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

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

CaseHPOFreeText: The proband was initially diagnosed with congenital nystagmus.

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

CaseNotHPOFreeText: N/A

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

CaseMethod1: Sanger sequencing

CaseMethod2: Restriction enzyme analysis using TaqI

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

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

ClinVar: 98625

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

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

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

CasePMIDs: N/A

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

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

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

CaseNotHPOs: HP:0000510 (Rod-cone dystrophy)

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

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

CaseMethod1: homozygosity mapping

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

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

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

ClinVar ID: 1299580

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

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

CaseAddInfo: The proband's family is reportedly consanguineous.

CasePMIDs: N/A

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

CasePresentingHPOs: N/A

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseMethod1: linkage mapping

CaseMethod2: Sanger sequencing of BBS1

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

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

ClinVar ID: 12144

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

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

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

CasePMIDs: N/A

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

CasePresentingHPOs: N/A

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseMethod1: linkage mapping

CaseMethod2: Sanger sequencing of BBS1

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

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

ClinVar ID: 12144, 12145

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

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

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

CasePMIDs: N/A

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

CasePresentingHPOs: N/A

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseMethod1: linkage mapping

CaseMethod2: Sanger sequencing of BBS1

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

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

ClinVar ID: 12144, 12143

gnomAD: The NM_024649.5(BBS1):c.1645G>T (p.Glu549Ter) variant is found in gnomAD v2.1.1 at a frequency of 0.00008675 (3 alleles out of 34584 total alleles, with 0 homozygotes) in the Admixed American population https://gnomad.broadinstitute.org/variant/11-66299163-G-T?dataset=gnomad_r2_1 gnomAD: The NM_024649.5(BBS1):c.1169T>G (p.Met390Arg) variant is found in gnomAD v2.1.1 at a frequency of 0.002773 in the European (non-Finnish) population, with 358 alleles / 129114 total alleles (0 homozygotes) https://gnomad.broadinstitute.org/variant/11-66293652-T-G?dataset=gnomad_r2_1

VariantEvidence: NM_024649.5(BBS1):c.1645G>T (p.Glu549Ter) is a nonsense variant in exon 16 of 17 that is predicted to not to trigger nonsense-mediated decay but rather to truncate the C-terminal 8% of the protein product. NM_024649.5(BBS1):c.1169T>G (p.Met390Arg) is a missense variant with mouse knock-in evidence of a similar disease-causing effect in the homozygous state (PMID: 18032602). This has not been taken into account in scoring, as the mouse model has been scored separately. However, it has provided a rationale not to down-score for the relatively high gnomAD frequency of this variant.

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

CasePMIDs: N/A

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

CasePresentingHPOs: N/A

CaseHPOFreeText: The patient has been diagnosed with macular dystrophy.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseMethod1: next generation sequencing-based RET.8 panel

CaseMethod2: N/A

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

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

ClinVar: 493439

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

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

CaseAddInfo: Segregation confirmation in family members is not available.

CasePMIDs: N/A

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

CasePresentingHPOs: N/A

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseMethod1: next generation sequencing-based RET.8 panel

CaseMethod2: N/A

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

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

ClinVar: 547007

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

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

CaseAddInfo: Segregation confirmation in family members is not available.

CasePMIDs: N/A

Case#: Haider_2000_Proband_5, female, age, and origin not reported

CasePresentingHPOs: N/A

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseMethod1: Sanger sequencing of NR2E3

CaseMethod2: SSCP analysis of PCR products from NR2E3

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

Variant: The individual harbors the NM_014249.4(NR2E3):c.290G>A (p.Arg97His) variant in the homozygous state.

ClinVarID: 867089

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

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

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

CasePMIDs: N/A

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

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

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

CaseNotHPOs: HP:0007663 (Reduced visual acuity), HP:0030469 (Abnormal dark-adapted electroretinogram)

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing appears to have been limited to Sanger sequencing-based screening of exon 7 of IMPG1.

CaseMethod1: Sanger sequencing of the 17 exons and flanking intronic sequences

CaseMethod2: N/A

CaseGenotypingMethod: Genotyping appears to have included Sanger-based sequencing of the 17 exons and intronic flanking sequences of the IMPG1 locus.

Variant: The proband harbors the NM_001563.4(IMPG1):c.461T>C (p.Leu154Pro) and NM_001563.4(IMPG1):c.1519C>T (p.Arg507Ter) variants in the compound heterozygous state.

ClinVar: 162136, 162135

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

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

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

CasePMIDs: N/A

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

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

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing for mutations in the CLN1, CLN2, CLN3, CLN6, and CLN8 had already occurred, using PCR amplification and Sanger sequencing to exclude the possibility of variants in the exons and surrounding noncoding regions. Genome-wide analysis methods were not used, as NCL had already been diagnosed based on clinical phenotypes.

CaseMethod1: PCR amplification of the coding and surrounding non-coding regions of each gene, followed by bidirectional Sanger sequencing.

CaseMethod2: as mentioned

CaseGenotypingMethod: CLN5 genotyping was performed by PCR amplification of the four exons and surrounding non-coding regions was performed, followed by bi-directional Sanger sequencing. Synthetic multiplex ligation-dependent probe amplification (MLPA) was then used to calculate average gene dosage ratio for each ratio, in order to detect large deletions.

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

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

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

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

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

CasePMIDs: N/A

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

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

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing for mutations in the CLN1, CLN2, CLN3, CLN6, and CLN8 had already occurred, using PCR amplification and Sanger sequencing to exclude the possibility of variants in the exons and surrounding noncoding regions. Genome-wide analysis methods were not used, as NCL had already been diagnosed based on clinical phenotypes.

CaseMethod1: PCR amplification of the coding and surrounding non-coding regions of each gene, followed by bidirectional Sanger sequencing

CaseMethod2: as mentioned

CaseGenotypingMethod: CLN5 genotyping was performed by PCR amplification of the four exons and surrounding non-coding regions was performed, followed by bi-directional Sanger sequencing. Synthetic multiplex ligation-dependent probe amplification (MLPA) was then used to calculate average gene dosage ratio for each ratio, in order to detect large deletions.

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

ClinVar: 2569, 2570

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

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

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

CasePMIDs: 19383612

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

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

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing for mutations in the CLN1, CLN2, CLN3, CLN6, and CLN8 had already occurred, using PCR amplification and Sanger sequencing to exclude the possibility of variants in the exons and surrounding noncoding regions. Genome-wide analysis methods were not used, as NCL had already been diagnosed based on clinical phenotypes.

CaseMethod1: PCR amplification of the coding and surrounding non-coding regions of each gene, followed by bidirectional Sanger sequencing.

CaseMethod2: as mentioned

CaseGenotypingMethod: CLN5 genotyping was performed by PCR amplification of the four exons and surrounding non-coding regions was performed, followed by bi-directional Sanger sequencing. Synthetic multiplex ligation-dependent probe amplification (MLPA) was then used to calculate average gene dosage ratio for each ratio, in order to detect large deletions.

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

ClinVar: 2565, 56543, 128783

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

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

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

CasePMIDs: N/A

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

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

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseMethod1: Genome-wide linkage analysis

CaseMethod2: Sanger sequencing of the candidate gene PDE6A

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

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

ClinVar: 437984

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

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

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

CasePMIDs: N/A

FamilyLabel: Riazuddin_2006_Three_Families

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

FamilyPresentingHPOFreeText: The affected family members have been diagnosed with retinitis pigmentosa segregating with an autosomal recessive mode of inheritance.

FamilyNotHPOs: N/A

FamilyNotHPOFreeText: N/A

CountryOrigin: Pakistan

Ethnicity: Pakistani (reportedly with origin from remote parts of Punjab province)

Race: Not specifically described

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

Family#Method1: Genome-wide linkage analysis

Family#Method2: Sanger sequencing of the candidate gene PDE6A

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

Affected: 12 genotyped

Unaffected: 7 genotyped

Segregations: 18 segregations are shown by the three pedigrees in Figure 3.

PublishedLOD: 7.4172

eLOD: N/A

AddSegregationInfo: N/A

ProbandLabel: Riazuddin_2006_Family_61019_Proband

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

ClinVar: 437984

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

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

FamilyAddInfo: All three families are reportedly consanguineous.

FamilyPMIDs: N/A

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

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

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

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

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

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

CaseMethod1: Linkage mapping and haplotype analysis

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

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

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

ClinVar: 10522

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

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

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

CasePMIDs: N/A

Case#: Gong_2001_Proband_6, no reported gender, age or national origin

CasePresentingHPOs: HP:0004349 (Reduced bone mineral density)

CaseHPOFreeText: The proband has been diagnosed with osteoporosis-pseudoglioma syndrome segregating with an autosomal recessive mode of inheritance. This implies a combination of ophthalmologic and radiographic features, but these have not been described in detail.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Genome-wide linkage mapping with 160 SSRP markers was performed on three different consanguineous kindreds (from Finland, South Africa, and Italy) (fig. 1), but it is not clear whether this proband was a member of one of these kindreds.

CaseMethod1: Linkage analysis with additional markers around a strong candidate marker

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

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

Variant: The patient harbors the NM_002335.4(LRP5):c.3804del (p.Glu1270fs) variant in the homozygous state.

ClinVar: 6273

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

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

CaseAddInfo: The family is reportedly consanguineous.

CasePMIDs: PMID: 8659519

Case#: Gong_2001_Proband_1, no reported gender, age or national origin

CasePresentingHPOs: HP:0004349 (Reduced bone mineral density)

CaseHPOFreeText: The proband has been diagnosed with osteoporosis-pseudoglioma syndrome segregating with an autosomal recessive mode of inheritance. This implies a combination of ophthalmologic and radiographic features, but these have not been described in detail.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Genome-wide linkage mapping with 160 SSRP markers was performed on three different consanguineous kindreds (from Finland, South Africa, and Italy) (fig. 1), but it is not clear whether this proband was a member of one of these kindreds.

CaseMethod1: Linkage analysis with additional markers around a strong candidate marker

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

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

Variant: The patient harbors the NM_002335.4(LRP5):c.29G>A (p.Trp10Ter) variant in the homozygous state.

ClinVar: 6268

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

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

CaseAddInfo: The family is reportedly consanguineous.

CasePMIDs: PMID: 8659519

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

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

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseMethod1: whole genome sequencing

CaseMethod2: Sanger sequencing of KCNJ13

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

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

ClinVar: 6585

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

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

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

CasePMIDs: N/A

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

CasePresentingHPOs: N/A

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseMethod1: next-generation sequencing of PRPF4 and EFTUD2 genes

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

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

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

ClinVar ID: 865751

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

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

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

CasePMIDs: N/A

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

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

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

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

CaseNotHPOFreeText: N/A

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

CaseMethod1: Whole exome sequencing

CaseMethod2: Sanger sequencing of IFT140

CaseGenotypingMethod: The patient and family members were genotyped by whole exome sequencing and confirmed by Sanger sequencing of IFT140.

Variant: The patient is a compound heterozygote harboring the paternal NM_014714.3(IFT140):c.1655_1656del (p.Glu522Glyfs6) and maternal NM_014714.3(IFT140):c.2368G>A (p.Glu790Lys) variants in IFT140*.

CAID: CA2201732453, CA7813927

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

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

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

CasePMIDs: N/A

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

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

CaseHPOFreeText: This proband was diagnosed with retinitis pigmentosa.

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

CaseNotHPOFreeText: N/A

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

CaseMethod1: Whole exome sequencing

CaseMethod2: Sanger sequencing of IFT140

CaseGenotypingMethod: Following the failure of retinal capture sequencing to identify retinitis pigmentosa gene variants, the patient and family members were genotyped by whole exome sequencing and confirmed by Sanger sequencing of IFT140.

Variant: The patient is a compound heterozygote harboring the paternal NM_014714.4(IFT140):c.1898_1901del (p.Asn633fs) and maternal NM_014714.4(IFT140):c.4196T>C (p.Leu1399Pro) variants in IFT140.

ClinVar: 446312, 446311

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

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

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

CasePMIDs: N/A

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

DiseaseAssertion: Sorsby's fundus dystrophy

FamilyInfo:

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

CaseHPOFreeText: Choroidal neovascular invasion of the macula was bilateral. This occurred early in the presentation and led to the disciform scar and loss of central vision. Granularity / abnormalities of the RPE were present in both eyes and preceded the onset of visual problems in the initially-unaffected eye. Serous detachment of sensory retina had underlying pigment epithelial detachment. CNV was accompanied by leakage from foveal avascular zone. Loss of visual acuity was progressive but possibly stabilized by argon green laser photocoagulation treatment.

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

CaseNOTHPOFreeText: N/A

CasePreviousTesting: N/A

GenotypingMethod: Sanger sequencing of Weber_1994_Family_M_patient_IV-2

PreviouslyPublished: PMID:2000899

SupplementalData: N/A

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

ClinVar: 12677

gnomAD: Variant is absent from gnomAD.

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

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

CasePresentingHPOs: N/A

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseMethod1: Sanger sequencing

CaseMethod2: N/A

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

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

ClinVar: 817370

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

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

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

CasePMIDs: N/A

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

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

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

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

CaseMethod1: 31-gene sequencing panel

CaseMethod2: N/A

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

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

ClinVar: 750796

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

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

CaseAddInfo: The possibility of family consanguinity was not mentioned.

CasePMIDs: N/A

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

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

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

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

CaseNotHPOFreeText: N/A

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

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

CaseMethod2: N/A

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

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

ClinVar: 9350, 98563

gnomAD: The NM_000180.4(GUCY2D):c.1694T>C (p.Phe565Ser) variant exhibits a maximum allele frequency of 0.000008790 in gnomAD version 2.1.1 (in the European non-Finnish population, with no homozygotes). https://gnomad.broadinstitute.org/variant/17-7912849-T-C?dataset=gnomad_r2_1 The NM_000180.4(GUCY2D):c.2302C>T (p.Arg768Trp) variant exhibits a maximum allele frequency of 0.0002943 in gnomAD version 2.1.1 (in the European non-Finnish population, with no homozygotes). https://gnomad.broadinstitute.org/variant/17-7917236-C-T

VariantEvidence: PMID: 9888789 provides evidence supporting the pathogenicity of the NM_000180.4(GUCY2D):c.1694T>C (p.Phe565Ser) variant by showing that the orthologous bovine F514S point mutation severely decreases the intrinsic cyclase activity of the protein and inactivates one of its calcium-responsive activating switches, CRM1. Multiple publications have found functional defects in the NM_000180.4(GUCY2D):c.2302C>T (p.Arg768Trp) variant. PMID: 25477517 shows defective binding to its interacting partner RD3, while PMID: 20050595 and PMID: 23035049 show reduced basal enzymatic activity and inability to interact with the activity-stimulating binding partner GCAP1.

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

CasePMIDs: N/A

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

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

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

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

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

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

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

CaseMethod2: N/A

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

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

ClinVar: 9350

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

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

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

CasePMIDs: N/A

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

CasePresentingHPOs: N/A

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

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

CaseMethod2: N/A

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

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

ClinVar: 9350

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

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

CaseAddInfo: The family is reportedly consanguineous.

CasePMIDs: PMID: 7581387, PMID: 8641699

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

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

CaseHPOFreeText: N/A

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

CaseMethod1: Sanger sequencing of PCR amplified exons from NYX

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

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

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

CAID: CA2573050962

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

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

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

CasePMIDs: N/A

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

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

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

CaseNotHPOs: HP:0000512 (Abnormal electroretinogram)

CaseNotHPOFreeText: RPE and Bruch's membrane appeared normal.

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

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

CaseMethod2: N/A

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

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

ClinVar: 1240016

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

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

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

CasePMIDs: N/A

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

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

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

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

CaseMethod2: N/A

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

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

ClinVar: 865770

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

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

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

CasePMIDs: N/A

Case#: Zou_2017_Patient_F1-II:1, male, age 4 at time of report, family national origin reported to be from China

CasePresentingHPOs: HP:0000639 (Nystagmus), HP:0000613 (Photophobia), HP:0007663 (Reduced visual acuity), HP:0007750 (Hypoplasia of the fovea), HP:0007894 (Hypopigmentation of the fundus)

CaseHPOFreeText: The proband has been diagnosed with ocular albinism 1. Foveal hypoplasia was described as severe. Best-corrected visual acuity was limited to light perception.

CaseNotHPOs: HP:0007730 (Iris hypopigmentation)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

CaseMethod1: Sanger sequencing

CaseMethod2: N/A

CaseGenotypingMethod: Patients were genotyped by Sanger sequencing of PCR products from the 9 exons of the GPR143 gene.

Variant: The proband harbors the NM_000273.3(GPR143):c.333_360+14delinsCTT variant in the hemizygous state.

CAID: CA2573320702

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

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

CaseAddInfo: N/A

CasePMIDs: N/A

Case#: Zou_2017_Patient_F3-III:3, male, age 24 at time of report, family national origin reported to be from China

CasePresentingHPOs: HP:0000639 (Nystagmus), HP:0000613 (Photophobia), HP:0007663 (Reduced visual acuity), HP:0007750 (Hypoplasia of the fovea), HP:0007894 (Hypopigmentation of the fundus), HP:0007730 (Iris hypopigmentation), HP:0030534 (Abnormal best corrected visual acuity test)

CaseHPOFreeText: The proband has been diagnosed with ocular albinism 1. Foveal hypoplasia was described as severe. Best-corrected visual acuity was limited to light perception.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

CaseMethod1: Sanger sequencing

CaseMethod2: N/A

CaseGenotypingMethod: Patients were genotyped by Sanger sequencing of PCR products from the 9 exons of the GPR143 gene.

Variant: The proband harbors the NM_000273.3(GPR143):c.733C>T (p.Arg245Ter) variant in the hemizygous state.

ClinVar: 1352731

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

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

CaseAddInfo: N/A

CasePMIDs: N/A

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

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

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

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

CaseMethod2: Sanger sequencing of PRPH2

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

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

ClinVar ID: 13179

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

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

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

CasePMIDs: N/A

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

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

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

CaseNotHPOs: N/A

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

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

CaseMethod1: Whole exome sequencing

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

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

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

ClinVar: 1477058

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

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

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

CasePMIDs: N/A

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

CasePresentingHPOs: HP:0000510 (Rod-cone dystrophy)

CaseHPOFreeText: The proband and affected family members have been diagnosed with retinitis pigmentosa, with an X-linked pattern of inheritance. Disease onset was reported as early.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

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

CaseMethod2: Sanger sequencing of the RPGR locus

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

Variant: The affected family members harbor the NM_001034853.2(RPGR):c.294C>A (p.His98Gln) variant in the hemizygous state.

ClinVar: 98775

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

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

CaseAddInfo: The proband is a member of Family 47.

CasePMIDs: N/A

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

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

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

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: Variants in REP1 and PRPH2 were initially excluded.

CaseMethod1: Candidate gene sequencing

CaseMethod2: Bidirectional, targeted Sanger sequencing within the RPE65 locus

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

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

ClinVar: 750796

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

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

CaseAddInfo: The possibility of family consanguinity was not mentioned.

CasePMIDs: N/A

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

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

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

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: Variants in REP1 and PRPH2 were initially excluded.

CaseMethod1: Candidate gene sequencing

CaseMethod2: Bidirectional, targeted Sanger sequencing within the RPE65 locus

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

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

ClinVar: 750796

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

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

CaseAddInfo: N/A

CasePMIDs: N/A

Case#: Pineda-Trujillo_Patient_NCL-22, male, age 9 at onset and age 14 at death, Colombian origin with family ethnicity reported as an admixture of Spanish, Native American, and African ancestry

CasePresentingHPOs: HP:0003208 (Fingerprint intracellular accumulation of autofluorescent lipopigment storage material), HP:0003621 (Juvenile onset), HP:0000572 (Visual loss), HP:0003678 (Rapidly progressive), HP:0011421 (Death in adolescence), HP:0025406 (Asthenia), HP:0200085 (Limb tremor), HP:0000618 (Blindness), HP:0002540 (Inability to walk), HP:0000708 (Behavioral abnormality), HP:0007064 (Progressive language deterioration), HP:0001336 (Myoclonus), HP:0001250 (Seizure), HP:0002120 (Cerebral cortical atrophy), HP:0001272 (Cerebellar atrophy), HP:0002392 (EEG with polyspike wave complexes)

CaseHPOFreeText: Onset was at age 9, with the first presenting phenotype being visual failure rather than mental retardation. Electron microscopy of skin biopsies found inclusions consisting of fingerprint profiles, which were often condensed and sometimes associated with lipid droplets. Tremor was observed in lower limbs. Blindness and inability to walk developed at approximately age 10 (within a year of symptom onset). Behavioral changes, gradual loss of language, myoclonus, and seizures all occurred within months of onset. Seizures were poorly responsive to valproate or clonazepam. Generalized cortical and cerebellar atrophy without signal intensity changes were seen by NMR at CT scans at age 12. EEG specifically showed a generalized pattern of high-voltage polyspike–slow waves. Patient died at age 14.

CaseNotHPOs: HP:0003205 (Curvilinear intracellular accumulation of autofluorescent lipopigment storage material), HP:0003226 (Rectilinear intracellular accumulation of autofluorescent lipopigment storage material), HP:0001922 (Vacuolated lymphocytes), HP:0003457 (EMG abnormality), HP:0100285 (EMG: impaired neuromuscular transmission)

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing relied on clinical testing to establish neuronal ceroid lipofuscinosis (CLN), then used 10 different microsatellite markers to evaluate the 6 loci known at the time to be associated with CLN. (Note: This list of CLN-associated loci has since expanded from 6 to 8-12 genes.) The pedigree indicates consistent segregation of the disease phenotype with biallelic inheritance of the three markers in the CLN5 locus. CLN genes were then PCR-amplified and subjected to Sanger sequencing, identifying a variant in CLN5. Genome-wide analysis methods were not used.

CaseMethod1: Linkage analysis with 10 microsatellite markers across 6 candidate loci known to be associated with CLN phenotypes.

CaseMethod2: CLN genes (specifically CLN3 and CLN5) were PCR-amplified and subjected to Sanger sequencing, identifying a variant in CLN5.

CaseGenotypingMethod: CLN5 PCR products were subjected to PshAI endonuclease digestion, as the variant abolishes a restriction site. Genome-wide analysis methods were not used.

Variant: Patient was homozygous for NM_006493.4(CLN5):c.188G>A (p.Arg63His), (although this variant is referred to in the article as c.1627G>A or p.Arg112His).

ClinVar: 2567

gnomAD: The variant is reported to have a maximum allele frequency of 0.00003274 (in the South Asian population, with no homozygous individuals). https://gnomad.broadinstitute.org/variant/13-77569212-G-A

VariantEvidence: The variant encodes a missense substitution, and exhibits defective localization to the ER rather than the lysosome (PMID:20052765).

CaseAddInfo: N/A

CasePMIDs: N/A

FamilyLabel: van_Lith-Verhoeven_2004_Family

Family#PresentingHPOs: HP:0007754 (Macular dystrophy), HP:0007769 (Peripheral retinal degeneration), HP:0032037 (Mildly reduced visual acuity, progressive), HP:0008179 (Decreased Arden ratio of electrooculogram)

FamilyPresentingHPOFreeText: The affected family members have been diagnosed with benign concentric annular macular dystrophy (BCAMD), segregating with an autosomal dominant mode of inheritance. Visual acuity was initially normal but progressed to phenotype similar to retinitis pigmentosa, including peripheral retinal involvement and photoreceptor cell dysfunction (shown by ERG).

FamilyNotHPOs: HP:0000613 (Photophobia), HP:0000551 (severe Color vision defect)

FamilyNotHPOFreeText: N/A

CountryOrigin: The family is reportedly Dutch.

Ethnicity: Not specifically described

Race: N/A

Family#PreviousTesting: Linkage analysis was performed using a combination of a whole genome scan and microsatellite markers within candidate retinal loci.

Family#Method1: Genome-wide and candidate-focused linkage analyses

Family#Method2: Sanger sequencing of the candidate genes ELOVL4, GABR1, GABR2 and IMPG1

Family#GenotypingMethod: Linkage analysis was performed using a genome-wide scan as well as microsatellite markers from candidate loci. Sanger sequencing then analyzed the candidate retina genes from the linkage region; ELOVL4, GABR1, GABR2 and IMPG1

Affected: 11 genotyped

Unaffected: 5 genotyped

Segregations: 10 segregations are shown by the pedigree in Figure 1.

PublishedLOD: 3.8

eLOD: N/A

AddSegregationInfo: N/A

ProbandLabel: van_Lith-Verhoeven_2004_Family_Proband_II-4

Variant: The affected family members harbor the NM_001563.4(IMPG1):c.1736T>C (p.Leu579Pro) variant in the heterozygous state.

ClinVar: 1008228

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

VariantEvidence: NM_001563.4(IMPG1):c.1736T>C (p.Leu579Pro) is a missense variant that does not have evidence confirming an impact on the gene product.

FamilyAddInfo: The family's national origin has been reported as Dutch.

FamilyPMIDs: 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

Case#: Chang_2009_Family_CHRO287_Proband_II:1, male, age and family origin not described

CasePresentingHPOs: HP:0011516 (Achromatopsia)

CaseHPOFreeText: The proband was previously diagnosed with achromatopsia.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The proband and his parents were initially subjected to genotyping of the CNGA3, GNGB3, and GNAT2 loci, confirming absence of causal variants in these known achromatopsia-related genes.

CaseMethod1: Sanger sequencing of CNGA3, GNGB3, and GNAT2

CaseMethod2: Sanger sequencing of the 22 exons and flanking regions of PDE6C

CaseGenotypingMethod: CNGA3, GNGB3, and GNAT2 were previously screened / known not to harbor causal variants for achromatopsia. The family members were then subjected to Sanger sequencing of the 22 exons and flanking regions of PDE6C.

Variant: The proband harbors the NM_006204.4(PDE6C):c.826C>T (p.Arg276Ter) and NM_006204.4(PDE6C):c.2457T>A (p.Tyr819Ter) variants in the compound heterozygous state.

ClinVar ID: 8773, 8774

gnomAD: The NM_006204.4(PDE6C):c.826C>T (p.Arg276Ter) variant is found in gnomAD v2.1.1 at a frequency of 0.00006152 (1 allele / 16256 total alleles) in the African / African-American population, with 0 homozygotes. The NM_006204.4(PDE6C):c.2457T>A (p.Tyr819Ter) variant was not found in gnomAD v2.1.1.

VariantEvidence: NM_006204.4(PDE6C):c.826C>T (p.Arg276Ter) is a nonsense variant in exon 4 of 22 and is predicted to trigger nonsense-mediated decay or to at least truncate the C-terminal 68% of the protein product. NM_006204.4(PDE6C):c.2457T>A (p.Tyr819Ter) is a nonsense variant in exon 21 of 22 and is predicted to trigger nonsense-mediated decay or to at least truncate the C-terminal 5% of the protein product.

CaseAddInfo: The patient has an affected brother who shares the same compound heterozygous genotype, while the parents and one other sibling are each unaffected carriers.

CasePMIDs: N/A

Case#: Chang_2009_Family_CHRO572_Proband_II:1, male, age and family origin not described

CasePresentingHPOs: HP:0011516 (Achromatopsia)

CaseHPOFreeText: The proband was previously diagnosed with achromatopsia.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The proband and his family members were initially subjected to genotyping of the CNGA3, GNGB3, and GNAT2 loci, confirming absence of causal variants in these known achromatopsia-related genes.

CaseMethod1: Sanger sequencing of CNGA3, GNGB3, and GNAT2

CaseMethod2: Sanger sequencing of the 22 exons and flanking regions of PDE6C

CaseGenotypingMethod: CNGA3, GNGB3, and GNAT2 were previously screened / known not to harbor causal variants for achromatopsia. The family members were then subjected to Sanger sequencing of the 22 exons and flanking regions of PDE6C.

Variant: The proband harbors the NM_006204.4(PDE6C):c.1682dup (p.Tyr561Ter) variant in the homozygous state.

ClinVar ID: 8775

gnomAD: The NM_006204.4(PDE6C):c.1682dup (p.Tyr561Ter) variant was not found in gnomAD v2.1.1.

VariantEvidence: NM_006204.4(PDE6C):c.1682dup (p.Tyr561Ter) is a nonsense variant in exon 13 of 22 and is predicted to trigger nonsense-mediated decay or to at least truncate the C-terminal 35% of the protein product.

CaseAddInfo: The patient's parents and sister are each unaffected heterozygous carriers of the variant.

CasePMIDs: N/A

FamilyLabel: Kajiwara_1991_Family_6935, family national origin not reported

Family#PresentingHPOs: Decreased light- and dark-adapted electroretinogram amplitude HP:0000654

FamilyHPOFreeText: The patient and affected family members have been diagnosed with retinitis pigmentosa.

Family#PresentingNotHPOs: N/A

Family#PresentingNotHPOFreeText: N/A

CountryOrigin: N/A

Ethnicity: Not mentioned

Race: Not mentioned

Family#PreviousTesting: Previous testing consisted of screening of the RHO locus for disease-causing variants.

Family#Method1: Single strand conformation polymorphism analysis of PCR-amplified cDNA products from the PRPH2 gene, followed by Sanger sequencing of the relevant PCR product to identify the variant

Family#Method2: SSCP to genotype family members

Family#GenotypingMethod: Previous testing of this family screening of the RHO locus for variants causing RP, with negative results. Genotyping started with single strand conformation polymorphism analysis of PCR-amplified products from the PRPH2 gene, followed by Sanger sequencing of the relevant PCR product to identify the variant. SSCP was subsequently performed to genotype family members.

Affected: 3

Unaffected: 5

Segregations: Two segregations are reported in the family, with none inconsistent. The family is not reported to be consanguineous. The pedigree is shown in Figure 3c.

PublishedLOD: N/A

eLOD: 2.40

AddSegregationInfo: N/A

ProbandLabel: Kajiwara_1991_Family_6935_Proband

Variant: The affected family members harbor the NM_000322.5(PRPH2):c.554T>C (p.Leu185Pro) variant in the heterozygous state.

ClinVarID: 13165

gnomAD: This variant was found in gnomAD v4.0.0 at a frequency of 0.00003587 (15 alleles / 418142 total alleles, with no homozygotes) in the European non-Finnish population https://gnomad.broadinstitute.org/variant/6-42721781-A-G?dataset=gnomad_r4

FamilyAddInfo: The family has not been reported as consanguineous.

FamilyPMIDs: N/A

FamilyLabel: Kajiwara_1991_Family_6948, family national origin not reported

Family#PresentingHPOs: Decreased light- and dark-adapted electroretinogram amplitude HP:0000654

FamilyHPOFreeText: The patient and affected family members have been diagnosed with retinitis pigmentosa.

Family#PresentingNotHPOs: N/A

Family#PresentingNotHPOFreeText: N/A

CountryOrigin: N/A

Ethnicity: Not mentioned

Race: Not mentioned

Family#PreviousTesting: Previous testing consisted of screening of the RHO locus for disease-causing variants.

Family#Method1: Single strand conformation polymorphism analysis of PCR-amplified cDNA products from the PRPH2 gene, followed by Sanger sequencing of the relevant PCR product to identify the variant

Family#Method2: SSCP to genotype family members

Family#GenotypingMethod: Previous testing of this family screening of the RHO locus for variants causing RP, with negative results. Genotyping started with single strand conformation polymorphism analysis of PCR-amplified products from the PRPH2 gene, followed by Sanger sequencing of the relevant PCR product to identify the variant. SSCP was subsequently performed to genotype family members.

Affected: 8

Unaffected: 7

Segregations: Eight segregations are reported in the family, with none inconsistent. The family is not reported to be consanguineous. The pedigree is shown in Figure 3b.

PublishedLOD: N/A

eLOD: 2.40

AddSegregationInfo: N/A

ProbandLabel: Kajiwara_1991_Family_6948_Proband

Variant: The affected family members harbor the NM_000322.5(PRPH2):c.647C>T (p.Pro216Leu) variant in the heterozygous state.

ClinVarID: 13164

gnomAD: This variant was found in gnomAD v4.0.0 at a frequency of 0.000002856 (1 allele / 350108 total alleles, with no homozygotes) in the European non-Finnish population https://gnomad.broadinstitute.org/variant/6-42704546-G-A?dataset=gnomad_r4

FamilyAddInfo: The family has not been reported as consanguineous.

FamilyPMIDs: N/A

FamilyLabel: Lebrun_2009_Family_1

Family#PresentingHPOs: HP:0001251 (Ataxia), HP:0001250 (Seizure), HP:0002463 (Language impairment), HP:0011463 (Childhood onset),

Family#PresentingHPOFreeText: Abnormalities on brain MRI scan

FamilyNotHPOs: N/A

FamilyNotHPOFreeText: N/A

CountryOrigin: United Kingdom

Ethnicity: Family is of Pakistani ethnic origin.

Race: N/A

Family#PreviousTesting: 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.

Family#Method1: 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.

Family#Method2: N/A

Family#GenotypingMethod: 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).

Affected: 2

Unaffected: 1

Segregations: 1 segregation is reported in the family.

PublishedLOD: N/A

eLOD: N/A

AddSegregationInfo: N/A

ProbandLabel: Lebrun_2009_Patient_1

Variant: Both affected patients are 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

FamilyAddInfo: The 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.

FamilyPMIDs: N/A

Case: Lin_2006_Family_1_patient_IV-8, female, 62 years of age at presentation, Eastern European Jewish ancestry

DiseaseAssertion: Sorsby's fundus dystrophy

FamilyInfo: N/A

CasePresentingHPOs: HP:0007663 (Reduced visual acuity), HP:0012508 (Metamorphopsia), HP:0011510 (Drusen), HP:0025148 (Dark choroid), HP:0011506 (Choroidal neovascularization), HP:0025094 (Disciform macular scar), HP:0000662 (Nyctalopia), HP:0007703 (Abnormality of retinal pigmentation),

CaseHPOFreeText: Patient presented with central visual field loss and metamorphopsia in one eye, 10 years after a normal results from fundus and vision exam. Fluorescein angiography of the other eye revealed drusen and dark choroid. Choroidal neovascularization progressed to a central disc-shaped scar despite several treatments with argon laser thermal photocoagulation. The less affected eye initially showed mild nyctalopia only, but progressed within 2 years to fibrovascular pigment epithelial detachment, circular blocking lesion, choroidal neovascularization, and visual acuity loss.

CaseNOTHPOs: N/A

CaseNOTHPOFreeText: N/A

CasePreviousTesting: Complete ophthalmological exam to define clinical features.

CaseGenotypingMethod: Bidirectional Sanger sequencing of PCR products from exons 1 through 5.

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: NM_000362.5(TIMP3):c.542A>G, p.His181Arg is a missense variant predicted to replace a conserved histidine residue in exon 5 with arginine (conservative substitution).

CAID: CA411540357

gnomAD: Variant is absent from gnomAD.

VariantEvidence: p.His181Arg is a missense variant predicted to replace a conserved histidine residue in exon 5 with arginine (conservative substitution). Molecular modeling predicts that the affected amino acid is located on a protein-protein interaction interface.

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

FamilyLabel: Jiao_2004_Three_Families

Family#PresentingHPOs: N/A

FamilyPresentingHPOFreeText: The affected family members have been diagnosed with familial exudative vitreoretinopathy segregating with an autosomal recessive mode of inheritance.

FamilyNotHPOs: N/A

FamilyNotHPOFreeText: Although bone density measurements are not available, at least two of the affected individuals lack bone fractures in the first three decades of life, distinguishing their phenotype from osteoporosis-pseudoglioma syndrome.

CountryOrigin: The three families are reportedly of European descent.

Ethnicity: Not specifically described

Race: The three families are reportedly of European descent.

Family#PreviousTesting: Candidate-locus-directed linkage analysis focused on chromosome 11q, with maximum LOD score of 3.6 associated with the D11S987 microsatellite marker linked to a 311-Mb region.

Family#Method1: Genome-wide linkage analysis

Family#Method2: Sanger sequencing of the candidate gene LRP5

Family#GenotypingMethod: Candidate-locus-directed linkage analysis was initially performed on all three families, focused on chromosome 11q, with maximum LOD score of 3.6 associated with the D11S987 microsatellite marker linked to a 311-Mb region. Sanger sequencing of the candidate gene LRP5 locus was subsequently performed.

Affected: 6 genotyped

Unaffected: 0 genotyped (although 6 unaffected individuals are genotyped but ineligible because they are from previous generations that lack affected members.

Segregations: 3 segregations are shown by the three pedigrees in Figure 1.

PublishedLOD: 3.6

eLOD: N/A

AddSegregationInfo: While none of the families would individually be eligible for inclusion in segregation evidence using an estimated LOD score, the published LOD score is sufficient for their inclusion.

ProbandLabel: Jiao_2004_Family_68001_Proband, Jiao_2004_Family_68002_Proband, Jiao_2004_Family_68003_Proband

Variant: The affected family members harbor one of the following three variants in homozygous state; NM_002335.4(LRP5):c.2254C>G (p.Arg752Gly), NM_002335.4(LRP5):c.4099G>A (p.Glu1367Lys), or NM_002335.4(LRP5):c.1709G>A (p.Arg570Gln)

ClinVar: 6290, 6291, 6289

gnomAD: NM_002335.4(LRP5):c.2254C>G (p.Arg752Gly) was not found in gnomAD v2.1.1. NM_002335.4(LRP5):c.4099G>A (p.Glu1367Lys) is present in gnomAD v2.1.1. at a frequency of 0.00001760 (2/113626) in the European non-Finnish population https://gnomad.broadinstitute.org/variant/11-68204455-G-A?dataset=gnomad_r2_1 NM_002335.4(LRP5):c.1709G>A (p.Arg570Gln) was not found in gnomAD v2.1.1.

VariantEvidence: NM_002335.4(LRP5):c.2254C>G (p.Arg752Gly) is a missense variant in exon 10 of 23 that does not have experimental evidence of impact on the protein product. NM_002335.4(LRP5):c.4099G>A (p.Glu1367Lys) is a missense variant in exon 19 of 23 that does not have experimental evidence of impact on the protein product. NM_002335.4(LRP5):c.1709G>A (p.Arg570Gln) is a missense variant in exon 8 of 23 that does not have experimental evidence of impact on the protein product.

FamilyAddInfo: All three families are reportedly consanguineous.

FamilyPMIDs: N/A

FamilyLabel: Saihan_2009_Family

Family#PresentingHPOs: HP:0000662 (Nyctalopia), HP:0000529 (Progressive visual loss), HP:0000572 (Visual loss), HP:0011510 (Drusen), HP:0011506 (Choroidal neovascularization)

FamilyHPOFreeText: First presenting phenotypes were reduction of night vision and slow dark adaptation (with onset in fifth decade, 1 to 11 years prior to vision loss). Nyctalopia was progressive, with onset in the fifth decade of life (age 45-47). Vision loss was sudden, in some cases bilateral, and occurred in the fifth or sixth decade of life (age 48-56). Drusen-like deposits were present at the posterior pole in all three patients but varied in severity (possibly in proportion to age at examination). The degree of vision loss also varied in severity between patients and between the left and right eyes of each patient. Choroidal neovascularization was hemorrhagic and initiated loss of central vision.

FamilyNotHPOs: HP:0004328 (Abnormal anterior eye segment morphology), HP:0000518 (Cataract)

FamilyNotHPOFreeText: No history of renal disease or systemic disease was consistently observed among the affected family members.

CountryOrigin: British (of Welsh origin)

Family#PreviousTesting: Family history (indicating autosomal dominant inheritance of retinal degeneration) and ophthalmic exams (including LogMAR visual acuities, slit-lamp biomicroscopy, color fundus photography, optical coherence tomography scans of the fovea, and autofluorescent imaging of the fundus)

Family#GenotypingMethod: Mutational screening of TIMP3 by bidirectional Sanger sequencing

Affected: 3

Unaffected: 2

Segregations: 2

PublishedLOD: N/A

eLOD: Insufficient information available

AddSegregationInfo: N/A

ProbandLabel: Saihan_2009_Family_patient_III:4

Variant: Variant used was NM_000362.5(TIMP3):c.484G>A (p.Glu162Lys) (CAID:CA411540222). The variant is referred to in this publication as "Glu139Lys" (due to the removal of a 23-amino acid N-terminal signal peptide from the polypeptide sequence) but encodes Glu162Lys in the full/updated polypeptide sequence.

CAID: CA411540222

gnomAD: Variant is absent from gnomAD.

FamilyAddInfo: The mother of the proband and affected siblings was unaffected and negative for the variant, while the father was affected but not genotyped.

FamilyPMIDs: N/A

Case#: Chatterjee_2022_proband_II:4, female, age 16 years at time of report, onset in second decade of life, geographic origin reported as north Indian

CasePresentingHPOs: HP:0410280 (Pediatric onset), HP:0000613 (Photophobia), HP:0000662 (Nyctalopia), HP:0030564 (Best corrected visual acuity 1.1 LogMAR), HP:0025147 (Beaten bronze macular sheen), HP:0011507 (Macular flecks), HP:0030619 (Reduced OCT-measured foveal thickness), HP:0025010 (Foveal atrophy)

CaseHPOFreeText: The patient and siblings have been diagnosed with Stargardt-like juvenile macular dystrophy.

CaseNotHPOs: HP:0007737 (Bone spicule pigmentation of the retina)

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping consisted of whole-exome sequencing.

CaseMethod1: whole-exome sequencing

CaseMethod2: Sanger sequencing of the 19 exons of the IMPG2 gene

CaseGenotypingMethod: Genotyping consisted of whole-exome sequencing followed by Sanger sequencing of the 19 exons of the IMPG2 gene.

Variant: The patient harbors the NM_016247.4:c.1239+1G>T variant in the homozygous state.

CAID: CA353864391

gnomAD: The variant was found in gnomAD v2.1.1.

VariantEvidence: NM_016247.4:c.1239+1G>T is a canonical splice site variant in intron 11 of the 19-exon locus that has been shown by mini-gene assay to trigger a splicing defect that leads to complete skipping of exon 11. Because this would lead to a shift of frame, the variant is predicted to lead to a premature stop after codon 385 and either NMD or truncation of 69% of the C-terminus of the protein product.

CaseAddInfo: The family is consanguineous, with the parents being first cousins and heterozygous carriers of the variant. The patient has two affected siblings who share the same genotype.

CasePMIDs: N/A

Case: Naessens_2019_Family_2_Patient_II:1, female, age of onset 53 years old, country of origin France (northern)

DiseaseAssertion: Sorsby's fundus dystrophy

FamilyInfo: Familial variant appears to come from a founder mutation shared by other families in Belgium and northern France with a distant common ancestor.

CasePresentingHPOs: HP:0011510 (Drusen), , HP:0000572 (Visual loss), HP:0007401 (Macular atrophy), HP:0007769 (Peripheral retinal degeneration), HP:0011506 (Choroidal neovascularization), HP:0007777 (Chorioretinal scar)

CaseHPOFreeText: Relatively late onset of phenotypes (at age 53, presenting with nyctalopia). Drusen was described as widespread and partially calcified. Macular atrophy was patchy, with round atrophic patches outside the vascular arcades.

CaseNOTHPOs: N/A

CaseNOTHPOFreeText: Pulmonary involvement

CasePreviousTesting: N/A

GenotypingMethod: PCR amplification of all 5 coding exons of TIMP3, followed by Sanger sequencing

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S3 from this paper (PMID: 30668888) provides some of the proband phenotype details.

Variant: The variant is NM_000362.5(TIMP3):c.113C>G (p.Ser38Cys), a missense variant predicted to introduce a new cysteine-encoding codon into exon 1.

ClinVar: 843268

gnomAD: Variant is absent from gnomAD.

VariantEvidence: Variant adds a Cys residue to TIMP3 and is predicted to disrupt tertiary structure. Patient fibroblasts reveal no change in expression of the variant at the mRNA level, no dimerization of the variant under non-reducing conditions, and no defect in its localization to the ECM. Variant showed a minor increase in glycosylation. An in vitro transcription and translation study found that the variant forms an aberrant intramolecular disulfide bond between the introduced Ser38Cys residue and Cys36 of TIMP3 (Figure 7). Aberrant intramolecular disulfide bonding caused by this variant would be consistent gain-of-function and an autosomal dominant mechanism of inheritance.

FamilyLabel: Felbor_1995_Family_1

Family#PresentingHPOs: HP:0030666 (Retinal neovascularization), HP:0007777 (Chorioretinal scar), HP:0000603 (Central scotoma), HP:0000556 (Retinal dystrophy), HP:0007737 (Bone spicule pigmentation of the retina), HP:0000630 (Abnormal retinal artery morphology), HP:0030491 (Choriocapillaris atrophy), HP:0007994 (Peripheral visual field loss), HP:0030469 (Abnormal dark-adapted electroretinogram), HP:0008275 (Abnormal light-adapted electroretinogram),

FamilyHPOFreeText: Patients were considered to exhibit early-onset SFD with a mean age of 25. The presenting symptom was central subretinal neovascularisation, which preceded extensive scarring. Second eye involvement generally occurred months later, indicating rapid progression. Retinal dystrophy was reported to be tapetal. Intraretinal arteries were attenuated. Dark adaptation was decreased.

FamilyNotHPOs: N/A

FamilyNotHPOFreeText: N/A

CountryOrigin: The family is described as German-Czech.

Family#PreviousTesting: Genetic linkage testing / genotyping of affected and unaffected family members with three microsatellite markers that were previously associated with SFD and that flank the TIMP3 locus. This was followed by single-stranded conformational polymorphism (SSCP) of all five TIMP3 exons, detecting a mobility shift in exon 5.

Family#GenotypingMethod: Bidirectional Sanger sequencing of exon 5 PCR products from two affected individuals.

Affected: 2 (Sanger sequenced)

Unaffected: 1 (Sanger sequenced)

Segregations: N/A

PublishedLOD: Maximum two-point LOD score of 4.75 was reported for marker D22S280 at a recombination fraction of 0.001. D22S280 is also tightly associated with the TIMP3 locus.

eLOD: Insufficient information available

AddSegregationInfo: Family pedigree (from microsatellite-based linkage testing) mapping the disease locus to chr22q13-qter is shown in Figure 1.

ProbandLabel: Felbor_1995_Family_1_patient_1

Variant: NM_000362.5(TIMP3):c.536C>G, (p.Ser179Cys) is a missense variant predicted to substitute a new cysteine residue into exon 5.

ClinVar: 12678

gnomAD: Variant is absent from gnomAD.

FamilyAddInfo: N/A

FamilyPMIDs: N/A

FamilyLabel: Farrar_1991_Family, family national origin reported as Irish

Family#PresentingHPOs: Nyctalopia HP:0000662, Peripheral visual field loss HP:0007994, Undetectable dark-adapted electroretinogram HP:0030474, Abnormal light-adapted electroretinogram HP:0008275, Pigmentary retinopathy HP:0000580, Optic disc pallor HP:0000543, Retinal arteriolar constriction HP:0008043, Bone spicule pigmentation of the retina HP:0007737

FamilyHPOFreeText: The patient and affected family members have been diagnosed with retinitis pigmentosa, with onset noted as late. Nyctalopia generally presented in the early third decade, while rod ERG responses showed reduced amplitudes in the teens.

Family#PresentingNotHPOs: N/A

Family#PresentingNotHPOFreeText: N/A

CountryOrigin: Ireland

Ethnicity: Not mentioned

Race: Not mentioned

Family#PreviousTesting: Previous testing did not occur in this family, although linkage mapping had previously identified PRPH2 as a candidate locus for variants causing RP.

Family#Method1: Single strand conformation polymorphism analysis of PCR-amplified cDNA products from the PRPH2 gene, followed by Sanger sequencing of the relevant PCR product to identify the variant

Family#Method2: allele-specific PCR to genotype family members

Family#GenotypingMethod: Previous testing of this family did not include linkage mapping, although this technique had previously identified PRPH2 as a candidate locus for variants causing RP. Genotyping started with single strand conformation polymorphism analysis of PCR-amplified cDNA products from the PRPH2 gene, followed by Sanger sequencing of the relevant PCR product to identify the variant. Allele-specific PCR was subsequently performed to genotype family members.

Affected: 9

Unaffected: 6

Segregations: Nine segregations are reported in the family, with none inconsistent. The family is not reported to be consanguineous. The pedigree is shown in Figure 2.

PublishedLOD: N/A

eLOD: 2.70

AddSegregationInfo: N/A

ProbandLabel: Farrar_1991_Proband

Variant: The affected family members harbor the NM_000322.5:c.356_358del (p.Cys119del) variant in the heterozygous state.

CAID: CA226222

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

FamilyAddInfo: The family has not been reported as consanguineous.

FamilyPMIDs: N/A

Case#: Bessa_Patient_1, female, age 3 at onset, Portuguese nationality

CasePresentingHPOs: HP:0000736 (Short attention span), HP:0002463 (Language impairment), HP:0002312 (Clumsiness), HP:0033044 (Motor regression), HP:0002376 (Developmental regression), HP:0000572 (Visual loss), HP:0002066 (Gait ataxia), HP:0001336 (Myoclonus), HP:0010819 (Atonic seizure), HP:0032794 (Myoclonic HP:0000648 (Optic atrophy), HP:0000546 (Retinal degeneration), HP:0012011 (EEG with occipital focal spike waves), HP:0002059 (Cerebral atrophy), HP:0001272 (Cerebellar atrophy), HP:0030891 (Periventricular white matter hyperdensities), HP:0001268 (Mental deterioration), HP:0031058 (Impairment of activities of daily living), HP:0011463 (Childhood onset), HP:0000712 (Emotional lability), HP:0002015 (Dysphagia), HP:0010864 (Intellectual disability, severe), HP:0001332 (Dystonia), HP:0007256 HP:0025357 (Erratic myoclonus), HP:0003205 (Curvilinear intracellular accumulation of autofluorescent lipopigment storage material), HP:0003208 (Fingerprint intracellular accumulation of autofluorescent lipopigment storage material)

CaseHPOFreeText: Progressive attention deficits and regression of language ability were the phenotypes at presentation (age 3). Motor clumsiness presented at age 4, initiating a larger pattern of developmental regression. Phenotypes with onset at age 7 included visual deterioration, gait ataxia, distal and axial myoclonus, atonic and myoclonic generalized epileptic seizures, bilateral optic atrophy, retinal degeneration, abnormal EEG showing diffuse slowing of background rhythm and occipital spike-wave activity, and abnormal brain MRI with cerebral and cerebellar atrophy as well as increased signal intensity of both the posterior limb of the capsula interna and the periventricular white matter. At age 8, any independence in daily activities was lost, as well as any language abilities. Ataxic gait was marked, and EEG activity showed slowing and disorganization, frequent multifocal high-voltage polyspike-slow wave complexes, and epileptic activity corresponding to myoclonus. At 15 years (time of study), the patient was bedridden and showed amaurotic behavior, emotional lability, marked dysphagia, severe mental retardation, dystonic postures of the limbs and trunk, pyramidal signs in the limbs, bilateral optic atrophy, and frequent myoclonus (both erratic and stimulus-induced). Intracellular accumulation of autofluorescent lipopigment storage material was also detected at age 15.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotype testing was not performed. While the PPT1 and TPP1 loci were not sequenced, their enzymatic activity in extracts from leucocyte and fibroblast cells was confirmed to be within the normal range.

CaseGenotypingMethod: Based on detailed clinical phenotypes consistent with variant NCL with late-infantile onset, coding regions and intron boundaries of the CLN3, CLN5, and CLN6 loci were PCR-amplified and subjected to Sanger sequencing. Genome-wide analysis methods were not used. Parents (and patient) were subsequently genotyped using single strand conformational polymorphisms and restriction digest of PCR products, to identify variants in cis and in trans with one another.

Variant: The patient is a compound heterozygote with a paternally inherited NM_006493.4(CLN5):c.418C>T (p.Gln140Ter) variant and maternally inherited NM_006493.4(CLN5):c.688G>A (p.Asp230Asn) and NM_006493.4(CLN5):c.188G>C (p.Arg63Pro) variants.

ClinVar: 56538, 2566, 56533

gnomAD: The maximum allele frequency of the NM_006493.4(CLN5):c.688G>A (p.Asp230Asn) variant is 0.00005437 (within the East Asian population, with no homozygous occurrences). https://gnomad.broadinstitute.org/variant/13-77574715-G-A The NM_006493.4(CLN5):c.418C>T (p.Gln140Ter) and NM_006493.4(CLN5):c.188G>C (p.Arg63Pro) variants are absent from gnomAD.

VariantEvidence: Reduced CLN5 expression by 45% at the mRNA level indicates that one of the two alleles may be subject to nonsense mediated decay and likely absence of the corresponding protein product. This may confirm the prediction that the nonsense variant NM_006493.4(CLN5):c.418C>T (p.Gln140Ter) is likely subject to nonsense mediated decay. One of the two maternally inherited variants, NM_006493.4(CLN5):c.688G>A (p.Asp230Asn), has been previously shown to introduce an additional N-glycosylation site within the C-terminal region of CLN5 (PMID:20052765) and to disturb its localization to the lysosome (PMID:20052765).

CaseAddInfo: Parents are healthy and non-consanguineous.

CasePMIDs: N/A

Case#: Li_2025_Proband_XXXVII, age 8 years at time of report, male, seen at a medical center in Beijing

CasePresentingHPOs: Abnormal morphology of the choroidal vasculature HP:0025568, High myopia HP:0011003, Best corrected visual acuity 0.1 LogMAR HP:0030554

CaseHPOFreeText: The choroidal vascular abnormality referred to in the text was described as a tesselated fundus. The patient's refractive error was reported as -14.00 and -12.88 in the two eyes, with, axial lengths of 27.01 and 26.64.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseMethod1: whole genome sequencing

CaseMethod2: possibly Sanger sequencing of OPN1LW

CaseGenotypingMethod: Genotyping of the proband was performed by whole genome sequencing, possibly followed by Sanger sequencing of OPN1LW.

Variant: The individual harbors the NM_020061.6(OPN1LW):c.843G>A (p.Trp281Ter) variant in the hemizygous state.

CAID: CA415308527

gnomAD: The variant is found in gnomAD version 4.1.0 at a frequency of 0.00002111 (1 / 47,376) in the Remaining population. https://gnomad.broadinstitute.org/variant/chrX-154156392-G-A?dataset=gnomad_r4

VariantEvidence: NM_020061.6(OPN1LW):c.843G>A (p.Trp281Ter) is a nonsense variant in exon 5 of 6 that is predicted to undergo nonsense-mediated decay.

CaseAddInfo: The proband was seen at a medical center in Beijing.

CasePMIDs: N/A

Case#: Family_22142_Proband_II-1, onset before age 7 years, male, seen at a medical center in Guangzhou

CasePresentingHPOs: High myopia HP:0011003, Blurred vision HP:0000622, Childhood onset HP:0011463, Protanopia HP:0011522

CaseHPOFreeText: The proband is part of a cohort in which all patients had a diagnosis of early onset high myopia, with onset in early childhood and either high myopia or axial length >25 mm before age 7, or refractive errors <-10 as an adult.

CaseNotHPOs: Nystagmus HP:0000639, Photophobia HP:0000613, Nyctalopia HP:0000662

CaseNotHPOFreeText: N/A

CasePreviousTesting: Genotyping of the proband was performed by either targeted exome sequencing or whole exome sequencing.

CaseMethod1: targeted exome or whole exome sequencing

CaseMethod2: Sanger sequencing of OPN1LW

CaseGenotypingMethod: Genotyping of the proband was performed by either targeted exome sequencing or whole exome sequencing, followed by Sanger sequencing of OPN1LW.

Variant: The individual harbors the NM_020061.6(OPN1LW):c.739C>T (p.Arg247Ter) variant in the hemizygous state.

ClinVarID: 10503

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

VariantEvidence: NM_020061.6(OPN1LW):c.739C>T (p.Arg247Ter) is a nonsense variant in exon 3 of 6 that is predicted to undergo nonsense-mediated decay.

CaseAddInfo: The proband was seen at a medical center in Guangzhou. The variant was inherited from the proband's unaffected mother.

CasePMIDs: N/A

Case#: van_Dorp_1992_Family_P9145_patient_IV-20, male, age not reported, family origin reported to be Dutch

CasePresentingHPOs: HP:0012263 (Immotile cilia), HP:0002205 (Recurrent respiratory infections), HP:0012261 (Abnormal respiratory motile cilium physiology), HP:0012255 (Dynein arm defect of respiratory motile cilia), HP:0012260 (Abnormal central microtubular pair morphology of respiratory motile cilia), HP:0012864 (Abnormal sperm morphology),

CaseHPOFreeText: The proband has been diagnosed with retinitis pigmentosa in combination with recurrent respiratory infections. The family exhibits an X-linked pattern of inheritance. Inner dynein arms of respiratory cilia were described as deficient. Cilia were described as disoriented.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The patient and his family members were subjected to linkage analysis using X chromosomal markers, followed by a chromosomal analysis of the patient that revealed no abnormalities (such as a translocation involving the X chromosome).

CaseMethod1: Linkage analysis (PMID: 1733835)

CaseMethod2: Sanger sequencing of PCR products from the RPGR locus (PMID: 10094550)

CaseGenotypingMethod: The patient and family members were subjected to linkage analysis using X chromosomal markers, and then the patient DNA underwent chromosomal analysis that revealed no abnormalities (such as a translocation involving the X chromosome). The family members were then genotyped by Sanger sequencing of PCR products from the RPGR locus (PMID: 10094550).

Variant: The patient harbors the NM_001034853.2(RPGR):c.469+1G>T variant in the hemizygous state.

ClinVar: 9912

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

VariantEvidence: NM_001034853.2(RPGR):c.469+1G>T is a canonical splice site variant in the final exon (exon 15) that disrupts the 5' splice site of intron 5. Functional evidence confirming the expected effect on splicing is not available.

CaseAddInfo: The proband is a member of Family P9145 (shown in Figure 1), which includes four other affected genotype-positive males and as well as three carrier females who showed no detectable abnormality. The detailed genotype for the affected and carrier individuals was later published in PMID: 10094550.

CasePMIDs: PMID: 10094550

Case#: Bin_2009_Family_04-01_Case_26, female, age 11.6 years at time of report, national origin reported as from Peru

CasePresentingHPOs: HP:0001513 (Obesity), HP:0010442 (Polydactyly), HP:0100543 (Cognitive impairment), HP:0012758 (Neurodevelopmental delay), HP:0003077 (Hyperlipidemia), HP:0034685 (Abnormal liver enzyme activity or concentration), HP:0000077 (Abnormality of the kidney), HP:0410042 (Abnormal liver morphology), HP:0030515 (Moderately reduced visual acuity), HP:0000548 (Cone/cone-rod dystrophy), HP:0001133 (Constriction of peripheral visual field)

CaseHPOFreeText: The patient has been diagnosed with Bardet-Biedl syndrome.

CaseNotHPOs: HP:0000639 (Nystagmus), HP:0000518 (Cataract)

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping consisted of Sanger sequencing of the TTC8 locus.

CaseMethod1: Sanger sequencing of the TTC8 locus

CaseMethod2: Sanger sequencing of the BBS7 locus

CaseGenotypingMethod: Genotyping consisted of Sanger sequencing of the TTC8 and BBS7 loci.

Variant: The patient harbors the NM_176824.3:c.712_715del (p.Arg238GlufsTer?) and NM_176824.3:c.1121C>G (Ser374Ter) variants in the compound heterozygous state.

CAID: CA3064432, CA358062298

gnomAD: The NM_176824.3:c.1121C>G (Ser374Ter) variant is found in gnomAD v2.1.1 at a maximum allele frequency of 0.0001633 (1/6124 in the Other population), with 0 homozygotes. https://gnomad.broadinstitute.org/variant/4-122766768-G-C The NM_176824.3:c.712_715del (p.Arg238GlufsTer?) variant is found in gnomAD v2.1.1 at a maximum allele frequency of 0.0001146 (13/113390) in the European non-FInnish population), with 0 homozygotes.

VariantEvidence: NM_176824.3:c.1121C>G (Ser374Ter) is a nonsense variant in exon 11 of 18 that is predicted to trigger nonsense-mediated decay or at least truncation of the C-terminal 48% of the protein product. NM_176824.3:c.712_715del (p.Arg238GlufsTer?)is a frameshift variant in exon 7 of 18 that is predicted to trigger nonsense-mediated decay or at least truncation of the C-terminal 67% of the protein product.

CaseAddInfo: Consanguinity in the proband's family has not been reported. The carrier status of her unaffected parents and an unaffected sibling have been confirmed by genotyping.

CasePMIDs: N/A

Case#: Preising_2001_Patient_IV.1, male, age 3 months at time of diagnosis, family ethnicity described as White

CasePresentingHPOs: HP:0006934 (Congenital nystagmus), HP:0012805 (Iris transillumination defect), HP:0007894 (Hypopigmentation of the fundus), HP:0001104 (Macular hypoplasia), HP:0007663 (Reduced visual acuity), HP:0030463 (Asymmetrical distribution of flash visual evoked potentials), HP:0025551 (Optic nerve misrouting)

CaseHPOFreeText: The proband and his family members have been diagnosed with congenital nystagmus.

CaseNotHPOs: HP:0009887 (Abnormality of hair pigmentation), HP:0001000 (Abnormality of skin pigmentation)

CaseNotHPOFreeText: N/A

CasePreviousTesting: The patients were initially genotyped by SSCP of PCR products from each exon, revealing an abnormality in exon 6.

CaseMethod1: SSCP

CaseMethod2: Sanger sequencing

CaseGenotypingMethod: The proband was initially genotyped by SSCP of PCR products from each exon, revealing an abnormality in exon 6, followed by Sanger sequencing and restriction enzyme analysis by Tsp509I digest of PCR products from all family members.

Variant: The proband harbors the NM_000273.3(GPR143):c.756_767+2del variant in the hemizygous state.

ClinVar: 98643

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

VariantEvidence: NM_000273.3(GPR143):c.756_767+2del is a 14-bp deletion variant removing the 3' end of exon 6 and the canonical splice donor site, and has been shown to trigger aberrant splicing that leads to frameshift at codon 252 and premature termination at codon 259 (Figure 4C).

CaseAddInfo: The proband is part of a family with at least 3 affected generations showing a pattern of X-linked inheritance, including a similarly affected maternal uncle.

CasePMIDs: N/A

Case#: Zhou_2008_Patient_III:22, male, age of onset not reported, family origin reported to be from China

CasePresentingHPOs: HP:0000639 (Nystagmus), HP:0000646 (Amblyopia)

CaseHPOFreeText: The proband has been diagnosed with congenital nystagmus.

CaseNotHPOs: HP:0040030 (Chorioretinal hypopigmentation)

CaseNotHPOFreeText: N/A

CasePreviousTesting: Genotyping was initially performed by linkage mapping using 26 short tandem repeat markers on the X chromosome.

CaseMethod1: linkage analysis

CaseMethod2: Sanger sequencing

CaseGenotypingMethod: Genotyping was initially performed by linkage mapping using 26 short tandem repeat markers on the X chromosome, followed by Sanger sequencing of PCR products from each exon of the GPR143 gene.

Variant: The proband harbors the NM_000273.3(GPR143):c.162_198del (p.Ala55fs) variant in the hemizygous state.

ClinVar: 10524

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

VariantEvidence: NM_000273.3(GPR143):c.162_198del (p.Ala55fs) is a frameshift variant in exon 1, and is predicted to trigger nonsense-mediated decay or to at least truncate the C-terminal 87% of the protein product.

CaseAddInfo: The proband is from a family with at least seven other affected males who also harbor the variant.

CasePMIDs: N/A

Case#: Fang_2008_Family_1_Patient_IV16, male, age 8 at time of report, family national origin reported to be from China

CasePresentingHPOs: HP:0000639 (Nystagmus), HP:0030534 (Abnormal best corrected visual acuity test), HP:0007750 (Hypoplasia of the fovea)

CaseHPOFreeText: The proband and his affected family members have been diagnosed with ocular albinism 1.

CaseNotHPOs: HP:0007730 (Iris hypopigmentation), HP:0007894 (Hypopigmentation of the fundus)

CaseNotHPOFreeText: albinotic fundus

CasePreviousTesting: N/A

CaseMethod1: Sanger sequencing

CaseMethod2: N/A

CaseGenotypingMethod: The proband was genotyped by Sanger sequencing of PCR products from the 9 exons of the GPR143 gene.

Variant: The proband harbors the NM_000273.3(GPR143):c.849del (p.Val284SerfsTer15) variant in the hemizygous state.

CAID: CA2573320706

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

VariantEvidence: NM_000273.3(GPR143):c.849del (p.Val284SerfsTer15) is a frameshift variant in exon 7 of 9, predicted to trigger nonsense-mediated decay or to at least truncate 30% of the protein product.

CaseAddInfo: The family of the proband includes at least 7 other affected males and 4 unaffected female carriers.

CasePMIDs: N/A

Case#: Savukoski_Fin_Minor_Patient_1, no demographic details, Finnish origin

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing relied on linkage analysis using PCR-amplifiable polymorphisms, including microsatellite markers. The marker D13S160 was found to co-segregate with disease with a LOD score of 4.78 across 14 Finnish pedigrees, mapping the disease locus to chromosome 13q21.1-q32 (PMID:7942847). A follow-up study used two additional microsatellite markers to map the locus to a 200-kb region (PMID:8661106), which was then analyzed in the present study and found to contain a single coding gene.

CaseMethod1: Linkage analysis using PCR-amplifiable polymorphisms, including microsatellite markers, followed by more detailed linkage analysis using two additional microsatellite markers to map the locus to a smaller 200-kb region (PMID:8661106).

CaseMethod2: N/A

CaseGenotypingMethod: PCR products from the four exons of CLN5 were generated from the affected individual and a control individual and subjected to Sanger sequencing. Genome-wide analysis methods were not used.

Variant: Patient is homozygous for NM_006493.4(CLN5):c.78G>A (p.Trp26Ter), although this variant is referred to in the article as c.G1517A or p.Trp75Stop.

ClinVar: 2565

gnomAD: The variant is reported to have a maximum allele frequency of 0.00005132 (in the European non-Finnish population, with no homozygous individuals). https://gnomad.broadinstitute.org/variant/13-77566311-G-A

VariantEvidence: This nonsense variant is predicted to introduce a stop codon near the N-terminus of the encoded protein, likely triggering NMD and the absence of a protein product (loss of function).

CaseAddInfo: N/A

CasePMIDs: PMID:7942847, PMID:8661106

FamilyLabel: Langton_2000_Family_1

Family#PresentingHPOs: HP:0031609 (Geographic atrophy), HP:0007663 (Reduced visual acuity), HP:0007703 (Abnormality of retinal pigmentation), HP:0000512 (Abnormal electroretinogram)

FamilyHPOFreeText: First presentation of symptoms was in the 3rd or 4th decade of life. Geographic macular atrophy was the cause of central vision loss. Retinal pigmentary disturbances were peripheral. Scotopic ERGs were abnormal. Other common SFD phenotypes were seen in some affected individuals but not uniformly across all affected family members.

FamilyNotHPOs: N/A

CountryOrigin: British (PMID:11734514)

Family#PreviousTesting: Family previously diagnosed with SFD, with details provided in PMID:11734514.

Family#GenotypingMethod: Sanger sequencing of PCR product from Exon 5 of the TIMP3 gene.

Affected: 3

Unaffected: 2

Segregations: N/A

PublishedLOD: N/A

eLOD: Insufficient information available

AddSegregationInfo: N/A

ProbandLabel: Langton_2000_Family_1_patient_II2

Variant: The NM_000362.5(TIMP3):c.484G>T, p.Glu139X variant converts the GAG codon to a TAG, resulting in early termination of the transcript. This nonsense substitution affects the final exon 5, so that truncation of the protein product is predicted but not nonsense-mediated decay of the transcript.

ClinVar: 12680

gnomAD: Variant is absent from gnomAD.

FamilyAddInfo: Variant is referred to in the paper as "Glu139X" but encodes Glu162X in the updated polypeptide sequence (which includes the 23-amino acid N-terminal signal peptide).

FamilyPMIDs: PMID:11734514

Case#: Dueñas Rey_2024_Proband_F11, sex and age not reported, part of cohort from Center for Medical Genetics Ghent

CasePresentingHPOs: Rod-cone dystrophy HP:0000510, Intellectual disability HP:0001249

CaseHPOFreeText: The proband has been diagnosed with rod-cone dystrophy and clinical signs of Bardet-Biedl syndrome. Intellectual disability may be part of the phenotype.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing in the proband consisted of whole exome sequencing with analysis focused on the 5' UTR regions of 378 genes highly expressed in the retina.

CaseMethod1: whole exome sequencing

CaseMethod2: Sanger sequencing of the coding regions of PRPF4

CaseGenotypingMethod: Genotyping of the proband initially consisted of whole exome sequencing, followed by Sanger sequencing of the coding regions of PRPF4.

Variant: The proband harbors the NM_001244926.2:c.-6C>T variant in the heterozygous state.

CAID: CA2579423618

gnomAD: The NM_001244926.2:c.-6C>T variant is found in gnomAD v4.1.0 at a frequency of 8.400e-7 (4 alleles / 1178930 total alleles, with 0 homozygotes) in the European (non-Finnish) population https://gnomad.broadinstitute.org/variant/9-113275738-C-T?dataset=gnomad_r4

VariantEvidence: NM_001244926.2:c.-6C>T is a 5' UTR variant located within the Kozak consensus sequence but has no direct evidence of an abnormal impact on PRPF4 expression.

CaseAddInfo: The proband has apparently unaffected parents.

CasePMIDs: N/A

Case#: Wang_2013_Patient_704, female, age 9 years at onset, family origin not reported

CasePresentingHPOs: HP:0007663 (Reduced visual acuity), HP:0000662 (Nyctalopia), HP:0007737 (Bone spicule pigmentation of the retina), HP:0000543 (Optic disc pallor), HP:0007843 (Attenuation of retinal blood vessels), HP:0000822 (Hypertension), HP:0000858 (Irregular menstruation), HP:0025502 (Overweight)

CaseHPOFreeText: The proband has a diagnosis of juvenile retinitis pigmentosa. Visual acuity was limited to hand movements and later to light perception. Patient is described as slightly overweight.

CaseNotHPOs: HP:0000639 (Nystagmus)

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 BBS1

CaseGenotypingMethod: The proband was genotyped by capture-based next-generation sequencing panel that included 163 known retinal disease genes. SNP array and Sanger sequencing of BBS1 were subsequently used to confirm the presence of the variant.

Variant: The proband harbors the NM_024649.5(BBS1):c.1169T>G (p.Met390Arg) variant in the homozygous state.

ClinVar ID: 12143

gnomAD: The variant is found in gnomAD v2.1.1 at a frequency of 0.002773 in the European (non-Finnish) population, with 358 alleles / 129114 total alleles (0 homozygotes) https://gnomad.broadinstitute.org/variant/11-66293652-T-G?dataset=gnomad_r2_1

VariantEvidence: NM_024649.5(BBS1):c.1169T>G (p.Met390Arg) is a missense variant with mouse knock-in evidence of a similar disease-causing effect in the homozygous state (PMID: 18032602). This has not been taken into account in scoring, as the mouse model has been scored separately. However, it has provided a rationale not to down-score for the relatively high gnomAD frequency of this variant.

CaseAddInfo: The variant reportedly segregates with disease within the proband's family, but details are not available.

CasePMIDs: N/A

Case: 24-year-old Caucasian woman with a rare variety of type 2M VWD

DiseaseAssertion: 2M VWD

FamilyInfo: family history was negative for easy bruisability, bleeding, or clotting disorder but maternal grandmother had lung cancer.

CaseNOTHPOFreeText: Von Willebrand factor antigen 45% on 9/12/17 and 37% on 9/19/17 with the ratio of VWF activity to the antigen is less than 0.7

ParentalGenotype(s):Unknown

CasePresentingHPOs: HP:0003010 (Prolonged bleeding time), HP:0000978 (Bruising susceptibility).

**CaseHPOFreeText: ** loss of weight over the last six months, The complete blood count, comprehensive metabolic panel, factor VIII, prothrombin time and partial thromboplastin time, D-Dimer, and antithrombin activity were normal. Her von Willebrand factor activity was much lower compared to the antigen.

CasePreviousTesting: None

GenotypingMethod: Patient have not been genotyped

PreviouslyPublished: N/A

Variant: N/A

ClinVarID: N/A

gnomAD: N/A

**Gene: ** VWF Inheritance mode autosomal dominant variety with normal, high molecular weight multimers

NM_000552.5(VWF):c.2560C>T (p.Arg854Trp)

Case# P4, 4yr onset, Pakistani

CasePresentingHPOs HP:0002151, HP:0001946, HP:0001942, HP:0001987

CasePreviousTesting negative for NAGS and CPS1 genes.

CaseGenotypingMethod sequence analysis of coding exons, including flanking intronic regions of CA5A and CA5B, was performed.

Variant NM_001739.1:c.555+4_555+183del180bp

CAID CA658820661

VariantEvidence intronic splice site

CaseAddInfo consanguineous

Case# P2, M, 1mo onset, Indian

CasePresentingHPOs HP:0001263, HP:0001250, HP:0001298, HP:0008344

CasePreviousTesting Biochemical testing (Leu + Ile- 1235 Val- 591) on Tandem Mass Spectrometry (TMS) and/or abnormal metabolites (elevated BCKAs, 2-keto isocaproate, 3-hydroxy butyrate, 2-hydroxy isovalerate, 2-hydroxy caproate, 2-keto 3-methyl valerate) on a urinary organic acid profile using Gas Chromatography Mass Spectrometry (GC–MS) was performed to make the diagnosis.

CaseMethod1 PCR

CaseMethod2 Direct

CaseGenotypingMethod Coding regions as well as flanking exon–intron boundaries of genes (BCKDHA- 9 exons, BCKDHB- 10 exons, and DBT- 11 exons) were amplified by PCR. Bidirectional Sequencing on products

Variant NM_000709.3(BCKDHA):c.844G>C (p.Asp282His)

ClinVar 204377

VariantEvidence none

CaseAddInfo consanguineous

Case#: P4, F, 13 days (onset)

CasePresentingHPOs: HP:0001250, HP:0007105

CasePresentingHPOs (free text): TMS/GC-MS: Leu+Ile- 1810, Val- 275. Diagnosed with classic form of MSUD.

CasePreviousTesting: Biochemical testing (elevated BCAAs) used to make diagnosis.

CaseMethod1: PCR

CaseMethod2: Sequencing

CaseGenotypingMethod: Genomic DNA extracted, coding regions (and flanking exon-intron boundaries) of BCKDHA, BCKDHB, and DBT were PCR-amplified, followed by bidirectional sequencing.

Variant: NM_001918.3(DBT):c.939G>C (p.Lys313Asn) (homozygous)

ClinVar: 94017

gnomAD: MAF (South Asian) 9.747e-5

VariantEvidence: None

Case#: P15, F, 2 months (onset)

CasePresentingHPOs: HP:0001263, HP:0200134

CasePresentingHPOs (free text): TMS/GC-MS: Leu+Ile- 517, Val- 315. Diagnosed with intermediate form of MSUD.

CasePreviousTesting: Biochemical testing (elevated BCAAs) used to make diagnosis.

CaseMethod1: PCR

CaseMethod2: Sequencing

CaseGenotypingMethod: Genomic DNA extracted, coding regions (and flanking exon-intron boundaries) of BCKDHA, BCKDHB, and DBT were PCR-amplified, followed by bidirectional sequencing.

Variant: NM_001918.3(DBT):c.939G>C (p.Lys313Asn) (homozygous)

ClinVar: 94017

gnomAD: MAF (South Asian) 9.747e-5

VariantEvidence: None

Case#: P15, F, 2 months (onset)

CasePresentingHPOs: HP:0001263, HP:0200134

CasePresentingHPOs (free text): TMS/GC-MS: Leu+Ile- 517, Val- 315. Diagnosed with intermediate form of MSUD.

CasePreviousTesting: Biochemical testing (elevated BCAAs) used to make diagnosis.

CaseMethod1: PCR

CaseMethod2: Sequencing

CaseGenotypingMethod: Genomic DNA extracted, coding regions (and flanking exon-intron boundaries) of BCKDHA, BCKDHB, and DBT were PCR-amplified, followed by bidirectional sequencing.

Variant: NM_001918.3(DBT):c.939G>C (p.Lys313Asn) (homozygous)

ClinVar: 94017

gnomAD: MAF (South Asian) 9.747e-5

VariantEvidence: None