Selection A - Gene is expressed in tissues relevant to disease:

ExperimentName: RPE65 expression is highly specific to the retinal pigment epithelium

TissueExpression: pigmented layer of retina (also known as retinal pigment epithelium, UBERON:0001782)

ExpressionEvidence: RPE65 protein was first detected using an RPE-specific monocolonal antibody raised against human retinal pigment epithelium (RPE) cells. Retina-specific gene expression data from a separate publication (PMID: 30239781, https://eyeintegration.nei.nih.gov/) confirm that RPE65 expression is highly specific to the retina relative to other tissues within the eye or the human body in general. Note where the evidence is found in the article.

PMID: 8474143

Gene: RPE65

HGNC: 10294

Disease: Leber congenital amaurosis 2

MONDO: 0008765

InheritancePattern: Autosomal Recessive

Prevalence: The overall prevalence of Leber congenital amaurosis is between 1 in 33,000 and 1 in 100,000 newborns, while the proportion of Leber congenital amaurosis caused by RPE65 variants is between 1% and 16.7%. Thus, the prevalence of Leber congenital amaurosis 2 is between 1 in 200,000 and 1 in 10,000,000.

Penetrance: Fully penetrant, with onset typically by 1 year of age

ExperimentName: Retinal dystrophy in dogs is caused by Rpe65 loss of function.

NonHumanModel: Canis familiaris

GeneAlteration: Swedish Briard / Briard Beagle dogs exhibit a biallelic 485delAAGA variant in the RPE65 locus that triggers a frameshift predicted to disrupt ~71% of the protein product.

ModelPhenotype: HP:0007642 (Congenital stationary night blindness), HP:0007663 (Reduced visual acuity), HP:0000618 (Blindness), HP:0007703 (Abnormality of retinal pigmentation), HP:0000556 (Retinal dystrophy), HP:0030483 (Reduced amplitude of dark-adapted bright flash electroretinogram a-wave), HP:0007984 (Electronegative electroretinogram), HP:0030479 (Abnormal amplitude of light-adapted flicker electroretinogram)

HumanPhenotype: HP:0000662 (Nyctalopia), HP:0000529 (Progressive visual loss), HP:0000618 (Blindness), HP:0030479 (Abnormal amplitude of light-adapted flicker electroretinogram), HP:0030474 (Undetectable dark-adapted electroretinogram)

ModelEvidence: The model system recapitulates the human phenotype in that the dogs exhibit severe vision loss (Table 1 in PMID: 2804031, describing the same animal model), structural abnormalities of the RPE (PMID: 7851218, studying the same animal model), and similar ERG abnormalities (Figures 2 and 3 in PMID: 2804031). Similar to the human patient families, the heterozygous individuals are unaffected (Figure 1 in this publication).

ModelVariant: The dogs harbor a spontaneously occurring frameshift variant in exon 5 of 14 (485delAAGA), rather than a targeted mutation equivalent to a particular human patient variant.

PMID: 10191083

Gene: RPE65

HGNC: 10294

Disease: Leber congenital amaurosis 2

MONDO: 0008765

InheritancePattern: Autosomal Recessive

Prevalence: The overall prevalence of Leber congenital amaurosis is between 1 in 33,000 and 1 in 100,000 newborns, while the proportion of Leber congenital amaurosis caused by RPE65 variants is between 1% and 16.7%. Thus, the prevalence of Leber congenital amaurosis 2 is between 1 in 200,000 and 1 in 10,000,000.

Penetrance: Fully penetrant, with onset typically by 1 year of age

ExperimentName: Rpe65 homozygous knockout abolishes rod photoreceptor function and disrupts RPE metabolism in mice.

NonHumanModel: Mus musculus

GeneAlteration: Rpe65 homozygous knockout was generated by replacing the 5' flanking region and the first three exons of Rpe65 with a PGK-Neo cassette.

ModelPhenotype: HP:0000479 (Abnormal retinal morphology), HP:0030469 (Abnormal dark-adapted electroretinogram), HP:0030483 (Reduced amplitude of dark-adapted bright flash electroretinogram a-wave), HP:0007984 (Electronegative electroretinogram)

HumanPhenotype: HP:0000662 (Nyctalopia), HP:0007688 (Undetectable light- and dark-adapted electroretinogram), HP:0001098 (Abnormal fundus morphology), HP:0000529 (Progressive visual loss)

ModelEvidence: The model system recapitulates the human phenotype in that the mice exhibit progressive onset of abnormalities in retinal morphology (specifically photoreceptor outer segment loss, Figures 2a-2e), accompanied by reduced responses in dark-adapted (Figure 4) but not light-adapted (Figure 5) ERG. These ERG results are characteristic of abolished rod function. The mice also recapitulate the molecular features of the human patients in that retinal esters accumulate in the retinal pigment epithelium of the mice (HPLC data in Figures 8a-8c).

ModelVariant: The model disrupts the entire Rpe65 locus rather than introducing a mutation equivalent to a human patient variant.

PMID: 9843205

Gene: RPE65

HGNC: 10294

Disease: Leber congenital amaurosis 2

MONDO: 0008765

InheritancePattern: Autosomal Recessive

Prevalence: The overall prevalence of Leber congenital amaurosis is between 1 in 33,000 and 1 in 100,000 newborns, while the proportion of Leber congenital amaurosis caused by RPE65 variants is between 1% and 16.7%. Thus, the prevalence of Leber congenital amaurosis 2 is between 1 in 200,000 and 1 in 10,000,000.

Penetrance: Fully penetrant, with onset typically by 1 year of age

FamilyLabel: Morimura_1998_Family_7828

FamilyPresentingHPOs: HP:0000546 (Retinal degeneration)

FamilyPresentingHPOFreeText: While specific phenotypes are not provided, the diagnosis of retinitis pigmentosa indicates that the affected family members maintained central vision during the first decade of life and subsequently experienced severe vision loss.

FamilyNotHPOs: N/A

FamilyNotHPOFreeText: N/A

CountryOrigin: The Dominican Republic

Ethnicity: Not mentioned

Race: Not mentioned

Family#PreviousTesting: All 14 RPE65 exons and flanking sequences were PCR-amplified and subjected to single-strand conformation polymorphism analysis (SSCA).

Family#GenotypingMethod: PCR-amplified exons identified by SSCA as candidates to harbor variants were subjected to Sanger sequencing in the probands and their family members.

Affected: 5

Unaffected: 5

Segregations: The pedigree (Figure 2A) shows 10 segregations, with none inconsistent.

PublishedLOD: N/A

eLOD: 3.03

AddSegregationInfo: While four of the affected family members are compound heterozygotes at the RPE65 locus, one harbors homozygous variants.

ProbandLabel: Morimura_1998_Patient_III-4

Variant: Four affected individuals are compound heterozygotes harboring the NM_000329.3(RPE65):c.1022T>C (p.Leu341Ser) and NM_000329.3(RPE65):c.1207_1210dup (p.Glu404fs) variants, while one affected individual is homozygous for the NM_000329.3(RPE65):c.1022T>C (p.Leu341Ser) variant.

ClinVar: 13118, 98831

gnomAD: Neither the NM_000329.3(RPE65):c.1022T>C (p.Leu341Ser) variant nor the NM_000329.3(RPE65):c.1207_1210dup (p.Glu404fs) variant is found within gnomAD.

FamilyAddInfo: The two variants were confirmed to be in trans, and heterozygous carriers were found to be unaffected. Potential consanguinity between the parents was not reported, at least within the first generation of the pedigree.

FamilyPMIDs: N/A

Case#: Morimura_1998_Family_7775_Patient_II-1, female, age and family origin not specified

CasePresentingHPOs: HP:0000546 (Retinal degeneration)

CaseHPOFreeText: While specific phenotypes are not provided, the initial diagnosis of Leber congenital amaurosis indicates that the proband was either born blind or lost vision within a period of months after birth.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: All 14 RPE65 exons and flanking sequences were PCR-amplified and subjected to single-strand conformation polymorphism analysis (SSCA).

CaseMethod1: Screening of PCR-amplified RPE65 exons using SSCA

CaseMethod2: Sanger sequencing of all 14 exons of RPE65

CaseGenotypingMethod: PCR-amplified exons identified by SSCA as candidates to harbor variants were subjected to Sanger sequencing.

Variant: The proband is a homozygote within the RPE65 locus, harboring the NM_000329.3(RPE65):c.271C>T (p.Arg91Trp) variant.

ClinVar: 13115 (homozygous)

gnomAD: The NM_000329.3(RPE65):c.271C>T (p.Arg91Trp) variant has a maximum allele frequency of 0.0002406 (within the African / African-American population, with no homozygotes): https://gnomad.broadinstitute.org/variant/1-68910541-G-A

VariantEvidence: The NM_000329.3(RPE65):c.271C>T (p.Arg91Trp) variant was also detected in this publication in a heterozygous state within two apparently unrelated probands with Retinitis pigmentosa (Figure 2A) and Leber congenital amaurosis (Figure 2B), respectively. A separate publication (PMID: 16754667) expressed this missense variant in non-patient cells and showed that it abolished the isomerohydrolase activity of the protein product, reduced its stability, and shifted the subcellular localization from predominantly membrane-associated to predominantly cytosolic.

CaseAddInfo: Genotyping of the proband's mother revealed NM_000329.3(RPE65):c.271C>T (p.Arg91Trp) in a heterozygous state. The father was not genotyped. Potential consanguinity between the parents was not reported.

CasePMIDs: N/A

Case#: Morimura_1998_Family_9148_Patient_II-1, male, age and family origin not specified

CasePresentingHPOs: HP:0000546 (Retinal degeneration)

CaseHPOFreeText: While specific phenotypes are not provided, the initial diagnosis of Leber congenital amaurosis indicates that the proband was either born blind or lost vision within a period of months after birth.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: All 14 RPE65 exons and flanking sequences were PCR-amplified and subjected to single-strand conformation polymorphism analysis (SSCA).

CaseMethod1: Screening of PCR-amplified RPE65 exons using SSCA

CaseMethod2: Sanger sequencing of all 14 exons of RPE65

CaseGenotypingMethod: PCR-amplified exons identified by SSCA as candidates to harbor variants were subjected to Sanger sequencing.

Variant: The proband is a compound heterozygote within the RPE65 locus, harboring the NM_000329.3(RPE65):c.118G>A (p.Gly40Ser) and NM_000329.3(RPE65):c.544C>T (p.His182Tyr) variants.

ClinVar: 98830, 98875

gnomAD: The NM_000329.3(RPE65):c.2T>C (p.Met1Thr) variant has a maximum allele frequency of 0.00009643 (within the Ashkenazi Jewish population, with no homozygotes): https://gnomad.broadinstitute.org/variant/1-68912520-C-T The NM_000329.3(RPE65):c.544C>T (p.His182Tyr) variant has a maximum allele frequency of 0.00009925 (within the Ashkenazi Jewish population, with no homozygotes): https://gnomad.broadinstitute.org/variant/1-68906635-G-A

VariantEvidence: The paternal NM_000329.3(RPE65):c.118G>A (p.Gly40Ser) and maternal NM_000329.3(RPE65):c.544C>T (p.His182Tyr) variants are missense variants that do not have evidence of gene impact.

CaseAddInfo: Genotyping of family members revealed the two variants to be in trans. The brother of the proband shares the same genotype and diagnosis of Leber congenital amaurosis.

CasePMIDs: N/A

PMID: 9501220

Gene: RPE65

HGNC: 10294

Disease: Leber congenital amaurosis 2

MONDO: 0008765

InheritancePattern: Autosomal Recessive

Prevalence: The overall prevalence of Leber congenital amaurosis is between 1 in 33,000 and 1 in 100,000 newborns, while the proportion of Leber congenital amaurosis caused by RPE65 variants is between 1% and 16.7%. Thus, the prevalence of Leber congenital amaurosis 2 is between 1 in 200,000 and 1 in 10,000,000.

Penetrance: Fully penetrant, with onset typically by 1 year of age

Case#: Morimura_1998_Family_3867_Patient_II-1, female, age and family origin not specified

CasePresentingHPOs: HP:0000546 (Retinal degeneration)

CaseHPOFreeText: While specific phenotypes are not provided, the initial diagnosis of Leber congenital amaurosis indicates that the proband was either born blind or lost vision within a period of months after birth.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: All 14 RPE65 exons and flanking sequences were PCR-amplified and subjected to single-strand conformation polymorphism analysis (SSCA).

CaseMethod1: Screening of PCR-amplified RPE65 exons using SSCA

CaseMethod2: Sanger sequencing of all 14 exons of RPE65

CaseGenotypingMethod: PCR-amplified exons identified by SSCA as candidates to harbor variants were subjected to Sanger sequencing.

Variant: The proband is a compound heterozygote within the RPE65 locus, harboring the NM_000329.3(RPE65):c.271C>T (p.Arg91Trp) and NM_000329.3(RPE65):c.304G>A (p.Glu102Lys) variants.

ClinVar: 13115, 98862

gnomAD: The NM_000329.3(RPE65):c.271C>T (p.Arg91Trp) variant has a maximum allele frequency of 0.0002406 (within the African / African-American population, with no homozygotes): https://gnomad.broadinstitute.org/variant/1-68910541-G-A The NM_000329.3(RPE65):c.304G>A (p.Glu102Lys) variant is not found within gnomAD.

VariantEvidence: NM_000329.3(RPE65):c.304G>A (p.Glu102Lys) is a missense variant that does not have evidence of gene impact. The NM_000329.3(RPE65):c.271C>T (p.Arg91Trp) variant was also detected in this publication in a heterozygous state within two apparently unrelated probands with Retinitis pigmentosa (Figure 2A) and Leber congenital amaurosis (Figure 2B), respectively. A separate publication (PMID: 16754667) expressed this missense variant in non-patient cells and showed that it abolished the isomerohydrolase activity of the protein product, reduced its stability, and shifted the subcellular localization from predominantly membrane-associated to predominantly cytosolic.

CaseAddInfo: Genotyping of the proband's parents revealed NM_000329.3(RPE65):c.271C>T (p.Arg91Trp) as the paternal variant and NM_000329.3(RPE65):c.304G>A (p.Glu102Lys) as a de novo variant.

CasePMIDs: N/A

PMID: 9501220

Gene: RPE65

HGNC: 10294

Disease: Retinitis pigmentosa 20

MONDO: 0013425

InheritancePattern: Autosomal Recessive

Prevalence: The overall prevalence of Retinitis pigmentosa is between 1 in 3,000 and 1 in 4,000 individuals, while the proportion of recessive Retinitis pigmentosa caused by RPE65 variants is ~2%. (PMID: 9501220) Thus, the prevalence of Retinitis pigmentosa 20 is between 1 in 150,000 and 1 in 200,000.

Penetrance: Fully penetrant, with onset typically in childhood

GroupName: Morimura_1998_Group_1

GroupPresentingHPOs: HP:0000546 (Retinal degeneration)

FamilyPresentingHPOFreeText: While specific phenotypes are not provided, the diagnosis of Leber congenital amaurosis or retinitis pigmentosa indicates that the affected family members experienced severe vision loss, either at birth / early infancy, or in childhood / adolescence.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

NumberMales: 8

NumberFemales: 9

CountryOrigin: Most residing within the United States or Canada

Ethnicity: Not mentioned

Race: Not mentioned

AgeRange: Not mentioned

TotalNumber: 17

FamilyInfo: 17

NoFamily: 0

VariantCount: 17

NonVariant: 0

OtherVariant: 0

GroupPreviousTesting: All 14 RPE65 exons and flanking sequences were PCR-amplified and subjected to single-strand conformation polymorphism analysis (SSCA).

GroupMethod1: Screening of PCR-products from 14 RPE65 exons by SSCA

GroupMethod2: Sanger sequencing of 14 RPE65 exons

GroupGenotypingMethod: PCR-amplified exons identified by SSCA as candidates to harbor variants were subjected to Sanger sequencing in the probands and their family members.

GroupAddInfo: N/A

Case#: Morimura_1998_Family_9404_Patient_II-3, male, age and family origin not specified

CasePresentingHPOs: HP:0000546 (Retinal degeneration)

CaseHPOFreeText: While specific phenotypes are not provided, the initial diagnosis of Leber congenital amaurosis indicates that the proband was either born blind or lost vision within a period of months after birth.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: All 14 RPE65 exons and flanking sequences were PCR-amplified and subjected to single-strand conformation polymorphism analysis (SSCA).

CaseMethod1: Screening of PCR-amplified RPE65 exons using SSCA

CaseMethod2: Sanger sequencing of all 14 exons of RPE65

CaseGenotypingMethod: PCR-amplified exons identified by SSCA as candidates to harbor variants were subjected to Sanger sequencing.

Variant: The proband is a homozygote within the RPE65 locus, harboring the NM_000329.3(RPE65):c.2T>C (p.Met1Thr) variant.

ClinVar: 98861 (homozygous)

gnomAD: The NM_000329.3(RPE65):c.2T>C (p.Met1Thr) variant was not found within gnomAD.

VariantEvidence: NM_000329.3(RPE65):c.2T>C (p.Met1Thr) is a missense variant that disrupts the start codon and is therefore predicted to have gene impact.

CaseAddInfo: Other family members were not genotyped, and potential consanguinity between the parents was not reported.

CasePMIDs: N/A

Case#: Morimura_1998_Family_0748_Patient_II-1, female, age and family origin not specified

CasePresentingHPOs: HP:0000546 (Retinal degeneration)

CaseHPOFreeText: While specific phenotypes are not provided, the initial diagnosis of Leber congenital amaurosis indicates that the proband was either born blind or lost vision within a period of months after birth.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: All 14 RPE65 exons and flanking sequences were PCR-amplified and subjected to single-strand conformation polymorphism analysis (SSCA).

CaseMethod1: Screening of PCR-amplified RPE65 exons using SSCA

CaseMethod2: Sanger sequencing of all 14 exons of RPE65

CaseGenotypingMethod: PCR-amplified exons identified by SSCA as candidates to harbor variants were subjected to Sanger sequencing.

Variant: The proband is a homozygote within the RPE65 locus, harboring the NM_000329.3(RPE65):c.643+2T>A variant.

ClinVar: 940479 (homozygous)

gnomAD: The NM_000329.3(RPE65):c.643+2T>A variant is not found within gnomAD.

VariantEvidence: NM_000329.3(RPE65):c.643+2T>A is an intron 6 variant strongly predicted to disrupt a canonical splice donor site (with a delta score of 0.98).

CaseAddInfo: While the variant is known to be homozygous, the proband's parents have not been genotyped. The potential consanguinity of the parents was not mentioned.

CasePMIDs: N/A

Case#: Morimura_1998_Family_9190_Patient_II-1, female, age and family origin not specified

CasePresentingHPOs: HP:0000546 (Retinal degeneration)

CaseHPOFreeText: While specific phenotypes are not provided, the initial diagnosis of Leber congenital amaurosis indicates that the proband was either born blind or lost vision within a period of months after birth.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: All 14 RPE65 exons and flanking sequences were PCR-amplified and subjected to single-strand conformation polymorphism analysis (SSCA).

CaseMethod1: Screening of PCR-amplified RPE65 exons using SSCA

CaseMethod2: Sanger sequencing of all 14 exons of RPE65

CaseGenotypingMethod: PCR-amplified exons identified by SSCA as candidates to harbor variants were subjected to Sanger sequencing.

Variant: The proband is a compound heterozygote within the RPE65 locus, harboring the NM_000329.3(RPE65):c.370C>T (p.Arg124Ter) and NM_000329.3(RPE65):c.962dup (p.Asn321fs) variants.

ClinVar: 98866, 98902

gnomAD: The NM_000329.3(RPE65):c.370C>T (p.Arg124Ter) variant has a maximum allele frequency of 0.0003676 (within the African / African-American population, with no homozygotes): https://gnomad.broadinstitute.org/variant/1-68910339-G-A The NM_000329.3(RPE65):c.962dup (p.Asn321fs) variant has a maximum allele frequency of 0.0001148 (within the African / African-American population, with no homozygotes): https://gnomad.broadinstitute.org/variant/1-68904660-A-AT

VariantEvidence: NM_000329.3(RPE65):c.370C>T (p.Arg124Ter) is a paternal nonsense variant predicted to either trigger NMD or truncate 77% of the protein product. NM_000329.3(RPE65):c.962dup (p.Asn321fs) is a maternal frameshift variant predicted to either trigger NMD or truncate 40% of the protein product.

CaseAddInfo: Genotyping of the proband's parents revealed that the variants are in trans. The possibility of parental consanguinity was not mentioned.

CasePMIDs: N/A

Case#: Morimura_1998_Family_E070_Patient_III-4, female, age and family origin not specified

CasePresentingHPOs: HP:0000546 (Retinal degeneration)

CaseHPOFreeText: While specific phenotypes are not provided, the initial diagnosis of isolate retinitis pigmentosa (later recategorized to recessive retinitis pigmentosa) indicates that the proband maintained central vision during the first decade of life and subsequently experienced severe vision loss.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: All 14 RPE65 exons and flanking sequences were PCR-amplified and subjected to single-strand conformation polymorphism analysis (SSCA).

CaseMethod1: Screening of PCR-amplified RPE65 exons using SSCA

CaseMethod2: Sanger sequencing of all 14 exons of RPE65

CaseGenotypingMethod: PCR-amplified exons identified by SSCA as candidates to harbor variants were subjected to Sanger sequencing.

Variant: The proband is a compound heterozygote harboring the NM_000329.3(RPE65):c.271C>T (p.Arg91Trp) and NM_000329.3(RPE65):c.1355T>G (p.Val452Gly) variants.

ClinVar: 13115, 13116

gnomAD: The NM_000329.3(RPE65):c.271C>T (p.Arg91Trp) variant has a maximum allele frequency of 0.0002406 (in the African / African-American population, with no homozygotes): https://gnomad.broadinstitute.org/variant/1-68910541-G-A The NM_000329.3(RPE65):c.1355T>G (p.Val452Gly) variant has a maximum allele frequency of 0.00005660 (in the Latino / Admixed American population, with no homozygotes): https://gnomad.broadinstitute.org/variant/1-68896843-A-C

VariantEvidence: The NM_000329.3(RPE65):c.271C>T (p.Arg91Trp) missense variant was also found in apparently unrelated patients diagnosed with Leber congenital amaurosis (Figure 2B). A separate publication (PMID: 16754667) expressed this missense variant in non-patient cells and showed that it abolished the isomerohydrolase activity of the protein product, reduced its stability, and shifted the subcellular localization from predominantly membrane-associated to predominantly cytosolic. The NM_000329.3(RPE65):c.1355T>G (p.Val452Gly) variant is a missense mutation without evidence of gene impact.

CaseAddInfo: The two variants are strongly suspected to be in trans, but one parent was not genotyped. A heterozygous carrier of the NM_000329.3(RPE65):c.1355T>G (p.Val452Gly) variant was found to be unaffected. Potential consanguinity between the parents was not reported.

CasePMIDs: N/A

Case#: Morimura_1998_Family_9145_Patient_II-1, female, age and family origin not specified

CasePresentingHPOs: HP:0000546 (Retinal degeneration)

CaseHPOFreeText: While specific phenotypes are not provided, the initial diagnosis of Leber congenital amaurosis indicates that the proband was either born blind or lost vision within a period of months after birth.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: All 14 RPE65 exons and flanking sequences were PCR-amplified and subjected to single-strand conformation polymorphism analysis (SSCA).

CaseMethod1: Screening of PCR-amplified RPE65 exons using SSCA

CaseMethod2: Sanger sequencing of all 14 exons of RPE65

CaseGenotypingMethod: PCR-amplified exons identified by SSCA as candidates to harbor variants were subjected to Sanger sequencing.

Variant: The proband is a homozygote within the RPE65 locus, harboring the NM_000329.3(RPE65):c.1418T>A (p.Val473Asp) variant.

ClinVar: 98846 (homozygous)

gnomAD: The NM_000329.3(RPE65):c.1418T>A (p.Val473Asp) variant is not found within gnomAD.

VariantEvidence: NM_000329.3(RPE65):c.1418T>A (p.Val473Asp) is a missense variant with unknown impact on gene function.

CaseAddInfo: While the variant is known to be homozygous, the proband's parents have not been genotyped. The potential consanguinity of the parents was not mentioned.

CasePMIDs: N/A

Case#: Morimura_1998_Family_7828_Patient_III-4, male, age not specified, from family originating in the Dominican Republic

CasePresentingHPOs: HP:0000546 (Retinal degeneration)

CaseHPOFreeText: While specific phenotypes are not provided, the diagnosis of retinitis pigmentosa indicates that the affected family members maintained central vision during the first decade of life and subsequently experienced severe vision loss.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: All 14 RPE65 exons and flanking sequences were PCR-amplified and subjected to single-strand conformation polymorphism analysis (SSCA).

CaseMethod1: Screening of PCR-amplified RPE65 exons using SSCA

CaseMethod2: Sanger sequencing of all 14 exons of RPE65

CaseGenotypingMethod: PCR-amplified exons identified by SSCA as candidates to harbor variants were subjected to Sanger sequencing.

Variant: The proband is a compound heterozygote harboring the NM_000329.3(RPE65):c.1022T>C (p.Leu341Ser) and NM_000329.3(RPE65):c.1207_1210dup (p.Glu404fs) variants.

ClinVar: 13118, 98831

gnomAD: Neither the NM_000329.3(RPE65):c.1022T>C (p.Leu341Ser) variant nor the NM_000329.3(RPE65):c.1207_1210dup (p.Glu404fs) variant is found within gnomAD.

VariantEvidence: The paternal frameshift variant is predicted to either trigger NMD or disrupt 24% of the protein product. The maternal missense variant does not have evidence of gene impact.

CaseAddInfo: The two variants were confirmed to be in trans, and heterozygous carriers were found to be unaffected. Potential consanguinity between the parents was not reported, at least within the first generation of the pedigree.

CasePMIDs: N/A

PMID: 12960219

Gene: RPE65

HGNC: 10294

Disease: Leber congenital amaurosis 2

MONDO: 0008765

InheritancePattern: Autosomal Recessive

Prevalence: The overall prevalence of Leber congenital amaurosis is between 1 in 33,000 and 1 in 100,000 newborns, while the proportion of Leber congenital amaurosis caused by RPE65 variants is between 1% and 16.7%. Thus, the prevalence of Leber congenital amaurosis 2 is between 1 in 200,000 and 1 in 10,000,000.

Penetrance: Fully penetrant, with onset typically by 1 year of age

PMID: 30996589

Gene: RPE65

HGNC: 10294

Disease: Leber congenital amaurosis 2

MONDO: 0008765

InheritancePattern: Autosomal Recessive

Prevalence: The overall prevalence of Leber congenital amaurosis is between 1 in 33,000 and 1 in 100,000 newborns, while the proportion of Leber congenital amaurosis caused by RPE65 variants is between 1% and 16.7%. Thus, the prevalence of Leber congenital amaurosis 2 is between 1 in 200,000 and 1 in 10,000,000.

Penetrance: Fully penetrant, with onset typically by 1 year of age

CaseControlLabel: Aggregated *RPE65 variants in 187 apparently-unrelated Chinese probands from 16 provinces of China diagnosed with LCA by retina specialists and 200 ethnically matched apparently-unrelated healthy control individuals.

CaseCohortLabel: 187 apparently-unrelated Chinese probands from 16 provinces of China diagnosed with LCA by retina specialists

ControlCohortLabel: 200 ethnically matched apparently-unrelated healthy control individuals

CaseControlPhenotype: HP:0003593 (Infantile onset), HP:0030555 (Best corrected visual acuity 0.2 LogMAR)

CaseControlPhenotypeFreeText: The above phenotypes are noted only for the subset of LCA patients later found to have RPE65-related disease. Age at onset was within the first few months after birth. The best corrected visual acuity for individuals over 30 years old was less than 0.2, with few exceptions.

CaseControlNOTPhenotype: N/A

CaseDemographics: Country of origin for all case and control individuals is China, with recruitment area including all 16 provinces. Numbers of males and females, race, and age range are unspecified.

ControlDemographics: Control individuals are stated to be ethnically matched to the cases, but details are not provided.

CaseMethod: Previous testing for cases appears to have been limited to diagnosis of Leber's congenital amaurosis by a retina expert. Genotyping method was Sanger sequencing of PCR products from all 14 exons of RPE65. Targeted exome sequencing (194-gene panel) appears to have been performed for a subset of affected cases harboring RPE65 variants.

ControlMethod: Previous testing was not described. Genotyping method was Sanger sequencing of PCR products from all 14 exons of RPE65.

CasePower: 187 cases were genotyped, and 14 were found to harbor RPE65 variants (12 biallelic and 2 apparently monoallelic), with 11 cases predicted to harbor biallelic pathogenic RPE65 variants.

ControlPower: The number of control individuals who harbored a variant in RPE65 is not mentioned.

CaseAddInfo: Cases may have overlapped with other studies of Leber congenital amaurosis in Chinese cohorts (PMID: 29133760, PMID: 25356976, PMID: 26047050, PMID: 23661369, PMID: 22509104, PMID: 25383945, PMID: 21602930, PMID: 23661368, PMID: 28393863). The possibility of overlap is not addressed in the text.

ControlAddInfo: Overlap of the control cohort with other PMIDs is not reported.

CaseControlEvaluation: The study type is Aggregate analysis. The study used Sanger sequencing of the 14 exons of the RPE65 gene as the detection method. Cases counted were those found to harbor biallelic RPE65 variants that were predicted to be pathogenic at the protein level or demonstrated to have transcript-level impact through a minigene in vitro splicing assay.

CaseControlStats: Test statistic value, p-value, and confidence interval are not included in the report.

CaseControlBias: Matching was performed on the basis of ethnicity. While it is possible that age, gender, and other demographics were not as well-matched between cases and controls, the early onset of the disease makes these unlikely sources of bias. Because the process of matching is not described in detail, it is difficult to evaluate other sources of potential bias such as differences in local origin between cases and controls that might lead to false assumptions that certain individuals are unrelated.

CaseControlComments: N/A

Case#: Marlhens_1997_Patient_III-2, female, age 20 years at time of report, unspecified ethnicity

CasePresentingHPOs: HP:0030506 (Yellow/white lesions of the retina), HP:0000580 (Pigmentary retinopathy), HP:0007843 (Attenuation of retinal blood vessels), HP:0000543 (Optic disc pallor), HP:0001141 (Severely reduced visual acuity)

CaseHPOFreeText: Pigmentary deposits, Attenuation of retinal blood vessels, and Optic disc pallor were all mild/moderate.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: All RPE65 coding exons and flanking sequences were PCR-amplified and subjected to single-strand conformation analysis. Exon 10 was identified as a likely candidate to harbor a variant.

CaseMethod1: Sanger sequencing of all 14 exons of RPE65

CaseMethod2: Screening of PCR products using SSCA for the maternal variant and AlwNI restriction digest for the paternal variant

CaseGenotypingMethod: All 14 exons of RPE65 were PCR-amplified and subjected to Sanger sequencing. Screening of PCR products was also performed using SSCA for the maternal variant and AlwNI restriction digest for the paternal variant.

Variant: Affected individuals are compound heterozygous for the NM_000329.3(RPE65):c.1067del (p.Asn356fs) (maternal) and NM_000329.3(RPE65):c.700C>T (p.Arg234Ter) (paternal) variants.

ClinVar: 98821, 13114

gnomAD: The maximum allele frequency for the NM_000329.3(RPE65):c.1067del (p.Asn356fs) variant is 0.00005458 (within the East Asian population, with no homozygotes). https://gnomad.broadinstitute.org/variant/1-68903930-AT-A The maximum allele frequency for the NM_000329.3(RPE65):c.700C>T (p.Arg234Ter) variant is 0.00008676 (within the Latino / Admixed American population, with no homozygotes). https://gnomad.broadinstitute.org/variant/1-68905269-G-A

VariantEvidence: The maternal frameshift variant occurs in exon 10 of 14 and is predicted to either trigger NMD or disrupt 33% of the protein product. The paternal nonsense variant occurs in exon 7 of 14 and is predicted to either trigger NMD or truncate 56% of the protein product. Both are likely to be null variants.

CaseAddInfo: The two variants were confirmed to be in trans, and heterozygous carriers were found to be unaffected. Potential parental consanguinity was not mentioned.

CasePMIDs: N/A

FamilyLabel: Marlens_1997_Family_1

FamilyPresentingHPOs: HP:0030506 (Yellow/white lesions of the retina), HP:0000580 (Pigmentary retinopathy), HP:0007843 (Attenuation of retinal blood vessels), HP:0000543 (Optic disc pallor), HP:0001141 (Severely reduced visual acuity)

FamilyPresentingHPOFreeText: Pigmentary deposits, Attenuation of retinal blood vessels, and Optic disc pallor were all mild/moderate.

FamilyNotHPOs: N/A

FamilyNotHPOFreeText: N/A

CountryOrigin: Not specified

Ethnicity: Not mentioned

Race: Not mentioned

Family#PreviousTesting: All RPE65 coding exons and flanking sequences were PCR-amplified and subjected to single-strand conformation analysis. Exon 10 was identified as a likely candidate to harbor a variant. All 14 exons of RPE65 were PCR-amplified and subjected to Sanger sequencing in both affected family members and their parents.

Family#GenotypingMethod: Screening of PCR products from affected and unaffected family members for the variants of interest was performed using SSCA for the maternal variant and AlwNI restriction digest for the paternal variant.

Affected: 2

Unaffected: 1

Segregations: The pedigree (Figure 1c) shows 1 segregation, with none inconsistent.

PublishedLOD: N/A

eLOD: N/A

AddSegregationInfo: N/A

ProbandLabel: Marlhens_1997_Patient_III-2

Variant: Affected individuals are compound heterozygous for the NM_000329.3(RPE65):c.1067del (p.Asn356fs) (maternal) and NM_000329.3(RPE65):c.700C>T (p.Arg234Ter) (paternal) variants.

ClinVar: 98821, 13114

gnomAD: The maximum allele frequency for the NM_000329.3(RPE65):c.1067del (p.Asn356fs) variant is 0.00005458 (within the East Asian population, with no homozygotes). https://gnomad.broadinstitute.org/variant/1-68903930-AT-A The maximum allele frequency for the NM_000329.3(RPE65):c.700C>T (p.Arg234Ter) variant is 0.00008676 (within the Latino / Admixed American population, with no homozygotes). https://gnomad.broadinstitute.org/variant/1-68905269-G-A

FamilyAddInfo: The two variants were confirmed to be in trans, and heterozygous carriers were found to be unaffected. Potential parental consanguinity was not mentioned.

FamilyPMIDs: N/A

PMID: 9326927

Gene: RPE65

HGNC: 10294

Disease: Leber congenital amaurosis 2

MONDO: 0008765

InheritancePattern: Autosomal Recessive

Prevalence: The overall prevalence of Leber congenital amaurosis is between 1 in 33,000 and 1 in 100,000 newborns, while the proportion of Leber congenital amaurosis caused by RPE65 variants is between 1% and 16.7%. Thus, the prevalence of Leber congenital amaurosis 2 is between 1 in 200,000 and 1 in 10,000,000.

Penetrance: Fully penetrant, with onset typically by 1 year of age

Case#: Gu_1997_Family_PMK30_Patient_V-5, male, unknown age, Indian ethnicity

CasePresentingHPOs: HP:0410280 (Pediatric onset), HP:0000662 (Nyctalopia), HP:0000505 (Visual impairment), HP:0008047 (Abnormality of the vasculature of the eye), HP:0000648 (Optic atrophy), HP:0007737 (Bone spicule pigmentation of the retina)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing consisted of linkage analysis using microsatellite repeat markers.

CaseMethod1: PCR products were screened by single-strand conformation polymorphism (SSCP) analysis.

CaseMethod2: Sanger sequencing of all RPE65 exons

CaseGenotypingMethod: After discovery of a band shift for exon 10, the patient sample was subjected to PCR and Sanger sequencing of all RPE65 exons.

Variant: Affected individuals are homozygous for the NM_000329.3(RPE65):c.1087C>A (p.Pro363Thr) variant.

ClinVar: 13117 (homozygous)

gnomAD: The maximum allele frequency for the NM_000329.3(RPE65):c.1087C>A (p.Pro363Thr) variant is 0.0001307 (within the South Asian population, with no homozygotes). https://gnomad.broadinstitute.org/variant/1-68903911-G-T

VariantEvidence: A different publication (PMID: 16828753) later used QBI-293A cells to establish that this variant decreases the stability of the RPE65 protein, shifts its localization from predominantly in the membrane fraction to predominantly in the cytosolic fraction, and abolishes its isomerohydrolase activity.

CaseAddInfo: The family pedigree shows consanguinity in the parents of all affected individuals.

CasePMIDs: N/A

Case#: Gu_1997_Patient_arRP181-II-1, female, 45, German ethnicity

CasePresentingHPOs: HP:0000662 (Nyctalopia), HP:0000572 (Visual loss), HP:0410280 (Pediatric onset), HP:0000546 (Retinal degeneration), HP:0000618 (Blindness)

CaseHPOFreeText: Visual loss had onset in childhood. Retinal degeneration was diagnosed at age 10. Legal blindness was found at age 18.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing was limited to clinical diagnosis of arRP.

CaseMethod1: PCR amplification and Sanger sequencing

CaseMethod2: N/A

CaseGenotypingMethod: RPE65 was subjected to PCR amplification and Sanger sequencing.

Variant: The patient is homozygous for the NM_000329.3(RPE65):c.11+5G>A variant.

ClinVar: 98825 (homozygous)

gnomAD: The maximum allele frequency of the NM_000329.3(RPE65):c.11+5G>A variant is 0.0001626 (in the European non-Finnish population, with no homozygotes): https://gnomad.broadinstitute.org/variant/1-68915573-C-T

VariantEvidence: The variant is located within intron 1 of the RPE65 transcript and affects part of the splice donor consensus sequence. SpliceAI calculates a delta score of 0.06 for loss of splice donor site.

CaseAddInfo: Consanguinity of the parents is not proven but considered possible due to their origin from the same village. One of the patient's three siblings is affected (similarly or more severely), but none have been genotyped.

CasePMIDs: N/A

PMID: 9326941

Gene: RPE65

HGNC: 10294

Disease: Retinitis pigmentosa 20

MONDO: 0013425

InheritancePattern: Autosomal Recessive

Prevalence: The overall prevalence of Retinitis pigmentosa is between 1 in 3,000 and 1 in 4,000 individuals, while the proportion of recessive Retinitis pigmentosa caused by RPE65 variants is ~2%. (PMID: 9501220) Thus, the prevalence of Retinitis pigmentosa 20 is between 1 in 150,000 and 1 in 200,000.

Penetrance: Fully penetrant, with onset typically in childhood

FamilyLabel: Gu_1997_Family_PMK18

FamilyPresentingHPOs: HP:0410280 (Pediatric onset), HP:0007663 (Reduced visual acuity), HP:0001098 (Abnormal fundus morphology)

FamilyPresentingHPOFreeText: Onset is early and course of disease is severe. The appearance of the fundus in adulthood is considered characteristic of retinitis pigmentosa.

FamilyNotHPOs: N/A

CountryOrigin: India

Ethnicity: Not mentioned

Race: Not mentioned

Family#PreviousTesting: Previous testing consisted of linkage analysis using microsatellite repeat markers (D152803, DJS1665, D1S438 and DJS1728) associated with the RPE65 locus.

Family#Method1: Linkage analysis

Family#GenotypingMethod: PCR products from affected and control family members were screened by restriction digest analysis using the Msel endonuclease.

Affected: 5

Unaffected: 4

Segregations: 7 segregations were reported, with one inconsistent (patient V-8 is heterozygous while the other affected patients are all homozygous). The pedigree (Figure 1) shows consanguinity between the parents of each affected individual.

PublishedLOD: N/A

eLOD: 2.91

AddSegregationInfo: N/A

ProbandLabel: Gu_1997_Family_PMK18_Patient_V-1

Variant: 4 out of 5 affected individuals are homozygous for the variant.

ClinVar: 98893

gnomAD: The NM_000329.3(RPE65):c.858+1G>T variant is not shown in gnomAD.

FamilyAddInfo: The family pedigree shows consanguinity in the parents of all affected individuals.

FamilyPMIDs: N/A

Case#: Gu_1997_Patient_arRP341-II-1, female, age 3 months at onset, German ethnicity

CasePresentingHPOs: HP:0000505 (Visual impairment), HP:0003593 (Infantile onset), HP:0030479 (Abnormal amplitude of light-adapted flicker electroretinogram), HP:0030474 (Undetectable dark-adapted electroretinogram), HP:0007663 (Reduced visual acuity)

CaseHPOFreeText: The first detectable phenotype was observed at age 3 months, when no reactions to objects or faces were observed. Rod ERG was extinguished at age 8 months, while cone ERG flicker response was significantly decreased. Low visual acuity was found at age 3 years.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing was limited to clinical diagnosis of arRP.

CaseMethod1: PCR amplification and Sanger sequencing

CaseMethod2: N/A

CaseGenotypingMethod: RPE65 was subjected to PCR amplification and Sanger sequencing.

Variant: The patient is a compound heterozygote with the NM_000329.3(RPE65):c.11+5G>A (paternal) and NM_000329.3(RPE65):c.89dup (p.Thr31fs) (maternal) variants in trans.

ClinVar: 98825, 98898

gnomAD: The maximum allele frequency of the NM_000329.3(RPE65):c.11+5G>A variant is 0.0001626 (in the European non-Finnish population, with no homozygotes): https://gnomad.broadinstitute.org/variant/1-68915573-C-T The NM_000329.3(RPE65):c.89dup (p.Thr31fs) variant was not found in gnomAD.

VariantEvidence: The paternal variant is located within intron 1 of the RPE65 transcript and affects part of the splice donor consensus sequence. SpliceAI calculates a delta score of 0.06 for loss of splice donor site. The maternal variant is located within exon 2 and encodes a frameshift predicted to truncate approximately 94% of the protein product.

CaseAddInfo: The proband's parents are reportedly healthy and non-consanguineous.

CasePMIDs: N/A

FamilyLabel: Gu_1997_Family_PMK30

FamilyPresentingHPOs: HP:0410280 (Pediatric onset), HP:0000662 (Nyctalopia), HP:0000505 (Visual impairment), HP:0008047 (Abnormality of the vasculature of the eye), HP:0000648 (Optic atrophy), HP:0007737 (Bone spicule pigmentation of the retina)

FamilyPresentingHPOFreeText: Onset of severe visual impairment between age 3 and age 7, progressing between the ages of 5 and 12. Vision was limited to counting fingers (at a distance of 1-3 meters) or seeing hand movements. Onset of severe

FamilyNotHPOs: N/A

CountryOrigin: India

Ethnicity: Not mentioned

Race: Not mentioned

Family#PreviousTesting: Previous testing consisted of linkage analysis using microsatellite repeat markers.

Family#Method1: PCR products from 2 affected and 1 control family members were screened by single-strand conformation polymorphism (SSCP) analysis. After discovery of a band shift for exon 10, those two patients were subjected to Sanger sequencing.

Family#Method2: A PCR-based assay was used to detect the variant of interest by introducing a BspMI restriction site into the wild-type PCR product.

Family#GenotypingMethod: Restriction enzyme-based screening of exon 10 PCR products

Affected: 4

Unaffected: 4

Segregations: 6 segregations were reported, with none inconsistent. The pedigree (Figure 1) shows consanguinity between the parents of each affected individual.

PublishedLOD: The LOD score was 3.57 at a 0.00 recombination fraction (for microsatellite repeat polymorphism D1S1665).

eLOD: 2.31

AddSegregationInfo: N/A

ProbandLabel: Gu_1997_Family_PMK30_Patient_V-5

Variant: Affected individuals are homozygous for the NM_000329.3(RPE65):c.1087C>A (p.Pro363Thr) variant.

ClinVar: 13117

gnomAD: The maximum allele frequency for the NM_000329.3(RPE65):c.1087C>A (p.Pro363Thr) variant is 0.0001307 (within the South Asian population, with no homozygotes). https://gnomad.broadinstitute.org/variant/1-68903911-G-T

FamilyAddInfo: The family pedigree shows consanguinity in the parents of all affected individuals.

FamilyPMIDs: N/A

Case#: Gu_1997_Family_PMK18_Patient_V-1, male, unknown age, Indian ethnicity

CasePresentingHPOs: HP:0410280 (Pediatric onset), HP:0007663 (Reduced visual acuity), HP:0001098 (Abnormal fundus morphology)

CaseHPOFreeText: Onset is early and course of disease is severe. The appearance of the fundus in adulthood is considered characteristic of retinitis pigmentosa.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing consisted of linkage analysis using microsatellite repeat markers (D152803, DJS1665, D1S438 and DJS1728) associated with the RPE65 locus.

CaseMethod1: Linkage analysis

CaseMethod2: PCR products were screened by restriction digest analysis using the Msel endonuclease.

CaseGenotypingMethod: The patient sample was subjected to PCR and Sanger sequencing of all RPE65 exons.

Variant: 4 out of 5 affected individuals are homozygous for the NM_000329.3(RPE65):c.858+1G>T variant.

ClinVar: 98893

gnomAD: The NM_000329.3(RPE65):c.858+1G>T variant is not shown in gnomAD.

VariantEvidence:

CaseAddInfo: The family pedigree shows consanguinity in the parents of all affected individuals. One of the affected individuals is a heterozygous carrier of the variant, rather than a homozygote.

CasePMIDs: N/A

PMID: 14962443

Gene: RPE65

HGNC: 10294

Disease: Leber congenital amaurosis 2

MONDO: 0008765

InheritancePattern: Autosomal Recessive

Prevalence: The overall prevalence of Leber congenital amaurosis is between 1 in 33,000 and 1 in 100,000 newborns, while the proportion of Leber congenital amaurosis caused by RPE65 variants is between 1% and 16.7%. Thus, the prevalence of Leber congenital amaurosis 2 is between 1 in 200,000 and 1 in 10,000,000.

Penetrance: Fully penetrant, with onset typically by 1 year of age

PMID: 16116091

Gene: RPE65

HGNC: 10294

Disease: Leber congenital amaurosis 2

MONDO: 0008765

InheritancePattern: Autosomal Recessive

Prevalence: The overall prevalence of Leber congenital amaurosis is between 1 in 33,000 and 1 in 100,000 newborns, while the proportion of Leber congenital amaurosis caused by RPE65 variants is between 1% and 16.7%. Thus, the prevalence of Leber congenital amaurosis 2 is between 1 in 200,000 and 1 in 10,000,000.

Penetrance: Fully penetrant, with onset typically by 1 year of age

Selection B - Gene function is consistent with phenotype.

GOterm: GO:0052885 (all-trans-retinyl-ester hydrolase, 11-cis retinol forming activity)

FunctionalEvidence: Exogenous co-expression of RPE65 and the LRAT enzyme in QBI-293A or COS-1 cells provides these cells with the enzymatic ability to generate 11-cis retinol from all-trans retinyl ester, identifying RPE65 as the human isomerohydrolase enzyme (Figures 4B-4F).

FunctionalHPO: HP:0007688 (Undetectable light- and dark-adapted electroretinogram), HP:0000529 (Progressive visual loss), HP:0000618 (Blindness)

PhenotypeEvidence: Maintenance of vision is dependent upon the visual retinoid cycle to enzymatically regenerate 11-cis retinal following the light-induced isomerization of this pigment to all-trans retinal. Isomerohydrolase is an enzymatic activity known to be responsible for this conversion and known to localize to the retinal pigment epithelium, but not previously mapped to a human gene prior to this study. The present paper identifies the RPE65 protein as the human isomerohydrolase enzyme, linking its biallelic loss to congenital blindness (Figures 4B-4F).

PMID: 16828753

Gene: RPE65

HGNC: 10294

Disease: Retinitis pigmentosa 20

MONDO: 0013425

InheritancePattern: Autosomal Recessive

Prevalence: The overall prevalence of Retinitis pigmentosa is between 1 in 3,000 and 1 in 4,000 individuals, while the proportion of recessive Retinitis pigmentosa caused by RPE65 variants is ~2%. (PMID: 9501220) Thus, the prevalence of Retinitis pigmentosa 20 is between 1 in 150,000 and 1 in 200,000.

Penetrance: Fully penetrant, with onset typically in childhood

ExperimentName: Recombinase-based variant knock-in to the mouse Rpe65 locus

NonHumanModel: Mus musculus

GeneAlteration: A substitution equivalent to the human NM_000329.3(RPE65):c.1430A>G (p.Asp477Gly) variant was knocked into the mouse Rpe65 locus by Flp-recombinase, which allowed the selection cassette to be subsequently excised.

ModelPhenotype: HP:0030602 (Abnormal fundus autofluorescence imaging), HP:0030329 (Retinal thinning), HP:0030483 (Reduced amplitude of dark-adapted bright flash electroretinogram a-wave), HP:0008275 (Abnormal light-adapted electroretinogram)

HumanPhenotype: HP:0000662 (Nyctalopia), HP:0007688 (Undetectable light- and dark-adapted electroretinogram), HP:0001098 (Abnormal fundus morphology), HP:0000529 (Progressive visual loss)

ModelEvidence: The mice exhibit reduced levels of RPE65 protein (Figure 3A) and enhanced ubiquitination (Figure 3B), indicating higher susceptibility to proteolysis. Despite normal 11-cis retinal levels (Figure 7C), the heterozygous knock-in animals exhibit abnormal accumulation of retinyl esters (Figure 7B), recapitulating a key molecular defect of the human patients. Photobleaching revealed defects in regeneration of 11-cis-retinal (Figure 7F) and accumulation of retinyl esters (Figure 7G). These defects were observable in both the heterozygous knock-in (mild) and homozygous knock-in (more severe). Accumulation of autofluorescent spots in the fundus (Figure 4), progressive thinning of the outer nuclear layer (Figure 5), and abnormal ERG responses (Figure 6) were seen in heterozygous knock-in and especially homozygous knock-in mice with age. Similar phenotypic results were observed with a third, similar knock-in mouse model (PMID: 28041994).

ModelVariant: The model knocks the NM_000329.3(RPE65):c.1430A>G (p.Asp477Gly) variant (ClinVar:750796) into the endogenous mouse Rpe65 locus.

PMID: 29659842

Gene: RPE65

HGNC: 10294

Disease: Retinitis pigmentosa 87 with choroidal involvement

MONDO: 0032873

InheritancePattern: Autosomal Dominant

Prevalence: The overall prevalence of Retinitis pigmentosa is between 1 in 3,000 and 1 in 4,000 individuals, while the proportion of Retinitis pigmentosa with a dominant mode of inheritance is estimated to be 15-35% (between 1 in 8,000 and 1 in 27,000). The prevalence of Retinitis pigmentosa 87 with choroidal involvement is considered to be much lower.

Penetrance: Incomplete penetrance, estimated at 80%

PMID: 11095629

Gene: RPE65

HGNC: 10294

Disease: Retinitis pigmentosa 20

MONDO: 0013425

InheritancePattern: Autosomal Recessive

Prevalence: The overall prevalence of Retinitis pigmentosa is between 1 in 3,000 and 1 in 4,000 individuals, while the proportion of recessive Retinitis pigmentosa caused by RPE65 variants is ~2%. (PMID: 9501220) Thus, the prevalence of Retinitis pigmentosa 20 is between 1 in 150,000 and 1 in 200,000.

Penetrance: Fully penetrant, with onset typically in childhood

Case#: Bowne_2011_Family_TCD-G_Patient_53, male, unspecified age, family origin in Ireland

CasePresentingHPOs: N/A

CaseHPOFreeText: The patient was initially diagnosed with retinitis pigmentosa prior to genotyping. Detailed phenotypes are not specified for individual patients.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: Candidate gene sequencing for variants in other known retinitis pigmentosa genes. SNP-based linkage analysis mapped the phenotype of autosomal dominant retinitis pigmentosa to an 8.8-Mb genomic region located at chr1 p31. It is not clear whether the patient was one of 3 affected individuals subjected to whole exome sequencing.

CaseMethod1: SNP-based linkage analysis and whole exome sequencing

CaseMethod2: Candidate gene sequencing

CaseGenotypingMethod: Sanger sequencing of 11 candidate genes among the 50 known genes from the mapped region, including RPE65 and PDE4B.

Variant: The patient harbors the NM_000329.3(RPE65):c.1430A>G (p.Asp477Gly) variant in one allele of RPE65.

ClinVar: 750796

gnomAD: The NM_000329.3(RPE65):c.1430A>G (p.Asp477Gly) variant was not found in gnomAD.

VariantEvidence: Exogenous expression of the variant reveals protein expression levels, cellular localization and retinoid isomerase activity comparable to the wild-type (PMID: 29659842). However, knock-in mouse models exhibit retinyl ester accumulation (PMID: 29659842), abnormally slow regeneration of 11-cis-retinal after light exposure, and ERG results indicative of delayed dark adaptation (PMID: 28041994). Mice with CRISPR-mediated knock-in of the variant also exhibit a splicing defect in RPE65 due to the introduction of a cryptic splice site, which likely triggers a frameshift, exclusion of exons 13 and 14 from the transcript, and premature truncation of the protein product (PMID: 30628748).

CaseAddInfo: N/A

CasePMIDs: PMID: 20861475, PMID: 16799052, PMID: 17982421, PMID: 17924349, PMID: 19520207, PMID: 17003455

FamilyLabel: Bowne_2011_Family_TCD-H

Family#PresentingHPOs: N/A

Family#PresentingHPOFreeText: Family members were provisionally diagnosed with choroideremia prior to genotyping.

FamilyNotHPOs: N/A

CountryOrigin: Ireland

Ethnicity: Not mentioned

Race: Not mentioned

Family#PreviousTesting: Candidate gene sequencing of the CHM locus to exclude the initial diagnosis of choroideremia

Family#Method1: Two-point linkage analysis of the RPE65 locus, as well as haplotype analysis using STR genotypes surrounding the variant of interest

Family#Method2: Candidate gene sequencing

Family#GenotypingMethod: Sanger sequencing of the RPE65 locus

Affected: 3

Unaffected: N/A

Segregations: 2 segregations were reported. The pedigree can be found in Figure 1c. Consanguinity of the family was not mentioned.

PublishedLOD: 5.3 (in combination with Family TCD-G, which shares a haplotype

eLOD: N/A

AddSegregationInfo: N/A

ProbandLabel: Bowne_2011_Family_TCD-H_Patient_01

Variant: Affected individuals harbor the NM_000329.3(RPE65):c.1430A>G (p.Asp477Gly) variant in one allele of RPE65.

ClinVar: 750796

gnomAD: The NM_000329.3(RPE65):c.1430A>G (p.Asp477Gly) variant was not found in gnomAD.

FamilyAddInfo: N/A

FamilyPMIDs: N/A

FamilyLabel: Bowne_2011_Family_TCD-G

Family#PresentingHPOs: HP:0030469 (Abnormal dark-adapted electroretinogram), HP:0007994 (Peripheral visual field loss), HP:0000533 (Chorioretinal atrophy), HP:0000546 (Retinal degeneration)

Family#PresentingHPOFreeText: Onset was in the 2nd to 5th decade of life, typically with impaired dark adaptation. Genotype-positive members of the family exhibited a wide range of phenotypes.

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

CountryOrigin: Ireland

Ethnicity: Not mentioned

Race: Not mentioned

Family#PreviousTesting: SNP-based linkage analysis was performed on all family members, mapping the phenotype of autosomal dominant retinitis pigmentosa to an 8.8-Mb genomic region located at chr1 p31. Whole exome sequencing of 3 affected an 1 unaffected family members then identified candidate variants of interest.

Family#Method1: SNP-based linkage analysis and whole exome sequencing of a subset of family members

Family#Method2: Candidate gene sequencing

Family#GenotypingMethod: Sanger sequencing of 11 candidate genes among the 50 known genes from the mapped region, including RPE65 and PDE4B.

Affected: 20

Unaffected: N/A

Segregations: 21 segregations were reported. 4 genotype-positive individuals were unaffected (reflecting reduced penetrance), with one of them having an affected child. The pedigree can be found in Figure 1a. Consanguinity of the family was not mentioned.

PublishedLOD: 3.6

eLOD: 6.32

AddSegregationInfo: 4 genotype-positive individuals were unaffected, with one of them having an affected child. Another non-genotyped but unaffected individual had an affected child as well. In combination with the 20 genotype-positive and phenotype-positive individuals, this reflects incomplete penetrance of approximately 80%.

ProbandLabel: Bowne_2011_Family_TCD-G_Patient_53

Variant: Affected individuals harbor the NM_000329.3(RPE65):c.1430A>G (p.Asp477Gly) variant in one allele of RPE65.

ClinVar: 750796

gnomAD: The NM_000329.3(RPE65):c.1430A>G (p.Asp477Gly) variant was not found in gnomAD.

FamilyAddInfo: N/A

FamilyPMIDs: PMID: 20861475

PMID: 21654732

Gene: RPE65

HGNC: 10294

Disease: Retinitis pigmentosa 87 with choroidal involvement

MONDO: 0032873

InheritancePattern: Autosomal Dominant

Prevalence: The overall prevalence of Retinitis pigmentosa is between 1 in 3,000 and 1 in 4,000 individuals, while the proportion of Retinitis pigmentosa with a dominant mode of inheritance is estimated to be 15-35% (between 1 in 8,000 and 1 in 27,000). The prevalence of Retinitis pigmentosa 87 with choroidal involvement is considered to be much lower.

Penetrance: Incomplete penetrance, estimated at 80%

Case#: Bowne_2011_Family_TCD-H_Patient_01, male, unspecified age, family origin in Ireland

CasePresentingHPOs: N/A

CaseHPOFreeText: The patient was provisionally diagnosed with choroideremia prior to genotyping that excluded the presence of a variant in the CHM locus.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Candidate gene sequencing of the CHM locus to exclude the initial diagnosis of choroideremia

CaseMethod1: Two-point linkage analysis of the RPE65 locus, as well as haplotype analysis using STR genotypes surrounding the variant of interest

CaseMethod2: Candidate gene sequencing

CaseGenotypingMethod: Sanger sequencing of the RPE65 locus

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

PMID: 15557452

Gene: RPE65

HGNC: 10294

Disease: Retinitis pigmentosa 20

MONDO: 0013425

InheritancePattern: Autosomal Recessive

Prevalence: The overall prevalence of Retinitis pigmentosa is between 1 in 3,000 and 1 in 4,000 individuals, while the proportion of recessive Retinitis pigmentosa caused by RPE65 variants is ~2%. (PMID: 9501220) Thus, the prevalence of Retinitis pigmentosa 20 is between 1 in 150,000 and 1 in 200,000.

Penetrance: Fully penetrant, with onset typically in childhood

FamilyLabel: Hull_2016_Family_1

Family#PresentingHPOs: HP:0003581 (Adult onset), HP:0007663 (Reduced visual acuity), HP:0000533 (Chorioretinal atrophy)

Family#PresentingHPOFreeText: N/A

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

CountryOrigin: Irish ancestry

Ethnicity: Not mentioned

Race: Not mentioned

Family#PreviousTesting: Variants in REP1 and PRPH2 were initially excluded.

Family#Method1: Candidate gene sequencing

Family#Method2: Bidirectional, targeted Sanger sequencing within the RPE65 locus

Family#GenotypingMethod: Bidirectional Sanger sequencing of exon 13 of the RPE65 gene and flanking sequences

Affected: 2

Unaffected: 0

Segregations: 1 segregation was reported. The pedigree can be found in Figure 5. The possibility of family consanguinity was not mentioned.

PublishedLOD: N/A

eLOD: N/A

AddSegregationInfo: N/A

ProbandLabel: Hull_2016_Patient_1.1

Variant: Affected individuals harbor the NM_000329.3(RPE65):c.1430A>G (p.Asp477Gly) variant in one allele of RPE65.

ClinVar: 750796

gnomAD: The NM_000329.3(RPE65):c.1430A>G (p.Asp477Gly) variant was not found in gnomAD.

FamilyAddInfo: N/A

FamilyPMIDs: N/A

PMID: 27307694

Gene: RPE65

HGNC: 10294

Disease: Retinitis pigmentosa 87 with choroidal involvement

MONDO: 0032873

InheritancePattern: Autosomal Dominant

Prevalence: The overall prevalence of Retinitis pigmentosa is between 1 in 3,000 and 1 in 4,000 individuals, while the proportion of Retinitis pigmentosa with a dominant mode of inheritance is estimated to be 15-35% (between 1 in 8,000 and 1 in 27,000). The prevalence of Retinitis pigmentosa 87 with choroidal involvement is considered to be much lower.

Penetrance: Incomplete penetrance, estimated at 80%

FamilyLabel: Hull_2016_Family_2

Family#PresentingHPOs: HP:0003581 (Adult onset), HP:0007663 (Reduced visual acuity)

Family#PresentingHPOFreeText: N/A

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

CountryOrigin: Irish ancestry

Ethnicity: Not mentioned

Race: Not mentioned

Family#PreviousTesting: Variants in REP1 and PRPH2 were initially excluded.

Family#Method1: Candidate gene sequencing

Family#Method2: Bidirectional, targeted Sanger sequencing within the RPE65 locus

Family#GenotypingMethod: Bidirectional Sanger sequencing of exon 13 of the RPE65 gene and flanking sequences

Affected: 3

Unaffected: 2

Segregations: 3 segregations were reported. 1 inconsistent segregation was observed, with a genotype-positive individual who did not exhibit phenotypes. The pedigree can be found in Figure 5. The possibility of family consanguinity was not mentioned.

PublishedLOD: N/A

eLOD: N/A

AddSegregationInfo: 1 genotype-positive family member was phenotype-negative, but had an affected child.

ProbandLabel: Hull_2016_Patient_2.1

Variant: Affected individuals harbor the NM_000329.3(RPE65):c.1430A>G (p.Asp477Gly) variant in one allele of RPE65.

ClinVar: 750796

gnomAD: The NM_000329.3(RPE65):c.1430A>G (p.Asp477Gly) variant was not found in gnomAD.

FamilyAddInfo: The possibility of family consanguinity was not mentioned.

FamilyPMIDs: 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

PMID: 11786058

Gene: RPE65

HGNC: 10294

Disease: Leber congenital amaurosis 2

MONDO: 0008765

InheritancePattern: Autosomal Recessive

Prevalence: The overall prevalence of Leber congenital amaurosis is between 1 in 33,000 and 1 in 100,000 newborns, while the proportion of Leber congenital amaurosis caused by RPE65 variants is between 1% and 16.7%. Thus, the prevalence of Leber congenital amaurosis 2 is between 1 in 200,000 and 1 in 10,000,000.

Penetrance: Fully penetrant, with onset typically by 1 year of age

ExperimentName: Exogenous expression of the RPE65 D477G variant in HEK293-F cells

NonPatientCell: HEK293-F cell line (EFO:0001182)

GeneFunction: all-trans-retinyl-ester hydrolase, 11-cis retinol forming activity (GO:0052885)

GeneAlteration: A substitution equivalent to the human NM_000329.3(RPE65):c.1430A>G (p.Asp477Gly) variant was introduced by site-directed mutagenesis into canine RPE65 and transiently transfected into HEK293-F cells.

FunctionalEvidence: The variant triggered a moderate decrease in retinoid isomerase activity / 11-cis retinol formation that appeared to be balanced out by the presence of the wild-type allele, rather than acting in a dominant negative fashion (Figure 1B). This loss of function was less dramatic than other hypomorphs known to be associated with autosomal recessive RPE65 retinopathy. Thus, loss of enzymatic function is unlikely to be the primary mechanism by which the variant contributes to autosomal dominantly inherited disease.

FAVariants: NM_000329.3(RPE65):c.1430A>G (p.Asp477Gly) variant (ClinVar:750796)

ExperimentName: Variant knock-in to the mouse Rpe65 locus triggers aberrant mRNA splicing.

NonHumanModel: Mus musculus

GeneAlteration: A substitution equivalent to the human NM_000329.3(RPE65):c.1430A>G (p.Asp477Gly) variant was knocked into the mouse Rpe65 locus by CRISPR/Cas9-based editing.

ModelPhenotype: HP:0000479 (Abnormal retinal morphology), HP:0030469 (Abnormal dark-adapted electroretinogram), HP:0030483 (Reduced amplitude of dark-adapted bright flash electroretinogram a-wave), Retinal thinning HP:0030329

HumanPhenotype: HP:0000662 (Nyctalopia), HP:0007688 (Undetectable light- and dark-adapted electroretinogram), HP:0001098 (Abnormal fundus morphology), HP:0000529 (Progressive visual loss)

ModelEvidence: Despite normal 11-cis retinal levels (Figure 3E), the heterozygous knock-in animals exhibit abnormal accumulation of retinyl esters (Figure 3F), recapitulating a key molecular defect of the human patients. The homozygous (but not heterozygous) knock-in animals also exhibit vacuole formation in the outer segment adjacent to the retinal pigment epithelium (Figure 3B) and abnormalities on dark-adapted ERG indicative of slower recovery of rod function (Figures 4A, 4B) and cone function (Figure 5D) as well as reduced retinal thickness (Figure 5A) after long-term chronic visual pigment bleaching.

ModelVariant: The model knocks the NM_000329.3(RPE65):c.1430A>G (p.Asp477Gly) variant (ClinVar:750796) into the mouse Rpe65 locus.

PMID: 30628748

Gene: RPE65

HGNC: 10294

Disease: Retinitis pigmentosa 87 with choroidal involvement

MONDO: 0032873

InheritancePattern: Autosomal Dominant

Prevalence: The overall prevalence of Retinitis pigmentosa is between 1 in 3,000 and 1 in 4,000 individuals, while the proportion of Retinitis pigmentosa with a dominant mode of inheritance is estimated to be 15-35% (between 1 in 8,000 and 1 in 27,000). The prevalence of Retinitis pigmentosa 87 with choroidal involvement is considered to be much lower.

Penetrance: Incomplete penetrance, estimated at 80%

ExperimentName: Rpe65 homozygous knockout triggers loss of cone response in certain mouse models.

NonHumanModel: Mus musculus

GeneAlteration: Rpe65 homozygous knockout was generated by replacing the 5' flanking region and the first three exons of Rpe65 with a PGK-Neo cassette (described in PMID: 9843205).

ModelPhenotype: HP:0008275 (Abnormal light-adapted electroretinogram), HP:0030465 (Undetectable light-adapted electroretinogram)

HumanPhenotype: HP:0030479 (Abnormal amplitude of light-adapted flicker electroretinogram)

ModelEvidence: The human phenotype includes both dark-adapted (rod) and light-adapted (cone) ERG defects. The Rpe65 homozygous knockout mouse model was previously found to have dark-adapted but not light-adapted response defects (PMID: 9843205). This study shows that in mice harboring homozygous knockout of Nrl (homozygous knockout) , Rpe65 homozygous knockout triggers light-adapted (cone) ERG defects as well (Figures 6A and 6B).

ModelVariant: The model disrupts the entire Rpe65 locus rather than introducing a mutation equivalent to a human patient variant.

PMID: 17251447

Gene: RPE65

HGNC: 10294

Disease: Leber congenital amaurosis 2

MONDO: 0008765

InheritancePattern: Autosomal Recessive

Prevalence: The overall prevalence of Leber congenital amaurosis is between 1 in 33,000 and 1 in 100,000 newborns, while the proportion of Leber congenital amaurosis caused by RPE65 variants is between 1% and 16.7%. Thus, the prevalence of Leber congenital amaurosis 2 is between 1 in 200,000 and 1 in 10,000,000.

Penetrance: Fully penetrant, with onset typically by 1 year of age

PMID: 28041994

Gene: RPE65

HGNC: 10294

Disease: Retinitis pigmentosa 87 with choroidal involvement

MONDO: 0032873

InheritancePattern: Autosomal Dominant

Prevalence: The overall prevalence of Retinitis pigmentosa is between 1 in 3,000 and 1 in 4,000 individuals, while the proportion of Retinitis pigmentosa with a dominant mode of inheritance is estimated to be 15-35% (between 1 in 8,000 and 1 in 27,000). The prevalence of Retinitis pigmentosa 87 with choroidal involvement is considered to be much lower.

Penetrance: Incomplete penetrance, estimated at 80%

PMID: 29947567

Gene: RPE65

HGNC: 10294

Disease: Retinitis pigmentosa 87 with choroidal involvement

MONDO: 0032873

InheritancePattern: Autosomal Dominant

Prevalence: The overall prevalence of Retinitis pigmentosa is between 1 in 3,000 and 1 in 4,000 individuals, while the proportion of Retinitis pigmentosa with a dominant mode of inheritance is estimated to be 15-35% (between 1 in 8,000 and 1 in 27,000). The prevalence of Retinitis pigmentosa 87 with choroidal involvement is considered to be much lower.

Penetrance: Incomplete penetrance, estimated at 80%

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

PMID: 16754667

Gene: RPE65

HGNC: 10294

Disease: Retinitis pigmentosa 20

MONDO: 0013425

InheritancePattern: Autosomal Recessive

Prevalence: The overall prevalence of Retinitis pigmentosa is between 1 in 3,000 and 1 in 4,000 individuals, while the proportion of recessive Retinitis pigmentosa caused by RPE65 variants is ~2%. (PMID: 9501220) Thus, the prevalence of Retinitis pigmentosa 20 is between 1 in 150,000 and 1 in 200,000.

Penetrance: Fully penetrant, with onset typically in childhood

PMID: 9808841

Gene: RPE65

HGNC: 10294

Disease: Leber congenital amaurosis 2

MONDO: 0008765

InheritancePattern: Autosomal Recessive

Prevalence: The overall prevalence of Leber congenital amaurosis is between 1 in 33,000 and 1 in 100,000 newborns, while the proportion of Leber congenital amaurosis caused by RPE65 variants is between 1% and 16.7%. Thus, the prevalence of Leber congenital amaurosis 2 is between 1 in 200,000 and 1 in 10,000,000.

Penetrance: Fully penetrant, with onset typically by 1 year of age

PMID: 17848510

Gene: RPE65

HGNC: 10294

Disease: Leber congenital amaurosis 2

MONDO: 0008765

InheritancePattern: Autosomal Recessive

Prevalence: The overall prevalence of Leber congenital amaurosis is between 1 in 33,000 and 1 in 100,000 newborns, while the proportion of Leber congenital amaurosis caused by RPE65 variants is between 1% and 16.7%. Thus, the prevalence of Leber congenital amaurosis 2 is between 1 in 200,000 and 1 in 10,000,000.

Penetrance: Fully penetrant, with onset typically by 1 year of age