Case#: 091-2009

DiseaseAssertion: Hemophilia A, severe

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: HP:0003125

CaseHPOFreeText: FVIII:C < 1%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

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

Gene: F8

Variant: NM_000132.3:c.2681delG

LegacyVariant:

ClinVar: No

CAID: No

gnomAD:

Case#: 003-2024

DiseaseAssertion: Hemophilia A, mild

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: HP:0003125

CaseHPOFreeText: 5% < FVIII:C < 40%, 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.5399G>A

LegacyVariant:

ClinVar: No

CAID: CA255162

gnomAD:

Case#: 071-1036

DiseaseAssertion: Hemophilia A, moderate

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: HP:0003125

CaseHPOFreeText: 1% < FVIII:C < 5%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

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

Gene: F8

Variant:

LegacyVariant:

ClinVar: No

CAID: No

gnomAD:

Case#: 060-2010

DiseaseAssertion: Hemophilia A, mild

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: HP:0003125

CaseHPOFreeText: 5% < FVIII:C < 40%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

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

Gene: F8

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

LegacyVariant:

ClinVar: No

CAID: CA255129

gnomAD:

Case#: 020-2024

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.437A>C

LegacyVariant:

ClinVar: No

CAID: CA414919724

gnomAD:

Case#: 001-2027

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.1869_1870delG

LegacyVariant:

ClinVar: No

CAID: No

gnomAD:

Case#: 015-2003

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.3637delA

LegacyVariant:

ClinVar: No

CAID: CA255146

gnomAD:

Case#: 020-2006

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.1492G>A

LegacyVariant:

ClinVar: No

CAID: CA255109

gnomAD:

Case#: 035-2022

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.5954G>A

LegacyVariant:

ClinVar: No

CAID: CA414905715

gnomAD:

Case#: 020-2027

DiseaseAssertion: Hemophilia A, severe

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: HP:0003125

CaseHPOFreeText: FVIII:C < 1%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

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

Gene: F8

Variant: NM_000132.3:c.5253A>C

LegacyVariant:

ClinVar: No

CAID: CA414911240

gnomAD:

Case#: 091-2008

DiseaseAssertion: Hemophilia A, moderate

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: HP:0003125

CaseHPOFreeText: 1% < FVIII:C < 5%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

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

Gene: F8

Variant: NM_000132.3:c.142A>G

LegacyVariant:

ClinVar: No

CAID: CA414920432

gnomAD:

Case#: 001-2051

DiseaseAssertion: Hemophilia A, moderate

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: HP:0003125

CaseHPOFreeText: 1% < FVIII:C < 5%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

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

Gene: F8

Variant: NM_000132.3:c.2134C>A

LegacyVariant:

ClinVar: No

CAID: CA414904092

gnomAD:

Case#: 042-1001

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.2144+2A>G

LegacyVariant:

ClinVar: No

CAID: No

gnomAD:

Case#: 38

DiseaseAssertion: Hemophilia A

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: NA

CaseHPOFreeText: FVIII:C 29%, Mild Phenotype, No inhibitors present

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

Gene: F8

Variant: NM_000132.3:c.7031G>C (p.Gly2344Ala)

ClinVar: NA

CAID: CA414896685

gnomAD: Not reported

Case#: 29

DiseaseAssertion: Hemophilia A

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: NA

CaseHPOFreeText: FVIII:C 10/8/14%, Mild Phenotype, No inhibitors present

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

Gene: F8

Variant: NM_000132.3:c.6118T>G (p.Cys2040Gly)

ClinVar: NA

CAID: CA414904332

gnomAD: Not reported

Case#: 42

DiseaseAssertion: Hemophilia B

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: NA

CaseHPOFreeText: FIX:C 4% (Moderate Phenotype)

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

Gene: F9

Variant: NM_000133.4(F9):c.422G>A (p.Cys141Tyr)

ClinVar: 811510 https://www.ncbi.nlm.nih.gov/clinvar/variation/811510/

CAID: CA414438897

gnomAD: Not reported

Case#: Belvini_Proband_16 (Italian)

DiseaseAssertion: Severe Hemophilia B

FamilyInfo: N/A

ParentalTesting: N/A

CasePresentingHPOs: HP:0011858

CaseHPOsFreeText: reduced factor IX activity

CaseNotHPOs: N/A

CasePreviousTesting: N/A

Gene: F9

Variant:NM_000133.4:c.135G>C (p.Lys45Asn)

ClinVar: Absent

CAID: CA414435574

gnomAD: Absent/Not Reported

Case#: 146, male, 13 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.209_212delTTGT

LegacyVariant:

ClinVar: No

CAID: CA255050

gnomAD:

Case#: 61, male, 7 years old, Chinese

DiseaseAssertion: Hemophilia A, moderate

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: HP:0003125

CaseHPOFreeText: FVIII:C = 1%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

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

Gene: F8

Variant: NM_000132.3:c.2066T>C

LegacyVariant:

ClinVar: No

CAID: CA414909145

gnomAD:

Case#: 132, male, 28 years old, Chinese

DiseaseAssertion: Hemophilia A, moderate

FamilyInfo: NA

ParentalTesting: Maternity confirmed

CasePresentingHPOs: HP:0003125

CaseHPOFreeText: FVIII:C = 2.7%

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.4379dupA

LegacyVariant:

ClinVar: No

CAID: CA645292749

gnomAD:

Case#: 7, male, 8 years old, Chinese

DiseaseAssertion: Hemophilia A, severe

FamilyInfo: NA

ParentalTesting: Maternity confirmed

CasePresentingHPOs: HP:0003125

CaseHPOFreeText: FVIII:C < 1%, Inhibitor present

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

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

Gene: F8

Variant: NM_000132.3:c.1063C>T

LegacyVariant:

ClinVar: 10139

CAID: CA255031

gnomAD:

Case#: 45, male, 75 years old, Chinese

DiseaseAssertion: Hemophilia A, mild

FamilyInfo: Noted Family History

ParentalTesting: Maternity confirmed

CasePresentingHPOs: HP:0003125

CaseHPOFreeText: FVIII:C = 6.5%

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.1172G>A

LegacyVariant:

ClinVar: 10111

CAID: CA120918

gnomAD:

Case#: 157, male, 30 years old, Chinese

DiseaseAssertion: Hemophilia A, moderate

FamilyInfo: Noted Family History

ParentalTesting: Maternity confirmed

CasePresentingHPOs: HP:0003125

CaseHPOFreeText: FVIII:C = 1.2%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

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

Gene: F8

Variant: NM_000132.3:c.3637delA

LegacyVariant:

ClinVar: No

CAID: CA255146

gnomAD:

Case#: 1, male, 30 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.36C>A

LegacyVariant:

ClinVar: No

CAID: CA414920668

gnomAD:

Case#: 84, male, 48 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.5821A>C

LegacyVariant:

ClinVar: No

CAID: CA414906679

gnomAD:

Case#: 20, male, 36 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.5953C>T

LegacyVariant:

ClinVar: 10300

CAID: CA255191

gnomAD:

Case#: S16, Iranian

DiseaseAssertion: Hemophilia A, severe

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: HP:0003125, HP:0005261

CaseHPOFreeText: FVIII:C < 1%, Inhibitor present

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: The F8 gene was directly sequenced for all 26 exons using the Sanger sequencing method. PCR was performed and subsequently analyzed

Gene: F8

Variant: NA

LegacyVariant:

ClinVar: No

CAID: No

gnomAD:

Case#: 12

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.248C>G (p.Pro83Arg)

ClinVar: NA

CAID: CA10568618

gnomAD: MAF for Pro83Arg in the Ashkenazi Jewish population 0.0001335<br>https://gnomad.broadinstitute.org/variant/X-154227771-G-C?dataset=gnomad_r2_1

Case#: 20

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.1487C>G (p.Pro477Arg)

ClinVar: NA

CAID: CA414912766

gnomAD: Not reported

Case1: Male, 9-months at time of diagnosis

DiseaseAssertion: Severe Hemophilia B

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: HP:0001933 (Subcutaneous hemorrhage), HP:0007420 (Spontaneous hematomas), HP:0012233 (Intramuscular hematoma), HP:0005261 (Joint hemorrhage)

CaseHPOFreeText: FIX: C <1%, recurrent anaphylactic reactions to FIX (abdominal pain, respiratory arrest, and severe hypotension)

CasePreviousTesting: F9 analysis (revealed a point mutation at exon H)

Gene: F9

Variant: NM_000133.3(F9):c.880C>T (p.Arg294Ter)

LegacyVariant: g 30863 C>T; Arg 248 stop

ClinVar: 10587 https://www.ncbi.nlm.nih.gov/clinvar/variation/10587/

gnomAD: Not reported

Case#: Cz5, Italy (Calabria)

DiseaseAssertion: Hemophilia A

FamilyInfo: Inherited

ParentalTesting: NA

CasePresentingHPOs: NA

CaseHPOFreeText: FVII:C 4%

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

Gene: F8

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

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

CAID: CA873354114

gnomAD: Not reported

Case#: Cz13, Italy (Calabria)

DiseaseAssertion: Hemophilia A

FamilyInfo: Inherited

ParentalTesting: NA

CasePresentingHPOs: NA

CaseHPOFreeText: FVII:C 4%

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

Gene: F8

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

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

CAID: CA873354114

gnomAD: Not reported

Case#: Cz7, Italy (Calabria)

DiseaseAssertion: Hemophilia A

FamilyInfo: Sporadic

ParentalTesting: NA

CasePresentingHPOs: NA

CaseHPOFreeText: FVII:C <1%

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

Gene: F8

Variant: NM_000132.3(F8):c.5143C>T (p.Arg1715Ter)

ClinVar: 10267 https://www.ncbi.nlm.nih.gov/clinvar/variation/10267/

CAID: CA255155

gnomAD: Not reported

Case#: Cz16, Italy (Calabria)

DiseaseAssertion: Hemophilia A

FamilyInfo: Sporadic

ParentalTesting: NA

CasePresentingHPOs: NA

CaseHPOFreeText: FVII:C 4%

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

Gene: F8

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

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

CAID: CA873354114

gnomAD: Not reported

Case#: Awidi_Variant_1 (9 patients, 2 families)

DiseaseAssertion: Severe Hemophilia B

FamilyInfo: Positive family history

ParentalTesting: Positive family history

CasePresentingHPOs: HP:0011858

CaseHPOsFreeText: reduced factor IX activity

CaseNotHPOs: None

CasePreviousTesting: N/A

Gene: F9

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

ClinVar: 810864

CAID: CA414435539

gnomAD: Absent/Not Reported

Case Info: P6 (female)

DiseaseAssertion: Carrier

FamilyInfo: N/A

ParentalTesting: N/A

CasePresentingHPOs: HP:0003125, HP:0001928, HP:0001892

CaseHPOFreeText: Low FVIII levels (in vitro results were similar to the WT control and led to a normal specific activity (82.7% ± 9.0)), abnormal blood coagulation, mild bleeding tendency

CaseNotHPOs: N/A

CaseNotHPOsFreeText: N/A

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

Gene: F8

Variant: NM_000132.4:c.6095T>C

CAID: CA414904631

gnomAD: Absent/Not Reported

Case#: Heit_Proband_HB541 (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.128G>A (p.Arg43Gln)

ClinVar: 810864

CAID: CA414435539

gnomAD: Absent/Not Reported

Case#: 3

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.128G>A

LegacyVariant:

ClinVar: No

CAID: CA414435539

gnomAD:

Case#: 16

DiseaseAssertion: Hemophilia B, mild

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: HP:0011858

CaseHPOFreeText: FIX:C = 12%

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.881G>A

LegacyVariant:

ClinVar: No

CAID: CA255368

gnomAD:

Case#: 10

DiseaseAssertion: Hemophilia B, moderate

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: HP:0011858

CaseHPOFreeText: FIX:C = 2.5%

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.571C>T

LegacyVariant:

ClinVar: No

CAID: CA255340

gnomAD:

Case#: 10

DiseaseAssertion: Hemophilia B, moderate

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: NA

CaseHPOFreeText: FIX:C = 1.8%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: All exons, UTRs, exon-intron junction regions, and the promotor of F9 were amplified by PCR and analyzed by direct DNA sequencing

Gene: F9

Variant:

LegacyVariant: NM_000133.3:c.880C>T

ClinVar: No

CAID: CA255344

gnomAD:

Case#: 4

DiseaseAssertion: Hemophilia B, severe

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: NA

CaseHPOFreeText: FIX:C < 1%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: All exons, UTRs, exon-intron junction regions, and the promotor of F9 were amplified by PCR and analyzed by direct DNA sequencing

Gene: F9

Variant: NM_000133.3:c.520G>C

LegacyVariant:

ClinVar: No

CAID: CA414439517

gnomAD:

Case#: Miller_Proband 2 (male)

DiseaseAssertion: Severe Hemophilia B

FamilyInfo: N/A

ParentalTesting: N/A

CasePresentingHPOs: HP:0011858

CaseHPOsFreeText: reduced factor IX activity

CaseNotHPOs: N/A

CasePreviousTesting: N/A

Gene: F9

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

ClinVar: 810864

CAID: CA414435539

gnomAD: Absent/Not Reported

Case#: A16

DiseaseAssertion: Hemophilia A, mild

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: HP:0003125

CaseHPOFreeText: FVIII:C = 7, FVIII:AG = 23, 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.5879G>A

LegacyVariant:

ClinVar: No

CAID: CA255019

gnomAD:

Case#: Lin_Patient 3 (assumed male, Chinese origin)

DiseaseAssertion: Severe Hemophilia B

FamilyInfo: N/A

ParentalTesting: None

CasePresentingHPOs: HP:0011858

CaseHPOsFreeText: reduced factor IX activity (FIX:C: <1 ; FIX:Ag: 38)

CaseNotHPOs: N/A

CasePreviousTesting: None

Gene: F9

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

ClinVar: 810864

CAID: CA414435539

gnomAD: Absent/Not Reported

Case#: Quadros_Proband_ ID_#2

DiseaseAssertion: Severe Hemophilia B

FamilyInfo: N/A

ParentalTesting: None

CasePresentingHPOs: HP:0011858

CaseHPOsFreeText: reduced factor IX activity

CaseNotHPOs: None

CasePreviousTesting: N/A

Gene: F9

Variant: NM_000133.4:c.112A>C (p.Asn38His)

ClinVar: Absent

CAID: CA414435439

gnomAD: Absent/Not Reported

Case#: Liu_Proband_316 (assumed male; Chinese)

DiseaseAssertion: Severe Hemophilia B

FamilyInfo: N/A

ParentalTesting: N/A

CasePresentingHPOs: HP:0011858

CaseHPOsFreeText: reduced factor IX activity

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

Gene: F9

Variant: NM_000133.4:c.82T>G (p.Cys28Gly)

ClinVar: Absent

CAID: CA414434482

gnomAD: Absent/Not Reported

Case#: Hadalin_2021_Family_1_Patient_III-1, male, 31 years old at first examination, family origin in Slovenia

CasePresentingHPOs: HP:0011463 (Childhood onset), HP:0000545 (Myopia), HP:0008020 (Cone dystrophy), HP:0007663 (Reduced visual acuity), HP:0012230 (Rhegmatogenous retinal detachment), HP:0000603 (Central scotoma), HP:0007814 (Retinal pigment epithelial mottling), HP:0008043 (Retinal arteriolar constriction), HP:0000543 (Optic disc pallor), HP:0030602 (Abnormal fundus autofluorescence imaging), HP:0200070 (Peripheral retinal atrophy), HP:0030465 (Undetectable light-adapted electroretinogram), HP:0000613 (Photophobia), HP:0011504 (Bull's eye maculopathy), HP:0007737 (Bone spicule pigmentation of the retina),

CaseHPOFreeText: The patient received a diagnosis of cone dystrophy. Myopia was present from childhood, while visual loss occurred in the early 30's.

CaseNotHPOs: N/A

CaseNotHPOFreeText: Dark-adapted ERG was normal at the time of the study.

CasePreviousTesting: The patient and an apparently unrelated proband from another family were subjected to whole-exome sequencing.

CaseMethod1: Whole-exome sequencing

CaseMethod2: Haplotype analysis using SNPs on the X chromosome

CaseGenotypingMethod: The patient and a proband from another family not known to be related were subjected to whole-exome sequencing, followed by haplotype analysis using SNPs on the X chromosome.

Variant: The patient harbors the NM_001034853.2(RPGR):c.3457T>A (p.Ter1153Lys) variant in the hemizygous state.

ClinVar: 931960

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

VariantEvidence: NM_001034853.2(RPGR):c.3457T>A (p.Ter1153Lys) is a stop-loss variant that triggers an extension of the C-terminus of RPGR by 38 amino acids. It is not predicted to undergo nonsense-mediated decay, and its inheritance pattern with largely unaffected female carriers is consistent with loss-of-function.

CaseAddInfo: The proband is a member of Family 1, with the mother being a female carrier with mild myopia, and an apparently affected maternal grandfather. Two other patients not known to be close relatives but harboring the same founder variant within a 29-megabase shared region received the same diagnosis of cone dystrophy.

CasePMIDs: N/A

Case#: Jespersgaard_2019_Patient_165, gender and age not specified, origin likely to be Danish based on cohort

CasePresentingHPOs: N/A

CaseHPOFreeText: The proband has been diagnosed with retinitis pigmentosa, as part of a larger group of generalized non-syndromic retinal dystrophies. Detailed phenotypes are not described.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Next-generation sequencing was performed focusing on a targeted panel of 125 genes known to be linked to inherited retinal disease.

CaseMethod1: NGS panel

CaseMethod2: N/A

CaseGenotypingMethod: Next-generation sequencing was performed focusing on a targeted panel of 125 genes known to be linked to inherited retinal disease. It is not clear whether Sanger sequencing was used to validate the genotyping of this particular case.

Variant: The proband harbors the NM_000440.3(PDE6A):c.1620+1G>A variant in the homozygous state.

ClinVar: 636054

gnomAD: The NM_000440.3(PDE6A):c.1620+1G>A variant is found in gnomAD v2.1.1 at a frequency of 0.00003267 (1/30608) in the South Asian population https://gnomad.broadinstitute.org/variant/5-149275918-C-T

VariantEvidence: The NM_000440.3(PDE6A):c.1620+1G>A variant disrupts a canonical splice site in intron 12, but does not have experimental confirmation of exon skipping or frameshift.

CaseAddInfo: N/A

CasePMIDs: N/A

Case#: Pattnaik_2015_Proband, male, age 10 years, family national origin described as Jordanian

CasePresentingHPOs: Nyctalopia HP:0000662, Childhood onset HP:0011463, Severely reduced visual acuity HP:0001141, Granular macular appearance HP:0007793, Retinal arteriolar constriction HP:0008043, Retinal degeneration HP:0000546, Abnormal choroid morphology (hypertrophy) HP:0000610

CaseHPOFreeText: The proband has been diagnosed at different times with Stargardt disease, retinitis pigmentosa, cone-rod dystrophy, and Leber congenital amaurosis, first presenting with night vision difficulties at age 2 years. Small focal sub-RPE deposits were observed.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The proband was initially genotyped by PCR-based screening for known LCA-associated variants and next-generation sequencing focused on a 19-gene LCA panel.

CaseMethod1: PCR-based screening for known LCA-associated variants as well as next-generation sequencing of a 19-gene LCA panel

CaseMethod2: Sanger sequencing of gaps and low-coverage regions as well as for confirmation of the variants detected by other methods.

CaseGenotypingMethod: The proband was initially genotyped by PCR-based screening for known LCA-associated variants and next-generation sequencing focused on a 19-gene LCA panel. Sanger sequencing of gaps and low-coverage regions as well as for confirmation of the variants detected by other methods.

Variant: The individual is homozygous for the NM_002242.4(KCNJ13):c.158G>A (p.Trp53Ter) variant.

ClinVar: 224857

gnomAD: The variant is not found in gnomAD version 4.1.0.

VariantEvidence: Heterologous expression of the NM_002242.4(KCNJ13):c.158G>A (p.Trp53Ter) variant in CHO-K1 cells revealed that the variant channel retained very little ability to enable the flow of current, with the measurement of -68.8pA more comparable to the negative control (-42.4pA) than to the wild-type control (-588.7pA).

CaseAddInfo: The family history does not reportedly indicate consanguinity.

CasePMIDs: N/A

Case#: Pusch_2000_Familly_9606_Proband, male, age and race not mentioned

CasePresentingHPOs: HP:0030640 (Complete congenital stationary night blindness), HP:0007663 (Reduced visual acuity), HP:0031624 (Moderate myopia), HP:0007984 (Electronegative electroretinogram)

CaseHPOFreeText: ERG with absent oscillatory-potential wavelets

CaseNotHPOs: HP:0001098 (Abnormal fundus morphology), HP:0030473 (Abnormal light-adapted flicker electroretinogram)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

CaseMethod1: Sanger sequencing of PCR amplified exons from NYX

CaseMethod2: N/A

CaseGenotypingMethod: The proband and family members were subjected to Sanger sequencing of NYX to identify the variant.

Variant: The proband harbors the NM_001378477.3(NYX):c.90C>A (p.Cys30Ter) variant on the X chromosome.

ClinVar: 11422

gnomAD: NM_001378477.3(NYX):c.90C>A (p.Cys30Ter) was not found in gnomAD.

VariantEvidence: This nonsense variant is located in exon 2/3 and is predicted to trigger NMD. It introduces a premature stop codon that would truncate 93% of the protein product.

CaseAddInfo: This variant appears not only in Family 9606, but also in Family 2438T, yet is not suspected to be a founder alelle.

CasePMIDs: N/A

Case#: Ashkenazy_2023_Proband, female, age 18 at time of report, family origin unknown due to adoption but reported in the United States

CasePresentingHPOs: Snowflake vitreoretinal degeneration HP:0011533, High myopia HP:0011003, Retinoschisis HP:0030502, Rhegmatogenous retinal detachment HP:0012230, Abnormal vitreous humor morphology HP:0004327, Full-thickness macular hole HP:0031152

CaseHPOFreeText: The patient exhibited fibrillar vitreous structure, crystalline retinopathy, and optic nerve flattening.

CaseNotHPOs: Corneal guttata HP:0012038, Presenile cataracts HP:0007819

CaseNotHPOFreeText: Perivascular sheathing was absent.

CasePreviousTesting: Genotyping of the proband was not described in detail, but reportedly did not include whole exome sequencing, due to the specificity of the phenotype. Genes implied to have been possibly examined were COL2A1, COL11A1, and CSPG2.

CaseMethod1: Sanger sequencing of KCNJ13

CaseMethod2: N/A

CaseGenotypingMethod: Genotyping of the proband was not described in detail, but reportedly did not include whole exome sequencing, due to the specificity of the phenotype. Genes implied to have been possibly examined were COL2A1, COL11A1, and CSPG2. Sanger sequencing of KCNJ13 was performed.

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 may or may not be a relative of the family previously reported with the same variant in PMID: 18179896, as both appear to have received medical care in the United States.

CasePMIDs: N/A

Case#: Patient 4, 64 years (at report), female

CaseHPOs: HP:0000613, HP:0007663, HP:0000551 (photophobia, reduced visual acuity, color vision defect)

CaseHPOsFreeText: Relatively late onset of disease (first symptoms around age 30 years). 1.7 LogMAR in both eyes. Refractive error was −2.00 sph in both eyes. Fundus exam showed a tigroid aspect with vessel thinning, macular atrophy, and optic pallor. Flash full-field ERG recordings showed a non-detectable response for the photopic component and a reduced response for the scotopic response. MfERG response was markedly reduced but still detectable in both eyes, presenting a residual foveal cone function. OCT macular scan showed a marked foveal thinning with advanced photo-receptor layer disruption (Fig 5)

CaseNotHPOs:

CasePreviousTesting: None mentioned but note that, in this study, DNA from all patients was analyzed by CORD NGS panel.

CaseMethod1: NGS panel

CaseGenotypingMethod: CORD NGS panel - ABCA4, ADAM9, AIPL1, C8orf37, CFAP410 (C21orf2), CACNA1F, CACNA2D4, CDHR1, CEP78, CNGA3, CRX, DRAM2, GUCA1A, GUCY2D, UNC119, IFT81, KCNV2, PDE6C, PITPNM3, POC1B, PROM1, PRPH2, RAB28, RAX2, RIMS1, RPGR, RPGRIP1, SEMA4A, TTLL5.

Variant: c.321G>A (p.Trp107Ter), homozygous

ClinVar: N/A

CAID: CA356373812

gnomAD: The variant is absent in gnomAD.

VariantEvidence: Structural analysis of p.Trp107Ter suggested that truncation of the protein sequence after residue W107 would break up helix α3, resulting in the absence of the C-terminal part of α3, β5, α4, β6, and α5. Missing structural elements β5, β6, and α5 would most probably result in failure to fold correctly or bind GTP/GDP causing degradation.

Case#: Patient 2, male, 33 (at report), 6 years old at onset

CaseHPOs: HP:0000613, HP:0007663, HP:0000551 (photophobia, reduced visual acuity, color vision defect)

CaseHPOsFreeText: BCVA LogMAR 1 for both eyes, refractive error −4.25 sph −2.00 cyl/180° D in right eye and −4.00 sph −2.50 cyl/30° D in left eye. The fundus exam showed normal optic disk, signs of foveal atrophy, and “salt and pepper” peripheral retinopathy. Fundus autofluorescence revealed a dark central area due to the absence of the RPE surrounded by an unusual hyperfluorescent perifoveal ring in both eyes while infrared retinography showed foveal atrophy. OCT imaging revealed a marked reduction of the foveal thickness associated with a photoreceptor layer disruption (Figure 3). Goldmann visual field test showed central scotoma with a mild peripheral constriction.

CaseNotHPOs:

CasePreviousTesting: None mentioned but note that, in this study, DNA from all patients was analyzed by CORD NGS panel.

CaseMethod1: NGS panel

CaseGenotypingMethod: CORD NGS panel - ABCA4, ADAM9, AIPL1, C8orf37, CFAP410 (C21orf2), CACNA1F, CACNA2D4, CDHR1, CEP78, CNGA3, CRX, DRAM2, GUCA1A, GUCY2D, UNC119, IFT81, KCNV2, PDE6C, PITPNM3, POC1B, PROM1, PRPH2, RAB28, RAX2, RIMS1, RPGR, RPGRIP1, SEMA4A, TTLL5.

Variant: c.37del (p.Leu13Ter) homozygous

ClinVar: N/A

CAID: CA2860243

gnomAD: The highest MAF in gnomAD v2.1.1 is 0.00003019 in European non-Finnish (no homozygotes in any population)

VariantEvidence: The variant would either result in nonsense-mediated mRNA decay, or retain few of the structural elements required for correct folding, causing degradation.

CaseAddInfo: Patient 3 is the affected sister of Patient 2. She is affected but has a milder phenotype. The father of these individual is unaffected and heterozygous for the variant. No details are provided about the mother.

Case#: Kelsell_1998_CORD6_Family_2_Proband, female, age 45 at time of report, nationality listed as British

CasePresentingHPOs: HP:0007401 (Macular atrophy), HP:0000548 (Cone/cone-rod dystrophy)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

CaseMethod1: Sanger sequencing of PCR products from each of the 18 exons of the GUCY2D locus

CaseMethod2: HhaI restriction digest of the PCR-amplified exon 13

CaseGenotypingMethod: The proband and her family members were subjected to sequencing of PCR products from each of the 18 exons of the GUCY2D locus. The PCR-amplified product from exon 13 was then subjected to HhaI restriction digest and resolved by agarose gel electrophoresis.

Variant: The proband harbors the NM_000180.4(GUCY2D):c.2512C>T (p.Arg838Cys) variant in the heterozygous state.

ClinVar: 9355

gnomAD: The variant is present in gnomAD at a frequency of 0.000007744 (1/129124) in the European non-Finnish population, with no homozygotes. https://gnomad.broadinstitute.org/variant/17-7918018-C-T

VariantEvidence: NM_000180.4(GUCY2D):c.2512C>T (p.Arg838Cys) is a missense variant located within the coiled-coil domain that mediates GUCY2D dimerization. Codon 838 has proven to be a hot spot disrupted in other families similarly affected with autosomal dominant cone-rod dystrophy (PMID: 11115851, PMID: 12552567, PMID: 26298565). The p.Arg838Cys substitution has been shown to disrupt the calcium sensitivity of GUCY2D and to trigger the inability to inactivate cyclase activity at high physiological calcium ion concentrations (PMID: 11115851).

CaseAddInfo: N/A

CasePMIDs: N/A

Case: Gliem_2000_Family_1_patient_II.1, female, country of origin Germany, onset at 47 years of age

DiseaseAssertion: Sorsby's fundus dystrophy

FamilyInfo: The variant was inherited by the proband rather than acquired de novo.

CasePresentingHPOs: HP:0000662 (Nyctalopia), HP:0007663 (Reduced visual acuity), HP:0011510 (Drusen), HP:0000533 (Chorioretinal atrophy)

CaseHPOFreeText: Presentation at age 47 with nyctalopia. Evaluation at age 61 showed drusen deposits in macular area, near optic disk and along vascular arcades, central and midperipheral atrophy, and reduced choroidal thickness.

CaseNOTHPOs: HP:0011506 (Choroidal neovascularization)

CaseNOTHPOFreeText: N/A

CasePreviousTesting: Phenotypic characterization only

GenotypingMethod: Sanger sequencing of PCR products from all 5 exons and flanking splice junctions of the TIMP3 gene.

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: Proband harbors the NM_000362.5(TIMP3):c.530A>G (p.Tyr177Cys) missense variant.

CAID: CA411540328

gnomAD: Variant is absent from gnomAD.

VariantEvidence: This missense variant within exon 5 of TIMP3 results in an unpaired Cys residue.

Case#: Olivier_2021_Family_K_Proband_II:3, male, age 43 years at the time of onset, national origin reported as Spanish

CasePresentingHPOs: HP:0000662 (Nyctalopia), HP:0001099 (Fundus atrophy), HP:0007737 (Bone spicule pigmentation of the retina)

CaseHPOFreeText: The proband has onset of retinitis pigmentosa at the age of 43 years.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: It is not clear whether previous testing methods included systematic genotyping of loci associated with VMD or RP.

CaseMethod1: Screening of IMPG1 using either gene panel testing or exome sequencing

CaseMethod2: Sanger sequencing-based confirmation

CaseGenotypingMethod: Genotyping is not entirely clear but has at least included panel-based analysis of the IMPG1 locus and Sanger sequencing-based confirmation.

Variant: The proband harbors the NM_001563.4(IMPG1):c.1982G>A (p.Arg661His) variant in the homozygous state.

ClinVar ID: 1056230

gnomAD: The NM_001563.4(IMPG1):c.1982G>A (p.Arg661His) variant is found in gnomAD v2.1.1 at a frequency of 0.00004006 (1/24964) in the African / African-American population, with 0 homozygotes https://gnomad.broadinstitute.org/variant/6-76657093-C-T

VariantEvidence: NM_001563.4(IMPG1):c.1982G>A (p.Arg661His) is a missense variant, which does not have experimental evidence of a functional effect on the protein product.

CaseAddInfo: The patient's affected sister shares the same homozygous genotype.

CasePMIDs: N/A

Case#: Olivier_2021_Family_H_Proband_II:1, male, age 53 years at the time of diagnosis, national origin reported as French

CasePresentingHPOs: HP:0007401 (Macular atrophy), HP:0007737 (Bone spicule pigmentation of the retina)

CaseHPOFreeText: The proband has been diagnosed with maculopathy at the age of 53 years, and exhibits retinal discoloration.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: It is not clear whether previous testing methods included systematic genotyping of loci associated with VMD or RP.

CaseMethod1: Screening of IMPG1 using either gene panel testing or exome sequencing

CaseMethod2: Sanger sequencing-based confirmation

CaseGenotypingMethod: Genotyping is not entirely clear but has at least included panel-based analysis of the IMPG1 locus and Sanger sequencing-based confirmation.

Variant: The proband harbors the NM_001563.4:c.2083G>T (p.Glu695Ter) variant in the heterozygous state.

CAID: CA364770054

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

VariantEvidence: NM_001563.4:c.2083G>T (p.Glu695Ter) is a nonsense variant in exon 15 of 17, which is predicted to trigger nonsense-mediated decay or to at least truncate the C-terminal 13% of the protein product.

CaseAddInfo: The patient's brother is an unaffected carrier of the variant.

CasePMIDs: N/A

Case#: Ebenezer_2005_Family_B_Patient_IV:11, male, age 44, family origin reported to be British

CasePresentingHPOs: HP:0003581 (Adult onset), HP:0000654 (Decreased light- and dark-adapted electroretinogram amplitude), HP:0000662 (Nyctalopia), HP:0007663 (Reduced visual acuity), HP:0000613 (Photophobia), HP:0000545 (Myopia), HP:0000483 (Astigmatism), HP:0007803 (Monochromacy), HP:0007722 (Retinal pigment epithelial atrophy), HP:0025159 (Hypoautofluorescent retinal lesion), HP:0007814 (Retinal pigment epithelial mottling)

CaseHPOFreeText: The proband has been diagnosed with progressive retinal degeneration / cone-rod dystrophy, with the family exhibiting an X-linked pattern of inheritance.

CaseNotHPOs: HP:0000639 (Nystagmus)

CaseNotHPOFreeText: N/A

CasePreviousTesting: The proband and family members were not genotyped outside of the RPGR locus.

CaseMethod1: Sanger sequencing of exon 15 of RPGR

CaseMethod2: N/A

CaseGenotypingMethod: The proband and family members were genotyped by Sanger sequencing of exon 15 of RPGR, but not by genome-wide methods.

Variant: The proband harbors the NM_001034853.2(RPGR):c.2929G>T (p.Gly977Ter) variant in the hemizygous state.

ClinVar: 9918

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

VariantEvidence: NM_001034853.2(RPGR):c.2929G>T (p.Gly977Ter) is a nonsense variant in the final exon (exon 15) that is not predicted to trigger nonsense-mediated decay, but disrupts ~15% of the C-terminus of the protein product.

CaseAddInfo: The proband is a member of Family B (shown in Figure 1), which includes four other affected genotype-positive males and as well as four carrier females who showed reduced visual acuity and golden tapetal reflex.

CasePMIDs: N/A

Case#: Ebenezer_2005_Family_A_Patient_III.4, male, age not specified, family origin reported to be British

CasePresentingHPOs: HP:0025710 (Late young adult onset), HP:0000662 (Nyctalopia), HP:0007663 (Reduced visual acuity), HP:0000613 (Photophobia), HP:0007803 (Monochromacy), HP:0031624 (Moderate myopia), HP:0001103 (Abnormal macular morphology), HP:0000533 (Chorioretinal atrophy), HP:0500087 (Peripapillary atrophy), HP:0025159 (Hypoautofluorescent retinal lesion), HP:0030844 (Undetectable pattern electroretinogram), HP:0000654 (Decreased light- and dark-adapted electroretinogram amplitude)

CaseHPOFreeText: The proband has been diagnosed with retinitis pigmentosa, with the family exhibiting an X-linked pattern of inheritance. Cone ERG was more severely reduced than rod ERG.

CaseNotHPOs: HP:0007769 (Peripheral retinal degeneration), HP:0000639 (Nystagmus)

CaseNotHPOFreeText: N/A

CasePreviousTesting: The proband and family members were not genotyped outside of the RPGR locus.

CaseMethod1: Sanger sequencing of exon 15 of RPGR

CaseMethod2: N/A

CaseGenotypingMethod: The proband and family members were genotyped by Sanger sequencing of exon 15 of RPGR, but not by genome-wide methods.

Variant: The proband harbors the NM_001034853.2(RPGR):c.2847_2848inv (p.Glu949_Glu950delinsAspTer) variant in the hemizygous state.

ClinVar: 9917

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

VariantEvidence: NM_001034853.2(RPGR):c.2847_2848inv (p.Glu949_Glu950delinsAspTer) is an indel in the final exon (exon 15) that introduces a premature stop codon. Although it is not predicted to trigger nonsense-mediated decay, it at least disrupts ~18% of the C-terminus of the protein product.

CaseAddInfo: The proband is a member of Family A (shown in Figure 1), which includes four other affected genotype-positive males and four carrier females who showed RPE abnormalities.

CasePMIDs: N/A

Case#: Georgiou_2024_Family_JP01_Proband_P12, male, reported at age 6 years, family origin reported as from Japan

CasePresentingHPOs: HP:0011003 (High myopia), HP:0030558 (Best corrected visual acuity 0.5 LogMAR)

CaseHPOFreeText: BCVA began at 0.20 logMAR and progressed to 0.57 logMAR.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping was by either next-generation sequencing panel, whole exome sequencing, or whole genome sequencing, but was unspecified.

CaseMethod1: NGS panel / WES / WGS

CaseMethod2: Sanger sequencing of RBP3

CaseGenotypingMethod: Previous genotyping by either next-generation sequencing panel, whole exome sequencing, or whole genome sequencing was followed by Sanger sequencing of RBP3.

Variant: The individual harbors the NM_002900.3(RBP3):c.632G>A (p.Trp211Ter) and NM_002900.3(RBP3):c.345_349del (p.Trp116AlafsTer7) variants in the compound heterozygous state.

ClinVar ID: 838965

CAID CA2953902720

gnomAD: The NM_002900.3(RBP3):c.345_349del (p.Trp116AlafsTer7) variant was not found in gnomAD version 4.1.1. The NM_002900.3(RBP3):c.632G>A (p.Trp211Ter) variant is found in gnomAD version 4.1.1 at a frequency of 0.00008913 (4 / 44878) in the East Asian population https://gnomad.broadinstitute.org/variant/chr10-47349116-G-A?dataset=gnomad_r4

VariantEvidence: NM_002900.3(RBP3):c.632G>A (p.Trp211Ter) is a nonsense variant within exon 1 of 4 that is predicted to trigger nonsense-mediated decay. NM_002900.3(RBP3):c.345_349del (p.Trp116AlafsTer7) is a frameshift variant within exon 1 of 4 that is predicted to trigger nonsense-mediated decay.

CaseAddInfo: Potential consanguinity within the proband's family has not been commented on.

CasePMIDs: N/A

Case#: Georgiou_2024_Family_NY01_Proband_P10, female, reported at age 56 years, family origin not reported

CasePresentingHPOs: HP:0011003 (High myopia), HP:0030558 (Best corrected visual acuity 0.5 LogMAR), HP:0000518 (Cataract)

CaseHPOFreeText: BCVA began at 0.51 logMAR and progressed to 0.54 logMAR. The proband had posterior chamber intraocular lenses. Myopia developed by age 7 years.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping was by either next-generation sequencing panel, whole exome sequencing, or whole genome sequencing, but was unspecified.

CaseMethod1: NGS panel / WES / WGS

CaseMethod2: Sanger sequencing of RBP3

CaseGenotypingMethod: Previous genotyping by either next-generation sequencing panel, whole exome sequencing, or whole genome sequencing was followed by Sanger sequencing of RBP3.

Variant: The individual harbors the NM_002900.3(RBP3):c.2824C>T (p.Gln942Ter) variant in the homozygous state.

ClinVar ID: 1069291

gnomAD: The variant is found in gnomAD version 4.1.1 at a frequency of 0.00001332 (1 / 75072) in the African / African-American population https://gnomad.broadinstitute.org/variant/chr10-47351308-C-T?dataset=gnomad_r4

VariantEvidence: NM_002900.3(RBP3):c.2824C>T (p.Gln942Ter) is a nonsense variant within exon 1 of 4 that is predicted to trigger nonsense-mediated decay.

CaseAddInfo: Potential consanguinity within the proband's family and their geographic origin have not been commented on.

CasePMIDs: N/A

Case

Case#: Meindl_1996_Family_F50_Proband, male, age not specified, family origin either German or British

CasePresentingHPOs: HP:0000510 (Rod-cone dystrophy)

CaseHPOFreeText: The proband has been diagnosed with retinitis pigmentosa. Disease onset was reported as early.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The family members previously underwent linkage analysis to map the underlying genetic cause to the region on chromosome Xp21.1 between the CYBB and OTC genes.

CaseMethod1: Hybridization analysis of amplified cDNA fragments from the RPGR locus to look for deletions, and SSCP analysis to look for point mutations

CaseMethod2: Sanger sequencing of the RPGR locus

CaseGenotypingMethod: The family members previously underwent linkage analysis to map the underlying genetic cause to the region on chromosome Xp21.1 between the CYBB and OTC genes. Amplified cDNA fragments from the RPGR locus were then screened by hybridization analysis to look for deletions and SSCP analysis to look for point mutations. The presence of the variant was confirmed by Sanger sequencing of the RPGR locus.

Variant: The affected family members harbor the NM_001034853.2(RPGR):c.581G>A (p.Trp194Ter) variant in the hemizygous state.

ClinVar: 98790

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

VariantEvidence: NM_001034853.2(RPGR):c.581G>A (p.Trp194Ter) is a nonsense variant predicted to trigger nonsense-mediated decay or to at least disrupt the C-terminal 76% of the protein product.

CaseAddInfo: The proband is a member of Family F50.

CasePMIDs: N/A

Case#: Gupta_2021_Proband_1, female, age 25 years at time of report, ethnic origin not reported

CasePresentingHPOs: HP:0000575 (Scotoma), HP:0007663 (Reduced visual acuity), HP:0030500 (Yellow/white lesions of the macula, specifically small foveal yellow spots), HP:0030627 (Foveal hyporeflective spaces on macular OCT), HP:0008323 (Abnormal light- and dark-adapted electroretinogram, specifically reduced response in the center of one retina)

CaseHPOFreeText: The patient has been diagnosed with foveomacular vitelliform dystrophy with adult onset.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing appears to have included genotyping of the

CaseMethod1:

CaseMethod2:

CaseGenotypingMethod: Genotyping appears to have included

Variant: The proband harbors the NM_001563.4(IMPG1):c.461T>C (p.Leu154Pro) variant in the heterozygous state.

ClinVar: 162136

gnomAD: This 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

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 apparently unrelated affected patients harboring this variant in the compound heterozygous state (PMID: 23993198), in trans with the NM_001563.4(IMPG1):c.1519C>T (p.Arg507Ter) variant.

CaseAddInfo: The variant is paternally inherited in this case, and the patient's father has been diagnosed with central serous chorioretinopathy but lacks other features of vitelliform macular dystrophy. This indicates that central serous chorioretinopathy is part of the spectrum of monoallelic disease.

CasePMIDs: N/A

Case#: Qin_2005_patient_8, female, age 14 years at report, national origin reported as Japanese

CasePresentingHPOs: HP:0001103 (Abnormal macular morphology), HP:0004349 (Reduced bone mineral density), HP:0003621 (Juvenile onset)

CaseHPOFreeText: The patient has been diagnosed with simplex FEVR, with bilateral dragged macula.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Genotyping appears to have been limited to the LRP5 and FZD4 loci.

CaseMethod1: Sanger sequencing of PCR-amplified exons and flanking regions of the LRP5 and FZD4 loci

CaseMethod2: N/A

CaseGenotypingMethod: Genotyping appears to have been limited to Sanger sequencing of PCR-amplified exons and flanking regions of the LRP5 and FZD4 loci.

Variant: The patient harbors the NM_002335.4(LRP5):c.804_813del (p.Gly269fs) and NM_002335.4(LRP5):c.1828G>A (p.Gly610Arg) variants in the compound heterozygous state.

ClinVar: 6295, 6294

gnomAD: The NM_002335.4(LRP5):c.804_813del (p.Gly269fs) variant was not found in gnomAD v2.1.1. The NM_002335.4(LRP5):c.1828G>A (p.Gly610Arg) variant was found in gnomAD v2.1.1 at a frequency of 0.00002644 (3/113484) in the European non-Finnish population https://gnomad.broadinstitute.org/variant/11-68174018-G-A

VariantEvidence: NM_002335.4(LRP5):c.1828G>A (p.Gly610Arg) is a missense variant in exon 9 that does not have experimental evidence of an impact on the protein product. NM_002335.4(LRP5):c.804_813del (p.Gly269fs) is a frameshift variant in exon 4 of 23 that is predicted to trigger nonsense-mediated decay or to at least disrupt the C-terminal 83% of the protein product.

CaseAddInfo: The patient has no family history of FEVR in her parents and brother, although bone mineral density was reduced in both parents. The mother is a carrier for p.Gly610Arg, while the father and brother are heterozygous for p.G268fsX272.

CasePMIDs: N/A

Case#: Harville_2010_Patient_A2885–II2, sex and age not reported, family origin reportedly from Saudi Arabia

CasePresentingHPOs: HP:0000510 (Rod-cone dystrophy), HP:0010442 (Polydactyly), HP:0001513 (Obesity), HP:0000077 (Abnormality of the kidney), HP:0001249 (Intellectual disability), HP:0004322 (Short stature), HP:0001263 (Global developmental delay), HP:0000823 (Delayed puberty)

CaseHPOFreeText: The proband has an initial clinical diagnosis of Bardet-Biedl syndrome.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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.124+1G>A variant in the homozygous state.

ClinVar ID: 557428

gnomAD: The NM_024649.5(BBS1):c.124+1G>A variant was not found in gnomAD v2.1.1.

VariantEvidence: NM_024649.5(BBS1):c.124+1G>A is a canonical splice site variant in intron 2 that is predicted but not confirmed to disrupt BBS1 splicing.

CaseAddInfo: The proband's family is reportedly consanguineous and includes a similarly affected sibling sharing the same homozygous genotype.

CasePMIDs: N/A

Case#: Lebrun_2009_Patient_2, male, age 2-3 at onset, age 15 at death, family ethnicity reported as Afghan

CasePresentingHPOs: HP:0001251 (Ataxia), HP:0002474 (Expressive language delay), HP:0001250 (Seizure), HP:0011463 (Childhood onset), HP:0011421 (Death in adolescence)

CaseHPOFreeText: Onset was at age 2-3, with the first presenting phenotypes being ataxia and delay in speech development. Seizures began at age 4. Death occurred at age 15.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The extent of previous testing within this patient is unclear.

CaseMethod1: N/A

CaseMethod2: N/A

CaseGenotypingMethod: CLN5 mRNA was reverse transcribed, PCR-amplified, and subjected to Sanger sequencing. This process was performed for both affected and control individuals (parents).

Variant: The patient is homozygous for the NM_006493.4(CLN5):c.990G>T (p.Trp330Cys) variant, (although this variant is referred to in the article as c.1137G>T (p.Trp379Cys)).

ClinVar: 56530

gnomAD: The variant is reported to have a maximum allele frequency of 0.00006484 (in the European non-Finnish population, with no homozygous individuals). https://gnomad.broadinstitute.org/variant/13-77575017-G-T

VariantEvidence: The missense variant introduces an additional cysteine into the protein product, potentially disrupting folding and three-dimensional structure. Immunofluorescent detection of the exogenously expressed variant in COS7 cells shows aberrant localization to the ER in contrast to the wild-type localization to the lysosome (Figure 3).

CaseAddInfo: The patient's family is consanguineous, as parents are described as first degree cousins. Parents were heterozygous for the variant. Family relationships between individuals were verified.

CasePMIDs: N/A

Case#: Lebrun_2009_Patient_1, male, age 5 at onset, U.K. origin with family ethnicity reported as Pakistani

CasePresentingHPOs: HP:0007010 (Poor fine motor coordination), HP:0007015 (Poor gross motor coordination), HP:0100952 (Enlarged sylvian cistern), HP:0001251 (Ataxia), HP:0001250 (Seizure), HP:0002465 (Poor speech), HP:0007064 (Progressive language deterioration), HP:0011463 (Childhood onset), HP:0000572 (Visual loss), HP:0030511 (Bradyopsia), HP:0000550 (Undetectable electroretinogram), HP:0003208 (Fingerprint intracellular accumulation of autofluorescent lipopigment storage material), HP:0002120 (Cerebral cortical atrophy), HP:0001272 (Cerebellar atrophy)

CaseHPOFreeText: Onset was at age 5, with the first presenting phenotypes being motor problems. Marked cerebellar sulcal widening with subarachnoidal space expansion was seen by brain MRI at age 5. Ataxia and language degradation were observed at age 6. Cortical and cerebellar atrophy presented by brain MRI scan at age 7. Visual problems presented at age 7.5, specifically with inability to focus on moving objects. Seizures first presented at age 8.5, along with bilaterally extinguished ERG. Skin biopsy showed fingerprint-type intralysosomal inclusions.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Genome-wide methods were not initially used, as clinical phenotypes were consistent with diagnosis of neuronal ceroid lipofuscinosis (NCL). Enzymatic tests ruled out defects in the CLN1, CLN2, and CLN10 loci, while CLN3, CLN6, and CLN8 defects were ruled out by Sanger sequencing of the coding regions. SNP array-based homozygosity mapping was performed, revealing 7 homozygous candidate regions in the affected members from the (consanguineous) family. These regions were analyzed for candidate NCL genes, finding CLN5 as the most likely locus to harbor the causative variant.

CaseMethod1: SNP array-based homozygosity mapping was performed, revealing 7 homozygous candidate regions in the affected members from the (consanguineous) family. These regions were analyzed for candidate NCL genes, finding CLN5 as the most likely candidate for further genotyping.

CaseMethod2: N/A

CaseGenotypingMethod: CLN5 mRNA was reverse transcribed, PCR-amplified, and subjected to Sanger sequencing. This process was performed for both affected and control individuals (parents and unaffected sibling).

Variant: Patient is homozygous for NM_006493.4(CLN5):c.924_925del (p.Leu309fs), (although this variant is referred to in the article as c.1072_1073delTT (p.Leu358AlafsX4)).

ClinVar: 56526

gnomAD: The variant is reported to have a maximum allele frequency of 0.0002603 (in the Latino / Admixed American population, with no homozygous individuals). https://gnomad.broadinstitute.org/variant/13-77574801-AAT-A

VariantEvidence: The frameshift variant results in premature truncation and disrupts approximately 14% of the protein product at the C-terminus. Immunofluorescent detection of the exogenously expressed variant in COS7 cells shows aberrant localization to the ER in contrast to the wild-type localization to the lysosome (Figure 3).

CaseAddInfo: The patient's family has some degree of consanguinity, as parents are described as distantly related. Parents were heterozygous for the variant. Family relationships between individuals were verified.

CasePMIDs: N/A

Case#: Wang_2013_Proband_741, female, age 30 years at time of report, family origin not reported

CasePresentingHPOs: Retinal dystrophy HP:0000556, Attenuation of retinal blood vessels HP:0007843, Retinal pigment epithelial mottling HP:0007814, Patchy atrophy of the retinal pigment epithelium HP:0007791, Abnormality of macular pigmentation HP:0008002, Perifoveal ring of hyperautofluorescence HP:0030629, Abnormal retinal morphology on macular OCT HP:0030612, Mildly reduced visual acuity HP:0032037, Subretinal deposits HP:0031528

CaseHPOFreeText: The proband has a diagnosis of juvenile retinitis pigmentosa.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The proband was subjected to capture-based next-generation sequencing panel that included 163 known retinal disease genes.

CaseMethod1: next-generation sequencing panel

CaseMethod2: SNP array and Sanger sequencing of PRPH2

CaseGenotypingMethod: The proband was genotyped by capture-based next-generation sequencing panel that included 163 known retinal disease genes. Sanger sequencing of PRPH2 was subsequently used to confirm the presence of the variant.

Variant: The proband harbors the NM_000322.5(PRPH2):c.554T>C (p.Leu185Pro) variant in the homozygous state.

ClinVar ID: 13165

gnomAD: The NM_000322.5(PRPH2):c.554T>C (p.Leu185Pro) variant is found in gnomAD v4.0.0 at a frequency of 0.00003587 in the European (non-Finnish) population, with 15 alleles / 418142 total alleles (0 homozygotes) https://gnomad.broadinstitute.org/variant/6-42721781-A-G?dataset=gnomad_r4

VariantEvidence: NM_000322.5(PRPH2):c.554T>C (p.Leu185Pro) is a missense variant with mouse knock-in evidence of a disease-causing effect in the heterozygous state (PMID: 11427722). Mouse phenotypes from PMID: 11427722 included reduced amplitude of dark-adapted bright flash electroretinogram a-wave HP:0030483 (Figure 4), Reduced OCT-measured macular thickness HP:0030607 (Figure 2), and immunoblot analysis showing reduced L185P in retinas, indicating instability or reduced transport to the outer segment (Figure 5b). Other experiments from PMID: 11297544 showed that the p.Leu185Pro variant successfully forms dimers but fails to assemble into higher order oligomers, particularly in the absence of wild-type PRPH2 (Figures 3, 5).

CaseAddInfo: The proband's parents are each heterozygous carriers of the variant who appear to be sub-clinically affected. The 56-year-old father showed macular pattern dystrophy with clear foveal changes, but normal visual acuity.

CasePMIDs: N/A

Case#: Sergouniotis_2011_Proband_B-3, male, age 33 years, family ethnic origin described as European

CasePresentingHPOs: Reduced visual acuity HP:0007663, Constriction of peripheral visual field HP:0001133, Infantile onset HP:0003593, Strabismus HP:0000486, Nystagmus HP:0000639, Progressive night blindness HP:0007675, Moderate myopia HP:0031624, Decreased light- and dark-adapted electroretinogram amplitude HP:0000654, Presenile cataracts HP:0007819, Nummular pigmentation of the fundus HP:0030505, Retinal pigment epithelial loss on macular OCT HP:0030611

CaseHPOFreeText: The proband received a diagnosis of Leber congenital amaurosis. His phenotype is described as similar to the other affected individuals, including "a distinct and unusual retinal appearance and a similar early onset of visual loss, suggesting both impaired retinal development and progressive retinal degeneration, involving both rod and cone pathways". The disease was described as mildly progressive. OCT showed distorted retinal microanatomy even in areas without cell death, possibly indicating disturbance of the early development of the neurosensory retina.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The proband was previously genotyped by screening for previously-reported LCA-causing variants by microarray chip, with no molecular diagnosis.

CaseMethod1: screening for previously-reported LCA-causing variants by microarray chip

CaseMethod2: Sanger sequencing of the KCNJ13 exons and intron-exon boundaries

CaseGenotypingMethod: The proband was previously genotyped by screening for previously-reported LCA-causing variants by microarray chip, with no molecular diagnosis. Sanger sequencing of the KCNJ13 exons and intron-exon boundaries was subsequently performed.

Variant: The individual is homozygous for the NM_002242.4(KCNJ13):c.722T>C (p.Leu241Pro) variant.

ClinVar: 30332

gnomAD: The variant was not found in gnomAD version 4.1.0.

VariantEvidence: NM_002242.4(KCNJ13):c.722T>C (p.Leu241Pro) is a missense variant that has no experimental evidence in this study but has separately been shown to severely decrease expression and abolish complex glycosylation of KCNJ13 (PMID: 30257863, Figure 10).

CaseAddInfo: The proband's family history is not known to include consanguinity but heterozygous parents originate from the same isolated geographic area.

CasePMIDs: N/A

Case#: Gong_2001_Proband_4, 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.2151dup (p.Asp718Ter) variant in the homozygous state.

ClinVar: 6271

gnomAD: The NM_002335.4(LRP5):c.2151dup (p.Asp718Ter) variant was not found in gnomAD v2.1.1.

VariantEvidence: NM_002335.4(LRP5):c.2151dup (p.Asp718Ter) is a nonsense variant in exon 10 out of 23 that is predicted to trigger nonsense-mediated decay or at least to truncate the C-terminal ~56% of the protein product.

CaseAddInfo: The family is reportedly consanguineous.

CasePMIDs: PMID: 8659519

Case#: Gong_2001_Proband_5, 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.2557C>T (p.Gln853Ter) variant in the homozygous state.

ClinVar: 6272

gnomAD: The NM_002335.4(LRP5):c.2557C>T (p.Gln853Ter) variant was not found in gnomAD v2.1.1.

VariantEvidence: NM_002335.4(LRP5):c.2557C>T (p.Gln853Ter) is a nonsense variant in exon 12 out of 23 that is predicted to trigger nonsense-mediated decay or at least to truncate the C-terminal ~47% 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#: Delvallée_2021_Proband_B.II-1, male, age not described, family origin reported as from western France, ancestry reported as European

CasePresentingHPOs: HP:0000556 (Retinal dystrophy), HP:0000639 (Nystagmus), HP:0001162 (Postaxial hand polydactyly), HP:0001156 (Brachydactyly), HP:0001513 (Obesity), HP:0001256 (Intellectual disability, mild), HP:0001270 (Motor delay), HP:0000054 (Micropenis), HP:0000028 (Cryptorchidism)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The proband was subjected to targeted exome sequencing to detect variants in BBS-related loci.

CaseMethod1: targeted exome sequencing

CaseMethod2: Sanger sequencing of BBS1

CaseGenotypingMethod: The proband was subjected to targeted exome sequencing to detect variants in BBS-related loci, followed by Sanger sequencing of BBS1 to identify the variant and perform segregation analysis within the family.

Variant: The proband harbors the NM_024649.5(BBS1):c.1169T>G (p.Met390Arg) and NM_024649.5(BBS1):c.1214_1215insSVA variants in the compound heterozygous state.

ClinVar ID: 12143, 981241

gnomAD: The NM_024649.5(BBS1):c.1169T>G (p.Met390Arg) variant is found in gnomAD v2.1.1 at a frequency of 0.002773 in the European (non-Finnish) population, with 358 alleles / 129114 total alleles (0 homozygotes) https://gnomad.broadinstitute.org/variant/11-66293652-T-G?dataset=gnomad_r2_1 The NM_024649.5(BBS1):c.1214_1215insSVA was not found in gnomAD v2.1.1.

VariantEvidence: NM_024649.5(BBS1):c.1169T>G (p.Met390Arg) is a missense variant with mouse knock-in evidence of a similar disease-causing effect in the homozygous state (PMID: 18032602). This has not been taken into account in scoring, as the mouse model has been scored separately. However, it has provided a rationale not to down-score for the relatively high gnomAD frequency of this variant. NM_024649.5(BBS1):c.1214_1215insSVA is an indel in exon 13 of 17 that is reported to shift the reading frame and trigger nonsense-mediated decay. Figure 3 confirms the likely occurrences of NMD by indicating that the compound heterozygous probands have approximately 50% of wild-type levels of both BBS1 mRNA and protein.

CaseAddInfo: The proband's family includes two similarly affected brothers sharing the same genotype.

CasePMIDs: N/A

Case#: Haider_2000_Proband_2, sex, age, and origin not reported

CasePresentingHPOs: N/A

CaseHPOFreeText: The proband is part of a cohort in which all patients had a diagnosis of enhanced S-cone syndrome, based on electroretinogram and/or psychophysics, as well as optical coherence tomography. Other phenotypes within the cohort members (but not tracked individually) included increased sensitivity to blue light; visual loss, night blindness occurring from early in life, varying degrees of L-cone and M-cone vision, and retinal degeneration.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping was limited to Sanger sequencing of NR2E3, followed by SSCP to screen other family members for the variant.

CaseMethod1: Sanger sequencing of NR2E3

CaseMethod2: SSCP analysis of PCR products from NR2E3

CaseGenotypingMethod: Genotyping was performed by Sanger sequencing of NR2E3, followed by SSCP to screen other family members for the variant.

Variant: The individual harbors the NM_014249.4(NR2E3):c.200_208del (p.Cys67_Gly69del) variant in the homozygous state.

ClinVarID: 5531

gnomAD: The variant was not found in gnomAD version 4.1.0.

VariantEvidence: NM_014249.4(NR2E3):c.200_208del (p.Cys67_Gly69del) is a short in-frame deletion variant within the zinc finger / DNA-binding domain of NR2E3.

CaseAddInfo: It is not clear whether the proband came from a consanguineous family.

CasePMIDs: N/A

Case#: Haider_2000_Proband_4, sex, age, and origin not reported

CasePresentingHPOs: N/A

CaseHPOFreeText: The proband is part of a cohort in which all patients had a diagnosis of enhanced S-cone syndrome, based on electroretinogram and/or psychophysics, as well as optical coherence tomography. Other phenotypes within the cohort members (but not tracked individually) included increased sensitivity to blue light; visual loss, night blindness occurring from early in life, varying degrees of L-cone and M-cone vision, and retinal degeneration.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping was limited to Sanger sequencing of NR2E3, followed by SSCP to screen other family members for the variant.

CaseMethod1: Sanger sequencing of NR2E3

CaseMethod2: SSCP analysis of PCR products from NR2E3

CaseGenotypingMethod: Genotyping was performed by Sanger sequencing of NR2E3, followed by SSCP to screen other family members for the variant.

Variant: The individual harbors the NM_014249.4(NR2E3):c.227G>A (p.Arg76Gln) variant in the homozygous state.

ClinVarID: 5530

gnomAD: The variant is found in gnomAD version 4.1.0 at a frequency of 0.0004046 in the South Asian population (36 alleles / 88,984 total alleles, with 1 homozygote) https://gnomad.broadinstitute.org/variant/chr15-71811591-G-A?dataset=gnomad_r4

VariantEvidence: NM_014249.4(NR2E3):c.227G>A (p.Arg76Gln) is a missense variant within the zinc finger / DNA-binding domain of NR2E3, and occurs at the same amino acid position as another missense substitution reported in the same article.

CaseAddInfo: It is not clear whether the proband came from a consanguineous family.

CasePMIDs: N/A

Case#: Huang_1995_Family_#3397_Patient_AR76, male, age and ethnic origin note mentioned

CasePresentingHPOs: HP:0011463 (Childhood onset), HP:0000662 (Nyctalopia), HP:0007994 (Peripheral visual field loss), HP:0000543 (Optic disc pallor), HP:0007843 (Attenuation of retinal blood vessels), HP:0007737 (Bone spicule pigmentation of the retina), HP:0000654 (Decreased light- and dark-adapted electroretinogram amplitude), HP:0007984 (Electronegative electroretinogram)

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Sanger sequencing of PDE6A has been performed in the patient and her affected family members.

CaseMethod1: SSCP

CaseMethod2: Sanger sequencing of PDE6A

CaseGenotypingMethod: The patient and his affected sibling were subjected to SSCP of PDE6A PCR products followed by Sanger sequencing to identify the variant.

Variant: The proband harbors the NM_000440.3(PDE6A):c.1032C>A (p.Ser344Arg) and NM_000440.3(PDE6A):c.1683G>A (p.Trp561Ter) variants in the compound heterozygous state.

ClinVar: 13111, 13112

gnomAD: NM_000440.3(PDE6A):c.1032C>A (p.Ser344Arg) was not found in gnomAD v2.1.1, while NM_000440.3(PDE6A):c.1683G>A (p.Trp561Ter) was found at a frequency of 0.000008792 (1/113736) in the European non-Finnish population. https://gnomad.broadinstitute.org/variant/5-149274791-C-T

VariantEvidence: NM_000440.3(PDE6A):c.1032C>A (p.Ser344Arg) is a missense variant in exon 7 of 22 total, and does not have evidence of a functional effect on the protein product. NM_000440.3(PDE6A):c.1683G>A (p.Trp561Ter) is a nonsense variant in exon 13 of 22 total, and is predicted to trigger NMD or to at least disrupt the C-terminal 35% of the protein product.

CaseAddInfo: The proband is from a family with an affected sibling and unaffected parents.

CasePMIDs: N/A

Case#: Huang_1995_Family_#3526_Patient_AR23, female, age and ethnic origin note mentioned

CasePresentingHPOs: HP:0011463 (Childhood onset), HP:0000662 (Nyctalopia), HP:0007994 (Peripheral visual field loss), HP:0000543 (Optic disc pallor), HP:0007843 (Attenuation of retinal blood vessels), HP:0007737 (Bone spicule pigmentation of the retina), HP:0000654 (Decreased light- and dark-adapted electroretinogram amplitude), HP:0007984 (Electronegative electroretinogram)

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Sanger sequencing of PDE6A has been performed in the patient and her affected family members.

CaseMethod1: SSCP

CaseMethod2: Sanger sequencing of PDE6A

CaseGenotypingMethod: The patient and her affected family members were subjected to SSCP of PDE6A PCR products followed by Sanger sequencing to identify the variant.

Variant: The proband harbors the NM_000440.3(PDE6A):c.1749C>G (p.Tyr583Ter) variant in the homozygous state.

ClinVar: 13110

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

VariantEvidence: NM_000440.3(PDE6A):c.1749C>G (p.Tyr583Ter) is a nonsense variant in exon 14 of 22 total, and is predicted to trigger NMD or to at least truncate ~32% of the protein product.

CaseAddInfo: The proband is from a family with two affected siblings, two unaffected siblings, and unaffected parents.

CasePMIDs: N/A

Case#: Zeitz_2006_Family_A_II-5, male, onset in early childhood, family ancestry reported as Swiss

CasePresentingHPOs: HP:0011463 (Childhood onset), HP:0000639 (Nystagmus), HP:0007663 (Reduced visual acuity), HP:0000613 (Photophobia)

CaseHPOFreeText: The proband and his sibling have diagnosis of congenital stationary night blindness, in the absence of family history of the disease. BCVA was 20/100 at age 15 years. Disease course was stationary for 30 years but later included a decrease in visual acuity and development of moderate photophobia.

CaseNotHPOs: HP:0000662 (Nyctalopia)

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping was limited to Sanger sequencing of PCR products from the CACNA1F gene. The authors also implied that similarly screening was performed all other known genes associated CSNB, which at the time included RHO, GNAT1, PDE6B, GRK1, SAG, NYX, and GRM6.

CaseMethod1: Sanger sequencing of CABP4

CaseMethod2: N/A

CaseGenotypingMethod: Genotyping was limited to Sanger sequencing of PCR products from the CACNA1F and CABP4 genes, with possible sequencing of other known CSNB-associated genes RHO, GNAT1, PDE6B, GRK1, SAG, NYX, and GRM6.

Variant: The individual harbors the NM_145200.3(CABP4):c.800_801delAG variant in the homozygous state.

ClinVar ID: 1952

gnomAD: The variant is found in gnomAD version 4.1.1 at a frequency of 0.00007043 in the European (non-Finnish) population, with 0 homozygotes https://gnomad.broadinstitute.org/variant/11-67226099-CAG-C?dataset=gnomad_r2_1

VariantEvidence: NM_145200.3(CABP4):c.800_801delAG is a frameshift variant within exon 6 of 6 that is predicted not to trigger nonsense-mediated decay but rather to disrupt the C-terminal 9 amino acids (3%) of the protein product and to extend the remaining protein by 91 additional amino acids. Analysis of patient mRNA indicates that splicing occurs normally but that expression at the mRNA level is decreased by more than 50% relative to the unaffected family member control.

CaseAddInfo: The proband's family is reportedly non-consanguineous, and includes a similarly affected brother who is also homozygous for the variant, as well as unaffected parents and 4 unaffected siblings who are heterozygous or lacking the variant (Figure 2A). Family history was negative for CSNB.

CasePMIDs: N/A

Case#: Manes_2013_Family_NA1863_Proband_II:1, male, age between 25 and 45 years at time of report, national origin reported as Italian

CasePresentingHPOs: HP:0007677 (Vitelliform-like macular lesions), HP:0030631 (Hyperautofluorescent macular lesion), HP:0008179 (Decreased Arden ratio of electrooculogram, specifically 1.53 and 1.61 in each eye), HP:0000654 (Decreased light- and dark-adapted electroretinogram amplitude)

CaseHPOFreeText: The patient has been diagnosed with vitelliform macular dystrophy, and has very mildly reduced visual acuity (20/22).

CaseNotHPOs: N/A

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.807+1G>T variant in the homozygous state.

ClinVar: 162134

gnomAD: The NM_001563.4(IMPG1):c.807+1G>T variant was found in gnomAD v2.1.1 at a frequency of 0.000008855 (1/112932) in the European non-Finnish population, with 0 homozygotes https://gnomad.broadinstitute.org/variant/6-76728434-C-A

VariantEvidence: NM_001563.4(IMPG1):c.807+1G>T is a canonical splice site variant in intron 7 that does not have evidence confirming an impact on the gene product.

CaseAddInfo: The proband has a similarly affected younger sister who shares the same genotype. Parents are clinically unaffected heterozygous carriers but each harbor tiny extramacular deposits in the fundus. Consanguinity is reported in this family.

CasePMIDs: N/A

Case#: Bech-Hansen_2000_Family_R5_proband, male, age and race not mentioned, national origin in the United States

CasePresentingHPOs: HP:0030640 (Complete congenital stationary night blindness), HP:0030469 (Abnormal dark-adapted electroretinogram)

CaseHPOFreeText: At least one of two ERG abnormalities were observed in each affected family member; absence of rod psychophysical dark adaptation and/or absence of rod ERG with low-intensity blue flash.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Linkage analysis was originally performed in PMID: 2574143 using 17 X-chromosomal restriction fragment length polymorphism markers.

CaseMethod1: Agarose gel electrophoresis of the relevant PCR product to monitor segregation in the proband and family members

CaseMethod2: Sanger sequencing of PCR amplified exons from NYX

CaseGenotypingMethod: Linkage analysis was initially performed in PMID: 2574143 using 17 X-chromosomal restriction endonuclease-based markers. The proband and family members were then subjected to gel electrophoresis analysis of PCR products and Sanger sequencing to identify the variant.

Variant: The proband harbors the NM_001378477.3(NYX):c.70_93del (p.Arg24_Ala31del) variant on the X chromosome.

ClinVar: 99841

gnomAD: NM_001378477.3(NYX):c.70_93del (p.Arg24_Ala31del) has a maximum allele frequency of 0.0001018 (1/9823, with no males or homozygous females) in the European non-Finnish population https://gnomad.broadinstitute.org/variant/X-41332781-GGCCTGCGCCCGCGCTTGTCCCGCC-G

VariantEvidence: This in-frame deletion variant does not have experimental evidence of impact on the protein product, but is a recurrent variant observed in multiple apparently unrelated families (PMID: 2574143 and Figure 5 from this paper).

CaseAddInfo: Family phenotypes were described in PMID: 2574143.

CasePMIDs: PMID: 2574143

Case#: Allen_2003_Familly_X03_Proband, male, age not mentioned, British national origin

CasePresentingHPOs: HP:0007642 (Congenital stationary night blindness), HP:0007663 (Reduced visual acuity), HP:0031624 (Moderate myopia), HP:0007984 (Electronegative electroretinogram)

CaseHPOFreeText: ERG with absent scotopic oscillatory potential, subnormal ON response

CaseNotHPOs: N/A

CaseNotHPOFreeText: Normal OFF response

CasePreviousTesting: N/A

CaseMethod1: Sanger sequencing of PCR-amplified exons from NYX and CACNA1F

CaseMethod2: Haplotype analysis using microsatellite markers surrounding the NYX locus

CaseGenotypingMethod: The proband and family members were subjected to Sanger sequencing of NYX to identify the variant, followed by microsatellite-based haplotype analysis of families sharing the same variant.

Variant: The proband harbors the NM_022567.2(NYX):c.37+1G>C (p.=) variant on the X chromosome.

CAID: CA412988630

gnomAD: NM_022567.2(NYX):c.37+1G>C (p.=) was not found in gnomAD.

VariantEvidence: This splice site variant disrupts a canonical splice site between the two coding exons (exon 2 and exon 3), and is therefore predicted to disrupt the protein product.

CaseAddInfo: N/A

CasePMIDs: N/A

Case#: Allen_2003_Familly_X04_Proband, male, age not mentioned, British national origin

CasePresentingHPOs: HP:0007642 (Congenital stationary night blindness), HP:0007663 (Reduced visual acuity), HP:0031624 (Moderate myopia), HP:0007984 (Electronegative electroretinogram)

CaseHPOFreeText: ERG with absent scotopic oscillatory potential, subnormal ON response

CaseNotHPOs: N/A

CaseNotHPOFreeText: Normal OFF response

CasePreviousTesting: N/A

CaseMethod1: Sanger sequencing of PCR-amplified exons from NYX and CACNA1F

CaseMethod2: Haplotype analysis using microsatellite markers surrounding the NYX locus

CaseGenotypingMethod: The proband and family members were subjected to Sanger sequencing of NYX to identify the variant, followed by microsatellite-based haplotype analysis of families sharing the same variant.

Variant: The proband harbors the NM_022567.2 (NYX):c.339_353del (p.Glu114_Ala118del) variant on the X chromosome.

CAID: CA2573050968

gnomAD: NM_022567.2 (NYX):c.339_353del (p.Glu114_Ala118del) was not found in gnomAD.

VariantEvidence: NM_022567.2:c.339_353del is an in-frame deletion variant that removes 5 amino acids from the center of the polypeptide sequence. It is a recurrent variant reported here in multiple apparently unrelated British families (X04 and X06).

CaseAddInfo: N/A

CasePMIDs: N/A