Case#: 82, male, 38 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.5720G>A

LegacyVariant:

ClinVar: No

CAID: CA414907651

gnomAD:

Case#: 55, male, 36 years old, Chinese

DiseaseAssertion: Hemophilia A, mild

FamilyInfo: NA

ParentalTesting: Maternity confirmed

CasePresentingHPOs: HP:0003125

CaseHPOFreeText: FVIII:C = 17%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA

Gene: F8

Variant: NM_000132.3:c.1834C>T

LegacyVariant:

ClinVar: 10236

CAID: CA255129

gnomAD:

Case#: 18, male, 15 years old, Chinese

DiseaseAssertion: Hemophilia A, mild

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: HP:0003125

CaseHPOFreeText: FVIII:C = 20%

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.3325C>T

LegacyVariant:

ClinVar: No

CAID: CA414897253

gnomAD:

Case#: 144, male, 14 years old, Chinese

DiseaseAssertion: Hemophilia A, moderate

FamilyInfo: Noted Family History

ParentalTesting: Maternity confirmed

CasePresentingHPOs: HP:0003125

CaseHPOFreeText: FVIII:C = 1.1%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA

Gene: F8

Variant: NM_000132.3:c.4320_4325delTAGAAA

LegacyVariant:

ClinVar: No

CAID: No

gnomAD:

Case#: 160, 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.3637delA

LegacyVariant:

ClinVar: No

CAID: CA255146

gnomAD:

Case#: 185, male, 29 years old, Chinese

DiseaseAssertion: Hemophilia A, severe

FamilyInfo: Noted Family History

ParentalTesting: Maternity confirmed

CasePresentingHPOs: HP:0003125

CaseHPOFreeText: FVIII:C < 1%, Inhibitor present

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA

Gene: F8

Variant: NM_000132.3:c.del exon26

LegacyVariant:

ClinVar: No

CAID: No

gnomAD:

Case#: 110, male, 9 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.7021G>C

LegacyVariant:

ClinVar: No

CAID: CA414896760

gnomAD:

Case#: 130, male, 16 years old, Chinese

DiseaseAssertion: Hemophilia A, mild

FamilyInfo: Noted Family History

ParentalTesting: Maternity confirmed

CasePresentingHPOs: HP:0003125

CaseHPOFreeText: FVIII:C = 17.5%

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.3802dupC

LegacyVariant:

ClinVar: No

CAID: No

gnomAD:

Case#: 50, male, 50 years old, Chinese

DiseaseAssertion: Hemophilia A, mild

FamilyInfo: Noted Family History

ParentalTesting: Maternity confirmed

CasePresentingHPOs: HP:0003125

CaseHPOFreeText: FVIII:C = 16.3%

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.1745G>A

LegacyVariant:

ClinVar: No

CAID: CA414911614

gnomAD:

Case#: 95, male, 76 years old, Chinese

DiseaseAssertion: Hemophilia A, mild

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: HP:0003125

CaseHPOFreeText: FVIII:C = 17%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA

Gene: F8

Variant: NM_000132.3:c.6506G>A

LegacyVariant:

ClinVar: 10315

CAID: CA255208

gnomAD:

Case#: 33, male, 25 years old, Chinese

DiseaseAssertion: Hemophilia A, moderate

FamilyInfo: NA

ParentalTesting: Maternity confirmed

CasePresentingHPOs: HP:0003125

CaseHPOFreeText: FVIII:C = 3.8%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA

Gene: F8

Variant: NM_000132.3:c.382T>C

LegacyVariant:

ClinVar: 811825

CAID: CA414919878

gnomAD:

Case#: 103, male, 10 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.6635C>T

LegacyVariant:

ClinVar: No

CAID: CA414905841

gnomAD:

Case#: 113, male, 27 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.388+5G>A

LegacyVariant:

ClinVar: No

CAID: CA873357439

gnomAD:

Case#: 22, male, 30 years old, Chinese

DiseaseAssertion: Hemophilia A, moderate

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: HP:0003125

CaseHPOFreeText: FVIII:C = 3.1%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA

Gene: F8

Variant: NM_000132.3:c.6496C>T

LegacyVariant:

ClinVar: 10096

CAID: CA255013

gnomAD:

Case#: 72, male, 31 years old, Chinese

DiseaseAssertion: Hemophilia A, moderate

FamilyInfo: Noted Family History

ParentalTesting: Maternity confirmed

CasePresentingHPOs: HP:0003125

CaseHPOFreeText: FVIII:C = 4.6%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA

Gene: F8

Variant: NM_000132.3:c.5399G>A

LegacyVariant:

ClinVar: 10274

CAID: CA255162

gnomAD:

Case#: 44, male, 9 years old, Chinese

DiseaseAssertion: Hemophilia A, moderate

FamilyInfo: Noted Family History

ParentalTesting: Maternity confirmed

CasePresentingHPOs: HP:0003125

CaseHPOFreeText: FVIII:C = 1.7%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA

Gene: F8

Variant: NM_000132.3:c.1171C>T

LegacyVariant:

ClinVar: 10125

CAID: CA255026

gnomAD:

Case#: Patient 63 (Spanish origin; assumed male)

DiseaseAssertion: Severe Hemophilia B

FamilyInfo: Not available

ParentalTesting: Not available

CasePresentingHPOs: HP:0011858

CaseHPOsFreeText: FIX:C = 3 (reduced factor IX activity)

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

Gene: F9

Variant: NM_000133.4:c.128G>A (p.Arg43Gln)

ClinVar: 810864

CAID: CA414435539

gnomAD: Absent/Not Reported

Case#: Patient 66 (Spanish origin; assumed male)

DiseaseAssertion: Mild Hemophilia B

FamilyInfo: Not available

ParentalTesting: Not available

CasePresentingHPOs: HP:0011858

CaseHPOsFreeText: Factor IX: C = 30% (reduced factor IX activity)

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

Gene: F9

Variant: NM_000133.4(F9):c.19A>T (p.Ile7Phe)

LegacyVariant: c.48A>T (p.Ile-40Phe)

ClinVar: 367997

CAID: CA10529708

gnomAD: Filtering AF: 0.0007752 (no homozygotes)

Case#: Patient 72 (Spanish origin; assumed male)

DiseaseAssertion: Severe Hemophilia B

FamilyInfo: Not available

ParentalTesting: Not available

CasePresentingHPOs: HP:0011858

CaseHPOsFreeText: FIX:C = <1 (reduced factor IX activity)

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

Gene: F9

Variant: NM_000133.4:c.127C>T (p.Arg43Trp)

ClinVar: 811505

CAID: CA414435537

gnomAD: Absent/Not Reported

Case#: 087-2003

DiseaseAssertion: Hemophilia A, severe

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: HP:0003125

CaseHPOFreeText: FVIII:C < 1%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification

Gene: F8

Variant: NM_000132.3:c.5122C>T

LegacyVariant:

ClinVar: No

CAID: CA120919

gnomAD:

Case#: 038-2016

DiseaseAssertion: Hemophilia A, severe

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: HP:0003125

CaseHPOFreeText: FVIII:C < 1%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification

Gene: F8

Variant: NM_000132.3:c.3531_3533delA

LegacyVariant:

ClinVar: No

CAID: No

gnomAD:

Case#: 020-2045

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.458A>T

LegacyVariant:

ClinVar: No

CAID: CA414919676

gnomAD:

Case#: 038-1003

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.331G>A

LegacyVariant:

ClinVar: No

CAID: CA414919991

gnomAD:

Case#: 035-1003

DiseaseAssertion: Hemophilia A, severe

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: HP:0003125

CaseHPOFreeText: FVIII:C < 1%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification

Gene: F8

Variant:

LegacyVariant:

ClinVar: No

CAID: No

gnomAD:

Case#: 084-2006

DiseaseAssertion: Hemophilia A, mild

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: HP:0003125

CaseHPOFreeText: 5% < FVIII:C < 40%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification

Gene: F8

Variant: NM_000132.3:c.1910A>G

LegacyVariant:

ClinVar: No

CAID: CA414909849

gnomAD:

Case#: 001-2045

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.1462G>A

LegacyVariant:

ClinVar: No

CAID: CA414912862

gnomAD:

Case#: 071-2032

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.308_319delGTGGTCATTACA

LegacyVariant:

ClinVar: No

CAID: No

gnomAD:

Case#: 001-2028

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.4379dupA

LegacyVariant:

ClinVar: No

CAID: CA645292749

gnomAD:

Case#: 038-2020

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.3637delA

LegacyVariant:

ClinVar: No

CAID: CA255146

gnomAD:

Case#: 035-2017

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:

Case#: P4 (female)

DiseaseAssertion: Carrier

FamilyInfo: N/A

ParentalTesting: N/A

CasePresentingHPOs: HP:0003125, HP:0001928

CaseHPOFreeText: Low FVIII levels (FVIII:Ag showed a moderate reduction (29.8% ± 1.7, p < 0.01) compared to the WT; FVIII:C undetectable), abnormal blood coagulation

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Molecular Analysis included a southern blot assay, PCR, dHPLC and a multiplex ligation-dependent probe amplification analysis. Plasmid mutagenesis, plasmid transfection and in silico analysis were also performed.

Gene: F8

Variant: NM_000132.4:c.1730C>A

CAID: CA414911649

gnomAD: Absent/Not Reported

Case#: Cz27, Italy (Calabria)

DiseaseAssertion: Hemophilia A

FamilyInfo: Inherited

ParentalTesting: NA

CasePresentingHPOs: NA

CaseHPOFreeText: FVII:C 3.5%

CasePreviousTesting: Polymerase chain reaction (PCR) analysis, Long PCR for detecting the intron 22 inversion was performed, Direct cycle sequence analysis using the Taq dye-deoxy terminator method

Gene: F8

Variant: NM_000132.3:c.1538-18G>A

ClinVar: 811357 https://www.ncbi.nlm.nih.gov/clinvar/variation/811357/

CAID: CA873354114

gnomAD: Not reported

Case#: 28

DiseaseAssertion: Hemophilia A

FamilyInfo: Sporadic

ParentalTesting: NA

CasePresentingHPOs: NA

CaseHPOFreeText: Mild

CasePreviousTesting: All 26 exons and exon-intron boundaries of the F8 gene were amplified using primers and PCR, analyzed by direct forward and reverse sequencing using a DNA sequencing kit

Gene: F8

Variant: NM_000132.3:c.6427A>G (p.Met2124Val)

ClinVar: NA

CAID: CA414899297

gnomAD: Not reported

Case#: 23

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.1910A>T (p.Asn618Ile)

ClinVar: NA

CAID: CA414909847

gnomAD: Not reported

Case#: 18, Spanish

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:c.1180G>T (p.Ala375Ser)

ClinVar: NA

CAID: CA414916327

gnomAD: Not reported

Case#: 8

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.5805T>A (p.Tyr1935Ter)

ClinVar: NA

CAID: CA414906924

gnomAD: Not Reported

Case#: 1

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.1251_1252insC (p.Val418ArgfsTer6)

ClinVar: NA

CAID: CA1139532040

gnomAD: Not reported

Case#: 37HBT150 (Turkish; assumed male)

DiseaseAssertion: Moderate Hemophilia B

FamilyInfo: N/A

ParentalTesting: Not provided

CasePresentingHPOs: HP:0011858

CaseHPOsFreeText: Reduced factor IX activity (FIX:C: 1.3)

CasePreviousTesting: N/A

Gene: F9

Variant: NM_000133.4:c.128G>T (p.Arg43Leu)

LegacyVariant: c.6365 G>T (p.Arg-4Leu)

ClinVar: 993549

CAID: CA414435545

gnomAD: Absent/Not Reported

Case#: 19

DiseaseAssertion: Hemophilia A

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: NA

CaseHPOFreeText: FVIII:C <1% (Severe Phenotype), No inhibitors present

CasePreviousTesting: Screened for IVS-22 and IVS-1, Possibility that sample was blinded for NGS and validated by comparing results with Sanger Sequencing

Gene: F8

Variant: NM_000132.3:c.4692del (p.Leu1566Ter)

ClinVar: NA

CAID: CA1139532037

gnomAD: NA

Case#: HB-125 (assumed male, India)

DiseaseAssertion: Severe Hemophilia B

FamilyInfo: N/A

ParentalTesting: None

CasePresentingHPOs: HP:0011858

CaseHPOsFreeText: reduced factor IX activity (FIX:C <1%)

CaseNotHPOs: None

CasePreviousTesting: None

Gene: F9

Variant: NM_000133.4:c.128G>A (p.Arg43Gln)

ClinVar: 810864

CAID: CA414435539

gnomAD: Absent/Not Reported

Case#: Heit_Proband_HB535 (assumed male, AmerIndian from Peru)

DiseaseAssertion: Severe Hemophilia B

FamilyInfo: N/A

ParentalTesting: N/A

CasePresentingHPOs: HP:0011858

CaseHPOsFreeText: reduced factor IX activity (FIX:C: <1%)

CaseNotHPOs: N/A

CasePreviousTesting: N/A

Gene: F9

Variant: NM_000133.4:c.127C>T (p.Arg43Trp)

LegacyVariant: c.6364C>T (Arg-4Trp)

ClinVar: 811505

CAID: CA414435537

gnomAD: Absent/Not Reported

Case#: Mülling_Proband_1 (55 y/o, male)

DiseaseAssertion: Severe Hemophilia B

FamilyInfo: N/A

ParentalTesting: N/A

CasePresentingHPOs: HP:0011858, HP:0100584, HP:0002094

CaseHPOsFreeText: Reduced factor IX activity (FIX activity: 3%), infective endocarditis, dyspnea

CaseNotHPOs: N/A

CasePreviousTesting: N/A

Gene: F9

Variant: NM_000133.4:c.110C>T (p.Ala37Val)

ClinVar: Absent

CAID: CA414435437

gnomAD: 0.00002186 in European (non-Finnish) population (highest frequency of variant found in this population)

AdditionalCaseInfo: Patient developed severe bleeding under therapy with phenprocoumon, aPTT was prolonged, while factor IX activity was significantly reduced. Acquired hemophilia was excluded, due to missing detection of inhibitors

Case#: Ghanem_Paris 2 (assumed male, from Paris) & Ghanem_ Caen 2 (assumed male, from Caen)

DiseaseAssertion: Severe Hemophilia B

FamilyInfo: N/A

ParentalTesting: None

CasePresentingHPOs: HP:0011858

CaseHPOsFreeText: reduced factor IX activity (Paris 2: FIX:C: <1, FIX:Ag: 28, Caen 2: FIX:C: <1

CaseNotHPOs: None

CasePreviousTesting: N/A

Gene: F9

Variant: NM_000133.4:c.127C>T (p.Arg43Trp)

ClinVar: 811505

CAID: CA414435537

gnomAD: Highest AF (South Asian population): 0.0004904

Case#: Calgary 15

DiseaseAssertion: Hemophilia B (severity not provided)

FamilyInfo: None

ParentalTesting: N/A

CasePresentingHPOs: HP:0011858

CaseHPOsFreeText: reduced factor IX activity (does not specify severity for probands) "patients from these kindreds have various disease severity, with plasma factor IX activity from < 0.01 U/mL to 0.30 U/mL." "FIX antigen was not available from patients from 6 kindreds, reduced in seven, normal in six, and not available from six."

CaseNotHPOs: None

CasePreviousTesting: N/A

Gene: F9

Variant: NM_000133.4:c.128G>A (p.Arg43Gln)

LegacyVariant: c.6365 G>A (p.Arg-4Gln)

ClinVar: 810864

CAID: CA414435539

gnomAD: Absent/Not Reported

Case#: N/A

DiseaseAssertion: Severe Hemophilia B

FamilyInfo: None

ParentalTesting: None

CasePresentingHPOs: HP:0001929

CaseHPOsFreeText: reduced factor IX activity

CaseNotHPOs: N/A

CasePreviousTesting: N/A

Gene: F9

Variant: NM_000133.4:c.50T>A (p.Ile17Asn)

ClinVar: Absent

CAID: CA414434315

gnomAD: Absent/Not Reported

Case#: S14, 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.575T>C

LegacyVariant:

ClinVar: No

CAID: CA414919417

gnomAD:

Case#: A4

DiseaseAssertion: Hemophilia A, mild

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: HP:0003125

CaseHPOFreeText: FVIII:C = 6, FVIII:AG = 15, 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.896A>T

LegacyVariant:

ClinVar: No

CAID: CA255078

gnomAD:

Case#: 36

DiseaseAssertion: Hemophilia B, severe

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: HP:0011858

CaseHPOFreeText: FIX:C < 1%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: All relevant sequences of F9 were PCR amplified and analyzed by DNA sequencing

Gene: F9

Variant: NM_000133.3:c.535G>T

LegacyVariant:

ClinVar: No

CAID: CA414440319

gnomAD:

Case#: Faugere_2003_Family_OA1-3_Patient_IV1, male, 26 years of age at time of report, family origin reported to be from the South of France with race described as Caucasian

CasePresentingHPOs: HP:0006934 (Congenital nystagmus), HP:0007750 (Hypoplasia of the fovea), HP:0007663 (Reduced visual acuity), HP:0001089 (Iris atrophy), HP:0012805 (Iris transillumination defect), HP:0007894 (Hypopigmentation of the fundus), HP:0030602 (Abnormal fundus autofluorescence imaging), HP:0030479 (Abnormal amplitude of light-adapted flicker electroretinogram)

CaseHPOFreeText: The proband was initially diagnosed with congenital nystagmus.

CaseNotHPOs: HP:0012632 (Abnormal intraocular pressure), HP:0000518 (Cataract)

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing was not described, however, the proband was examined for whole-exon deletions using PCR amplification of the 9 exons from the GPR143 locus.

CaseMethod1: Sanger sequencing

CaseMethod2: Restriction enzyme analysis using TaqI

CaseGenotypingMethod: The proband was examined for whole-exon deletions using PCR amplification of the 9 exons from the GPR143 locus, followed by Sanger-based sequencing and restriction enzyme-based screening of family members using TaqI.

Variant: The proband harbors the NM_000273.3(GPR143):c.310del (p.Asp104fs) variant in the hemizygous state.

ClinVar: 98625

gnomAD: This variant was not found in gnomAD v2.1.1.

VariantEvidence: NM_000273.3(GPR143):c.310del (p.Asp104fs) is a frameshift variant in exon 2 of 9, and is predicted to trigger nonsense-mediated decay or to at least truncate the C-terminal 75% of the protein product.

CaseAddInfo: While the proband was initially thought to be a sporadic case, the variant was later found to be maternally inherited, with an uncle found to harbor the variant and to be affected with decreased visual acuity. Further details of the family member are not described.

CasePMIDs: N/A

Case#: Harville_2010_Patient_A2014-II1, sex assumed to be male based on phenotypes, age not reported, family origin reportedly from Turkey

CasePresentingHPOs: HP:0010442 (Polydactyly), HP:0001513 (Obesity), HP:0000135 (Hypogonadism), HP:0000077 (Abnormality of the kidney)

CaseHPOFreeText: The proband has an initial clinical diagnosis of Bardet-Biedl syndrome. Secondary signs are noted as present, but specifics are not reported.

CaseNotHPOs: HP:0000510 (Rod-cone dystrophy)

CaseNotHPOFreeText: The proband reportedly does not have retinitis pigmentosa. Age has not been reported in the study.

CasePreviousTesting: The proband was initially subjected to homozygosity mapping to identify parts of the genome to search for the basis of recessive disease.

CaseMethod1: homozygosity mapping

CaseMethod2: Sanger sequencing of the exons of any of the 14 BBS-associated loci (BBS1, BBS2, ARL6, BBS4, BBS5, MKKS, BBS7, TTC8, BBS9, BBS10, TRIM32, BBS12, MKS1, and CEP290) that showed homozygosity.

CaseGenotypingMethod: The proband was initially subjected to homozygosity mapping to identify parts of the genome to search for the basis of recessive disease. This was followed by Sanger sequencing of the exons of any of the 14 BBS-associated loci (BBS1, BBS2, ARL6, BBS4, BBS5, MKKS, BBS7, TTC8, BBS9, BBS10, TRIM32, BBS12, MKS1, and CEP290) that showed homozygosity.

Variant: The proband harbors the NM_024649.5(BBS1):c.48-1G>A variant in the homozygous state.

ClinVar ID: 1299580

gnomAD: The NM_024649.5(BBS1):c.48-1G>A variant is found in gnomAD v2.1.1 at a frequency of 0.000008790 in the European (non-Finnish) population, with 1 allele / 113768 total alleles (0 homozygotes) https://gnomad.broadinstitute.org/variant/11-66278483-G-A?dataset=gnomad_r2_1

VariantEvidence: NM_024649.5(BBS1):c.48-1G>A is a canonical splice site variant predicted but not confirmed to disrupt BBS1 splicing.

CaseAddInfo: The proband's family is reportedly consanguineous.

CasePMIDs: N/A

Case#: Mykykyn_2002_Proband_PR2-1, gender not specified, age not described, family origin reported as from Puerto Rico

CasePresentingHPOs: N/A

CaseHPOFreeText: The proband has been previously diagnosed with Bardet-Biedl syndrome based on at least three of the following features; obesity, polydactyly, renal anomalies, retinopathy, hypogonadism, and/or mental retardation.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The proband and their affected and unaffected family members were subjected to mapping of the disease-associated locus to chromosome 11, followed by PCR- and Sanger sequencing-based genotyping of chromosome 11 markers.

CaseMethod1: linkage mapping

CaseMethod2: Sanger sequencing of BBS1

CaseGenotypingMethod: The proband and their affected and unaffected family members were subjected to linkage mapping of the disease-associated locus to chromosome 11, followed by PCR- and Sanger sequencing-based genotyping of chromosome 11 markers. Sanger sequencing of BBS1 was subsequently used to identify the variant.

Variant: The proband harbors the NM_024649.5(BBS1):c.1645G>T (p.Glu549Ter) variant in the homozygous state.

ClinVar ID: 12144

gnomAD: The variant is found in gnomAD v2.1.1 at a frequency of 0.00008675 (3 alleles out of 34584 total alleles, with 0 homozygotes) in the Admixed American population https://gnomad.broadinstitute.org/variant/11-66299163-G-T?dataset=gnomad_r2_1

VariantEvidence: NM_024649.5(BBS1):c.1645G>T (p.Glu549Ter) is a nonsense variant in exon 16 of 17 that is predicted to not to trigger nonsense-mediated decay but rather to truncate the C-terminal 8% of the protein product.

CaseAddInfo: The proband's family is described as consanguineous.

CasePMIDs: N/A

Case#: Mykykyn_2002_Proband_PR5-1, gender not specified, age not described, family origin reported as from Puerto Rico

CasePresentingHPOs: N/A

CaseHPOFreeText: The proband has been previously diagnosed with Bardet-Biedl syndrome based on at least three of the following features; obesity, polydactyly, renal anomalies, retinopathy, hypogonadism, and/or mental retardation.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The proband and their affected and unaffected family members were subjected to mapping of the disease-associated locus to chromosome 11, followed by PCR- and Sanger sequencing-based genotyping of chromosome 11 markers.

CaseMethod1: linkage mapping

CaseMethod2: Sanger sequencing of BBS1

CaseGenotypingMethod: The proband and their affected and unaffected family members were subjected to linkage mapping of the disease-associated locus to chromosome 11, followed by PCR- and Sanger sequencing-based genotyping of chromosome 11 markers. Sanger sequencing of BBS1 was subsequently used to identify the variant.

Variant: The proband harbors the NM_024649.5(BBS1):c.1645G>T (p.Glu549Ter) and NM_024649.5(BBS1):c.432+1G>A variants in the compound heterozygous state.

ClinVar ID: 12144, 12145

gnomAD: The NM_024649.5(BBS1):c.1645G>T (p.Glu549Ter) variant is found in gnomAD v2.1.1 at a frequency of 0.00008675 (3 alleles out of 34584 total alleles, with 0 homozygotes) in the Admixed American population https://gnomad.broadinstitute.org/variant/11-66299163-G-T?dataset=gnomad_r2_1 The NM_024649.5(BBS1):c.432+1G>A variant was not found in gnomAD v2.1.1.

VariantEvidence: NM_024649.5(BBS1):c.1645G>T (p.Glu549Ter) is a nonsense variant in exon 16 of 17 that is predicted to not to trigger nonsense-mediated decay but rather to truncate the C-terminal 8% of the protein product. NM_024649.5(BBS1):c.432+1G>A is a canonical splice site variant in intron 4 that does not have experimental evidence of impact on the gene product.

CaseAddInfo: The proband's family has not been described as consanguineous.

CasePMIDs: N/A

Case#: Mykykyn_2002_Proband_PR3-1, gender not specified, age not described, family origin reported as from Puerto Rico

CasePresentingHPOs: N/A

CaseHPOFreeText: The proband has been previously diagnosed with Bardet-Biedl syndrome based on at least three of the following features; obesity, polydactyly, renal anomalies, retinopathy, hypogonadism, and/or mental retardation.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The proband and their affected and unaffected family members were subjected to mapping of the disease-associated locus to chromosome 11, followed by PCR- and Sanger sequencing-based genotyping of chromosome 11 markers.

CaseMethod1: linkage mapping

CaseMethod2: Sanger sequencing of BBS1

CaseGenotypingMethod: The proband and their affected and unaffected family members were subjected to linkage mapping of the disease-associated locus to chromosome 11, followed by PCR- and Sanger sequencing-based genotyping of chromosome 11 markers. Sanger sequencing of BBS1 was subsequently used to identify the variant.

Variant: The proband harbors the NM_024649.5(BBS1):c.1645G>T (p.Glu549Ter) and NM_024649.5(BBS1):c.1169T>G (p.Met390Arg) variants in the compound heterozygous state.

ClinVar ID: 12144, 12143

gnomAD: The NM_024649.5(BBS1):c.1645G>T (p.Glu549Ter) variant is found in gnomAD v2.1.1 at a frequency of 0.00008675 (3 alleles out of 34584 total alleles, with 0 homozygotes) in the Admixed American population https://gnomad.broadinstitute.org/variant/11-66299163-G-T?dataset=gnomad_r2_1 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

VariantEvidence: NM_024649.5(BBS1):c.1645G>T (p.Glu549Ter) is a nonsense variant in exon 16 of 17 that is predicted to not to trigger nonsense-mediated decay but rather to truncate the C-terminal 8% of the protein product. 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.

CaseAddInfo: The proband's family has not been described as consanguineous.

CasePMIDs: N/A

Case#: Weisschuh_2020_Patient_MDS_342, male, age 73 years at diagnosis, age 75 years at report, national origin reported as German

CasePresentingHPOs: N/A

CaseHPOFreeText: The patient has been diagnosed with macular dystrophy.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping consisted of next generation sequencing-based RET.8 panel.

CaseMethod1: next generation sequencing-based RET.8 panel

CaseMethod2: N/A

CaseGenotypingMethod: Genotyping was performed using a next-generation sequencing-based RET.8 panel.

Variant: The patient harbors the NM_001563.4(IMPG1):c.378G>A (p.Trp126Ter) variant in the heterozygous state.

ClinVar: 493439

gnomAD: The NM_001563.4(IMPG1):c.378G>A (p.Trp126Ter) variant is found in gnomAD v2.1.1 at a maximum allele frequency of 0.00006533 (2/30616) in the South Asian population, with no homozygotes https://gnomad.broadinstitute.org/variant/6-76744428-C-T

VariantEvidence: NM_001563.4(IMPG1):c.378G>A (p.Trp126Ter) is a nonsense variant in exon 3 of 17, and is predicted to trigger nonsense-mediated decay or to at least truncate the C-terminal 84% of the protein product.

CaseAddInfo: Segregation confirmation in family members is not available.

CasePMIDs: N/A

Case#: Weisschuh_2020_Patient_ARRP_339, male, age 32 years at diagnosis, age 34 years at report, national origin reported as German

CasePresentingHPOs: N/A

CaseHPOFreeText: The patient has been diagnosed with autosomal recessive retinitis pigmentosa.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping consisted of next generation sequencing-based RET.8 panel.

CaseMethod1: next generation sequencing-based RET.8 panel

CaseMethod2: N/A

CaseGenotypingMethod: Genotyping was performed using a next-generation sequencing-based RET.8 panel.

Variant: The patient harbors the NM_001563.4(IMPG1):c.1291+1G>T variant in the homozygous state.

ClinVar: 547007

gnomAD: The NM_001563.4(IMPG1):c.1291+1G>T variant was not found in gnomAD v2.1.1.

VariantEvidence: NM_001563.4(IMPG1):c.1291+1G>T is a canonical splice site variant in intron 12 of the 17-exon locus, and does not have evidence of impact on the protein product.

CaseAddInfo: Segregation confirmation in family members is not available.

CasePMIDs: N/A

Case#: Haider_2000_Proband_5, female, 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.290G>A (p.Arg97His) variant in the homozygous state.

ClinVarID: 867089

gnomAD: The variant is found in gnomAD version 4.1.0 at a frequency of 0.00002441 in the European non-Finnish population (28 alleles / 1147036 total alleles, with 0 homozygotes). https://gnomad.broadinstitute.org/variant/chr15-71811810-G-A?dataset=gnomad_r4

VariantEvidence: NM_014249.4(NR2E3):c.290G>A (p.Arg97His) is a missense variant within the zinc finger / DNA-binding domain of NR2E3,.

CaseAddInfo: The proband comes from a consanguineous family with mother and father being first cousins, and two similarly affected sisters sharing the same homozygous genotype.

CasePMIDs: N/A

Case#: Manes_2013_Family_NAL69_Proband_II:4, male, age 43 years at time of report, national origin reported as French

CasePresentingHPOs: HP:0007677 (Vitelliform-like macular lesions), HP:0030631 (Hyperautofluorescent macular lesion), HP:0008179 (Decreased Arden ratio of electrooculogram, specifically 1.58 and 1.68 in each eye), HP:0008275 (Abnormal light-adapted electroretinogram, slightly decreased)

CaseHPOFreeText: The patient has been diagnosed with vitelliform macular dystrophy.

CaseNotHPOs: HP:0007663 (Reduced visual acuity), HP:0030469 (Abnormal dark-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.461T>C (p.Leu154Pro) and NM_001563.4(IMPG1):c.1519C>T (p.Arg507Ter) variants in the compound heterozygous state.

ClinVar: 162136, 162135

gnomAD: The NM_001563.4(IMPG1):c.461T>C (p.Leu154Pro) variant was found in gnomAD v2.1.1 at a frequency of 0.00007924 (9/113576) in the European non-Finnish population, with 0 homozygotes https://gnomad.broadinstitute.org/variant/6-76744345-A-G The NM_001563.4(IMPG1):c.1519C>T (p.Arg507Ter) variant was found in gnomAD v2.1.1 at a frequency of 0.00004007 (1/24958) in the African / African-American population, with 0 homozygotes https://gnomad.broadinstitute.org/variant/6-76660584-G-A?dataset=gnomad_r2_1

VariantEvidence: NM_001563.4(IMPG1):c.461T>C (p.Leu154Pro) is a missense variant that does not have evidence confirming an impact on the gene product. However, another study has reported an apparently unrelated affected patient harboring this variant in the heterozygous state (PMID: 30688845). The NM_001563.4(IMPG1):c.1519C>T (p.Arg507Ter) variant is a nonsense variant in exon 13 of 17 and is predicted to trigger nonsense-mediated decay or to at least truncate the C-terminal 37% of the protein product.

CaseAddInfo: The proband has a similarly affected older sister who shares the same genotype. One carrier child is unaffected while the other has a slight defect in one eye within the line separating the inner and outer segments, consistent with incomplete penetrance in the heterozygous state. Consanguinity is not reported in this family.

CasePMIDs: N/A

Case#: Xin_Patient_5, sex not mentioned, age 17 at onset, U.S. nationality, admixed European non-Finnish ethnicity

CasePresentingHPOs: HP:0004302 (Functional motor deficit), HP:0000572 (Visual loss), HP:0001250 (Seizure), HP:0001268 (Mental deterioration), HP:0003581 (Adult onset), HP:0003208 (Fingerprint intracellular accumulation of autofluorescent lipopigment storage material)

CaseHPOFreeText: Motor difficulty was the phenotype at presentation (age 17). Visual loss (age 18), Cognitive regression (age 25), and seizure (age 18) subsequently developed. Granular type inclusions were observed in blood by electron microscopy. Fingerprint inclusions were observed in the brain.

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 harbors the NM_006493.4(CLN5):c.974A>G (p.Tyr325Cys) variant as well as a chromosomal deletion that includes exon 4.

ClinVar: 2570 (in trans with exon 4 deletion with undefined boundaries)

gnomAD: Maximum allele frequency for NM_006493.4(CLN5):c.974A>G (p.Tyr325Cys) is 0.00002784 (in the European non-Finnish population, no homozygotes). https://gnomad.broadinstitute.org/variant/13-77575001-A-G

VariantEvidence: The variant encodes a missense substitution that adds a cysteine to the CLN5 protein and may disrupt its structure. In a previous publication from an overlapping group of authors, mass spectrometry confirmed absence of CLN5 protein expression in samples from an individual harboring this variant, but in not control samples (PMID:19383612).

CaseAddInfo: Although parents do not appear to have been genotyped, the missense variant (in exon 4) can be inferred to be in trans with the exon 4 deletion.

CasePMIDs: N/A

Case#: Xin_Patient_3, sex not mentioned, age 17 at onset, U.S. nationality, admixed European non-Finnish ethnicity

CasePresentingHPOs: HP:0004302 (Functional motor deficit), HP:0000572 (Visual loss), HP:0001250 (Seizure), HP:0001268 (Mental deterioration), HP:0003581 (Adult onset), HP:0003205 (Curvilinear intracellular accumulation of autofluorescent lipopigment storage material), HP:0003208 (Fingerprint intracellular accumulation of autofluorescent lipopigment storage material), HP:0003226 (Rectilinear intracellular accumulation of autofluorescent lipopigment storage material)

CaseHPOFreeText: Cognitive regression was the phenotype at presentation (age 17). Visual loss (age 20), motor difficulty (age 23), and seizure (age 23) subsequently developed. Granular type inclusions were observed by electron microscopy. Fingerprint inclusions were observed in the skin, rectilinear inclusions were observed in the muscle, and curvilinear inclusions were observed in neurons, glial cells, muscle, and spleen.

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 harbors the NM_006493.4(CLN5):c.230G>A (p.Cys77Tyr) and NM_006493.4(CLN5):c.974A>G (p.Tyr325Cys) variants.

ClinVar: 2569, 2570

gnomAD: The NM_006493.4(CLN5):c.230G>A (p.Cys77Tyr) variant is not found in gnomAD. Maximum allele frequency for NM_006493.4(CLN5):c.974A>G (p.Tyr325Cys) is 0.00002784 (in the European non-Finnish population, no homozygotes). https://gnomad.broadinstitute.org/variant/13-77575001-A-G

VariantEvidence: Both variants encode missense substitutions in the protein product. Because both change the total number of cysteines in the CLN5 protein, they may disrupt its structure. In a previous publication from an overlapping group of authors, mass spectrometry confirmed absence of CLN5 protein expression in samples from this individual, but in not control samples (PMID:19383612).

CaseAddInfo: Parents do not appear to have been genotyped, so it is not clear whether the two variants are confirmed to be in trans.

CasePMIDs: 19383612

Case#: Xin_Patient_6, sex not mentioned, age 8 at onset, Swedish nationality

CasePresentingHPOs: HP:0004302 (Functional motor deficit), HP:0000572 (Visual loss), HP:0001250 (Seizure), HP:0001268 (Mental deterioration), HP:0003621 (Juvenile onset), HP:0003208 (Fingerprint intracellular accumulation of autofluorescent lipopigment storage material), HP:0003205 (Curvilinear intracellular accumulation of autofluorescent lipopigment storage material)

CaseHPOFreeText: Motor difficulty was the phenotype at presentation (age 8). Seizures (age 8), Visual loss (age 12), and Cognitive regression (age 11) subsequently developed. Curvilinear inclusions were observed in the skin specifically.

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 harbors the NM_006493.4(CLN5):c.78G>A (p.Trp26Ter) and NM_006493.4(CLN5):c.522dup (p.Trp175LeufsTer30) variants, as well as the likely benign NM_006493.4(CLN5):c.381T>G (p.Thr127=) variant.

ClinVar: 2565, 56543, 128783

gnomAD: Maximum allele frequency for NM_006493.4(CLN5):c.78G>A (p.Trp26Ter) is 0.00005132 (in the European non-Finnish population, no homozygotes). https://gnomad.broadinstitute.org/variant/13-77566311-G-A Maximum allele frequency for NM_006493.4(CLN5):c.522dup (p.Trp175fs) is 0.00007033 (in the European non-Finnish population, no homozygotes). Maximum allele frequency for the NM_006493.4(CLN5):c.381T>G (p.Thr127=) variant is 0.06570 (in the East Asian population, 48 homozygotes) https://gnomad.broadinstitute.org/variant/13-77570078-T-G

VariantEvidence: The NM_006493.4(CLN5):c.78G>A (p.Trp26Ter) nonsense variant is likely to be subject to nonsense mediated decay. The NM_006493.4(CLN5):c.522dup (p.Trp175fs) frameshift variant is predicted to truncate ~51% of the protein. On the other hand, the synonymous NM_006493.4(CLN5):c.381T>G (p.Thr127=) variant appears unlikely to have a gene impact.

CaseAddInfo: Parents do not appear to have been genotyped, so it is unclear whether the two variants with predicted gene impact have been shown or simply assumed to be in trans. The same is true for the benign, synonymous variant.

CasePMIDs: N/A

Case#: Riazuddin_2006_Family_61019_patient_20, female, age 18 years at time of study, Pakistani family origin from remote Punjab province

CasePresentingHPOs: HP:0000543 (Optic disc pallor), HP:0007843 (Attenuation of retinal blood vessels), HP:0007737 (Bone spicule pigmentation of the retina), HP:0000550 (Undetectable electroretinogram)

CaseHPOFreeText: The proband and her affected family members have been diagnosed with autosomal recessive retinitis pigmentosa.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Genome-wide linkage analysis, with maximum LOD score associated with the D5S2015 microsatellite marker on chromosome 5q31-33.

CaseMethod1: Genome-wide linkage analysis

CaseMethod2: Sanger sequencing of the candidate gene PDE6A

CaseGenotypingMethod: Genome-wide linkage analysis was initially performed on all four families, with maximum LOD score associated with the D5S2015 microsatellite marker on chromosome 5q31-33. Sanger sequencing was then performed on PCR products of exons and flanking regions from the PDE6A candidate locus.

Variant: The affected members of Family 61019 harbor the NM_000440.3(PDE6A):c.769C>T (p.Arg257Ter) variant in the homozygous state.

ClinVar: 437984

gnomAD: In gnomAD v2.1.1, NM_000440.3(PDE6A):c.769C>T (p.Arg257Ter) has a frequency of 0.0001633 (5/30612) in the South Asian population, with 0 homozygotes https://gnomad.broadinstitute.org/variant/5-149310680-G-A

VariantEvidence: NM_000440.3(PDE6A):c.769C>T (p.Arg257Ter) is a nonsense variant in exon 4 of 22 that is predicted to trigger nonsense-mediated decay or at least to truncate ~70% of the protein product.

CaseAddInfo: The patient is from a family with consanguineous unions.

CasePMIDs: N/A

Case#: Liu_2007_Family_Patient_V-10, male, age <6 months at time of onset, family origin reported to be Chinese

CasePresentingHPOs: HP:0006934 (Congenital nystagmus), HP:0000666 (Horizontal nystagmus), HP:0007750 (Hypoplasia of the fovea), HP:0000483 (Astigmatism), HP:0007663 (Reduced visual acuity), HP:0007814 (Retinal pigment epithelial mottling), HP:0000646 (Amblyopia)

CaseHPOFreeText: The proband and his affected family members have been diagnosed with congenital nystagmus segregating with an X-linked mode of inheritance.

CaseNotHPOs: HP:0001000 (Abnormality of skin pigmentation), HP:0009887 (Abnormality of hair pigmentation), HP:0012805 (Iris transillumination defect), HP:0007894 (Hypopigmentation of the fundus), HP:0000545 (Myopia)

CaseNotHPOFreeText: The patient did not exhibit abnormalities of the optic nerve head on functional MRI.

CasePreviousTesting: Linkage mapping has been performed in affected and unaffected family members using 33 polymorphic markers along the entire X chromosome. Haplotype analysis identified a shared region of approximately 10.6 Mb in all affected males.

CaseMethod1: Linkage mapping and haplotype analysis

CaseMethod2: Sanger sequencing of 21 candidate genes in the linkage region

CaseGenotypingMethod: Linkage mapping has been performed in the proband and affected and unaffected family members using 33 polymorphic markers along the entire X chromosome. Haplotype analysis identified a shared region of approximately 10.6 Mb in all affected males. Sanger sequencing was then performed for 21 candidate genes in the linkage region, followed by RFLP analysis in a subset of affected and unaffected family members.

Variant: The proband harbors the NM_000273.3(GPR143):c.266C>T (p.Ser89Phe) variant in the hemizygous state.

ClinVar: 10522

gnomAD: This variant was not found in gnomAD v2.1.1.

VariantEvidence: NM_000273.3(GPR143):c.266C>T (p.Ser89Phe) is a missense variant in exon 2 of 9 total, and is located in a transmembrane domain but does not have experimental evidence of gene impact.

CaseAddInfo: The proband is from a family with at least four other affected males and one affected female family member who also harbor the variant.

CasePMIDs: N/A

Case#: Gong_2001_Proband_6, 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.3804del (p.Glu1270fs) variant in the homozygous state.

ClinVar: 6273

gnomAD: The NM_002335.4(LRP5):c.3804del (p.Glu1270fs) variant was not found in gnomAD v2.1.1.

VariantEvidence: NM_002335.4(LRP5):c.3804del (p.Glu1270fs) is a frameshift variant in exon 18 out of 23 that is predicted to trigger nonsense-mediated decay or at least to truncate the C-terminal ~21% of the protein product. It appears to be stable at the protein level but is not secreted in the exogenous expression system, consistent with loss-of-function rather than dominant negative effect.

CaseAddInfo: The family is reportedly consanguineous.

CasePMIDs: PMID: 8659519

Case#: Gong_2001_Proband_1, 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.29G>A (p.Trp10Ter) variant in the homozygous state.

ClinVar: 6268

gnomAD: The NM_002335.4(LRP5):c.29G>A (p.Trp10Ter) variant was not found in gnomAD v2.1.1.

VariantEvidence: NM_002335.4(LRP5):c.29G>A (p.Trp10Ter) is a nonsense variant in exon 1 out of 23 that is predicted to trigger nonsense-mediated decay or at least to truncate the C-terminal ~99% of the protein product.

CaseAddInfo: The family is reportedly consanguineous.

CasePMIDs: PMID: 8659519

Case#: Schroeder_2022_Proband, female, age 32 at time of diagnosis, family national origin reported as Swedish

CasePresentingHPOs: Optic disc pallor HP:0000543, Retinal detachment HP:0000541, Presenile cataracts HP:0007819, Decreased light- and dark-adapted electroretinogram amplitude HP:0000654, Retinal hole HP:0011530, Abnormal fundus autofluorescence imaging HP:0030602

CaseHPOFreeText: The patient optic discs were described as slightly gliotic. OCT showed lacunar retinal substance losses in the fovea and attenuation in all segments of the macula. FAF showed a paracentral ring of fine granular increase of autofluorescence around the fovea in the posterior pole.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Genotyping of the proband was performed by whole genome sequencing.

CaseMethod1: whole genome sequencing

CaseMethod2: Sanger sequencing of KCNJ13

CaseGenotypingMethod: Genotyping of the proband was performed by whole genome sequencing, followed by Sanger sequencing of KCNJ13.

Variant: The individual harbors the NM_002242.4(KCNJ13):c.484C>T (p.Arg162Trp) variant in the heterozygous state.

ClinVar: 6585

gnomAD: The variant is found in gnomAD version 4.1.0 at a frequency of 0.0000008536 (1 / 1,171,470) in the European (non-Finnish) population https://gnomad.broadinstitute.org/variant/chr2-232768790-G-A?dataset=gnomad_r4

VariantEvidence:NM_002242.4(KCNJ13):c.484C>T (p.Arg162Trp) is a missense variant that has functional evidence of electrophysiological abnormalities and loss of sensitivity to different K+ concentrations, when exogenously expressed in CHO cells (PMID: 18179896, Figure 2).

CaseAddInfo: The proband has three affected family members who also harbored the variant in the heterozygous state. Consanguinity was not reported.

CasePMIDs: N/A

Case#: Benaglio_2014_Proband_001-417, sex not reported, age not reported, national origin German

CasePresentingHPOs: N/A

CaseHPOFreeText: The proband has been diagnosed with autosomal dominant retinitis pigmentosa.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing in the proband consisted of screening either by Sanger sequencing of 90% of known adRP genes, by genotyping microarray of known RP variants, or sequencing-based genotyping of RHO, RDS, PRPF31, RP1, PRPF8, IMPDH1, NRL, PRPF3, NR2E3, and SNRNP200.

CaseMethod1: next-generation sequencing of PRPF4 and EFTUD2 genes

CaseMethod2: Sanger sequencing of the coding regions of NHP2L1 and AAR2

CaseGenotypingMethod: Genotyping of the proband initially consisted of either Sanger sequencing of 90% of known adRP genes, genotyping microarray of known RP variants, or sequencing-based genotyping of RHO, RDS, PRPF31, RP1, PRPF8, IMPDH1, NRL, PRPF3, NR2E3, and SNRNP200. Subsequent genotyping was performed by next-generation sequencing of PRPF4 and EFTUD2 genes and Sanger sequencing of the coding regions of NHP2L1 and AAR2.

Variant: The proband harbors the NM_001244926.2(PRPF4):c.556C>G (p.Pro186Ala) variant in the heterozygous state.

ClinVar ID: 865751

gnomAD: The NM_001244926.2(PRPF4):c.556C>G (p.Pro186Ala) variant is found in gnomAD v4.1.0 at a frequency of 0.00006609 (90 alleles / 1180038 total alleles, with 0 homozygotes) in the European (non-Finnish) population https://gnomad.broadinstitute.org/variant/9-113283207-C-G?dataset=gnomad_r4

VariantEvidence: NM_001244926.2(PRPF4):c.556C>G (p.Pro186Ala) is a missense variant located 5 bp from the 3' end of exon 5 with no direct evidence of an abnormal impact on the PRPF4 protein.

CaseAddInfo: The proband has an affected sibling who also harbors the variant.

CasePMIDs: N/A

Case#: Xu_2012_Patient_SRF92, male, 11 years of age at time of study, of Chinese ethnicity

CasePresentingHPOs: HP:0011463 (Childhood onset), HP:0000556 (Retinal dystrophy), HP:0000580 (Pigmentary retinopathy), HP:0030609 (Photoreceptor layer loss on macular OCT), HP:0001105 (Retinal atrophy), HP:0000026 (Male hypogonadism)

CaseHPOFreeText: This proband was diagnosed with Leber congenital amaurosis, and has mild fatty liver disease.

CaseNotHPOs: HP:0000924 (Abnormality of the skeletal system), HP:0000077 (Abnormality of the kidney)

CaseNotHPOFreeText: N/A

CasePreviousTesting: It is not clear whether the patient was previously subjected to genotyping.

CaseMethod1: Whole exome sequencing

CaseMethod2: Sanger sequencing of IFT140

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_014714.3(IFT140):c.1655_1656del (p.Glu522Glyfs6) and maternal NM_014714.3(IFT140):c.2368G>A (p.Glu790Lys) variants in IFT140*.

CAID: CA2201732453, CA7813927

gnomAD: The NM_014714.3(IFT140):c.1655_1656del (p.Glu522Glyfs*6) variant was not found in gnomAD. The NM_014714.3(IFT140):c.2368G>A (p.Glu790Lys) variant is present in gnomAD at a frequency of 0.0001087 in the East Asian population (2/18394, with no homozygotes) https://gnomad.broadinstitute.org/variant/16-1607967-C-T

VariantEvidence: NM_014714.3(IFT140):c.1655_1656del (p.Glu522Glyfs*6) is a frameshift variant that introduces a premature stop codon in exon 15/31 and is predicted to trigger NMD or at least to truncate ~64% of the protein product. NM_014714.3(IFT140):c.2368G>A (p.Glu790Lys) is a missense variant that does not have functional evidence of gene impact.

CaseAddInfo: The proband's parents are each heterozygous for one variant.

CasePMIDs: N/A

Case#: Xu_2012_Patient_SRF71, male, 43 years of age at time of study, of Han Chinese ethnicity

CasePresentingHPOs: HP:0011463 (Childhood onset), HP:0000662 (Nyctalopia), HP:0000572 (Visual loss), HP:0007737 (Bone spicule pigmentation of the retina), HP:0030609 (Photoreceptor layer loss on macular OCT)

CaseHPOFreeText: This proband was diagnosed with retinitis pigmentosa.

CaseNotHPOs: HP:0000924 (Abnormality of the skeletal system), HP:0001410 (Decreased liver function), HP:0000077 (Abnormality of the kidney)

CaseNotHPOFreeText: N/A

CasePreviousTesting: The patient was previously subjected to retinal capture sequencing focused on genes known to be associated with retinitis pigmentosa, without detecting suspected pathogenic variants.

CaseMethod1: Whole exome sequencing

CaseMethod2: Sanger sequencing of IFT140

CaseGenotypingMethod: Following the failure of retinal capture sequencing to identify retinitis pigmentosa gene variants, 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.1898_1901del (p.Asn633fs) and maternal NM_014714.4(IFT140):c.4196T>C (p.Leu1399Pro) variants in IFT140.

ClinVar: 446312, 446311

gnomAD: The NM_014714.4(IFT140):c.1898_1901del (p.Asn633fs) variant was not found in gnomAD. The NM_014714.4(IFT140):c.4196T>C (p.Leu1399Pro) variant is present in gnomAD at a frequency of 0.0001578 in the East Asian population (3/19014, with no homozygotes) https://gnomad.broadinstitute.org/variant/16-1561138-A-G

VariantEvidence: NM_014714.4(IFT140):c.1898_1901del (p.Asn633fs) is a frameshift variant that introduces a premature stop codon in exon 16/31 and is predicted to trigger NMD or at least to truncate ~57% of the protein product. NM_014714.4(IFT140):c.4196T>C (p.Leu1399Pro) is a missense variant that does not have functional evidence of gene impact.

CaseAddInfo: The proband's parents are each heterozygous for one variant, while his unaffected sister does not harbor a variant.

CasePMIDs: N/A

Case: Weber_1994_Family_M_Patient_IV-2, male, age 28 at onset of symptoms

DiseaseAssertion: Sorsby's fundus dystrophy

FamilyInfo:

CasePresentingHPOs: HP:0011506 (Choroidal neovascularization), HP:0025094 (Disciform macular scar), HP:0007663 (Reduced visual acuity), HP:0000819 (Diabetes mellitus), HP:0007703 (Abnormality of retinal pigmentation), HP:0012805 (Iris transillumination defect), HP:0012231 (Exudative retinal detachment), HP:0030604 (Abnormal fundus fluorescein angiography), HP:0011506 (Choroidal neovascularization), HP:0000603 (Central scotoma), HP:0000654 (Decreased light- and dark-adapted electroretinogram amplitude)

CaseHPOFreeText: 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. Granularity / abnormalities of the RPE were present in both eyes and preceded the onset of visual problems in the initially-unaffected eye. Serous detachment of sensory retina had underlying pigment epithelial detachment. CNV was accompanied by leakage from foveal avascular zone. Loss of visual acuity was progressive but possibly stabilized by argon green laser photocoagulation treatment.

CaseNOTHPOs: HP:0030584 (Color vision test abnormality), HP:0007957 (Corneal opacity), HP:0000518 (Cataract)

CaseNOTHPOFreeText: N/A

CasePreviousTesting: N/A

GenotypingMethod: Sanger sequencing of Weber_1994_Family_M_patient_IV-2

PreviouslyPublished: PMID:2000899

SupplementalData: N/A

Variant: The variant is NM_000362.5(TIMP3):c.572A>G, p.Tyr191Cys, which was first referred to in PMID:7894485 as "Tyr168Cys" (due to the removal of a 23-amino acid N-terminal signal peptide from the polypeptide sequence) but encodes Tyr191Cys in the full/updated polypeptide sequence.

ClinVar: 12677

gnomAD: Variant is absent from gnomAD.

VariantEvidence: Variant adds a Cys residue to TIMP3 and is predicted to disrupt tertiary structure.

Case#: Paavo_2018_Patient_6, male, 43.1 years of age at time of report, family origin reported as Hispanic

CasePresentingHPOs: N/A

CaseHPOFreeText: The proband has been diagnosed with ocular albinism 1.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: It is not clear whether previous genotyping was performed.

CaseMethod1: Sanger sequencing

CaseMethod2: N/A

CaseGenotypingMethod: The patient's family appears to have been genotyped by Sanger sequencing of the 9 exons from the GPR143 gene.

Variant: The proband harbors the NM_000273.3(GPR143):c.461del (p.Ile154fs) variant in the hemizygous state.

ClinVar: 817370

gnomAD: This variant was not found in gnomAD v2.1.1.

VariantEvidence: NM_000273.3(GPR143):c.461del (p.Ile154fs) is a frameshift variant in exon 4 of 9, and is predicted to trigger nonsense-mediated decay or to at least truncate the C-terminal 62% of the protein product.

CaseAddInfo: The proband has three daughters who carry the variant in the heterozygous state but are reportedly unaffected, other than one daughter reporting difficulty seeing in the dark.

CasePMIDs: N/A

Case#: Jauregui_2018_Patient_1, male, 53 years of age at onset, Scottish ancestry

CasePresentingHPOs: HP:0003581 (Adult onset), HP:0000662 (Nyctalopia), HP:0007994 (Peripheral visual field loss), HP:0000533 (Chorioretinal atrophy), HP:0030979 (Dilatation of large choroidal vessels), HP:0007703 (Abnormality of retinal pigmentation), HP:0007663 (Reduced visual acuity), HP:0200070 (Peripheral retinal atrophy), HP:0007722 (Retinal pigment epithelial atrophy), HP:0000518 (Cataract)

CaseHPOFreeText: The patient presented at age 53 with nyctalopia and peripheral visual loss.

CaseNotHPOs: HP:0003593 (Infantile onset), HP:0011463 (Childhood onset)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

CaseMethod1: 31-gene sequencing panel

CaseMethod2: N/A

CaseGenotypingMethod: Variants in CHM and 29 other genes involved in Retinitis pigmentosa or Leber congenital amaurosis were excluded by genotyping panel, which also detected the variant in RPE65.

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: The possibility of family consanguinity was not mentioned.

CasePMIDs: N/A

Case#: Yzer_2006_Patient_441, female, age 3 months at diagnosis, Belgian maternal and Moroccan paternal origin

CasePresentingHPOs: HP:0003593 (Infantile onset), HP:0000662 (Nyctalopia), HP:0000639 (Nystagmus), HP:0007663 (Reduced visual acuity), HP:0001483 (Eye poking), HP:0000550 (Undetectable electroretinogram)

CaseHPOFreeText: The individual is described as having Leber congenital amaurosis. Age was 15 months at time of last evaluation.

CaseNotHPOs: HP:0000613 (Photophobia), HP:0000563 (Keratoconus), HP:0001098 (Abnormal fundus morphology)

CaseNotHPOFreeText: N/A

CasePreviousTesting: An LCA-specific microarray ChIP was used for initial genotyping, using antisense oligos to screen for 301 known disease-associated variants 6 LCA genes (AIPL1, CRB1, CRX, GUCY2D, RPE65, and RPGRIP1) and two early-onset RP genes (LRAT and MERTK).

CaseMethod1: Sanger sequencing of PCR products from the relevant exon of GUCY2D (or from each of the 20 exons of GUCY2D in the compound heterozygous individual with a novel variant).

CaseMethod2: N/A

CaseGenotypingMethod: The individual was initially screened using an LCA-specific microarray ChIP with antisense oligos to detect 301 known disease-associated variants 6 LCA genes (AIPL1, CRB1, CRX, GUCY2D, RPE65, and RPGRIP1) and two early-onset RP genes (LRAT and MERTK). Subsequent genotyping was performed by Sanger sequencing of PCR products from the relevant exons of the GUCY2D locus.

Variant: The individual is compound heterozygous for the NM_000180.4(GUCY2D):c.1694T>C (p.Phe565Ser) and NM_000180.4(GUCY2D):c.2302C>T (p.Arg768Trp) variants.

ClinVar: 9350, 98563

gnomAD: The NM_000180.4(GUCY2D):c.1694T>C (p.Phe565Ser) variant exhibits a maximum allele frequency of 0.000008790 in gnomAD version 2.1.1 (in the European non-Finnish population, with no homozygotes). https://gnomad.broadinstitute.org/variant/17-7912849-T-C?dataset=gnomad_r2_1 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

VariantEvidence: PMID: 9888789 provides evidence supporting the pathogenicity of the NM_000180.4(GUCY2D):c.1694T>C (p.Phe565Ser) variant by showing that the orthologous bovine F514S point mutation severely decreases the intrinsic cyclase activity of the protein and inactivates one of its calcium-responsive activating switches, CRM1. 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: Parents were not reported to be consanguineous. Segregation / phasing of two variants was confirmed by parental genotyping.

CasePMIDs: N/A

Case#: Yzer_2006_Patient_22597, female, diagnosed soon after birth, family origin not described

CasePresentingHPOs: HP:0003593 (Infantile onset), HP:0006934 (Congenital nystagmus), HP:0030532 (Visual acuity test abnormality), HP:0007843 (Attenuation of retinal blood vessels), HP:0000550 (Undetectable electroretinogram)

CaseHPOFreeText: The individual is described as having Leber congenital amaurosis. Diagnosis was made soon after birth, but an exact age is not described. Visual acuity was limited to light perception.

CaseNotHPOs: HP:0000543 (Optic disc pallor), HP:0007703 (Abnormality of retinal pigmentation)

CaseNotHPOFreeText: Most recent fundus examination was relatively normal at 25 years of age.

CasePreviousTesting: An LCA-specific microarray ChIP was used for initial genotyping, using antisense oligos to screen for 301 known disease-associated variants 6 LCA genes (AIPL1, CRB1, CRX, GUCY2D, RPE65, and RPGRIP1) and two early-onset RP genes (LRAT and MERTK).

CaseMethod1: Sanger sequencing of PCR products from the relevant exon of GUCY2D.

CaseMethod2: N/A

CaseGenotypingMethod: The individual was initially screened using an LCA-specific microarray ChIP with antisense oligos to detect 301 known disease-associated variants 6 LCA genes (AIPL1, CRB1, CRX, GUCY2D, RPE65, and RPGRIP1) and two early-onset RP genes (LRAT and MERTK). Subsequent genotyping was performed by Sanger sequencing of PCR products from the relevant exon of the GUCY2D locus.

Variant: The individual is homozygous for the NM_000180.4(GUCY2D):c.1694T>C (p.Phe565Ser) variant.

ClinVar: 9350

gnomAD: The NM_000180.4(GUCY2D):c.1694T>C (p.Phe565Ser) variant exhibits a maximum allele frequency of 0.000008790 in gnomAD version 2.1.1 (in the European non-Finnish population, with no homozygotes). https://gnomad.broadinstitute.org/variant/17-7912849-T-C?dataset=gnomad_r2_1

VariantEvidence: PMID: 9888789 provides evidence supporting the pathogenicity of the NM_000180.4(GUCY2D):c.1694T>C (p.Phe565Ser) variant by showing that the orthologous bovine F514S point mutation severely decreases the intrinsic cyclase activity of the protein and inactivates one of its calcium-responsive activating switches, CRM1.

CaseAddInfo: Parents were reported to be consanguineous. Segregation / phasing of two variants was not confirmed by parental genotyping.

CasePMIDs: N/A

Case#: Perrault_2000_Family_9_Proband, male, age unknown, family origin in Algeria with Arab ancestry

CasePresentingHPOs: N/A

CaseHPOFreeText: The individual is described as having Leber congenital amaurosis.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Linkage mapping of the disease locus to chromosome 17p13.1 (PMID: 7581387, PMID: 8641699)

CaseMethod1: Sanger sequencing of PCR products from each of the 20 exons

CaseMethod2: N/A

CaseGenotypingMethod: The individual was included in multi-family homozygosity mapping, establishing linkage to chromosome 17p13.1 and particularly between the D17S1353 and D17S1854 markers (PMID: 7581387, PMID: 8641699). Subsequent genotyping was performed by Sanger sequencing of PCR products from the GUCY2D locus.

Variant: The individual is homozygous for the NM_000180.4(GUCY2D):c.1694T>C (p.Phe565Ser) variant.

ClinVar: 9350

gnomAD: The variant exhibits a maximum allele frequency of 0.000008790 in gnomAD version 2.1.1 (in the European non-Finnish population, with no homozygotes). https://gnomad.broadinstitute.org/variant/17-7912849-T-C?dataset=gnomad_r2_1

VariantEvidence: The evidence supporting the pathogenicity of the variant is limited to computational prediction alone.

CaseAddInfo: The family is reportedly consanguineous.

CasePMIDs: PMID: 7581387, PMID: 8641699

Case#: Leroy_2009_Family_A_Patient_III-14, male, age 58 years, family of Flemish ethnicity and Belgian national origin

CasePresentingHPOs: HP:0030640 (Complete congenital stationary night blindness), HP:0007663 (Reduced visual acuity), HP:0007984 (Electronegative electroretinogram), HP:0000639 (Nystagmus), HP:0003593 (Infantile onset), HP:0025404 (Abnormal visual fixation), HP:0000545 (Myopia), HP:0001104 (Macular hypoplasia), HP:0001417 (X-linked inheritance)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0000613 (Photophobia), HP:0030526 (Severe constriction of peripheral visual field), HP:0030602 (Abnormal fundus autofluorescence imaging), HP:0025158 (Hyperautofluorescent retinal lesion)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

CaseMethod1: Sanger sequencing of PCR amplified exons from NYX

CaseMethod2: Haplotype analysis using microsatellite markers surrounding the NYX locus, in multiple apparently unrelated patients sharing the same variant

CaseGenotypingMethod: The proband and family members were subjected to Sanger sequencing of NYX to identify the variant, followed by haplotype analysis in comparison to apparently unrelated patients harboring the same variant.

Variant: The proband harbors the NM_022567.2:c.856del (p.Asp286ThrfsTer62) variant on the X chromosome.

CAID: CA2573050962

gnomAD: NM_022567.2:c.856del (p.Asp286ThrfsTer62) was not found in gnomAD.

VariantEvidence: The NM_022567.2:c.856del (p.Asp286ThrfsTer62) variant is located in exon 2/2 and is not predicted to trigger NMD. It is predicted to introduce a premature stop codon that would disrupt the C-terminal 41% of the protein product while adding 62 different amino acids.

CaseAddInfo: The proband comes from a large family with inheritance through an unaffected carrier mother and transmission to a grandson through an unaffected carrier daughter. This variant appears in 3 different families of Flemish Belgian origin, and is suspected to be a founder mutation in this population.

CasePMIDs: N/A

Case#: Brandl_2017_Family_11-151_Proband_#2, male, age 10 years at time of report, national origin reported as Turkish

CasePresentingHPOs: HP:0007677 (Vitelliform-like macular lesions), HP:0007663 (Reduced visual acuity, 0.2 logMAR), HP:0000493 (Abnormal foveal morphology, specifically bilateral central foveal detachment of neurosensory retina), HP:0008179 (Decreased Arden ratio of electrooculogram), HP:0030612 (Abnormal retinal morphology on macular OCT)

CaseHPOFreeText: The patient has been diagnosed with vitelliform macular dystrophy with onset in early childhood. The abnormal foveal morphology refers specifically to foveal detachment. Photoreceptor outer segments were elongated.

CaseNotHPOs: HP:0000512 (Abnormal electroretinogram)

CaseNotHPOFreeText: RPE and Bruch's membrane appeared normal.

CasePreviousTesting: Previous testing appears to have been limited to Sanger sequencing of the BEST1 and PRPH2 loci.

CaseMethod1: Sanger sequencing of the exons and flanking intronic sequences of IMPG1 and IMPG2.

CaseMethod2: N/A

CaseGenotypingMethod: Previous testing appears to have been limited to Sanger sequencing of the BEST1 and PRPH2 loci, while subsequent genotyping included Sanger sequencing of the exons and flanking intronic sequences of IMPG1 and IMPG2.

Variant: The proband harbors the NM_001563.4(IMPG1):c.807+5G>A variant in the homozygous state.

ClinVar: 1240016

gnomAD: The NM_001563.4(IMPG1):c.807+5G>A variant was not found in gnomAD v2.1.1.

VariantEvidence: NM_001563.4(IMPG1):c.807+5G>A is an intron 7 variant that has mini-gene assay evidence from this article (Figure 1) confirming a partial deleterious impact on the splicing of the transcript. The variant triggers skipping of exon 7 in approximately half of the transcripts. This partial defect appears to lead to in-frame loss of 141 bp (47 amino acids) corresponding to ~6% of the protein product.

CaseAddInfo: The parents of the proband are consanguineous and are clinically asymptomatic at ages 35 and 40 years, respectively.

CasePMIDs: N/A

Case#: Brandl_2017_Family_13-501_Proband_#1, male, age 13 years at time of report, national origin reported as German

CasePresentingHPOs: HP:0007677 (Vitelliform-like macular lesions), HP:0007663 (Reduced visual acuity, 0.1 to 0.2 logMAR), HP:0007703 (Abnormality of retinal pigmentation, particularly in the center), HP:0000493 (Abnormal foveal morphology, specifically foveal detachment)

CaseHPOFreeText: The patient has been diagnosed with vitelliform macular dystrophy with onset in early childhood. The abnormal foveal morphology refers specifically to foveal detachment.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing appears to have been limited to Sanger sequencing of the BEST1 and PRPH2 loci.

CaseMethod1: Sanger sequencing of the exons and flanking intronic sequences of IMPG1 and IMPG2.

CaseMethod2: N/A

CaseGenotypingMethod: Previous testing appears to have been limited to Sanger sequencing of the BEST1 and PRPH2 loci, while subsequent genotyping included Sanger sequencing of the exons and flanking intronic sequences of IMPG1 and IMPG2.

Variant: The proband harbors the NM_001563.4(IMPG1):c.713T>C (p.Leu238Pro) variant in the heterozygous state.

ClinVar: 865770

gnomAD: The NM_001563.4(IMPG1):c.713T>C (p.Leu238Pro) variant was found in gnomAD v2.1.1 at a frequency of 0.00006598 (2/30310) in the South Asian population, with 0 homozygotes https://gnomad.broadinstitute.org/variant/6-76728530-G-A?dataset=gnomad_r2_1

VariantEvidence: NM_001563.4(IMPG1):c.713T>C (p.Leu238Pro) is a missense variant that does not have evidence confirming an impact on the gene product. However, it has been reported by an independent group of researchers in multiple families with vitelliform macular dystrophy (PMID: 23993198).

CaseAddInfo: The proband is the only family member affected, with clinical and genetic testing data on the parents unavailable.

CasePMIDs: N/A

Case#: Zou_2017_Patient_F1-II:1, male, age 4 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.333_360+14delinsCTT variant in the hemizygous state.

CAID: CA2573320702

gnomAD: This variant was not found in gnomAD v2.1.1.

VariantEvidence: NM_000273.3(GPR143):c.333_360+14delinsCTT is an indel variant removing the 3' end of exon 2 including the canonical splice donor site, and is predicted to either introduce a premature stop codon or exon skipping.

CaseAddInfo: N/A

CasePMIDs: N/A

Case#: Zou_2017_Patient_F3-III:3, male, age 24 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), HP:0007730 (Iris hypopigmentation), HP:0030534 (Abnormal best corrected visual acuity test)

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: N/A

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.733C>T (p.Arg245Ter) variant in the hemizygous state.

ClinVar: 1352731

gnomAD: This variant was not found in gnomAD v2.1.1.

VariantEvidence: NM_000273.3(GPR143):c.733C>T (p.Arg245Ter) is a nonsense variant in exon 6 of 9, and is predicted to trigger nonsense-mediated decay or to at least truncate the C-terminal 40% of the protein product.

CaseAddInfo: N/A

CasePMIDs: N/A

Case#: Meins_1993_Proband, male, age 58 years at time of report, national origin reported as German

CasePresentingHPOs: Nyctalopia HP:0000662, Reduced visual acuity HP:0007663, Peripheral visual field loss HP:0007994, Central scotoma HP:0000603, Decreased light- and dark-adapted electroretinogram amplitude HP:0000654, Decreased Arden ratio of electrooculogram HP:0008179, Bone spicule pigmentation of the retina HP:0007737, Macular flecks HP:0011507

CaseHPOFreeText: The proband has been diagnosed with retinitis pigmentosa, following a previous diagnosis of Stargardt's macular dystrophy almost 1 decade earlier. First onset of night vision loss was reportedly in his teens.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing in the proband is not described but genotyping appears to have been limited to the PRPH2 locus and did not include other candidate genes.

CaseMethod1: single-strand conformational polymorphism (SSCP) analysis of PCR products from the 3 exons of PRPH2

CaseMethod2: Sanger sequencing of PRPH2

CaseGenotypingMethod: Previous testing in the proband is not described but genotyping appears to have been limited to the PRPH2 locus and did not include other candidate genes. Genotyping was performed by SSCP analysis of PCR products from the 3 exons of PRPH2 and Sanger sequencing of PRPH2.

Variant: The proband harbors the NM_000322.5(PRPH2):c.136C>T (p.Arg46Ter) variant in the heterozygous state.

ClinVar ID: 13179

gnomAD: The NM_000322.5(PRPH2):c.136C>T (p.Arg46Ter) variant is found in gnomAD v4.0.0 at a frequency of 0.00004005 (3 alleles / 74906 total alleles, with 0 homozygotes) in the African / African-American population https://gnomad.broadinstitute.org/variant/6-42722199-G-A?dataset=gnomad_r4

VariantEvidence: NM_000322.5(PRPH2):c.136C>T (p.Arg46Ter) is a nonsense variant in exon 1 of 3 that is predicted to trigger nonsense-mediated decay or at least to truncate the C-terminal 87% of the protein product.

CaseAddInfo: The proband has a similarly affected father and grandfather who have not been genotyped.

CasePMIDs: N/A

Case#: Zhang_2016_Pedigree_C_Proband_C001, male, 32 years old at time of report, national origin reported to be Indian.

CasePresentingHPOs: HP:0007770 (Hypoplasia of the retina), HP:0007685 (Peripheral retinal avascularization), HP:0030666 (Retinal neovascularization)

CaseHPOFreeText: The proband has been diagnosed with familial exudative vitreoretinopathy (FEVR).

CaseNotHPOs: N/A

CaseNotHPOFreeText: Premature birth, maternal drug intake during pregnancy, or other ocular disease associated with osteopenia / osteoporosis

CasePreviousTesting: Whole exome sequencing was performed, ruling out variations in the NDP, FZD4, TSPAN12, and ZNF408 loci.

CaseMethod1: Whole exome sequencing

CaseMethod2: Sanger sequencing of PCR-amplified exons and flanking regions of the LRP5 locus

CaseGenotypingMethod: Whole exome sequencing was performed, ruling out variations in the NDP, FZD4, TSPAN12, and ZNF408 loci. This was followed by Sanger sequencing of PCR-amplified exons and flanking regions of the LRP5 locus.

Variant: The patient harbors the NM_002335.4(LRP5):c.1870C>T (p.Arg624Trp) variant in the homozygous state.

ClinVar: 1477058

gnomAD: The NM_002335.4(LRP5):c.1870C>T (p.Arg624Trp) variant was found in gnomAD v2.1.1 at a maximum allele frequency of 0.000008796 (1/113688) in the European non-Finnish population https://gnomad.broadinstitute.org/variant/11-68174060-C-T

VariantEvidence: NM_002335.4(LRP5):c.1870C>T (p.Arg624Trp) is a missense variant in exon 9 out of 23 that has evidence of a functional impact on the protein product. The variant was expressed in STF cells harboring a luciferase reporter construct, showing a reduced (hypomorphic) ability to induce luciferase reporter activity compared with wild-type control LRP5. (Figure 3).

CaseAddInfo: The proband shares the homozygous genotype with his affected mother, although the father's genotype is not available. The asymptomatic uncle and aunt are heterozygous.

CasePMIDs: N/A

Case#: Meindl_1996_Family_F47_Proband, male, age not specified, family origin either German or British

CasePresentingHPOs: HP:0000510 (Rod-cone dystrophy)

CaseHPOFreeText: The proband and affected family members have been diagnosed with retinitis pigmentosa, with an X-linked pattern of inheritance. 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.294C>A (p.His98Gln) variant in the hemizygous state.

ClinVar: 98775

gnomAD: The variant was not found in gnomAD v.2.1.1.

VariantEvidence: NM_001034853.2(RPGR):c.294C>A (p.His98Gln) is a missense variant and does not have associated evidence of impact on RPGR function.

CaseAddInfo: The proband is a member of Family 47.

CasePMIDs: N/A

Case#: Hull_2016_Patient_2.1, female, 45 years of age at onset, Irish ancestry

CasePresentingHPOs: HP:0003581 (Adult onset), HP:0007663 (Reduced visual acuity), HP:0001141 (Severely reduced visual acuity), HP:0200065 (Chorioretinal degeneration), HP:0000580 (Pigmentary retinopathy), HP:0030474 (Undetectable dark-adapted electroretinogram), HP:0008275 (Abnormal light-adapted electroretinogram)

CaseHPOFreeText: The patient presented at age 45 with central visual disturbance. Anterior retina was well-preserved.

CaseNotHPOs: HP:0003593 (Infantile onset), HP:0011463 (Childhood onset)

CaseNotHPOFreeText: N/A

CasePreviousTesting: Variants in REP1 and PRPH2 were initially excluded.

CaseMethod1: Candidate gene sequencing

CaseMethod2: Bidirectional, targeted Sanger sequencing within the RPE65 locus

CaseGenotypingMethod: Bidirectional Sanger sequencing of exon 13 of the RPE65 gene and flanking sequences

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: The possibility of family consanguinity was not mentioned.

CasePMIDs: N/A

Case#: Hull_2016_Patient_1.2, male, 18 years of age at onset, Irish ancestry

CasePresentingHPOs: HP:0003581 (Adult onset), HP:0007663 (Reduced visual acuity), HP:0000533 (Chorioretinal atrophy), HP:0000662 (Nyctalopia), HP:0007722 (Retinal pigment epithelial atrophy), HP:0000533 (Chorioretinal atrophy), HP:0030602 (Abnormal fundus autofluorescence imaging), HP:0000510 (Rod-cone dystrophy), HP:0008179 (Decreased Arden ratio of electrooculogram), HP:0000512 (Abnormal electroretinogram)

CaseHPOFreeText: The patient presented at age 18 with nyctalopia, progressed to central visual disturbance at age 33, and was limited to hand movement vision by age 48, with preserved peripheral vision.

CaseNotHPOs: HP:0003593 (Infantile onset), HP:0011463 (Childhood onset)

CaseNotHPOFreeText: N/A

CasePreviousTesting: Variants in REP1 and PRPH2 were initially excluded.

CaseMethod1: Candidate gene sequencing

CaseMethod2: Bidirectional, targeted Sanger sequencing within the RPE65 locus

CaseGenotypingMethod: Bidirectional Sanger sequencing of exon 13 of the RPE65 gene and flanking sequences

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: N/A