and PRPF8 are all splicing factors involved in mRNA processing and are encoded by genes that harbor variants associated with retinitis pigmentosa.
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
To express the human CORD6 cyclase mutation in mouse rods, cDNA coding for the R838S RetGC1 was transferred from the expression vector used in HEK293 cells (Fig. 1) and inserted under the control of rod opsin promoter (47.Lem J. Applebury M.L. Falk J.D. Flannery J.G. Simon M.I. Tissue-specific and developmental regulation of rod opsin chimeric genes in transgenic mice.Neuron. 1991; 6: 201-210Abstract Full Text PDF PubMed Scopus (155) Google Scholar) in the transgene construct (Fig. 2A) injected in mouse eggs (see “Experimental Procedures” for details). Although CORD6 affects both rods and cones, we chose the promoter that is efficient only in rods to keep the non-expressing cones as a negative control group of photoreceptors in the same transgenic retinas and thus verify that any physiological changes we may observe specifically originate from the transgene-targeted photoreceptors. Founders screened for the presence of the transgenic construct (Fig. 2A) and passing the transgene to the progeny were then bred to wild type C67B6J mice for at least 4 consecutive generations to establish the R838S RetGC1 expressing lines (R838S+) 379 and 362 for subsequent detailed analysis. As will be demonstrated further in this article, the line 379 developed more gradually deterioration (arbitrarily dubbed “slower” line) and the line 362, a more severe phenotype (“faster” line).
ExperimentName: Transgenic mouse expressing human GUCY2D R838S
NonHumanModel: Mus musculus
GeneAlteration: A human GUCY2D transgene encoding the R838S substitution was placed under the control of the rod opsin promoter and injected into mouse eggs, creating a mouse model with rod-specific expression of the variant (and only inefficient expression in cones).
ModelPhenotype: HP:0030469 (Abnormal dark-adapted electroretinogram), HP:0030483 (Reduced amplitude of dark-adapted bright flash electroretinogram a-wave), HP:0030478 (Abnormal amplitude of dark-adapted bright flash electroretinogram), HP:0030609 (Photoreceptor layer loss on macular OCT), HP:0410280 (Pediatric onset), HP:0000546 (Retinal degeneration)
HumanPhenotype: HP:0000548 (Cone/cone-rod dystrophy), HP:0007663 (Reduced visual acuity), HP:0007994 (Peripheral visual field loss), HP:0000613 (Photophobia), HP:0011504 (Bull's eye maculopathy), HP:0030465 (Undetectable light-adapted electroretinogram), HP:0030469 (Abnormal dark-adapted electroretinogram)
ModelEvidence: The model system approximately recapitulates the mode of inheritance (autosomal dominant) of the human disease state. At the molecular level, it increases the sensitivity of cGMP synthesis to calcium ion concentration (Figures 2B, 7A). At the ocular level, rod response (dark-adapted ERG) amplitudes were diminished starting at one month of age (Figure 4A, 4B), particularly by 6 months (Figure 5A, 5B), while cones lacking transgene expression remained functional (Figure 5A, 5C). Retinal morphology between 3 and 5 months of age showed outer nuclear layer reduction (Figures 6A, 7C) linked to photoreceptor loss (Figures 6B, 7D).
ModelVariant: NM_000180.4(GUCY2D):c.2512C>A (p.Arg838Ser) (ClinVar: 98568)
recessive mutations
FamilyLabel: van_Huet_2014_Family_F, family national origin reported as from Pakistan
Family#PresentingHPOs: HP:0410280 (Pediatric onset), HP:0000662 (Nyctalopia), HP:0000545 (Myopia), HP:0007663 (Reduced visual acuity), HP:0000543 (Optic disc pallor), HP:0007843 (Attenuation of retinal blood vessels), HP:0007737 (Bone spicule pigmentation of the retina)
FamilyHPOFreeText: The patient and family members have been diagnosed with retinitis pigmentosa, with macular abnormalities present in all cases.
Family#PresentingNotHPOs: N/A
CountryOrigin: Pakistan
Ethnicity: Not mentioned
Race: Not mentioned
Family#PreviousTesting: Previous genotyping outside of the IMPG2 locus has not been described for this family.
Family#Method1: Sanger sequencing of the 19 exons of the IMPG2 gene
Family#Method2: N/A
Family#GenotypingMethod: Genotyping may have been limited to Sanger sequencing of the 19 exons of the IMPG2 gene, as previous genotyping of other loci has not been described for this family.
Affected: 3
Unaffected: 3
Segregations: Two segregations are reported in the family, with none inconsistent. The family is apparently consanguineous, with the parents being first cousins. The pedigree is shown in Figure 1.
PublishedLOD: N/A
eLOD: 1.50
AddSegregationInfo: N/A
ProbandLabel: van_Huet_2014_Patient_F-II:2
Variant: The affected family members harbor the NM_016247.4(IMPG2):c.1680T>A (p.Tyr560Ter) variant in the homozygous state.
ClinVar: 437938
gnomAD: This variant was not found in gnomAD v2.1.1.
FamilyAddInfo: The family is reportedly consanguineous, with the parents being first cousins.
FamilyPMIDs: N/A
A novel Ser156Cys mutation in the tissue inhibitor of metalloproteinases-3 (TIMP3) in Sorsby's fundus dystrophy with unusual clinical features
PMID: 8634721
Gene: TIMP3
HGNC: 11822
Disease: Sorsby fundus dystrophy (SFD), also known as Sorsby's fundus dystrophy, Sorsby pseudoinflammatory fundus dystrophy, or hemorrhagic macular dystrophy
MONDO: 0007640
InheritancePattern: Autosomal Dominant
Prevalence: Estimated at 1 in 220,000 (PMID: 28847738)
Penetrance: Fully penetrant, onset between the third and sixth decades of life
The whole-genome sequence contained a homozygous nonsense mutation: CLN5:c.619C>T. All 4 DNA samples from clinically affected dogs tested homozygous for the variant allele. Both parents of the fifth affected dog were heterozygotes.
ExperimentName: Genotyping of 4 Australian Cattle Dogs affected with NCL
NonHumanModel: Canis familiaris
GeneAlteration: While the model does not have an engineered gene alteration, all four affected animals are homozygous for the CLN5:c.619C>T variant. The unaffected parents of a fifth affected dog were both heterozygotes for this variant.
ModelPhenotype: HP:0001250 (Seizure), HP:0000572 (Visual loss), HP:0000708 (Behavioral abnormality), HP:0002370 (Poor coordination), HP:0002312 (Clumsiness), HP:0001251 (Ataxia), HP:0100299 (Muscle fiber inclusion bodies), HP:0002283 (Global brain atrophy), HP:0002119 (Ventriculomegaly), Note: inclusion bodies are membrane-associated and autofluorescent. Onset of phenotypes was between 12-18 months, and the condition was rapidly progressive, with euthanasia occurring between 20-27 months of age.
HumanPhenotype: 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:0100952 (Enlarged sylvian cistern), HP:0002059 (Cerebral atrophy), HP:0001272 (Cerebellar atrophy)
ModelEvidence: The model phenotypes closely match the human patient phenotypes in the timing of onset and rapid progression (Table 3), neurological details, vision problems, loss of coordination, and microscopic accumulation of storage/inclusion bodies (Figure 4, Figure 5).
ModelVariant: CLN5:c.619C>T p.Gln207Ter
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
Identification of GUCY2D gene mutations in CORD5 families and evidence of incomplete penetrance
PMID: 12552567
Gene: GUCY2D
HGNC: 4689
Disease: Cone-rod dystrophy 6
MONDO: 0011143
InheritancePattern: Autosomal Dominant
Prevalence: The overall prevalence of cone-rod dystrophy is between 1 in 30,000 and 1 in 40,000 (PMID: 17270046), while the proportion of cone-rod dystrophy caused by GUCY2D variants is between 19% and 23% (PMID: 22183351, PMID: 25515582). Thus, the prevalence of cone-rod dystrophy 6 is between 1 in 130,000 and 1 in 215,000.
Penetrance: Penetrance is age-dependent, with onset between the 1st and 6th decades of life.
We generated D477G RPE65 KI mice by replacing the endogenous RPE65 gene with a targeting vector including exons 8–14 along with the D477G mutation (Fig. 2A). A neomycin (Neo) cassette flanked by Flp-recombinase target (FRT) sites was used for clonal selection and later excised by FLP recombinase expressed in the embryonic stem cells. The embryonic stem cells carrying the Neo deleted targeting vector were microinjected into C57Bl/6 blastocysts.
ExperimentName: Recombinase-based variant knock-in to the mouse Rpe65 locus
NonHumanModel: Mus musculus
GeneAlteration: A substitution equivalent to the human NM_000329.3(RPE65):c.1430A>G (p.Asp477Gly) variant was knocked into the mouse Rpe65 locus by Flp-recombinase, which allowed the selection cassette to be subsequently excised.
ModelPhenotype: HP:0030602 (Abnormal fundus autofluorescence imaging), HP:0030329 (Retinal thinning), HP:0030483 (Reduced amplitude of dark-adapted bright flash electroretinogram a-wave), HP:0008275 (Abnormal light-adapted electroretinogram)
HumanPhenotype: HP:0000662 (Nyctalopia), HP:0007688 (Undetectable light- and dark-adapted electroretinogram), HP:0001098 (Abnormal fundus morphology), HP:0000529 (Progressive visual loss)
ModelEvidence: The mice exhibit reduced levels of RPE65 protein (Figure 3A) and enhanced ubiquitination (Figure 3B), indicating higher susceptibility to proteolysis. Despite normal 11-cis retinal levels (Figure 7C), the heterozygous knock-in animals exhibit abnormal accumulation of retinyl esters (Figure 7B), recapitulating a key molecular defect of the human patients. Photobleaching revealed defects in regeneration of 11-cis-retinal (Figure 7F) and accumulation of retinyl esters (Figure 7G). These defects were observable in both the heterozygous knock-in (mild) and homozygous knock-in (more severe). Accumulation of autofluorescent spots in the fundus (Figure 4), progressive thinning of the outer nuclear layer (Figure 5), and abnormal ERG responses (Figure 6) were seen in heterozygous knock-in and especially homozygous knock-in mice with age. Similar phenotypic results were observed with a third, similar knock-in mouse model (PMID: 28041994).
ModelVariant: The model knocks the NM_000329.3(RPE65):c.1430A>G (p.Asp477Gly) variant (ClinVar:750796) into the endogenous mouse Rpe65 locus.
two Japanese
FamilyLabel: Tabata_1998_Family_Ch
Family#PresentingHPOs: HP:0007663 (Reduced visual acuity), HP:0025094 (Disciform macular scar), HP:0000529 (Progressive visual loss)
FamilyHPOFreeText: Onset of decreased central vision was seen in the 6th or 7th decade of life (between the ages of 52 and 66), although abnormal findings on ophthalmoscopy (early macular degeneration) found in 4th decade of life.
FamilyNotHPOs: HP:0007994 (Peripheral visual field loss)
FamilyNotHPOFreeText: Although central vision was progressively lost, peripheral fundi remained uninvolved and affected individuals continued to walk unguided into the 8th decade of life and beyond.
CountryOrigin: Japan
Family#PreviousTesting: PCR-based heteroduplex analysis using gel electophoresis
Family#GenotypingMethod: Sanger sequencing
Affected: 2
Unaffected: 3
Segregations: N/A
PublishedLOD: N/A
eLOD: Insufficient information available
AddSegregationInfo: N/A
ProbandLabel: Tabata_1998_Family_Ch_patient_1
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.
FamilyAddInfo: While Family Ue and Family Ch are two distinct families, united by the NM_000362.5:c.439-2dup (TIMP3) variant harbored by their affected family members, they share a geographical place of origin within Japan (PMID:9760202).
FamilyPMIDs: 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.
A novel splice site mutation in the tissue inhibitor of the metalloproteinases-3 gene in Sorsby’s fundus dystrophy with unusual clinical features
PMID: 9760202
Gene: TIMP3
HGNC: 11822
Disease: Sorsby fundus dystrophy (SFD), also known as Sorsby's fundus dystrophy, Sorsby pseudoinflammatory fundus dystrophy, or hemorrhagic macular dystrophy
MONDO: 0007640
InheritancePattern: Autosomal Dominant
Prevalence: Estimated at 1 in 220,000 (PMID: 28847738)
Penetrance: Fully penetrant, onset between the third and sixth decades of life
The rhodopsin cycle is preserved in IRBP "knockout" mice despite abnormalities in retinal structure and function
PMID: 10750831
Gene: RBP3
HGNC: 9921
Disease: retinitis pigmentosa 66
MONDO: 0014093
InheritancePattern: autosomal recessive
Prevalence: RBP3-related cases are believed to be very rare (possibly with estimated prevalence of less than 1 in 1,000,000), however, it is believed that there may be under-diagnosis (PMID: 37806543).
Penetrance: RBP3 disease-causing variants appear to have complete penetrance.
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
Leber congenital amaurosis
PMID: 9501220
Gene: RPE65
HGNC: 10294
Disease: Leber congenital amaurosis 2
MONDO: 0008765
InheritancePattern: Autosomal Recessive
Prevalence: The overall prevalence of Leber congenital amaurosis is between 1 in 33,000 and 1 in 100,000 newborns, while the proportion of Leber congenital amaurosis caused by RPE65 variants is between 1% and 16.7%. Thus, the prevalence of Leber congenital amaurosis 2 is between 1 in 200,000 and 1 in 10,000,000.
Penetrance: Fully penetrant, with onset typically by 1 year of age
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
MDC-9 (ADAM-9/Meltrin gamma) functions as an adhesion molecule by binding the alpha(v)beta(5) integrin
PMID: 11162558
Gene: ADAM9
HGNC: 216
Disease: cone-rod dystrophy 9
MONDO: MONDO:0013002
InheritancePattern: autosomal recessive
Prevalence: The prevalence of cone-rod dystrophy in general is estimated to be 1 in 40,000 (PMID: 17270046), however, the specific prevalence of cone-rod dystrophy 9 is unknown.
Penetrance: Penetrance appears to be complete in reported families, but it is possible that incomplete penetrance may be associated with some variants.
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
The antibody produced strong immunolabeling of Bruch's membrane and drusen and weak labeling of retina blood vessels in unfixed human and baboon eyes. Unfixed chicken, cow, pig, and rat tissues showed no reactivity. After antigen retrieval, all fixed human eyes showed specific labeling of Bruch's membrane and drusen, which was strongest in eyes from elderly donors. The results indicate that TIMP-3 is an extracellular matrix component of Bruch's membrane.
Selection A- Gene is expressed in tissues relevant to disease:
ExperimentName: Immunohistochemical localization of TIMP3 expression to Bruch's membrane and drusen deposits
TissueExpression: Strong expression was observed in Bruch's membrane (UBERON:0003957) and associated drusen, while weak expression was observed in retinal blood vessels (UBERON:0003501).
ExpressionEvidence: TIMP3 was detected in human eye sections (from patients aged 24 to 85 years) using a monoclonal antibody and a TIMP-3 synthetic peptide for specificity. Bruch's membrane was specifically labeled by the antibody (Figure 2B), with strong labeling observed from the RPE to the elastin sublayer. Drusen associated with Bruch's membrane (particularly smaller deposits) also stained strongly for TIMP3 (Figure 2D), while retinal blood vessels showed weak staining as well. Overall, staining was particularly intense in sections from older patients.
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
Presentation of TRPM1-Associated Congenital Stationary Night Blindness in Children
PMID: 29522070
Gene: TRPM1
HGNC: 7146
Disease: congenital stationary night blindness 1C
MONDO: MONDO:0013183
InheritancePattern: autosomal recessive
Prevalence: Congenital stationary night blindness has an estimated prevalence between 1 in 6,000 (PMID: 31427709) and 1 in 300,000 (PMID: 3487908). However, the prevalence of congenital stationary night blindness 1C specifically is unknown.
Penetrance: Penetrance is thought to be complete.
Identification of a 2 Mb Human Ortholog of Drosophila eyes shut/spacemaker that Is Mutated in Patients with Retinitis Pigmentosa
PMID: 18976725
Gene: EYS
HGNC: 21555
Disease: Retinitis pigmentosa 25
MONDO: MONDO:0011272
InheritancePattern: autosomal recessive
Prevalence: The overall prevalence of retinitis pigmentosa is between 1 in 3,000 and 1 in 4,000 individuals, while the proportion of retinitis pigmentosa caused by homozygous or compound heterozygous EYS variants is estimated to be 12% in the French population (PMID: 20333770), implying in an overall prevalence between 1 in 25,000 and 1 in 33,000.
Penetrance: The disease appears to be completely penetrant among published families.
Decreased catalytic activity and altered activation properties of PDE6C mutants associated with autosomal recessive achromatopsia
PMID: 21127010
Gene: PDE6C
HGNC: 8787
Disease: cone dystrophy 4
MONDO: 0013129
InheritancePattern: recessive
Prevalence: cone dystrophy in general is estimated to have a prevalence of 1 in 40,000 (PMID: 30578485).
Penetrance: The penetrance of the phenotype among homozygous cases appears to be complete.
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
Rpe65 is necessary for production of 11-cis-vitamin A in the retinal visual cycle
PMID: 9843205
Gene: RPE65
HGNC: 10294
Disease: Leber congenital amaurosis 2
MONDO: 0008765
InheritancePattern: Autosomal Recessive
Prevalence: The overall prevalence of Leber congenital amaurosis is between 1 in 33,000 and 1 in 100,000 newborns, while the proportion of Leber congenital amaurosis caused by RPE65 variants is between 1% and 16.7%. Thus, the prevalence of Leber congenital amaurosis 2 is between 1 in 200,000 and 1 in 10,000,000.
Penetrance: Fully penetrant, with onset typically by 1 year of age
Genetics and phenotypes of RPE65 mutations in inherited retinal degeneration
PMID: 11095629
Gene: RPE65
HGNC: 10294
Disease: Retinitis pigmentosa 20
MONDO: 0013425
InheritancePattern: Autosomal Recessive
Prevalence: The overall prevalence of Retinitis pigmentosa is between 1 in 3,000 and 1 in 4,000 individuals, while the proportion of recessive Retinitis pigmentosa caused by RPE65 variants is ~2%. (PMID: 9501220) Thus, the prevalence of Retinitis pigmentosa 20 is between 1 in 150,000 and 1 in 200,000.
Penetrance: Fully penetrant, with onset typically in childhood
Primate Retinal Signaling Pathways: Suppressing ON-Pathway Activity in Monkey With Glutamate Analogues Mimics Human CSNB1-NYX Genetic Night Blindness
PMID: 15331616
Gene: NYX
HGNC: 8082
Disease: Congenital stationary night blindness 1A
MONDO: 0010690
InheritancePattern: X-linked recessive
Prevalence: Congenital stationary night blindness has an estimated prevalence between 1 in 6,000 (PMID: 31427709) and 1 in 300,000 (PMID: 3487908). However, the prevalence of congenital stationary night blindness 1A specifically is unknown.
Penetrance: Penetrance is thought to be complete.
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
Characterization of a canine model of autosomal recessive retinitis pigmentosa due to a PDE6A mutation
PMID: 18775863
Gene: PDE6A
HGNC: 8785
Disease: retinitis pigmentosa 43
MONDO: MONDO:0013437
InheritancePattern: autosomal recessive
Prevalence: The overall prevalence of retinitis pigmentosa is between 1 in 3,000 and 1 in 4,000 individuals, while the proportion of retinitis pigmentosa with a recessive mode of inheritance is estimated to be 65-85% (between 1 in 3,500 and 1 in 6,200). Retinitis pigmentosa 43 is considered to be make up 2-5% of these cases, with an overall prevalence estimated between 1 in 70,000 and 1 in 310,000.
Penetrance: Known disease-causing alleles appear to be completely penetrant.
Mutations in spliceosomal proteins and retina degeneration
PMID: 27302685
review article
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
Photoreceptor Structure in GNAT2-Associated Achromatopsia
PMID: 32203983
GeneName: GNAT2
HGNC: 4394
Disease: achromatopsia 4
MonDO ID: MONDO_0013465
Inheritance: autosomal recessive
Frequency and Clinical Pattern of Vitelliform Macular Dystrophy Caused by Mutations of Interphotoreceptor Matrix IMPG1 and IMPG2 Genes
PMID: 25085631
Gene: IMPG2
HGNC: 18362
Disease: retinitis pigmentosa 56
MONDO: 0013314
InheritancePattern: semi-dominant
Prevalence: Vitelliform macular dystrophy in general is estimated to have a prevalence of 1 in 5,500 (PMID: 27120116).
Penetrance: The penetrance of the phenotype among homozygous cases appears to be complete, while heterozygous carriers of deleterious variants show incomplete penetrance and variable expressivity.
A previously described one-step protocol that combines both an episomal-based reprogramming strategy and CRISPR/Cas9-mediated gene editing27 was used to generate clonal uncorrected and gene-corrected iPSC lines within a single experiment (Figure 2A). The Cas9 repair template included correction of the c.634G>A variant as well as an additional synonymous 3 bp change to facilitate the identification of corrected clones and prevent Cas9-mediated cleavage after successful homology-directed repair (Figure 2A). Gene correction was identified in 1 of 44 screened iPSC clones (2.3%). One uncorrected proband (henceforth referred to as PR) and the isogenic, gene-corrected clone (GC) were carried forward to further experiments. Pluripotency was confirmed by culture morphology and staining for common pluripotency markers and subsequent flow cytometry (Figures S1A and S1B).
ExperimentName: Rescue in patient-derived IPSC cells harboring IFT140 variants
RescueProband: Forbes_2018_Proband_1 has been diagnosed with retinitis pigmentosa (age 1), end-stage kidney disease (age 6), and Mainzer-Saldino syndrome (at the time of this study). The proband and her non-consanguineous parents were genotyped by Trio whole exome sequencing, identifying compound heterozygous (paternal and maternal) IFT140 variants in the proband.
GeneAlteration: The proband harbors the NM_014714.4(IFT140):c.634G>A (p.Gly212Arg) and NM_014714.4(IFT140):c.2176C>G (p.Pro726Ala) variants in trans. The former variant has been shown to mislocalize when exogenously expressed as a cDNA, and is predicted to disrupt a donor splice site (SpliceAI change score of 0.61).
RescueVariant: The variant rescued by CRISPR/Cas9-based gene editing was NM_014714.4(IFT140):c.634G>A (p.Gly212Arg), (ClinVar ID: 31683). This variant was corrected at the same time as a synonymous 3 bp change was introduced to facilitate the detection of the editing event.
RescuedPhenotype: Patient IPSC-derived organoids exhibit Short / clubbed cilia with swollen sips (Figure 3A-3C), Approximately 50% expression of IFT140 at both the mRNA and protein levels (Figures 2D, 2E), and Disturbed apicobasal polarity compromising the ability of iPSC cells to establish polarized spheroids (Figures 5C, 5D).
RescueMethod: CRISPR/Cas9-based gene editing was used to correct one of the proband's two variants (NM_014714.4(IFT140):c.634G>A (p.Gly212Arg), (ClinVar ID: 31683)). A synonymous 3 bp change was simultaneously introduced to facilitate the detection of the editing event.
RescueEvidence: Gene-corrected cells had longer ciliary length with reduced clubbing (Figure 3), approximately twice the expression of IFT140 at the mRNA and protein levels (Figures 2D, 2E), and a higher percentage of polarized spheroids established in organoid culture (indicating recovery of apicobasal polarity).
A Complex of BBS1 and NPHP7 Is Required for Cilia Motility in Zebrafish
PMID: 24069149
Gene: BBS1
HGNC: 966
Disease: Bardet-Biedl syndrome 1
MONDO: 0008854
InheritancePattern: autosomal recessive
Prevalence: The prevalence of BBS1 variants among Bardet-Biedl syndrome cohorts has been reported as at least 20% (PMID: 19402160), while the prevalence of Bardet-Biedl syndrome overall has been estimated between 1 in 13,500 and 1 in 160,000 live births, depending on the population (PMID: 22713813).
Penetrance: The penetrance of the phenotype among homozygous cases appears to be complete.
Morpholino oligonucleotide (MO)-mediated knockdown of zbbs1 and znphp7.2 in zebrafish embryos caused phenotypic changes characteristic for “ciliopathies”. Detailed analysis of cilia revealed that despite normal morphology, the cilia in the pronephric tubule and the nasal pit of zBbs1- and zNphp7.2-depleted embryos showed aberrant motility, suggesting that the observed phenotypes are due to the disruption of the normal ciliary beating pattern.
ExperimentName: Morpholino-based knockdown of zbbs1 disrupts ciliary beating pattern.
NonHumanModel: Danio rerio
GeneAlteration: The model animals have been subjected to morpholino-based knockdown of zbbs1, the zebrafish ortholog of human BBS1.
ModelPhenotype: HP:0012262 (Abnormal ciliary motility), HP:0000107 (Renal cyst)
HumanPhenotype: HP:0000639 (Nystagmus), HP:0000510 (Rod-cone dystrophy), HP:0007663 (Reduced visual acuity), HP:0000662 (Nyctalopia), HP:0000518 (Cataract), HP:0008323 (Abnormal light- and dark-adapted electroretinogram), HP:0000107 (Renal cyst), HP:0001513 (Obesity), HP:0010442 (Polydactyly), HP:0002463 (Language impairment), HP:0000026 (Male hypogonadism)
ModelEvidence: Morpholino-based knockdown of the zbbs1 gene causes hydrocephalus (Figure 3B), formation of pronephritic cysts (Figure 3G), embyronic body axis abnormalities (Figure 4B), heart looping defects (Figure 5B), longer cilia (Figure 7F), and normal ciliary ultrastructure (Figure 7I), and aberrant ciliary motility in the pronephritic tubule and nasal pit (Supplementary Movies).
ModelVariant: This model did not introduce a disease-associated variant known from an affected human patient, but rather studied the effects of silencing the gene product.
We developed two independent Impg2 knockout (KO) mouse models using the CRISPR/Cas9 technique to assess the in vivo functions of Impg2 in the retina. Impg2 ablation in mice recapitulated the RP phenotypes of patients, including an attenuated electroretinogram (ERG) response and the progressive degeneration of photoreceptors. The histopathological examination of Impg2-KO mice revealed irregularly arranged rod cells and mislocalized rhodopsin protein in the inner segment at 6 months of age. In addition to the pathological changes in rod cells, cone cells were also affected in KO retinas. KO retinas exhibited progressive cone cell death and impaired cone cell elongation. Further immunoblotting analysis revealed increased levels of endoplasmic reticulum (ER) stress-related proteins, including C/EBP homologous protein (CHOP), immunoglobulin heavy-chain-binding protein (BIP) and protein disulfide isomerase (PDI), in Impg2-KO mouse retinas. Increased gliosis and apoptotic cell death were also observed in the KO retinas.
ExperimentName: CRISPR/Cas9-based disruption of mouse Impg2
NonHumanModel: Mus musculus
GeneAlteration: Model animals were subjected to CRISPR/Cas9-based deletion of 166bp from exon 2 of Impg2, and analyzed in the homozygous state. Absence of Impg2 signal was confirmed by RT-PCR. Mice were studied at ages 3, 6, and 13 months.
ModelPhenotype: HP:0000654 (Decreased light- and dark-adapted electroretinogram amplitude), HP:0000580 (Pigmentary retinopathy), HP:0030609 (Photoreceptor layer loss on macular OCT)
HumanPhenotype: HP:0000529 (Progressive visual loss), HP:0000662 (Nyctalopia), HP:0000551 (Color vision defect), HP:0008002 (Abnormality of macular pigmentation), HP:0000543 (Optic disc pallor), HP:0007843 (Attenuation of retinal blood vessels), HP:0000533 (Chorioretinal atrophy), HP:0000518 (Cataract), HP:0008323 (Abnormal light- and dark-adapted electroretinogram), HP:0007737 (Bone spicule pigmentation of the retina), HP:0007994 (Peripheral visual field loss), HP:0000603 (Central scotoma)
ModelEvidence: Abnormalities of the homozygous Impg2 deletion mice included reduction in the amplitudes of ERG responses from both rods and cones at age 6 months (Figure 2). Pigmentary retinopathy was also observed (Figure 2C), as well as progressive photoreceptor layer loss (Figure 3). Cone markers such as PNA and M-opsin were mislocalized (Figure 4), indicating cone cell disorganization. Enhanced apoptosis was also observed in the photoreceptor cell segments (Figure 5), consistent with the decreased outer nuclei layer thickness.
ModelVariant: The model does not introduce a variant previously observed in human patients, but rather disrupts the expression of the Impg2 ortholog.
Clinical and biochemical effects of the E139K missense mutation in the TIMP3 gene, associated with Sorsby fundus dystrophy
PMID: 19536307
Gene: TIMP3
HGNC: 11822
Disease: Sorsby fundus dystrophy (SFD), also known as Sorsby's fundus dystrophy, Sorsby pseudoinflammatory fundus dystrophy, or hemorrhagic macular dystrophy
MONDO: 0007640
InheritancePattern: Autosomal Dominant
Prevalence: Estimated at 1 in 220,000 (PMID: 28847738)
Penetrance: Fully penetrant, onset between the third and sixth decades of life
X-linked retinitis pigmentosa in two families with a missense mutation in the RPGR gene and putative change of glycine to valine at codon 60
PMID: 9855162
Gene: RPGR
HGNC: 10295
Disease: RPGR-related retinopathy
MONDO: MONDO:0100437
InheritancePattern: X-linked
Prevalence: The prevalence of RPGR-related retinopathy is calculated to be approximately 1 in 214,000, based on the known incidence of retinitis pigmentosa at 1 in 3,000, the proportion of retinitis pigmentposa that is X-linked at 20%, and the proportion of X-linked retinitis pigmentosa that is RPGR-associated at 70% (PMID: 34985506).
Penetrance: Penetrance is nearly 100% in hemizygous males but is incomplete and dependent upon the variant in heterozygous female carriers.
Exome analysis identified a novel mutation in the RBP4 gene in a consanguineous pedigree with retinal dystrophy and developmental abnormalities
PMID: 23189188
To address the function of OA1 in melanosome biogenesis, we have used siRNA inactivation and combined morphological and biochemical methods to investigate melanosome ultrastructure, melanosomal protein localization and expression in human pigmented melanocytic cells. OA1 loss of function leads to decreased pigmentation and causes formation of enlarged aberrant premelanosomes harboring disorganized fibrillar structures and displaying proteins of mature melanosomes and lysosomes at their membrane.
ExperimentName: GPR143 silencing in melanoma cells
NonPatientCell: CL:1000458 (melanocyte of skin, specifically the highly pigmented MNT-1 human melanoma cell line)
GeneFunction: GO:1903232 (melanosome assembly)
GeneAlteration: GPR143 silencing was accomplished by transient transfection of MNT-1 cells with specific siRNA, alongside a non-targeting siRNA control.
FunctionalEvidence: siRNA-treated cells exhibited 50% reduction in mature melanosomes and melanin-containing cells by immunofluorescence (Figures 2E, 2F, 2G). This was confirmed by electron microscopy (Figures 2H, 2I, 2J, 2K). GPR143 silencing also resulted in a combination of normal sized melanosomes and enlarged macromelanosome precursors (Figures 2I, S2A). These cellular defects are an approximate match to the giant melanosomes in the melanocytes of the human patients as well as the hypopigmentation of the fundus.
FAVariants: GPR143 disruption was siRNA-based, and patient-associated variants were not studied.
Photoreceptor Guanylate Cyclase (GUCY2D) Mutations Cause Retinal Dystrophies by Severe Malfunction of Ca2+-Dependent Cyclic GMP Synthesis
PMID: 30319355
Gene: GUCY2D
HGNC: 4689
Disease: Cone-rod dystrophy 6
MONDO: 0011143
InheritancePattern: Autosomal Dominant
Prevalence: The overall prevalence of cone-rod dystrophy is between 1 in 30,000 and 1 in 40,000 (PMID: 17270046), while the proportion of cone-rod dystrophy caused by GUCY2D variants is between 19% and 23% (PMID: 22183351, PMID: 25515582). Thus, the prevalence of cone-rod dystrophy 6 is between 1 in 130,000 and 1 in 215,000.
Penetrance: Penetrance is age-dependent, with onset between the 1st and 6th decades of life.
Identification of the Gene and the Mutation Responsible for the Mouse nob Phenotype
PMID: 12506099
Gene: NYX
HGNC: 8082
Disease: Congenital stationary night blindness 1A
MONDO: 0010690
InheritancePattern: X-linked recessive
Prevalence: Congenital stationary night blindness has an estimated prevalence between 1 in 6,000 (PMID: 31427709) and 1 in 300,000 (PMID: 3487908). However, the prevalence of congenital stationary night blindness 1A specifically is unknown.
Penetrance: Penetrance is thought to be complete.
Mutations in KCNJ13 Cause Autosomal-Dominant Snowflake Vitreoretinal Degeneration
PMID: 18179896
Gene: KCNJ13
HGNC: 6259
Disease: snowflake vitreoretinal degeneration
MONDO: 0008663
InheritancePattern: autosomal dominant
Prevalence: The overall prevalence of snowflake vitreoretinal degeneration is ~1 in 1,000,000 (https://www.orpha.net/en/disease/detail/91496).
Penetrance: Known disease-causing alleles appear to be completely penetrant (PMID: 14644728).
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
Identification of the gene (BBS1) most commonly involved in Bardet-Biedl syndrome, a complex human obesity syndrome
PMID: 12118255
Gene: BBS1
HGNC: 966
Disease: Bardet-Biedl syndrome 1
MONDO: 0008854
InheritancePattern: autosomal recessive
Prevalence: The prevalence of BBS1 variants among Bardet-Biedl syndrome cohorts has been reported as at least 20% (PMID: 19402160), while the prevalence of Bardet-Biedl syndrome overall has been estimated between 1 in 13,500 and 1 in 160,000 live births, depending on the population (PMID: 22713813).
Penetrance: The penetrance of the phenotype among homozygous cases appears to be complete.
To facilitate in vivo investigation of mutant TIMP3, the authors generated a knock-in mouse carrying a disease-related Ser156Cys mutation in the orthologous murine Timp3 gene.
ExperimentName: Phenotypic characterization of the heterozygous Timp3Ser179Cys Knock-In Mouse
NonHumanModel: Mus musculus (129/Sv and hybrid C57BL/6 × 129/SvJ background)
GeneAlteration: The mouse Timp3 ortholog was subjected to site-directed mutagenesis to introduce a change equivalent to the human variant encoding the Ser179Cys substitution associated with Sorsby Fundus Dystrophy (PMID:8634721). This variant was introduced into embryonic stem cells by homologous recombination, generating animals for germline transmission of the Timp3Ser179Cys knock-in allele of interest.
ModelPhenotype: HP:0007703 (Abnormality of retinal pigmentation), Abnormalities of the inner aspect of Bruch's membrane
HumanPhenotype: HP:0007703 (Abnormality of retinal pigmentation, PMID:27601084, PMID:16989765), thickening of the inner part of Bruch's membrane
ModelEvidence: While the model system phenotype does not recapitulate all of the human SFD phenotypes, most of which represent the later stages of disease progression, it does recapitulate some early events from the human phenotype, such as abnormalities of Bruch's membrane and the retinal pigment epithelium. The retinal pigment epithelium exhibits structural abnormalities in mutant animals relative to wild-type controls, at both 8 months and 30 months. At 8 months specifically, 15%–20% of RPE areas analyzed showed loss of vertical orientation and increased distances between processes at the cellular bases (Fig. 3) . Patchy thinning of basal microvilli was observed adjacent to Bruch’s membrane, with disrupted packing of microvilli and caverns extending from the basal labyrinth (Figure 3). Timp3 western blots of RPE-choroid ECM extracts from knock-in mice also accumulated higher-molecular weight complexes of Timp3 (Figure 5), similar to the exogenously expressed human variant (PMID:10854443).
ModelVariant: The model variant is a knock-in modification to the mouse Timp3 ortholog that is equivalent to the human NM_000362.5(TIMP3):c.536C>G, (p.Ser179Cys) missense variant (ClinVar:12678). While the article refers to the variant as "Ser156Cys", the updated nomenclature should be Ser179Cys (including the 23-amino acid N-terminal signal peptide).
A Mouse Model for Sorsby Fundus Dystrophy
PMID: 12147610
Gene: TIMP3
HGNC: 11822
Disease: Sorsby fundus dystrophy (SFD), also known as Sorsby's fundus dystrophy, Sorsby pseudoinflammatory fundus dystrophy, or hemorrhagic macular dystrophy
MONDO: 0007640
InheritancePattern: Autosomal Dominant
Prevalence: Estimated at 1 in 220,000 (PMID: 28847738)
Penetrance: Fully penetrant, onset between the third and sixth decades of life
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
Pigmented paravenous chorioretinal atrophy is associated with a mutation within the crumbs homolog 1 (CRB1) gene
PMID: 15623792
Gene: CRB1
HGNC: 2343
Disease: pigmented paravenous retinochoroidal atrophy
MONDO: 0008246
InheritancePattern: autosomal dominant
Prevalence: Orphanet defines pigmented paravenous retinochoroidal atrophy as a rare disorder with incidence lower than 1 in 1,000,000. However, the incidence is not well-reported in published papers and may be more common than this.
Penetrance: The paper reporting affected family members shows 6 affected genotype-positive individuals and 1 unaffected genotype-negative individual. On the other hand, the high frequency of the variant in gnomAD would be consistent with incomplete penetrance or low rate of diagnosis.
A frameshift homozygous germline mutation in BBS7 was detected by WES and identified by Sanger sequencing in affected individuals. This mutation was predicted to result in premature termination of exon5 (c.389_390delAC, p.Asn130ThrfsX3; RefSeq NM_176824.2) and lead to a 133 amino acid truncated protein. The inheritance patterns in the families are consistent with autosomal recessive inheritance, and no such homozygous mutation was found in the other 981 controls.
Case#: Shen_2019_Patient_III-10, female, age 39 years at time of report, national origin reported as Chinese, ethnicity reported as Miao
CasePresentingHPOs: HP:0001513 (Obesity), HP:0000822 (Hypertension), HP:0000107 (Renal cyst), HP:0010442 (Polydactyly), HP:0000750 (Delayed speech and language development), HP:0000678 (Dental crowding), HP:0011342 (Mild global developmental delay), HP:0001156 (Brachydactyly), HP:0000470 (Short neck), HP:0005280 (Depressed nasal bridge), HP:0000140 (Abnormality of the menstrual cycle)
CaseHPOFreeText: The patient has been diagnosed with Bardet-Biedl syndrome.
CaseNotHPOs: HP:0000134 (Female hypogonadism), HP:0002194 (Delayed gross motor development), HP:0000708 (Atypical behavior), HP:0000819 (Diabetes mellitus), HP:0000365 (Hearing impairment), HP:0000518 (Cataract), HP:0000639 (Nystagmus)
CaseNotHPOFreeText: N/A
CasePreviousTesting: Previous genotyping consisted of exome sequencing.
CaseMethod1: exome sequencing
CaseMethod2: Sanger sequencing of the BBS7 locus
CaseGenotypingMethod: Genotyping consisted of exome sequencing, followed by Sanger sequencing of the BBS7 locus.
Variant: The patient harbors the NM_176824.3(BBS7):c.389_390del (p.Asn130fs) variant in the homozygous state.
ClinVar ID: 216138
gnomAD: The NM_176824.3(BBS7):c.389_390del (p.Asn130fs) variant was not found in gnomAD v2.1.1.
VariantEvidence: NM_176824.3(BBS7):c.389_390del (p.Asn130fs) is an out-of-frame deletion variant in exon 5 of 18 that is predicted to trigger nonsense-mediated decay or at least truncation of the C-terminal 82% of the protein product.
CaseAddInfo: Consanguinity in the proband's family is suspected but has not been confirmed. She has two similarly affected cousins who share the same homozygous genotype. The carrier status of her unaffected parents and an unaffected sibling have been confirmed by genotyping.
CasePMIDs: N/A
A Homozygosity-Based Search for Mutations in Patients with Autosomal Recessive Retinitis Pigmentosa, Using Microsatellite Markers
PMID: 15557452
Gene: RPE65
HGNC: 10294
Disease: Retinitis pigmentosa 20
MONDO: 0013425
InheritancePattern: Autosomal Recessive
Prevalence: The overall prevalence of Retinitis pigmentosa is between 1 in 3,000 and 1 in 4,000 individuals, while the proportion of recessive Retinitis pigmentosa caused by RPE65 variants is ~2%. (PMID: 9501220) Thus, the prevalence of Retinitis pigmentosa 20 is between 1 in 150,000 and 1 in 200,000.
Penetrance: Fully penetrant, with onset typically in childhood
Spectrum of retGC1 mutations in Leber's congenital amaurosis
PMID: 10951519
Gene: GUCY2D
HGNC: 4689
Disease: Leber congenital amaurosis 1
MONDO: 0008764
InheritancePattern: Autosomal Recessive
Prevalence: The overall prevalence of Leber congenital amaurosis is between 1 in 33,000 and 1 in 100,000 newborns, while the proportion of Leber congenital amaurosis caused by GUCY2D variants is between 10% and 20% (PMID: 10951519). Thus, the prevalence of Leber congenital amaurosis 1 is between 1 in 165,000 and 1 in 1,000,000.
Penetrance: Fully penetrant, with onset in neonates or in infancy
Here, we report the identification of the p.R192H variant of the tri-snRNP factor PRPF4 in a patient with RP. The mutation affects a highly conserved arginine residue that is crucial for PRPF4 function. Introduction of a corresponding mutation into the zebrafish homolog of PRPF4 resulted in a complete loss of function in vivo. A series of biochemical experiments suggested that p.R192H disrupts the binding interface between PRPF4 and its interactor PRPF3. This interferes with the ability of PRPF4 to integrate into the tri-snRNP, as shown in a human cell line and in zebrafish embryos. These data suggest that the p.R192H variant of PRPF4 represents a functional null allele. The resulting haploinsufficiency of PRPF4 compromises the function of the tri-snRNP, reinforcing the notion that this spliceosomal particle is of crucial importance in the physiology of the retina.
Case#: Linder_2014_Proband_RP-106, female, age 20 years at time of onset / first visual complaints, age 73 year at time of report, family origin not reported
CasePresentingHPOs: Nyctalopia HP:0000662, Constriction of peripheral visual field HP:0001133, Cataract HP:0000518, Attenuation of retinal blood vessels HP:0007843, Bone spicule pigmentation of the retina HP:0007737, Undetectable dark-adapted electroretinogram HP:0030474, Decreased light- and dark-adapted electroretinogram amplitude HP:0000654
CaseHPOFreeText: The proband has been diagnosed with sporadic retinitis pigmentosa. Phenotypes included pale papillae in fundus.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: Previous testing in the proband was not clearly described, but she was part of a cohort of patients with no previously-identified retinitis pigmentosa-associated variants.
CaseMethod1: SSCP analysis of 14 PCR-amplified PRPF4 exons
CaseMethod2: Sanger sequencing of PRPF4
CaseGenotypingMethod: Previous testing in the proband was not clearly described, but she was part of a cohort of patients with no previously-identified retinitis pigmentosa-associated variants. SSCP was performed on each of 14 PCR-amplified exons of PRPF4, followed by Sanger sequencing analysis.
Variant: The proband harbors the NM_001244926.2(PRPF4):c.572G>A (p.Arg191His) variant in the heterozygous state.
ClinVar ID: 967144
gnomAD: The NM_001244926.2(PRPF4):c.572G>A (p.Arg191His) variant is found in gnomAD v4.1.0 at a frequency of 0.00004999 (3 / 60014, with 0 homozygotes) in the Admixed American population https://gnomad.broadinstitute.org/variant/9-113283400-G-A?dataset=gnomad_r4
VariantEvidence: NM_001244926.2(PRPF4):c.572G>A (p.Arg191His) is a missense variant. When overexpressed in zebrafish, the variant fails to rescue the lethality of Prpf4 silencing, unlike overexpression of the wild-type gene (Figure 2). Co-immunoprecipitation experiments show that the variant localizes normally but disrupts interaction with PRPF3 (Figure 3) and blocks PRPF4 integration into snRNP complexes (Figure 4).
CaseAddInfo: The proband has two daughters at ages 52 and 54 years who harbor the variant but showed no retinal abnormalities in ophthalmological examinations.
CasePMIDs: N/A
The first family had a choroideremia-like phenotype.
FamilyLabel: Hull_2016_Family_1
Family#PresentingHPOs: HP:0003581 (Adult onset), HP:0007663 (Reduced visual acuity), HP:0000533 (Chorioretinal atrophy)
Family#PresentingHPOFreeText: N/A
FamilyNotHPOs: HP:0003593 (Infantile onset), HP:0011463 (Childhood onset)
CountryOrigin: Irish ancestry
Ethnicity: Not mentioned
Race: Not mentioned
Family#PreviousTesting: Variants in REP1 and PRPH2 were initially excluded.
Family#Method1: Candidate gene sequencing
Family#Method2: Bidirectional, targeted Sanger sequencing within the RPE65 locus
Family#GenotypingMethod: Bidirectional Sanger sequencing of exon 13 of the RPE65 gene and flanking sequences
Affected: 2
Unaffected: 0
Segregations: 1 segregation was reported. The pedigree can be found in Figure 5. The possibility of family consanguinity was not mentioned.
PublishedLOD: N/A
eLOD: N/A
AddSegregationInfo: N/A
ProbandLabel: Hull_2016_Patient_1.1
Variant: Affected individuals harbor 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.
FamilyAddInfo: N/A
FamilyPMIDs: N/A
The clinical features of retinal disease due to a dominant mutation in RPE65
PMID: 27307694
Gene: RPE65
HGNC: 10294
Disease: Retinitis pigmentosa 87 with choroidal involvement
MONDO: 0032873
InheritancePattern: Autosomal Dominant
Prevalence: The overall prevalence of Retinitis pigmentosa is between 1 in 3,000 and 1 in 4,000 individuals, while the proportion of Retinitis pigmentosa with a dominant mode of inheritance is estimated to be 15-35% (between 1 in 8,000 and 1 in 27,000). The prevalence of Retinitis pigmentosa 87 with choroidal involvement is considered to be much lower.
Penetrance: Incomplete penetrance, estimated at 80%
In this study, we have investigated the biosynthesis and intracellular localization of this protein in transiently transfected BHK-21 cells using a CLN5-specific peptide antibody.
ExperimentName: Intracellular localization of exogenously expressed wild-type and variant CLN5
NonPatientCell: BKH-21 cells (fibroblast-derived cell line, EFO:0002009)
GeneFunction: Localization to lysosome (GO:0005764)
GeneAlteration: The variant was introduced into the construct encoding CLN5 using site-directed mutagenesis.
FunctionalEvidence: Localization studies were performed in BHK-21 cells transiently transfected with wild-type or variant CLN5. The wild-type co-localized with lysosome and late endosome markers, while the variant co-localized with a Golgi marker (Fig. 3D–F) and showed some ER staining and vesicular-like staining. The stability of the variant following cyclohexamide treatment was also shorter than the wild-type. (Fig. 4G-4H).
FAVariants: The variant used was NM_006493.4(CLN5):c.1028_1029del (p.Thr342_Tyr343insTer) (ClinVar:2564).
c.276G>A (p.W92X)
Case#: Zou_2017_Patient_F2-II:1, male, age 3 at time of report, family national origin reported to be from China
CasePresentingHPOs: HP:0000639 (Nystagmus), HP:0000613 (Photophobia), HP:0007663 (Reduced visual acuity), HP:0007750 (Hypoplasia of the fovea), HP:0007894 (Hypopigmentation of the fundus)
CaseHPOFreeText: The proband has been diagnosed with ocular albinism 1. Foveal hypoplasia was described as severe. Best-corrected visual acuity was limited to light perception.
CaseNotHPOs: HP:0007730 (Iris hypopigmentation)
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
CaseMethod1: Sanger sequencing
CaseMethod2: N/A
CaseGenotypingMethod: Patients were genotyped by Sanger sequencing of PCR products from the 9 exons of the GPR143 gene.
Variant: The proband harbors the NM_000273.3(GPR143):c.276G>A (p.Trp92Ter) variant in the hemizygous state.
CAID: CA411999243
gnomAD: This variant was not found in gnomAD v2.1.1.
VariantEvidence: NM_000273.3(GPR143):c.276G>A (p.Trp92Ter) is a nonsense variant in exon 2 of 9, and is predicted to trigger nonsense-mediated decay or to at least truncate the C-terminal 77% of the protein product.
CaseAddInfo: N/A
CasePMIDs: N/A
Arg768Trp
Case#: Stunkel_2018_Patient_5, female, age 45 at diagnosis with congenital night blindness, at least as early as age 4 at time of onset, 52 years old at time of report, ethnic origin not mentioned
CasePresentingHPOs: HP:0011463 (Childhood onset), HP:0000662 (Nyctalopia), HP:0000552 (Tritanomaly), HP:0000539 (Abnormality of refraction), HP:0001133 (Constriction of peripheral visual field), HP:0007737 (Bone spicule pigmentation of the retina), HP:0008043 (Retinal arteriolar constriction), HP:0030469 (Abnormal dark-adapted electroretinogram), HP:0008275 (Abnormal light-adapted electroretinogram),
CaseHPOFreeText: Refractive error was minimal. Progression of nyctalopia was noticed at 44 years of age. Rod-based ERG was not detectable at age 52.
CaseNotHPOs: HP:0030586 (Abnormal Ishihara plate test), HP:0000539 (Abnormality of refraction), HP:0000639 (Nystagmus), HP:0000486 (Strabismus), HP:0007663 (Reduced visual acuity), HP:0030473 (Abnormal light-adapted flicker electroretinogram), HP:0030617 (Abnormal OCT-measured foveal thickness)
CaseNotHPOFreeText: N/A
CasePreviousTesting: Patient 5 was tested for known LCA-causing variants using an allele-specific method.
CaseMethod1: It is not clear whether Sanger sequencing was used to confirm the initial genotyping method.
CaseMethod2: N/A
CaseGenotypingMethod: Patient 5 was tested for known LCA-causing variants using an allele-specific method, leading to the detection of 2 variants in GUCY2D.
Variant: The individual is compound heterozygous for the NM_000180.4(GUCY2D):c.2302C>T (p.Arg768Trp) and NM_000180.4(GUCY2D):c.2281C>T (p.p.Arg761Trp) variants.
ClinVar: 98563, 854601
gnomAD: The NM_000180.4(GUCY2D):c.2302C>T (p.Arg768Trp) variant exhibits a maximum allele frequency of 0.0002943 in gnomAD version 2.1.1 (in the European non-Finnish population, with no homozygotes). https://gnomad.broadinstitute.org/variant/17-7917236-C-T The NM_000180.4(GUCY2D):c.2281C>T (p.p.Arg761Trp) variant has a maximum allele frequency of 0.00004007 in gnomAD version 2.1.1 (in the African / African-American population, with no homozygotes). https://gnomad.broadinstitute.org/variant/17-7917215-C-T
VariantEvidence: Evidence supporting the pathogenicity of the NM_000180.4(GUCY2D):c.2281C>T (p.p.Arg761Trp) variant is limited to computational prediction. Multiple publications have found functional defects in the NM_000180.4(GUCY2D):c.2302C>T (p.Arg768Trp) variant. PMID: 25477517 shows defective binding to its interacting partner RD3, while PMID: 20050595 and PMID: 23035049 show reduced basal enzymatic activity and inability to interact with the activity-stimulating binding partner GCAP1.
CaseAddInfo: The possibility of consanguinity and variant phase have not been reported in detail.
CasePMIDs: N/A
Mutations in RPE65
FamilyLabel: Marlens_1997_Family_1
FamilyPresentingHPOs: HP:0030506 (Yellow/white lesions of the retina), HP:0000580 (Pigmentary retinopathy), HP:0007843 (Attenuation of retinal blood vessels), HP:0000543 (Optic disc pallor), HP:0001141 (Severely reduced visual acuity)
FamilyPresentingHPOFreeText: Pigmentary deposits, Attenuation of retinal blood vessels, and Optic disc pallor were all mild/moderate.
FamilyNotHPOs: N/A
FamilyNotHPOFreeText: N/A
CountryOrigin: Not specified
Ethnicity: Not mentioned
Race: Not mentioned
Family#PreviousTesting: All RPE65 coding exons and flanking sequences were PCR-amplified and subjected to single-strand conformation analysis. Exon 10 was identified as a likely candidate to harbor a variant. All 14 exons of RPE65 were PCR-amplified and subjected to Sanger sequencing in both affected family members and their parents.
Family#GenotypingMethod: Screening of PCR products from affected and unaffected family members for the variants of interest was performed using SSCA for the maternal variant and AlwNI restriction digest for the paternal variant.
Affected: 2
Unaffected: 1
Segregations: The pedigree (Figure 1c) shows 1 segregation, with none inconsistent.
PublishedLOD: N/A
eLOD: N/A
AddSegregationInfo: N/A
ProbandLabel: Marlhens_1997_Patient_III-2
Variant: Affected individuals are compound heterozygous for the NM_000329.3(RPE65):c.1067del (p.Asn356fs) (maternal) and NM_000329.3(RPE65):c.700C>T (p.Arg234Ter) (paternal) variants.
ClinVar: 98821, 13114
gnomAD: The maximum allele frequency for the NM_000329.3(RPE65):c.1067del (p.Asn356fs) variant is 0.00005458 (within the East Asian population, with no homozygotes). https://gnomad.broadinstitute.org/variant/1-68903930-AT-A The maximum allele frequency for the NM_000329.3(RPE65):c.700C>T (p.Arg234Ter) variant is 0.00008676 (within the Latino / Admixed American population, with no homozygotes). https://gnomad.broadinstitute.org/variant/1-68905269-G-A
FamilyAddInfo: The two variants were confirmed to be in trans, and heterozygous carriers were found to be unaffected. Potential parental consanguinity was not mentioned.
FamilyPMIDs: N/A