Individual

Case#: 16885

Caseprevioustesting: SSCP Scan

Casemethod1: PCR, Sanger Sequencing

Variant: NM_000268.3:c.1387G>T (nonsense)

CAID: CA021321

Caseaddinfo:

gnomad: 0.00020

Case# Arno P2, German, Female

CasePresentingHPOs HP:0007675, HP:0000486, HP:0007663

CaseNotHPOs HP:0031605

CaseMethod1 WES

CaseMethod2 Sanger

CaseGenotypingMethod Sanger of RBP3 exons

Variant NM_002900.2:c.3454G>T

CAID CA376677245

CaseAddInfo nonsense variant

Case#: Arno_2015_Family_GC19774_Patient_3, male, first seen at age 2 years, family origin not reported

CasePresentingHPOs: HP:0025313 (Exophoria), HP:0000545 (Myopia), HP:6001439 (Tigroid fundus), HP:0012795 (Abnormal optic disc morphology, specifically myopic discs), HP:0007663 (Reduced visual acuity), HP:0008323 (Abnormal light- and dark-adapted electroretinogram), HP:0030844 (Undetectable pattern electroretinogram)

CaseHPOFreeText: BCVA was 0.350 / 0.325 logMAR (Snellen 20/50 or 20/40). OCT showed loss of inner segment-ellipsoid over peripheral macular areas. Initial ERG showed rod more affected than cone. Later ERG showed more severe cone deterioration. Overall phenotype was summarized as "high myopia and retinal dystrophy in childhood with no significant fundus changes".

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping was by whole exome sequencing.

CaseMethod1: WES

CaseMethod2: Sanger sequencing of RBP3

CaseGenotypingMethod: Genotyping was performed by whole exome sequencing, followed by Sanger sequencing of RBP3.

Variant: The individual harbors the NM_002900.3(RBP3):c.1530T>A (p.Tyr510Ter) variant in the homozygous state.

CAID: CA376670175

gnomAD: The variant was not found in gnomAD version 4.1.1.

VariantEvidence: NM_002900.3(RBP3):c.1530T>A (p.Tyr510Ter) is a nonsense variant within exon 1 of 4 that is predicted to trigger nonsense-mediated decay.

CaseAddInfo: The proband comes from a consanguineous family with a similarly affected younger sibling sharing the same homozygous genotype.

CasePMIDs: N/A

Case#: Arno_2015_Family_GC17452_Patient_2, female, first seen at age 4 years, family origin not reported

CasePresentingHPOs: HP:0011003 (High myopia), HP:0000662 (Nyctalopia), HP:0030534 (Abnormal best corrected visual acuity test), HP:6001439 (Tigroid fundus), HP:0030602 (Abnormal fundus autofluorescence imaging, specifically patchy increased FAF in the vascular arcades), HP:0030603 (Abnormal optical coherence tomography, specifically showing loss of inner segment-ellipsoid over peripheral macular areas), HP:0008275 (Abnormal light-adapted electroretinogram, specifically showing delay and amplitude reduction of cone responses)

CaseHPOFreeText: BCVA was 0.550 / 0.575 logMAR (Snellen 20/80). FAF showed increased signal in vascular arcades, OCT showed loss of inner segment-ellipsoid over peripheral macular areas, ERG showed delay and amplitude reduction of cone responses. Overall phenotype was summarized as "high myopia and retinal dystrophy in childhood with no significant fundus changes".

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping was by whole exome sequencing.

CaseMethod1: WES

CaseMethod2: Sanger sequencing of RBP3

CaseGenotypingMethod: Genotyping was performed by whole exome sequencing, followed by Sanger sequencing of RBP3.

Variant: The individual harbors the NM_002900.3(RBP3):c.3454G>T (p.Glu1152Ter) variant in the homozygous state.

CAID: CA376677245

gnomAD: The variant was not found in gnomAD version 4.1.1.

VariantEvidence: NM_002900.3(RBP3):c.3454G>T (p.Glu1152Ter) is a nonsense variant within exon 4 of 4 that is predicted not to trigger nonsense-mediated decay but rather to truncate the C-terminal 8% of the protein product.

CaseAddInfo: The proband comes from a consanguineous family with a similarly affected older sibling sharing the same homozygous genotype.

CasePMIDs: N/A

Case# Arno P3, German, Male

CasePresentingHPOs HP:0000545, HP:0025313, HP:0007994

CaseMethod1 WES

CaseMethod2 Sanger

CaseGenotypingMethod Sanger of RBP3 exons

Variant NM_002900.2:c.1530T>A

CAID CA376670175

CaseAddInfo in trans

Case# Postma 2:2, female, 6yo, white

CasePresentingHPOs HP:0004758

CasePreviousTesting no

CaseMethod1 PCR

CaseGenotypingMethod amplified/screen of CASQ2, SCN5A, HRC, PLN, RYR2, KCNQ1, KCNH2, and KCNK1 genes

Variant NM_001232.3(CASQ2):c.62delA (p.Glu21Glyfs)

ClinVar 41042 link

VariantEvidence not in this article

Case# Baskin EK, Female, 47

CasePresentingHPOs HP:0010872, HP:0100660

CasePreviousTesting patients referred to our high-risk hereditary heart disorders clinic for assessment of possible ARVC, as well as DNA-bearing blood or tissue samples sent for clinical ARVC gene-testing from other physicians, clinics or institutions to our CLIA-approved molecular genetics laboratory at the Hospital for Sick Children (listed on www.genetests.org).

CaseMethod1 PCR

CaseGenotypingMethod direct sequence analysis of all exons and flanking intron sequences of DSP (MIM 125647), PKP2 (MIM 602861), DSC2 (MIM 125645), DSG2 (MIM 125671) and TMEM43.

Variant NM_024334.2(TMEM43):c.424G>A (p.Glu142Lys)

ClinVar 46147

gnomAD 0.001121 link

Case# Baskin YH, Male, 12

CasePreviousTesting patients referred to our high-risk hereditary heart disorders clinic for assessment of possible ARVC, as well as DNA-bearing blood or tissue samples sent for clinical ARVC gene-testing from other physicians, clinics or institutions to our CLIA-approved molecular genetics laboratory at the Hospital for Sick Children (listed on www.genetests.org).

CaseMethod1 PCR

CaseGenotypingMethod direct sequence analysis of all exons and flanking intron sequences of DSP (MIM 125647), PKP2 (MIM 602861), DSC2 (MIM 125645), DSG2 (MIM 125671) and TMEM43.

Variant NM_024334.2(TMEM43):c.1111T>C (p.Tyr371His)

ClinVar 46140

gnomAD 0.01076 link

Case# Patient 3, male, 2yo report, Italy(Compania)

CasePresentingHPOs HP:0001397, HP:0010837, HP:0001976, HP:0002240, HP:0003155, HP:0011967, HP:0001976 (Steatosis, Decreased serum ceruloplasmin, Reduced antithrombin III activity, Hepatomegaly, Elevated alkaline phosphatase, Copper deficiency, Reduced antithrombin III activity)

HPOsFreeText Mild hypertransaminasemia (10mo), slight hepatomegaly, mild speech delay(1.4yo)

CaseNotHPOs n/a

CasePreviousTesting serum metabolic testing: AST 656[nv < 41 U/L], ALT 437[nv < 45 U/L], ALP 1235[nv < 475 U/L], total cholesterol 140[nv < 200 mg/dL], HDL chol 49[nv > 45 mg/dL], LDL chol 96[nv < 160 mg/dL] CK 510 [nv 0-170 U/L], Ceruloplasmin 8 [nv 20-46 mg/dL], Haptoglobin 30[nv 30-250 mg/dL], Copper <40[nv 69-122 μg/dL], type 2 CDG pattern recorded at 1.4yo, retested with similar outcome at 2.4yo

CaseMethod1 Sanger

CaseMethod2 n/a

CaseGenotypingMethod Direct Sanger of TMEM199, no parent testing

Variant (1) NM_152464.2:c.13_14del (p.Leu5AlafsTer30) (2) NM_152464.2(TMEM199):c.92G>C (p.Arg31Pro)

ClinVar (2) 218964

CAID (1) CA8456913

gnomAD (1) 0.00004607(European (Non-Finnish)), 0.00002063(total)-5 heterozygotes (2) 0.00008933(Latino), 0.00004108(Total)-10 heterozygotes

VariantEvidence western blot was not done on this patient's cells, but he has the same TMEM199 variants as the cells that were tested.

CaseAddInfo same variant as "unrelated" family also from Compania, Italy

CasePMIDs 26833330

Case# Gamundi II:6, female, Spanish

CasePresentingHPOs HP:0007843, HP:0007791, HP:0007675

CasePreviousTesting no

CaseMethod1 PCR

CaseGenotypingMethod scanned cDNA

Variant NM_004698.3(PRPF3):c.1466C>A (p.Ala489Asp)

ClinVar 3354

gnomAD n/a

VariantEvidence n/a

Case# 135, Male, Chinese

CasePresentingHPOs HP:0007737, HP:0007843, HP:0007924, HP:0007675, HP:0000543, HP:0007994

CaseGenotypingMethod Sanger

Variant NM_000087.3(CNGA1):c.472delC(p.L158FfsX3)

ClinVar 225315

gnomAD 0.001378 link

CaseAddInfo homozygous

Case 2: male, dx at 16 yrs, no family history of HCM, both parents genotype neg

HP:0001639, HP:0002094, HP:0100749, HP:0002321

HCM, dyspnea, chest pain

Variant: NM_020433.4(JPH2):c.1213G>T (p.Ala405Ser)

ClinVar ID: 372724, https://www.ncbi.nlm.nih.gov/clinvar/variation/372724/

ExAC Frequency: 1.45e-5, http://gnomad.broadinstitute.org/variant/20-42747220-C-A

Case# Katagiri094, Male, Japanese

CasePresentingHPOs HP:0007987, HP:0007675, HP:0000551, HP:0007737

CaseMethod1 WES

CaseMethod2 Sanger

CaseGenotypingMethod PCR of exons 4-11 of CNGA1

Variant NM_000087.3(CNGA1):c.265delC (p.Leu89Phefs)

ClinVar 225315 link

gnomAD 0.001378 link

Case# Katagiri029, female, Japanese

CasePresentingHPOs HP:0007987, HP:0007675, HP:0000551, HP:0007737

CaseMethod1 WES

CaseMethod2 Sanger

CaseGenotypingMethod PCR of exons 4-11 of CNGA1

Variant NM_000087.3(CNGA1):c.265delC (p.Leu89Phefs)

ClinVar 225315 link

gnomAD 0.001378 link

Case# Katagiri019, Female, Japanese

CasePresentingHPOs HP:0007987, HP:0007675, HP:0000551, HP:0007737

CaseMethod1 WES

CaseMethod2 Sanger

CaseGenotypingMethod PCR of exons 4-11 of CNGA1

Variant NM_000087.3(CNGA1):c.265delC (p.Leu89Phefs) and novel "c.1429delG(p.V477YfsX17)"

ClinVar 1st 225315

CAID 2nd CA658820612

gnomAD 0.001378

Case 3: Female, diagnosed at 30 yrs, 18mm septal wall thickness, no mutations in HCM associated genes, no family history

HP:0002094, HP:0006689, (dyspnea, bacterial endocarditis)

Variant: NM_020433.4(JPH2):c.494C>T (p.Ser165Phe),

ClinVar ID: 30457

https://www.ncbi.nlm.nih.gov/clinvar/variation/30457/

not in ExAC

Case# Monnier 3:12, died age 30, male, French

CasePresentingHPOs HP:0001649, HP:0006682, HP:0012416, HP:0001695, HP:0001945

CasePreviousTesting N/A

CaseMethod1 PCR

CaseGenotypingMethod PCR and sequencing gel for CACNL1A3.PCR1 amplimer

Variant NM_000069.2(CACNA1S):c.3257G>A (p.Arg1086His)

ClinVar 17626

gnomAD 0.00002978 link

VariantEvidence N/A

Case# Subject 1, F, 4yo onset, Hispanic

CasePresentingHPOs HP:0002373, HP:0001260, HP:0006957, HP:0002913, HP:0007359, HP:0002104, HP:0003236, HP:0001987, HP:0001943, HP:0002058, HP:0000252, HP:0006801, HP:0003487, HP:0000577, HP:0002376, HP:0003236, HP:0001249, HP:0003201, HP:0000252

HPOcont: Febrile seizures, Dysarthria, loss of ability to walk, Myoglobinuria, Focal autonomic seizures, Apnea, Hyperammonemia, Hypoglycemia, Myopathic facies, Microcephaly, Brisk DTR, Babinski sign, Exotropia, Developmental regression, Elevated CPK, Hypoglycemia, Intellectual Disability, Rhabdomyolysis, Microcephaly

HPOFreeText: Febrile seizure at 1 year of age, developmental regression in the following 3 years with recurrent seizures, losing the ability to ambulate and speak, as well as right focal seizure, apnea, and unresponsiveness triggered by fever. On hospital admission she was noted to have elevated urine myoglobin, elevated creatine phosphokinase, aspartate aminotransferase, alanine aminotransferase, ammonia and hypoglycemia. MRI showed mild diffuse atrophy of the left cerebral hemisphere. "Ophthalmology evaluation showed intermittent exotropia. Echocardiogram and electrocardiogram (ECG) were unremarkable. Hysical examination was relevant for microcephaly (FOC 47.5 cm; <5th percentile for age), myopathic facies with drooling, increased tone in all extremities, and brisk deep tendon reflexes (DTRs) throughout with positive Babinski sign.

CaseNotHPOs HP:0011675

NotHPOcont: Arrhythmia

CasePreviousTesting "urine myoglobin of 94 ng/ml (normal range 10–65 ng/ml), serum creatine phosphokinase (CPK) of 205,000 U/l (normal range 75–230 U/l), elevated aspartate aminotransferase (AST) of 1,618 U/l (normal range 15–50 U/l), alanine aminotransferase (ALT) of 571 U/l (normal range 10–25 U/l), ammonia of 122 μmol/l (normal range 22–48 μmol/l), and hypoglycemia (blood glucose 30 mg/dl; normal range 70–110 mg/dl)."

CaseMethod1 WES

CaseMethod2 Sanger

CaseGenotypingMethod WES and cSNP results confirmed with Sanger

Variant (1) NM_152906.6:c.460G>A (p.Gly154Arg)

ClinVar (1) 208823

CAID (1) CA358646

gnomAD (1) 0.001549(Other), 0.0001208(Overall)

VariantEvidence (Figure 3) using "EBV-transformed B-lymphoblastoid cell lines (BLCLs) from another individual, subject 4 with homozygous c.460G>A (p.Gly154Arg) mutation, and evaluated the Golgi by intracellular staining with WGA, as well as cis Golgi marker, anti-GM130 antibody." WGA stain resolved lower area of golgi bodies in p.Gly154Arg cells than WT. Measured immunoglobulin heavy chain binding protein levels in WT and and patient fibroblasts, BiP levels in patient cells lower than WT after ER induced stress by Brefeldin A.

CaseAddInfo nonconsanguineous, mother tested heterozygous, father unavailable. cSNP data showed no evidence of deletion or uniparental isodisomy of the region.

CasePMIDs n/a

Case# Subject 4, M, 8yo onset, Hispanic

CasePresentingHPOs HP:0001249, HP:0001289, HP:0002066, HP:0009053, HP:0007340, HP:0001987, HP:0002925, HP:0005184, HP:0002058, HP:0002169, HP:0003201, HP:0001250, HP:0003236, HP:0000821, HP:0006801

HPOcont: Intellectual Disability, Confusion, Gait ataxia, Lower limb muscle weakness, Dysarthria, Hyperammonemia, Elevated TSH, Prolonged QTc interval, Myopathic facies, Clonus, Rhabdomyolysis, Seizures, Elevated CPK, Hypothyroidism, Brisk DTR

HPOFreeText: (2 years) uncoordinated gait and intellectual disability. (8 years) disorientation, ataxic gait, weakness in lower extremities, and dysarthria. (12 years) myopathic facies, brisk tendom reflexes, clonus, and impaired gait.

CaseNotHPOs HP:0001943, HP:0002151, HP:0002913

NotHPOcont: Hypoglycemia, Elevated Lactate, Myoglobinuria

CasePreviousTesting "lactate and glucose normal; elevated ammonia(111 μmol/l), elevated CPK (16,674 U/l). Urine was negative for myoglobin. TSH level was increased to 30.8 μIU/ml (range 0.32–5.00 μIU/ml), T3 was 166 ng/dl (range 90–260 ng/dl), and T4 was 5.2 μg/dl (range 6.4–13.3 μg/dl). Urine organic acids were normal."Muscle biopsy showed normal respiratory chain studies. Mitochondrial genome sequencing for common point mutations and deletions were normal."

CaseMethod1 WES

CaseMethod2 Sanger

CaseGenotypingMethod WES and cSNP results confirmed with Sanger

Variant (1) NM_152906.6:c.460G>A (p.Gly154Arg)

ClinVar (1) 208823

CAID (1) CA358646

gnomAD (1) 0.001549(Other), 0.0001208(Overall)

VariantEvidence (Figure 3) using "EBV-transformed B-lymphoblastoid cell lines (BLCLs) from subject 4 with homozygous c.460G>A (p.Gly154Arg) mutation, and evaluated the Golgi by intracellular staining with WGA, as well as cis Golgi marker, anti-GM130 antibody." WGA stain resolved lower area of golgi bodies in p.Gly154Arg cells than WT. Measured immunoglobulin heavy chain binding protein levels in WT and and patient fibroblasts, BiP levels in patient cells lower than WT after ER induced stress by Brefeldin A.

CaseAddInfo nonsanguineous, confirmed heterozygosity of both parents

CasePMIDs n/a

Case# Subject 2, F, 6mo onset, Hispanic/European

CasePresentingHPOs HP:0001942, HP:0003128, HP:0002919, HP:0001987, HP:0002094, HP:0006682, HP:0004756, HP:0045045, HP:0001288, HP:0002013, HP:0007340, HP:0002913, HP:0002058, HP:0002307, HP:0001260, HP:0001251, HP:0003201, HP:0002151, HP:0001249, HP:0001943, HP:0003236, HP:0005184, HP:0002910, HP:0012544, HP:0006956, HP:0100960, HP:0001254

HPOcont: Metabolic acidosis, Lactic acidosis, Ketonuria, Hyperammonemia, Dyspnea, Ventricular extrasystoles, Ventricular tachycardia, Elevated acylcarnitine, Gait abnormality, Emesis, Lower limb muscle weakness, Myoglobinuria, Myopathic facies, Drooling, Dysarthria, Ataxia, Rhabdomyolysis, Elevated Lactate, Intellectual Disability, Hypoglycemia, Elevated CPK, Prolonged QTc interval, Elevated Transaminases, Elevated aldolase, Lateral ventrical dilation, Asymmetric ventricles, Lethargy

HPOFreeText: (6 months) metabolic acidosis, lactic acidemia, ketonuria, elevated blood ammonia and Kussmaul breathing, in addition to prolonged QTc interval, premature ventricular contractions just short of ventricular tachycardia, and elevated acycarnitine profile. (16 months) gait abnormality, weakness, sore troat, and vomiting. (5 years) after infection, lethargy, lower limb weakness, myoglobinuria, elevated CPK, transaminases, lactate, and aldolase in additon to myopathic face, drooling, dysarthric speech and ataxia.

CaseNotHPOs HP:0001250

NotHPOcont: Seizures

CasePreviousTesting "metabolic acidosis (pH of 7.0; base deficit of 20 mEq/l) and lactic acidemia of 15 mmol/l (normal range 0.2–2.0 mmol/l), serum ammonia was mildly elevated to 138 μmol/l. Acylcarnitine profile showed a primary peak of C14:1 in addition to C14:2, C16, C18, and some hydroxy derivatives." At 15 months of age "CPK of 1,126 U/l, AST of 158 U/L, mildly elevated ammonia of 71 μmol/l, and lactate of 7.0 mmol/l, then at 5 years, CPK of 287,230 U/l, hypoglycemia (glucose of 17 mg/dl), elevated transaminases (AST of 7,618 U/l and ALT of 2,564 U/l), lactate was 2.0 mmol/l, aldolase level was 595 U/l (normal range 2.7–8.8 U/l). Renal function tests remained stable throughout admission. Etiologic evaluations, including DNA sequencing of ACADVL for VLCAD deficiency, muscle histopathology, quantitative mtDNA studies in muscle, and mitochondrial genome sequencing for common point mutations and deletions, were normal."

CaseMethod1 WES

CaseMethod2 PCR

CaseGenotypingMethod WES and cSNP array, validated deletion variant with PCR

Variant (1) NM_152906.6:c.460G>A (p.Gly154Arg), (2) ~34kb, exon3-9del

ClinVar (1) 208823

CAID (1) CA358646

gnomAD (1) 0.001549(Other), 0.0001208(Overall)

VariantEvidence (1)(Figure 3) using "EBV-transformed B-lymphoblastoid cell lines (BLCLs) from another individual, subject 4 with homozygous c.460G>A (p.Gly154Arg) mutation, and evaluated the Golgi by intracellular staining with WGA, as well as cis Golgi marker, anti-GM130 antibody." WGA stain resolved lower area of golgi bodies in p.Gly154Arg cells than WT. Measured immunoglobulin heavy chain binding protein levels in WT and and patient fibroblasts, BiP levels in patient cells lower than WT after ER induced stress by Brefeldin A.

CaseAddInfo nonconsanguineous, found deletion variant in with PCR father and mother carried missense

CasePMIDs n/a

Case# Subject 6, M, 1yo onset, Hispanic

CasePresentingHPOs HP:0001263, HP:0002098, HP:0002013, HP:0001943, HP:0001942, HP:0002151, HP:0001290, HP:0001987, HP:0001249, HP:0001946, HP:0045045, HP:0040145, HP:0001508, HP:0003648

HPOcont: Global developmental delay, Respiratory Distress, Emesis, Hypoglycemia, Metabolic acidosis, Elevated Lactate, Generalized hypotonia, Hyperammonemia, Intellectual Disability, Ketosis, Elevated acylcarnitine, Dicarboxylic acidemia, Failure to thrive, Lacticaciduria

HPOFreeText: (1 year) developmental delay, emesis, difficulty breathing, elevate metabolites, elevated urine organic acids, elevations of 3-hydroxy-N-butyric and acetoacetic acids (ketone bodies), as well as adipic, suberic, sebacic, and 3-hydroxysebacic (dicarboxylic) acids. Found to also have a head circumference in 6th percentile and hypotonia.

CaseNotHPOs HP:0001250, HP:0011675, HP:0003201

NotHPOcont: Seizures, Arrhythmia, Rhabdomyolysis

CasePreviousTesting Tested blood gas pH (7.1), serum bicarbonate(16 mEq/L (normal range 22-28 mEq/L)), serum lactate(11.7 mmol/L), serum ammonia( 102 μmol/L), elevated very long chain acylcarnitine species, especially C14, normal serum CPK. Chromosomal microarray and Fragile X results were normal.

CaseMethod1 WES

CaseMethod2 n/a

CaseGenotypingMethod WES and cSNP array

Variant NM_152906.6(TANGO2):c.605+1G>C

ClinVar 521699

CAID CA358646

VariantEvidence splice site

CaseAddInfo consanguineous parents

CasePMIDs n/a

Family A autosomal recessive variant found in CHST9 (MIM: 610191; c.1133A>G [p.Asn378Ser] [GenBank: NM_031422])

Case# Subject 2, male, 8mo report, Hispanic

CasePresentingHPOs HP:0001276, HP:0000341, HP:0000294, HP:0000316, HP:0000286, HP:0000494, HP:0000664, HP:0008589, HP:0005989, HP:0001257 (Hypertonia, Narrow forehead, Low anterior hairline, Hypertelorism, Downslanted palpebral fissures, Epicanthus, Synophrys, Hypoplastic helices, Redundant neck skin, Spasticity)

HPOFreeText: Hypertonic(postnatal), bifrontal narrowing, low anterior hairline, mild hypertelorism, bilateral epicanthal folds, downslanted palpebral fissures, synophrys, mild hypoplastic helices, redundant nuchal skin, and spasticity of all four extremities with upper limbs being more affected than lower limbs (8 months old)

CaseNotHPOs HP:0002194, HP:0001252, HP:0012443, HP:0012372, HP:0000453, HP:0001627, HP:0000077, HP:0002650 (Gross motor delay, Hypotonia, Abnormality of the brain, Abnormal eye morphology, Choanal atresia, Congenital heart defects, Renal anomaly, Scoliosis)

CasePreviousTesting Screen for BRAF, CBL, HRAS, KRAS, MAP2K1, NRAS, PTPN11, RAF1, SCHOC2, and SOS1 was normal.

CaseMethod1 WES

CaseMethod2 Sanger

CaseGenotypingMethod WES confirmed with sanger in patient and parents

Variant NM_012102.3:c.248dup (p.Ser84ValfsTer4), de novo

ClinVar n/a

CAID CA658820860

gnomAD n/a

VariantEvidence n/a

CaseAddInfo n/a

CasePMIDs n/a

Case# Subject 4, female, 17yo report, European

CasePresentingHPOs HP:0001252, HP:0001263, HP:0010864, HP:0007033, HP:0000750 (Hypotonia, Global developmental delay, Severe intellectual disability, Cerebellar dysplasia, Speech delay

HPOFreeText: hemispheric cerebellar dysplasia with abnormal lobule and fissure orientation in the inferior hemispheres(5 years); severe intellectual disability/speech delay(13 years)

CaseNotHPOs HP:0011968, HP:0012372, HP:0000453, HP:0001627, HP:0000077, HP:0002650 (Poor feeding, Abnormal eye morphology, Choanal atresia, Congenital heart defects, Renal anomaly, Scoliosis)

CasePreviousTesting n/a

CaseMethod1 WES

CaseMethod2 Sanger

CaseGenotypingMethod WES confirmed with sanger in patient and parents

Variant NM_012102.3:c.4303C>T(p.His1435Tyr), de novo

ClinVar n/a

CAID CA338168785

gnomAD n/a

VariantEvidence n/a

CaseAddInfo n/a

CasePMIDs n/a

Case# Subject 3, male, 21yo report, European

CasePresentingHPOs HP:0030842, HP:0001631, HP:0001263, HP:0001249, HP:0001252, HP:0001251, HP:0000722, HP:0002474, HP:0001488, HP:0000565, HP:0010535, HP:0002650, HP:0002079, HP:0002363, HP:0000961, HP:0000733, HP:0002058, HP:0000490, HP:0000218, HP:0001222, HP:0001795 (Choking episodes, Atrial septal defect, Developmental delay, Intellectual disability, Hypotonia, Ataxia, OCD, Expressive language deficit, Bilateral ptosis, Esotropia, Sleep apnea, Scoliosis, Thin corpus callosum, Cyanosis, Stereotypy, Myopathic facies, Deep set eyes, High-arched palate, Spatulate thumbs, Hyperconvex nails

HPOFreeText: Choking episodes and atrial septal defect in infancy; recurrent cyanosis, mild hypotonia, ataxia, scoliosis, bilateral ptosis, esotropia, developmental delay and OCD (7 years); sleep apnea, throbbing headaches, thin corpus callosum, flattening of braistem, thin rim of sella, chronic right temporal membrane perforation and mild left sensorineural hearing loss(8 years); repetitive hand movements, limited speech, elongated/myopathic face/midfacial retraction, bilateral ptosis, deep-set eyes, high arched palate, spatulate thumbs and finger/toenail hyperconvexity(19 years).

CaseNotHPOs HP:0012372, HP:0000453, , HP:0000077 (Abnormal eye morphology, Choanal atresia, Renal anomaly)

CasePreviousTesting Reduced succinate cytochrome c reductaseactivity (19%), NADH and NADH cytochrome c activity were 40% of control.

CaseMethod1 WES

CaseMethod2 Sanger

CaseGenotypingMethod WES confirmed with sanger in patient and parents

Variant NM_012102.3:c.4300T>C(p.Ser1434Pro), de novo

ClinVar n/a

CAID CA338168793

gnomAD n/a

VariantEvidence n/a

CaseAddInfo n/a

CasePMIDs n/a

Case# Tun66275, Female, 20, Tunisia

CasePresentingHPOs HP:0002066, HP:0001260, HP:0001257

CaseNotHPOs HP:0001272

CaseMethod1 Exome

CaseMethod2 Sanger

Variant NM_005186.3:c.1534C>T(p.R512C)

CAID CA6093457

gnomAD 0.000008977

VariantEvidence none

CaseAddInfo in supplement

Case#: Jespersgaard_2019_Patient_167, gender and age not specified, origin likely to be Danish based on cohort

CasePresentingHPOs: N/A

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseMethod1: NGS panel

CaseMethod2: N/A

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

Variant: The proband harbors the NM_000440.3(PDE6A):c.627+2T>G variant in the homozygous state.

ClinVar: 636057

gnomAD: The NM_000440.3(PDE6A):c.627+2T>G variant is not found in gnomAD v2.1.1.

VariantEvidence: The NM_000440.3(PDE6A):c.627+2T>G variant disrupts a canonical splice site in intron 2, but does not have experimental confirmation of exon skipping or frameshift.

CaseAddInfo: N/A

CasePMIDs: N/A

Case#: Jespersgaard_2019_Patient_162, gender and age not specified, origin likely to be Danish based on cohort

CasePresentingHPOs: N/A

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseMethod1: NGS panel

CaseMethod2: N/A

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

Variant: The proband harbors the NM_000440.3(PDE6A):c.1287G>A (p.Trp429Ter) and NM_000440.3(PDE6A):c.1054C>T (p.Gln352Ter) variants in the compound heterozygous state.

ClinVar: 636052, 636051

gnomAD: The NM_000440.3(PDE6A):c.1287G>A (p.Trp429Ter) and NM_000440.3(PDE6A):c.1054C>T (p.Gln352Ter) variants are not found in gnomAD v2.1.1.

VariantEvidence: NM_000440.3(PDE6A):c.1287G>A (p.Trp429Ter) and NM_000440.3(PDE6A):c.1054C>T (p.Gln352Ter) are nonsense variants in exons 10 and 7, respectively. They are predicted to result in nonsense-mediated decay or at least to respectively truncate the C-terminal ~59% or ~50% of the protein product.

CaseAddInfo: N/A

CasePMIDs: N/A

Case#: Jespersgaard_2019_Patient_168, gender and age not specified, origin likely to be Danish based on cohort

CasePresentingHPOs: N/A

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseMethod1: NGS panel

CaseMethod2: N/A

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

Variant: The proband harbors the NM_000440.3(PDE6A):c.1407+1G>A variant in the homozygous state.

ClinVar: 636053

gnomAD: The NM_000440.3(PDE6A):c.1407+1G>A variant is found in gnomAD v2.1.1 at a frequency of 0.0003267 (1/30606 with no homozygotes) in the South Asian population https://gnomad.broadinstitute.org/variant/5-149277925-C-T

VariantEvidence: The NM_000440.3(PDE6A):c.1407+1G>A variant disrupts a canonical splice site in intron 10, but does not have experimental confirmation of exon skipping or frameshift.

CaseAddInfo: N/A

CasePMIDs: N/A

Case#: Holmberg_Patient_6, male, age 2 at onset and age 13 at death, Dutch origin

CasePresentingHPOs: HP:0003208 (Fingerprint intracellular accumulation of autofluorescent lipopigment storage material), HP:0011463 (Childhood onset), HP:0001268 (Mental deterioration), HP:0000572 (Visual loss), HP:0001251 (Ataxia), HP:0011421 (Death in adolescence), HP:0002540 (Inability to walk), HP:0001250 (Seizure), HP:0000550 (Undetectable electroretinogram), HP:0012018 (EEG with temporal focal spikes), HP:0100952 (Enlarged sylvian cistern), HP:0006855 (Cerebellar vermis atrophy), HP:0002198 (Dilated fourth ventricle), HP:0033725 (Thin corpus callosum), HP:0030891 (Periventricular white matter hyperdensities), HP:0012690 (T2 hypointense thalamus)

CaseHPOFreeText: This patient exhibited the most rapid clinical course from the group of 8 patients. Age of onset was 2, while mental decline was present at age 3 and visual deterioration at age 5. Ataxia, seizures, and abolished electroretinogram were found at age 7. Loss of independent walking occurred at age 8. Posterior EEG spikes in response to low-frequency photic stimuli were observed. T2-weighted images showed increased signal intensity of the periventricular white matter and posterior limb of the capsula interna. The thalamus had abnormally low signal intensity compared to the putamen, caudate nuclei, and white matter.

CaseNotHPOs: HP:0001312 (Giant somatosensory evoked potentials)

CaseNotHPOFreeText: Flash visual evoked potential (fVEP) was found to be normal at age 7.

CasePreviousTesting: Other than clinical phenotype characterization, it is not clear what genotype tests preceded CLN5 sequencing.

CaseMethod1: N/A

CaseMethod2: N/A

CaseGenotypingMethod: Each exon of CLN5 was PCR-amplified and Sanger sequenced in both directions.

Variant: The patient is homozygous for the NM_006493.4(CLN5):c.688G>A (p.Asp230Asn) variant.

ClinVar: 2566 (homozygous)

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

VariantEvidence: NM_006493.4(CLN5):c.688G>A (p.Asp230Asn) is a recurring missense variant that 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: N/A

CasePMIDs: N/A

Case#: Holmberg_Patient_8, female, age 3 at onset and age 19 at time of study, Swedish origin

CasePresentingHPOs: HP:0003208 (Fingerprint intracellular accumulation of autofluorescent lipopigment storage material), HP:0011463 (Childhood onset), HP:0001268 (Mental deterioration), HP:0000572 (Visual loss), HP:0001251 (Ataxia), HP:0002540 (Inability to walk), HP:0001250 (Seizure), HP:0012018 (EEG with temporal focal spikes), HP:0100952 (Enlarged sylvian cistern), HP:0006855 (Cerebellar vermis atrophy), HP:0002198 (Dilated fourth ventricle), HP:0033725 (Thin corpus callosum), HP:0030891 (Periventricular white matter hyperdensities), HP:0012690 (T2 hypointense thalamus), HP:0001312 (Giant somatosensory evoked potentials), HP:0002059 (Cerebral atrophy), HP:0001272 (Cerebellar atrophy)

CaseHPOFreeText: Age of onset was 3, while mental decline was found at age 7. Visual deterioration and Seizures developed at age 8. Ataxia and Giant flash visual evoked potentials had onset at age 9. Loss of independent walking occurred at age 10. Posterior EEG spikes in response to low-frequency photic stimuli were observed. T2-weighted images showed increased signal intensity of the periventricular white matter and posterior limb of the capsula interna. The thalamus had abnormally low signal intensity compared to the putamen, caudate nuclei, and white matter. Cerebral atrophy was slight at age 8.9 years, but had progressed to severe cerebral and cerebellar atrophy by age 17.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Other than clinical phenotype characterization, it is not clear what genotype tests preceded CLN5 sequencing.

CaseMethod1: N/A

CaseMethod2: N/A

CaseGenotypingMethod: Each exon of CLN5 was PCR-amplified and Sanger sequenced in both directions.

Variant: The patient is a compound heterozygote harboring the NM_006493.4(CLN5):c.78G>A (p.Trp26Ter) and NM_006493.4(CLN5):c.522dup (p.Trp175LeufsTer30) variants.

ClinVar: 2565, 56543

gnomAD: The maximum allele frequency of the NM_006493.4(CLN5):c.78G>A (p.Trp26Ter) variant is 0.00005132 (within the European non-Finnish population, with no homozygous occurrences). https://gnomad.broadinstitute.org/variant/13-77566311-G-A The maximum allele frequency of the NM_006493.4(CLN5):c.522dup (p.Trp175LeufsTer30) variant is 0.00007033 (within the European non-Finnish population, with no homozygotes) https://gnomad.broadinstitute.org/variant/13-77570218-A-AC

VariantEvidence: NM_006493.4(CLN5):c.78G>A (p.Trp26Ter) is a recurring nonsense variant that is predicted to trigger nonsense-mediated decay of CLN5. NM_006493.4(CLN5):c.522dup (p.Trp175LeufsTer30) is a frameshift variant, is predicted to disrupt ~51% of the protein product, and exhibits defective localization to the ER rather than the lysosome (PMID:20052765).

CaseAddInfo: N/A

CasePMIDs: N/A

Case#: Holmberg_Patient_4, female, age 3 at onset and age 13 at time of study, Finnish origin

CasePresentingHPOs: HP:0003208 (Fingerprint intracellular accumulation of autofluorescent lipopigment storage material), HP:0011463 (Childhood onset), HP:0001268 (Mental deterioration), HP:0000572 (Visual loss), HP:0001251 (Ataxia), HP:0002540 (Inability to walk), HP:0001250 (Seizure), HP:0000550 (Undetectable electroretinogram), HP:0012018 (EEG with temporal focal spikes), HP:0100952 (Enlarged sylvian cistern), HP:0006855 (Cerebellar vermis atrophy), HP:0002198 (Dilated fourth ventricle), HP:0033725 (Thin corpus callosum), HP:0030891 (Periventricular white matter hyperdensities), HP:0012690 (T2 hypointense thalamus), HP:0001312 (Giant somatosensory evoked potentials)

CaseHPOFreeText: Age of onset was 3, while visual deterioration was found at age 6. Mental decline was found at age 7, while abolished ERG and Giant flash visual evoked potentials were present at age 8. Ataxia, Seizures, and Loss of independent walking occurred at age 11. Posterior EEG spikes in response to low-frequency photic stimuli were observed. T2-weighted images showed increased signal intensity of the periventricular white matter and posterior limb of the capsula interna. The thalamus had abnormally low signal intensity compared to the putamen, caudate nuclei, and white matter.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Other than clinical phenotype characterization, it is not clear what genotype tests preceded CLN5 sequencing.

CaseMethod1: N/A

CaseMethod2: N/A

CaseGenotypingMethod: Each exon of CLN5 was PCR-amplified and Sanger sequenced in both directions.

Variant: The patient is homozygous for the NM_006493.4(CLN5):c.78G>A (p.Trp26Ter) variant.

ClinVar: 2565 (homozygous)

gnomAD: The maximum allele frequency of the NM_006493.4(CLN5):c.78G>A (p.Trp26Ter) variant is 0.00005132 (within the European non-Finnish population, with no homozygous occurrences). https://gnomad.broadinstitute.org/variant/13-77566311-G-A

VariantEvidence: NM_006493.4(CLN5):c.78G>A (p.Trp26Ter) is a recurring nonsense variant that is predicted to trigger nonsense-mediated decay of CLN5.

CaseAddInfo: N/A

CasePMIDs: N/A

Case#: Georgiou_2024_Family_GC29680_Proband_P09, female, reported at age 30 years, family origin reported as from Bangladesh

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

CaseHPOFreeText: BCVA began at 0.39 logMAR and progressed to 0.54 logMAR.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseMethod1: NGS panel / WES / WGS

CaseMethod2: Sanger sequencing of RBP3

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

Variant: The individual harbors the NM_002900.3(RBP3):c.3399T>G (p.Tyr1133Ter) variant in the homozygous state.

ClinVar ID: 3675731

gnomAD: The variant is found in gnomAD version 4.1.1 at a frequency of 0.00001098 (1 / 91070) in the South Asian population https://gnomad.broadinstitute.org/variant/chr10-47357112-T-G?dataset=gnomad_r4

VariantEvidence: NM_002900.3(RBP3):c.3399T>G (p.Tyr1133Ter) is a nonsense variant within exon 4 of 4 that is predicted to trigger nonsense-mediated decay.

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

CasePMIDs: N/A

Case#: Georgiou_2024_Family_GC19393_Proband_P06, female, reported at age 14 years, family origin reported as from Pakistan

CasePresentingHPOs: HP:0011003 (High myopia), HP:0030555 (Best corrected visual acuity 0.2 LogMAR)

CaseHPOFreeText: BCVA began at 0.20 logMAR and progressed to 0.30 logMAR.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseMethod1: NGS panel / WES / WGS

CaseMethod2: Sanger sequencing of RBP3

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

Variant: The individual harbors the NM_002900.3(RBP3):c.160C>T (p.Gln54Ter) variant in the homozygous state.

ClinVar ID: 964958

gnomAD: The variant is found in gnomAD version 4.1.1 at a frequency of 0.0003184 (29 / 91094) in the South Asian population https://gnomad.broadinstitute.org/variant/10-47348644-C-T?dataset=gnomad_r4

VariantEvidence: NM_002900.3(RBP3):c.160C>T (p.Gln54Ter)) is a nonsense variant within exon 1 of 4 that is predicted to trigger nonsense-mediated decay.

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

CasePMIDs: N/A

Case#: Wells_1993_Proband_III/5, female, age 44 years at time of first examination, family origin not reported

CasePresentingHPOs: Adult onset HP:0003581, Visual impairment HP:0000505, Subretinal deposits HP:0031528, Abnormal light-adapted single flash electroretinogram HP:0030472.

CaseHPOFreeText: The proband has been diagnosed with adult vitelliform macular dystrophy, with onset in the mid-thirties. Foveal deposits are small, yellow, and at the RPE level.

CaseNotHPOs: Abnormal light-adapted flicker electroretinogram HP:0030473

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing consisted of screening of the RHO locus for disease-causing variants.

CaseMethod1: Sanger sequencing of PRPH2

CaseMethod2: N/A

CaseGenotypingMethod: Previous testing of this family consisted of screening of the RHO locus for variants causing RP, with negative results. Genotyping was performed by Sanger sequencing of the PCRs product to identify the variant.

Variant: The proband harbors the NM_000322.5(PRPH2):c.774C>A (p.Tyr258Ter) variant in the heterozygous state.

ClinVar ID: 98707

gnomAD: The NM_000322.5(PRPH2):c.774C>A (p.Tyr258Ter) variant was not found in gnomAD v4.0.0.

VariantEvidence: NM_000322.5(PRPH2):c.774C>A (p.Tyr258Ter) is a nonsense variant in exon 2 of 3 that is predicted to trigger nonsense-mediated decay or to at least truncate the C-terminal 26% of the protein product.

CaseAddInfo: Although the proband is the only family member genotyped and examined by the authors, her father was confirmed to be similarly affected. Family consanguinity was not reported.

CasePMIDs: N/A

Case#: Xin_Patient_9, sex not mentioned, age 6 at onset, U.S. nationality, Egyptian ethnicity

CasePresentingHPOs: HP:0004302 (Functional motor deficit), HP:0000572 (Visual loss), HP:0001250 (Seizure), HP:0001268 (Mental deterioration), HP:0011463 (Childhood onset), HP:0003736 (Autophagic vacuoles)

CaseHPOFreeText: Motor difficulty was the phenotype at presentation (age 6). Cognitive regression, Seizures, and Visual loss had onset at age 7. EM finding of vacuoles was made specifically in muscle.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

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

CaseMethod2: as mentioned

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

Variant: The patient is believed to be homozygous for the NM_006493.4(CLN5):c.772del p.Arg258GlufsTer29 variant.

ClinVar: 56546 (homozygous)

gnomAD: The NM_006493.4(CLN5):c.772del p.Arg258GlufsTer29 variant is absent from gnomAD.

VariantEvidence: NM_006493.4(CLN5):c.772del p.Arg258GlufsTer29 is a frameshift variant that disrupts ~28% of the protein product.

CaseAddInfo: Parents have not been subjected to genotyping, so homozygosity of variants is assumed. This conclusion was supported by failure to detect a deletion, and by family history of consanguinity.

CasePMIDs: N/A

Case#: Xin_Patient_2, sex not mentioned, age 5-6 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:0011463 (Childhood onset), HP:0003205 (Curvilinear intracellular accumulation of autofluorescent lipopigment storage material), HP:0003208 (Fingerprint intracellular accumulation of autofluorescent lipopigment storage material)

CaseHPOFreeText: Seizure was the phenotype at presentation (age 5). Motor difficulty, visual loss, and cognitive regression had onset at age 6.

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.524G>A (p.Trp175Ter) and NM_006493.4(CLN5):c.760_947del (p.Thr254CysfsTer10) variants.

ClinVar: 56544

CAID: CA2017997733

gnomAD: Maximum allele frequency for NM_006493.4(CLN5):c.524G>A (p.Trp175Ter) is 0.00003517 (in the European non-Finnish population, no homozygotes). https://gnomad.broadinstitute.org/variant/13-77570221-G-A The NM_006493.4(CLN5):c.760_947del (p.Thr254CysfsTer10) variant is not found in gnomAD.

VariantEvidence: NM_006493.4(CLN5):c.524G>A (p.Trp175Ter) is a nonsense variant that results in truncation of approximately 51% of the protein product. The NM_006493.4(CLN5):c.760_947del (p.Thr254CysfsTer10) variant triggers a frameshift that affects the final 106 amino acids (approximately 29%) of the protein product. While neither variant is predicted to trigger NMD, the C-terminal region disrupted in both cases has been shown to be glycosylated and is important for proper localization of the protein (PMID:19309691).

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: N/A

Case#: Xin_Patient_7, sex not mentioned, age 4 at onset, U.S. nationality, Chinese ethnicity

CasePresentingHPOs: HP:0004302 (Functional motor deficit), HP:0000572 (Visual loss), HP:0001250 (Seizure), HP:0001268 (Mental deterioration), HP:0011463 (Childhood onset)

CaseHPOFreeText: Visual loss was the phenotype at presentation (age 4). Motor difficulty (age 5), Cognitive regression (age 5), and Seizure (age 6) had later onset.

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.473G>C (p.Trp158Ser) and NM_006493.4(CLN5):c.924_925del (p.Leu309AlafsTer4) variants.

ClinVar: 56542, 56526

gnomAD: Both the NM_006493.4(CLN5):c.473G>C (p.Trp158Ser) and NM_006493.4(CLN5):c.924_925del (p.Leu309AlafsTer4) variants are absent from gnomAD.

VariantEvidence: NM_006493.4(CLN5):c.924_925del (p.Leu309AlafsTer4) is a frameshift variant that disrupts approximately 14% of the protein product. The NM_006493.4(CLN5):c.473G>C (p.Trp158Ser) missense variant affects a conserved residue but does not have other evidence of gene impact.

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: 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#: Shroyer_1999_Proband_AR534-07, female, age 68 years at time of diagnosis, family origin from the United States (Utah or Boston)

CasePresentingHPOs: HP:0000505 (Visual impairment), HP:0000608 (Macular degeneration), HP:0003584 (Late onset)

CaseHPOFreeText: The proband has been diagnosed with exudative age-related macular degeneration.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The proband and her family members have been genotyped by heteroduplex and SSCP analysis of ABCA4 PCR products, followed by Sanger sequencing-based confirmation.

CaseMethod1: SSCP

CaseMethod2: Sanger sequencing of ABCA4

CaseGenotypingMethod: The proband and her family members have been genotyped by heteroduplex and SSCP analysis of ABCA4 PCR products, followed by Sanger sequencing-based confirmation.

Variant: The proband harbors the NM_000350.3(ABCA4):c.4139C>T (p.Pro1380Leu) variant in the heterozygous state.

ClinVar ID: 7904

gnomAD: The variant is found in gnomAD v4.1.0 at frequencies of 0.0003059 in the European (non-Finnish) population and 0.001723 in the Ashkenazi Jewish population. https://gnomad.broadinstitute.org/variant/1-94031110-G-A?dataset=gnomad_r4

VariantEvidence: NM_000350.3(ABCA4):c.4139C>T (p.Pro1380Leu) is a missense variant without functional evidence of a damaging impact on ABCA4.

CaseAddInfo: The proband is the grandmother of four patients with a diagnosis of Stargardt disease. Her 52-year-old daughter carries the same variant but is unaffected (normal fundus).

CasePMIDs: N/A

Case#: Olivier_2021_Family_C_Proband_II:1, female, age 48 years at the time of diagnosis, national origin reported as Spanish

CasePresentingHPOs: HP:0000543 (Optic disc pallor), HP:0007843 (Attenuation of retinal blood vessels), HP:0030329 (Retinal thinning), HP:0007737 (Bone spicule pigmentation of the retina)

CaseHPOFreeText: The proband was diagnosed with moderate retinitis pigmentosa at age 48 years.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseMethod1: Screening of IMPG1 using gene panel testing and Sanger sequencing-based confirmation

CaseMethod2: Haplotype analysis using the microsatellite markers D6S1622, D6S456, D6S1589 and D6S251, spanning a 7.2-Mb region surrounding IMPG1.

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

Variant: The affected family members harbor the NM_001563.4:c.1824+1G>A variant in the heterozygous state.

ClinVar ID: 1240018

gnomAD: This variant is found in gnomAD v2.1.1 at a frequency of 0.00002980 (1 / 33554 alleles total in the Latino / Admixed American population. https://gnomad.broadinstitute.org/variant/6-76660278-C-T

VariantEvidence: NM_001563.4:c.1824+1G>A is an intronic variant disrupting a canonical splice site in intron 13 (of the 17-exon gene), with unknown consequences for IMPG1 splicing.

CaseAddInfo: This family helps establish the incomplete penetrance of the variant, as the patient's carrier mother was clinically asymptomatic with no retinal vessel abnormalities, despite the presence of hard drusen-like deposits in the macula.

CasePMIDs: N/A

Case#: Olivier_2021_Family_B_Proband_II:2, female, age not specified, ethnic origin reported as French

CasePresentingHPOs: HP:0007663 (Reduced visual acuity), HP:0030643 (Vitelliform-like retinal lesions), HP:0011506 (Choroidal neovascularization),

CaseHPOFreeText: The patient has a diagnosis of vitelliform macular dystrophy, and reportedly has a hyperreflective deposit in one eye.

CaseNotHPOs: HP:0000512 (Abnormal electroretinogram), HP:0030454 (Abnormal electrooculogram)

CaseNotHPOFreeText: N/A

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

CaseMethod1: Screening of IMPG1 using gene panel testing and Sanger sequencing-based confirmation

CaseMethod2: Haplotype analysis using the microsatellite markers D6S1622, D6S456, D6S1589 and D6S251, spanning a 7.2-Mb region surrounding IMPG1.

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

Variant: The affected family members harbor the NM_001563.4:c.1824+1G>A variant in the heterozygous state.

ClinVar ID: 1240018

gnomAD: This variant is found in gnomAD v2.1.1 at a frequency of 0.00002980 (1 / 33554 alleles total in the Latino / Admixed American population. https://gnomad.broadinstitute.org/variant/6-76660278-C-T

VariantEvidence: NM_001563.4:c.1824+1G>A is an intronic variant disrupting a canonical splice site in intron 13 (of the 17-exon gene), with unknown consequences for IMPG1 splicing.

CaseAddInfo: This family has helped establish the incomplete penetrance of the variant, as the patient's two sisters were asymptomatic carriers with normal fundus findings at ages 45 and 50 years respectively. The patient's 70-year-old mother was also a carrier and exhibited low vision.

CasePMIDs: N/A

Case: Felbor_1995_Family_1_patient_1, gender and age not specified, German-Czech family origin

DiseaseAssertion: Sorsby's fundus dystrophy

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

CasePresentingHPOs: 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)

CaseHPOFreeText: 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.

CaseNOTHPOs: N/A

CaseNOTHPOFreeText: N/A

CasePreviousTesting: 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.

CaseGenotypingMethod: Bidirectional Sanger sequencing of exon 5 PCR products from two affected individuals.

PreviouslyPublished: N/A

SupplementalData: N/A

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.

VariantEvidence: This variant substitutes an additional cysteine residue into the C-terminal region encoded by TIMP3 exon 5. Additional variant evidence is presented in PMID:10854443 and PMID:16223891.

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

CasePresentingHPOs: HP:0000546 (Retinal degeneration)

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseMethod1: Screening of PCR-amplified RPE65 exons using SSCA

CaseMethod2: Sanger sequencing of all 14 exons of RPE65

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

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

ClinVar: 98861 (homozygous)

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

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

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

CasePMIDs: N/A

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

CasePresentingHPOs: HP:0000546 (Retinal degeneration)

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseMethod1: Screening of PCR-amplified RPE65 exons using SSCA

CaseMethod2: Sanger sequencing of all 14 exons of RPE65

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

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

ClinVar: 940479 (homozygous)

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

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

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

CasePMIDs: N/A

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

CasePresentingHPOs: HP:0000546 (Retinal degeneration)

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseMethod1: Screening of PCR-amplified RPE65 exons using SSCA

CaseMethod2: Sanger sequencing of all 14 exons of RPE65

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

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

ClinVar: 98866, 98902

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

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

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

CasePMIDs: N/A

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

CasePresentingHPOs: HP:0000546 (Retinal degeneration)

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseMethod1: Screening of PCR-amplified RPE65 exons using SSCA

CaseMethod2: Sanger sequencing of all 14 exons of RPE65

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

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

ClinVar: 13115, 13116

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

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

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

CasePMIDs: N/A

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

CasePresentingHPOs: HP:0000546 (Retinal degeneration)

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseMethod1: Screening of PCR-amplified RPE65 exons using SSCA

CaseMethod2: Sanger sequencing of all 14 exons of RPE65

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

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

ClinVar: 98846 (homozygous)

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

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

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

CasePMIDs: N/A

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

CasePresentingHPOs: HP:0000546 (Retinal degeneration)

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseMethod1: Screening of PCR-amplified RPE65 exons using SSCA

CaseMethod2: Sanger sequencing of all 14 exons of RPE65

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

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

ClinVar: 13118, 98831

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

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

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

CasePMIDs: N/A

Case#: Meindl_1996_Family_RP49_Proband, male, age not specified, family origin either German or British

CasePresentingHPOs: HP:0000510 (Rod-cone dystrophy)

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

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

CaseMethod2: Sanger sequencing of the RPGR locus

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

Variant: The affected family members harbor the NM_001034853.2(RPGR):c.644G>T (p.Gly215Val) variant in the hemizygous state.

ClinVar: 98794

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

VariantEvidence: NM_001034853.2(RPGR):c.644G>T (p.Gly215Val) is a missense variant in exon 7 of 15 and has been shown to disrupt the ability of the protein product to interact with PDE6D, INPP5E, and RPGRIP1L (PMID: 30622176, Figure 4).

CaseAddInfo: The proband is a member of Family RP49.

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#: Hejtmancik_2008_Family_55001_Proband, sex and age not specified, family origin described as American of European ancestry

CasePresentingHPOs: Snowflake vitreoretinal degeneration HP:0011533, Corneal guttata HP:0012038, Presenile cataracts HP:0007819, Abnormal vitreous humor morphology HP:0004327, Retinal detachment HP:0000541

CaseHPOFreeText: All family members have been diagnosed with Snowflake vitreoretinal degeneration between the ages of 12 and 85 years of age. Please note that detailed phenotypes were found in PMID: 14644728, and included fibrillar vitreous degeneration.

CaseNotHPOs: N/A

CaseNotHPOFreeText: Orofacial features, early-onset hearing loss, and arthritis were absent.

CasePreviousTesting: The proband was previously subjected to linkage analysis mapping the causal locus to chromosome 2 (PMID: 15557460).

CaseMethod1: linkage analysis

CaseMethod2: Sanger sequencing of KCNJ13, COL4A3, SLC19A3, DNER, SLC17, 16A14, LOC646839, CAB39, PSMD1, ARMC9, NCL, PTMA, PDE6D, COPS7B, ECEL1, EFHD1, TNRC15, ATG16L1, SAG, USP40, and CENTG2

CaseGenotypingMethod: The family was previously genotyped by linkage analysis mapping the causal locus to chromosome 2 (PMID: 15557460), followed by Sanger sequencing of KCNJ13, COL4A3, SLC19A3, DNER, SLC17, 16A14, LOC646839, CAB39, PSMD1, ARMC9, NCL, PTMA, PDE6D, COPS7B, ECEL1, EFHD1, TNRC15, ATG16L1, SAG, USP40, and CENTG2.

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 (Figure 2).

CaseAddInfo: The proband's family includes 12 other affected individuals carrying the variant, and 14 unaffected individuals (as well as 4 unaffected spouses) without the variant.

CasePMIDs: PMID: 15557460, PMID: 14644728

Case#: Riazuddin_2006_61074_patient_10, male, age 25 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 multiple 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 61074 harbor the NM_000440.3(PDE6A):c.1408-2A>G variant in the homozygous state.

ClinVar: 225119

gnomAD: This variant is present in gnomAD v2.1.1 at a frequency of 0.00003266 (1/30616 with no homozygotes) in the South Asian population https://gnomad.broadinstitute.org/variant/5-149276341-T-C

VariantEvidence: NM_000440.3(PDE6A):c.1408-2A>G is a variant disrupting a splice acceptor site in intron 10 that is predicted to result in exon 11 skipping, truncating 22 amino acids (~3%) of the protein product.

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

CasePMIDs: N/A

Case#: Riazuddin_2006_61021_patient_12, female, age 33 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 multiple 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 61021 harbor the NM_000440.3:c.2098dup (p.Tyr700LeufsTer21) variant in the homozygous state.

CAID: CA2573332091

gnomAD: This variant is absent from gnomAD v2.1.1.

VariantEvidence: NM_000440.3:c.2098dup (p.Tyr700LeufsTer21) is a frameshift variant in exon 17 of 22 that is predicted to trigger nonsense-mediated decay or at least to truncate ~19% of the protein product.

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

CasePMIDs: N/A

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

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

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseMethod1: Genome-wide linkage analysis

CaseMethod2: Sanger sequencing of the candidate gene PDE6A

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

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

ClinVar: 437984

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

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

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

CasePMIDs: N/A

Case#: Fu_2013_Patient_4263_1, male, age 9 at time of report, family origin reported to be Chinese

CasePresentingHPOs: HP:0030534 (Abnormal best corrected visual acuity test), HP:0000662 (Nyctalopia), HP:0007663 (Reduced visual acuity), HP:0000654 (Decreased light- and dark-adapted electroretinogram amplitude), HP:0007984 (Electronegative electroretinogram), HP:0410280 (Pediatric onset)

CaseHPOFreeText: The proband was initially diagnosed with retinitis pigmentosa with an autosomal recessive pattern of inheritance, and subsequently re-diagnosed with cone-rod dystrophy with early-onset retinal dystrophy.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The proband was initially genotyped by next-generation sequencing focusing on a panel of 163 known retinal disease genes.

CaseMethod1: Next-generation sequencing panel (163 genes)

CaseMethod2: Sanger sequencing of ADAM9

CaseGenotypingMethod: The proband was initially genotyped by next-generation sequencing focusing on a panel of 163 known retinal disease genes, followed by Sanger sequencing of ADAM9.

Variant: The proband harbors the NM_003816.3(ADAM9):c.1786C>T (p.Arg596Ter) variant in the homozygous state.

CAID: CA370746588

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

VariantEvidence: NM_003816.3(ADAM9):c.1786C>T (p.Arg596Ter) is a nonsense variant in exon 16 of 21, which is predicted to trigger NMD or to truncate the C-terminal ~27% of the protein product.

CaseAddInfo: The proband's parents are consanguineous and are each heterozygous for the variant, while his unaffected sister does not carry the variant.

CasePMIDs: N/A

Case#: Yzer_2006_Patient_20955, female, diagnosed in the weeks after birth, Dutch or Belgian family origin

CasePresentingHPOs: HP:0003593 (Infantile onset), HP:0000639 (Nystagmus), HP:0007663 (Reduced visual acuity), HP:0000563 (Keratoconus), HP:0001483 (Eye poking), HP:0008043 (Retinal arteriolar constriction), HP:0007814 (Retinal pigment epithelial mottling), HP:0007688 (Undetectable light- and dark-adapted electroretinogram)

CaseHPOFreeText: The individual is described as having Leber congenital amaurosis. Retinal pigment epithelium mottling in the mid- and far periphery was minimal.

CaseNotHPOs: HP:0000662 (Nyctalopia), HP:0000613 (Photophobia), HP:0001098 (Abnormal fundus morphology), HP:0000543 (Optic disc pallor), HP:0030825 (Absent foveal reflex)

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.

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.2302C>T (p.Arg768Trp) variant.

ClinVar: 98563

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

VariantEvidence: 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_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#: Lazar_2014_Family_MOL0430_Patient_1, male, age 31 at time of report, national origin in Israel, ethnicity listed as North African Jewish

CasePresentingHPOs: HP:0410280 (Pediatric onset), HP:0030515 (Moderately reduced visual acuity), HP:0011003 (High myopia), HP:0030479 (Abnormal amplitude of light-adapted flicker electroretinogram), HP:0000613 (Photophobia), HP:0007703 (Abnormality of retinal pigmentation), HP:0008179 (Decreased Arden ratio of electrooculogram)

CaseHPOFreeText: The patient has been diagnosed with cone-rod dystrophy.

CaseNotHPOs: HP:0030480 (Abnormal timing of light-adapted flicker electroretinogram), HP:0030470 (Abnormal dark-adapted bright flash electroretinogram)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

CaseMethod1: Whole exome sequencing of the proband

CaseMethod2: Confirmation by Sanger sequencing

CaseGenotypingMethod: The proband was genotyped by whole exome sequencing, followed by confirmation by Sanger sequencing.

Variant: The proband harbors the NM_000180.4(GUCY2D):c.2538G>C (p.Lys846Asn) variant in the heterozygous state.

ClinVar: 812329

gnomAD: The variant was not found in gnomAD.

VariantEvidence: NM_000180.4(GUCY2D):c.2538G>C (p.Lys846Asn) is a missense variant located within the coiled-coil domain that mediates dimerization. Codon 838 has proven to be a hot spot disrupted in other families similarly affected with autosomal dominant cone-rod dystrophy (PMID: 11115851, PMID: 12552567, PMID: 26298565). Cases from this family may be less severely affected, possibly similar to a reported variant at codon 849 (PMID: 26298565).

CaseAddInfo: The proband is an isolated case without family member phenotypes and genotypes available.

CasePMIDs: N/A

Case#: Lazar_2014_Family_MOL0508_Patient_III:1, female, age 25 at time of report, national origin in Israel, ethnicity listed as Ashkenazi Jewish

CasePresentingHPOs: HP:0410280 (Pediatric onset), HP:0030515 (Moderately reduced visual acuity), HP:0011003 (High myopia), HP:0000552 (Tritanomaly), HP:0030479 (Abnormal amplitude of light-adapted flicker electroretinogram), HP:0030500 (Yellow/white lesions of the macula), HP:0025158 (Hyperautofluorescent retinal lesion)

CaseHPOFreeText: The patient has been diagnosed with maculopathy and cone dystrophy.

CaseNotHPOs: HP:0030480 (Abnormal timing of light-adapted flicker electroretinogram), HP:0030470 (Abnormal dark-adapted bright flash electroretinogram)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

CaseMethod1: Whole exome sequencing

CaseMethod2: Confirmation by Sanger sequencing

CaseGenotypingMethod: The proband was genotyped by whole exome sequencing, followed by confirmation by Sanger sequencing.

Variant: The proband harbors the NM_000180.4(GUCY2D):c.2521G>A (p.Glu841Lys) variant in the heterozygous state.

ClinVar: 812328

gnomAD: The variant was not found in gnomAD.

VariantEvidence: NM_000180.4(GUCY2D):c.2521G>A (p.Glu841Lys) is a missense variant located within the coiled-coil domain that mediates dimerization. Codon 838 has proven to be a hot spot disrupted in other families similarly affected with autosomal dominant cone-rod dystrophy (PMID: 11115851, PMID: 12552567, PMID: 26298565). Cases from this family may be less severely affected, possibly similar to a reported variant at codon 849 (PMID: 26298565).

CaseAddInfo: The proband is a member of a family with an affected mother who was not genotyped.

CasePMIDs: N/A

Case#: Stunkel_2018_Patient_2, male, age 9 at diagnosis with congenital night blindness, age 14 at time of report, ethnic origin not mentioned

CasePresentingHPOs: HP:0003621 (Juvenile onset), HP:0000662 (Nyctalopia), HP:0030474 (Undetectable dark-adapted electroretinogram), HP:0007987 (Progressive visual field defects), HP:0001133 (Constriction of peripheral visual field), HP:0002527 (Falls), HP:0030329 (Retinal thinning)

CaseHPOFreeText: Minor color vision errors were detected by D15 testing.

CaseNotHPOs: HP:0003593 (Infantile onset), HP:0030534 (Abnormal best corrected visual acuity test), HP:0030586 (Abnormal Ishihara plate test), HP:0000539 (Abnormality of refraction), HP:0000639 (Nystagmus), HP:0000486 (Strabismus), HP:0007663 (Reduced visual acuity), HP:0030473 (Abnormal light-adapted flicker electroretinogram)

CaseNotHPOFreeText: N/A

CasePreviousTesting: Negative screening for variants in NYX, CACNA1F, RHO, or TRPM1

CaseMethod1: Whole exome sequencing

CaseMethod2: N/A

CaseGenotypingMethod: This individual was initially subjected to screening for variants in NYX, CACNA1F, RHO, or TRPM1, with negative results. Whole exome sequencing then detected 2 variants in GUCY2D.

Variant: The individual is compound heterozygous for the NM_000180.4(GUCY2D):c.247C>T (p.Arg83Cys) and NM_000180.4(GUCY2D):c.1633C>T (p.Gln545Ter) variants.

CAID: CA397943039

ClinVar: 689384

gnomAD: Neither variant was found in gnomAD.

VariantEvidence: Evidence supporting the pathogenicity of the NM_000180.4(GUCY2D):c.247C>T (p.Arg83Cys) variant is limited to computational prediction. NM_000180.4(GUCY2D):c.1633C>T (p.Gln545Ter) is a nonsense variant in exon 7 predicted to trigger NMD or to at least disrupt ~51% of the protein product through truncation.

CaseAddInfo: The mother of Patient 2 has been found to carry one of the variants in a heterozygous state, consistent with the expected segregation pattern.

CasePMIDs: N/A

Case#: Badano_2003_Family_KK26_Proband_05, gender, age, and origin not reported.

CasePresentingHPOs: N/A

CaseHPOFreeText: The patient has been diagnosed with Bardet-Biedl syndrome. Specific phenotypes have not been described in detail.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping consisted of linkage mapping using a 10-cM linkage map set to identify regions of homozygosity unique to the affected family member only.

CaseMethod1: Homozygosity analysis

CaseMethod2: Sanger sequencing of the BBS7 locus

CaseGenotypingMethod: Genotyping first identify regions of homozygosity unique to the affected family member, then performed Sanger sequencing of the BBS7 locus.

Variant: The patient harbors the NM_176824.3(BBS7):c.709_712del (p.Lys237fs) variant in the homozygous state.

ClinVar ID: 3017

gnomAD: The NM_176824.3(BBS7):c.709_712del (p.Lys237fs) variant was not found in gnomAD v2.1.1.

VariantEvidence: NM_176824.3(BBS7):c.709_712del (p.Lys237fs) is an out-of-frame deletion variant in exon 7 of 18 and is predicted to trigger nonsense-mediated decay or to at least truncate the C-terminal 67% of the protein product.

CaseAddInfo: The proband is a member of family KK26, which is known to be consanguineous. The proband has two unaffected carrier parents, 5 unaffected carrier siblings, and 1 unaffected non-carrier sibling.

CasePMIDs: N/A

Case#: Khan_2019_proband_1, male, age 8 years at time of report, national origin reported as Emirati

CasePresentingHPOs: HP:0000613 (Photophobia), HP:0000545 (Myopia), HP:0000577 (Exotropia), HP:0007663 (Reduced visual acuity), HP:0410280 (Pediatric onset), HP:0025158 (Hyperautofluorescent retinal lesion), HP:0030609 (Photoreceptor layer loss on macular OCT), HP:0000654 (Decreased light- and dark-adapted electroretinogram amplitude)

CaseHPOFreeText: The patient has been diagnosed with childhood-onset rod-cone dystrophy with early macular involvement.

CaseNotHPOs: HP:0000639 (Nystagmus)

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping consisted of a retinal dystrophy gene panel.

CaseMethod1: retinal dystrophy gene panel

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

CaseGenotypingMethod: Genotyping consisted of a retinal dystrophy gene panel followed by Sanger sequencing of the 19 exons of the IMPG2 gene.

Variant: The patient harbors the NM_016247.4(IMPG2):c.189dup (p.Gln64fs) variant in the homozygous state.

ClinVar: 978976

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

VariantEvidence: NM_016247.4(IMPG2):c.189dup (p.Gln64fs) is a frameshift variant in exon 2 of 19 that is predicted to trigger NMD or to at least truncate the C-terminal 95% of the protein product.

CaseAddInfo: The family is consanguineous, with the parents being first cousins and heterozygous carriers of the variant.

CasePMIDs: N/A

Case#: van_Huet_2014_Patient_H-II:6, female, age 17 years at time of onset, age 46 years at the time of report, national origin reported as Dutch

CasePresentingHPOs: Nyctalopia HP:0000662, HP:0011462 (Young adult onset), HP:0000545 (Myopia), HP:0007663 (Reduced visual acuity), HP:0000518 (Cataract), HP:0000543 (Optic disc pallor), HP:0007843 (Attenuation of retinal blood vessels), HP:0007737 (Bone spicule pigmentation of the retina), HP:0000550 (Undetectable electroretinogram), HP:0011510 (Drusen)

CaseHPOFreeText: The patient and her family members have been diagnosed with retinitis pigmentosa, with macular abnormalities present in all cases.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping consisted of autozygosity mapping (PMID: 20673862).

CaseMethod1: Homozygosity mapping

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

CaseGenotypingMethod: Genotyping consisted of autozygosity mapping (PMID: 20673862) followed by Sanger sequencing of the 19 exons of the IMPG2 gene.

Variant: The affected family members harbor the NM_016247.4(IMPG2):c.513T>G (p.Tyr171Ter) and NM_016247.4(IMPG2):c.2716C>T (p.Arg906Ter) variants in the compound heterozygous state.

ClinVar: 191181, 3548

gnomAD: These two variants were not found in gnomAD v2.1.1.

VariantEvidence: The NM_016247.4(IMPG2):c.513T>G (p.Tyr171Ter) variant is a nonsense variant in exon 4 of 19 that is predicted to lead to nonsense mediated decay or at least to C-terminal truncation of 86% of the protein product. The NM_016247.4(IMPG2):c.2716C>T (p.Arg906Ter) variant is a nonsense variant in exon 13 of 19 that is predicted to lead to nonsense mediated decay or at least to C-terminal truncation of 27% of the protein product.

CaseAddInfo: The family is reportedly non-consanguineous, and the patient has a similarly affected sister with the same genotype. Segregation of the two variants has been demonstrated within the family.

CasePMIDs: PMID: 20673862

Case#: van_Huet_2014_Patient_B-II:1, female, in childhood at time of onset, age 66 at the time of report, national origin reported as Iraqi Jewish

CasePresentingHPOs: HP:0011463 (Childhood onset), HP:0011003 (High myopia), HP:0007663 (Reduced visual acuity), HP:0007787 (Posterior subcapsular cataract), HP:0100018 (Nuclear cataract), HP:0030856 (Posterior staphyloma), HP:0007401 (Macular atrophy), HP:0000543 (Optic disc pallor), HP:0007843 (Attenuation of retinal blood vessels), HP:0007722 (Retinal pigment epithelial atrophy), HP:0007737 (Bone spicule pigmentation of the retina), HP:0007688 (Undetectable light- and dark-adapted electroretinogram)

CaseHPOFreeText: The patient and her family members have been diagnosed with retinitis pigmentosa, with macular abnormalities present in all cases.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping outside of the IMPG2 locus has not been described for this family.

CaseMethod1: Sanger sequencing of the 19 exons of the IMPG2 gene

CaseMethod2: N/A

CaseGenotypingMethod: Genotyping may have been limited to Sanger sequencing of the 19 exons of the IMPG2 gene, as previous genotyping of other loci has not been described for this family.

Variant: The affected family members harbor the NM_016247.4(IMPG2):c.635C>G (p.Ser212Ter) variant in the homozygous state.

ClinVar: 3546

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

VariantEvidence: The NM_016247.4(IMPG2):c.635C>G (p.Ser212Ter) variant is a nonsense variant in exon 6 of 19 that is predicted to lead to nonsense mediated decay or at least to C-terminal truncation of 83% of the protein product.

CaseAddInfo: The family is reportedly consanguineous, with the parents being first cousins. The proband has two affected sisters who share the same genotype, and each parent is a heterozygous carrier.

CasePMIDs: PMID: 20673862

Case#: Hughes_2012_CACD_Family_Proband, male, age not specified, origin listed as Northern Irish

CasePresentingHPOs: HP:0003581 (Adult onset), HP:0032037 (Mildly reduced visual acuity), HP:0007722 (Retinal pigment epithelial atrophy), HP:0000580 (Pigmentary retinopathy), HP:0030491 (Choriocapillaris atrophy), HP:0001105 (Retinal atrophy)

CaseHPOFreeText: The patient has been diagnosed with central areolar choroidal dystrophy. Onset was during the 30s or 40s, and the presenting symptom was mild loss of central vision.

CaseNotHPOs: HP:0000613 (Photophobia), HP:0000551 (Color vision defect), HP:0012511 (Temporal optic disc pallor)

CaseNotHPOFreeText: N/A

CasePreviousTesting: Linkage analysis previously mapped the disease-causing variant to chr17p13 (PMID: 9733038, PMID: 8733141).

CaseMethod1: Custom sequence capture array (next-generation) focusing on the linkage region on chromosome 17p13 (146 genes), using DNA from the proband and pooled affected and control samples.

CaseMethod2: Confirmation by Sanger sequencing of exon 15.

CaseGenotypingMethod: The proband and family members were genotyped by a combination of linkage analysis within the large pedigree, custom sequence capture array focusing on 146 genes within the linkage region on chromosome 17p13, and Sanger-based confirmation within exon 15.

Variant: The proband harbors the NM_000180.4(GUCY2D):c.2798T>C (p.Val933Ala) variant in the heterozygous state.

ClinVar: 617917

gnomAD: The variant was not found in gnomAD.

VariantEvidence: NM_000180.4(GUCY2D):c.2798T>C (p.Val933Ala) is a missense variant located in exon 15, which is part of the catalytic domain rather than the coiled-coil domain that mediates dimerization. Other variants for this disease entity are located within the coiled-coil domain instead. Phenotypic differences between this case and those may reflect genotype-phenotype correlation or differences in mechanism.

CaseAddInfo: The proband is a member of a large family (from the second generation) with other affected genotype-positive members.

CasePMIDs: PMID: 9733038, PMID: 8733141

Case#: Fattahi_2014_Patient_40302, male, age not specified, ethnicity reported as Fars, national origin reported as Iranian

CasePresentingHPOs: HP:0001513 (Obesity), HP:0000510 (Rod-cone dystrophy), HP:0000545 (Myopia), HP:0001161 (Hand polydactyly), HP:0001829 (Foot polydactyly), HP:0000077 (Abnormality of the kidney), HP:0000026 (Male hypogonadism), HP:0002463 (Language impairment), HP:0000639 (Nystagmus), HP:0001627 (Abnormal heart morphology), HP:0000708 (Atypical behavior), HP:0002251 (Aganglionic megacolon), HP:0001156 (Brachydactyly), HP:0001511 (Intrauterine growth retardation)

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

CaseNotHPOs: HP:0000518 (Cataract), HP:0000662 (Nyctalopia), HP:0000486 (Strabismus), HP:0001328 (Specific learning disability)

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping consisted of Sanger sequencing of the BBS1, BBS2, BBS10, BBS3, BBS4, BBS6, BBS9, and BBS12 genes.

CaseMethod1: Sanger sequencing of the BBS1, BBS2, BBS10, BBS3, BBS4, BBS6, BBS9, and BBS12 loci

CaseMethod2: Sanger sequencing of the BBS7 locus.

CaseGenotypingMethod: Genotyping was performed using Sanger sequencing of the BSB1, BBS2, BBS10, BBS3, BBS4, BBS6, BBS7, BBS9, and BBS12 genes.

Variant: The patient harbors the NM_018190.4:c.1342_1346del (p.Gln448Argfs*13) and NM_018190.4:c.1443T>A (p.Cys481Ter) variants in the compound heterozygous state.

CAID: CA2580617740, CA358058685

gnomAD: The NM_018190.4:c.1342_1346del (p.Gln448Argfs*13) and NM_018190.4:c.1443T>A (p.Cys481Ter) variants were not found in gnomAD v2.1.1.

VariantEvidence: NM_018190.4:c.1342_1346del (p.Gln448Argfs*13) is a frameshift variant in exon 13 of 18 that is predicted to trigger nonsense-mediated decay or to at least truncate the C-terminal 37% of the protein product. NM_018190.4:c.1443T>A (p.Cys481Ter) is a nonsense variant in exon 14 of 18 that is predicted to trigger nonsense-mediated decay or to at least truncate the C-terminal 33% of the protein product..

CaseAddInfo: Consanguinity is not present in the proband's family.

CasePMIDs: N/A

Case#: Zito_2003_Family_4462_Patient_IV.3, male, age 25 years. ethnicity not specified

CasePresentingHPOs: HP:0011463 (Childhood onset), HP:0000662 (Nyctalopia), HP:0001133 (Constriction of peripheral visual field), HP:0000618 (Blindness), HP:0007737 (Bone spicule pigmentation of the retina), HP:0000545 (Myopia), HP:0007663 (Reduced visual acuity), HP:0410018 (Recurrent ear infections), HP:0000365 (Hearing impairment), HP:0011108 (Recurrent sinusitis), HP:0002783 (Recurrent lower respiratory tract infections), HP:0002837 (Recurrent bronchitis), HP:0100582 (Nasal polyposis), HP:0000083 (Renal insufficiency)

CaseHPOFreeText: The proband has been diagnosed with retinitis pigmentosa, with the family exhibiting an X-linked pattern of inheritance.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The proband and family members were subjected to haplotype analysis using microsatellite markers on the X chromosome.

CaseMethod1: Haplotype analysis

CaseMethod2: Sanger sequencing of PCR products from the RP2, RPGR, and TCTE1L loci

CaseGenotypingMethod: The proband and family members were subjected to haplotype analysis using microsatellite markers on the X chromosome, followed by Sanger sequencing of PCR products from the RP2, RPGR, and TCTE1L loci.

Variant: The proband harbors the NM_001034853.2(RPGR):c.789_790del (p.Thr265fs) variant in the hemizygous state.

ClinVar: 9915

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

VariantEvidence: NM_001034853.2(RPGR):c.789_790del (p.Thr265fs) is a frameshift variant in exon 8 of exon 15 that is predicted to trigger nonsense-mediated decay or at least to disrupt ~68% of the C-terminus of the protein product.

CaseAddInfo: The proband is a member of Family 4462 (shown in Figure 1), which includes two other affected genotype-positive males and two confirmed carrier females described as having myopia and sparse peripheral intra-retinal pigmentation.

CasePMIDs: N/A

Case#: Hove_2016_Proband_59, sex not reported, onset in early childhood, family ancestry reported as Danish

CasePresentingHPOs: HP:0007750 (foveal hypoplasia)

CaseHPOFreeText: The proband has a diagnosis of Aland Island eye disease and showed foveal hypoplasia in both eyes (supplement 2).

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping may have been limited to Sanger sequencing of PCR products from the CACNA1F gene, or may have performed screening of other known genes associated with this phenotype.

CaseMethod1: Sanger sequencing of CABP4

CaseMethod2: N/A

CaseGenotypingMethod: Genotyping was limited to Sanger sequencing of PCR products from the CACNA1F and CABP4 genes, with possible panel-based sequencing of other inherited retinal disease-associated genes.

Variant: The individual harbors the NM_145200.5(CABP4):c.773A>T (p.Asn258Ile) variant in the homozygous state.

ClinVar ID: 636004

gnomAD: The variant is found in gnomAD version 4.1.1 at a frequency of 0.000001695 in the European (non-Finnish) population, with 0 homozygotes https://gnomad.broadinstitute.org/variant/chr11-67458492-A-T?dataset=gnomad_r4

VariantEvidence: NM_145200.5(CABP4):c.773A>T (p.Asn258Ile) is a missense variant that does not have a characterized functional impact on CABP4..

CaseAddInfo: No details are available regarding the potential for parental consanguinity.

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#: Perrault_2000_Family_11_Proband, FEmale, 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#: Perrault_2000_Family_12_Proband, Female, age unknown, family origin in Tunisia 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: Single strand conformational polymorphism analysis

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 SSCP and by Sanger sequencing of PCR products from all 20 exons of the GUCY2D locus.

Variant: The individual is homozygous for the NM_000180.4(GUCY2D):c.622del (p.Arg208GlyfsTer8) variant.

ClinVar: 98607

gnomAD: The variant is absent from gnomAD version 2.1.1.

VariantEvidence: The NM_000180.4(GUCY2D):c.622del (p.Arg208GlyfsTer8) variant is predicted to trigger nonsense mediated decay or to disrupt ~81% of the protein product by frameshift.

CaseAddInfo: The family is reportedly consanguineous.

CasePMIDs: PMID: 7581387, PMID: 8641699

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: Gliem_2000_Family_3_patient_III.5, male, country of origin Germany, onset at 31 years of age

DiseaseAssertion: Sorsby's fundus dystrophy

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

CasePresentingHPOs: HP:0000662 (Nyctalopia), HP:0007663 (Reduced visual acuity), HP:0011510 (Drusen), HP:0000533 (Chorioretinal atrophy), HP:0007737 (Bone spicule pigmentation of the retina),

CaseHPOFreeText: Relatively early presentation at age 31 with nyctalopia and prolonged dark adaptation. Evaluation at age 56 showed widespread central and peripheral atrophy, central fibrosis, and reduced choroidal thickness.

CaseNOTHPOs: N/A

CaseNOTHPOFreeText: N/A

CasePreviousTesting: Targeted next-generation sequencing of the proband (for a 74-gene panel of retinal dystrophy genes), identifying the TIMP3 variant as well as a heterozygous c.1107G>A (p.Trp369) variant in RP1L1*

GenotypingMethod: Sanger sequencing of PCR products from the TIMP3 and RP1L1 genes

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: Patients harbor the NM_000362.5(TIMP3):c.452A>G (p.Tyr151Cys) missense variant.

CAID: CA411540149

gnomAD: Variant is absent from gnomAD.

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

Case#: Gong_2001_Proband_3, 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.1468del (p.Asp490fs) variant in the homozygous state.

ClinVar: 6270

gnomAD: The NM_002335.4(LRP5):c.1468del (p.Asp490fs) variant was not found in gnomAD v2.1.1.

VariantEvidence: NM_002335.4(LRP5):c.1468del (p.Asp490fs) is a frameshift variant in exon 7 out of 23 that is predicted to trigger nonsense-mediated decay or at least to truncate the C-terminal ~70% of the protein product.

CaseAddInfo: The family is reportedly consanguineous.

CasePMIDs: PMID: 8659519

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#: Perez-Roustit_2017_Proband, male, age 31 years, family ethnic origin not reported

CasePresentingHPOs: Nystagmus HP:0000639, Childhood onset HP:0011463, Reduced visual acuity HP:0007663, Presenile cataracts HP:0007819, Pigmentary retinopathy HP:0000580, Patchy atrophy of the retinal pigment epithelium HP:0007791, Undetectable light- and dark-adapted electroretinogram HP:0007688

CaseHPOFreeText: The proband received a diagnosis of Leber congenital amaurosis. His phenotype included increased retinal thickness and presence of hyper-reflective formations around the optic disc and periphery. Visual impairment was severe but did not evolve significantly during the first 30 years of age.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The proband was previously genotyped by screening for ABCA4 variants.

CaseMethod1: Sanger sequencing of the ABCA4 gene

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

CaseGenotypingMethod: The proband was previously genotyped by screening for ABCA4 variants, followed by Sanger sequencing of the KCNJ13 exons and intron-exon boundaries.

Variant: The individual is compound heterozygous with the maternal NM_002242.4(KCNJ13):c.314G>T (p.Ser105Ile) and paternal NM_002242.4(KCNJ13):c.655C>T (p.Gln219Ter) variants.

ClinVar: 978434, 978433

gnomAD: The NM_002242.4(KCNJ13):c.314G>T (p.Ser105Ile) variant was not found in gnomAD version 4.1.0. The NM_002242.4(KCNJ13):c.655C>T (p.Gln219Ter) variant is found in gnomAD version 4.1.0 at a frequency of 0.00002669 (2/74924) in the African / African-American population https://gnomad.broadinstitute.org/variant/2-232768619-G-A?dataset=gnomad_r4

VariantEvidence: NM_002242.4(KCNJ13):c.314G>T (p.Ser105Ile) is a missense variant that has no experimental evidence in this study. NM_002242.4(KCNJ13):c.655C>T (p.Gln219Ter) is a nonsense variant in exon 3 of 3 that is not predicted to trigger NMD but rather to truncate the C-terminal 39% of the protein product.

CaseAddInfo: The proband's family history is not known to include parental consanguinity or history of retinal disease.

CasePMIDs: N/A

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

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

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseMethod1: PCR amplification and Sanger sequencing

CaseMethod2: N/A

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

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

ClinVar: 98825, 98898

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

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

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

CasePMIDs: N/A

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

Case#: Allikmets_1997_Proband_1, female, age described as between 55 and 70 years at time of diagnosis, family origin not reported

CasePresentingHPOs: HP:0000505 (Visual impairment), HP:0000608 (Macular degeneration)

CaseHPOFreeText: The proband has been diagnosed with age-related macular degeneration. She belongs to a cohort in which most AMD cases were diagnosed with dry rather than wet AMD, with a broad range of phenotypes including; drusen in the macular and/or peripheral retina and macular / RPE atrophy.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The proband and her family members have been genotyped by SSCP analysis of ABCA4 PCR products, followed by Sanger sequencing-based confirmation.

CaseMethod1: SSCP

CaseMethod2: Sanger sequencing of ABCA4

CaseGenotypingMethod: The proband and her family members have been genotyped by SSCP analysis of ABCA4 PCR products, followed by Sanger sequencing-based confirmation of the variant.

Variant: The proband harbors the NM_000350.3(ABCA4):c.6519_6529del (p.Lys2175fs) variant in the heterozygous state.

ClinVar ID: 99466

gnomAD: The variant was not found in gnomAD v4.1.0.

VariantEvidence: NM_000350.3(ABCA4):c.6519_6529del (p.Lys2175fs) is a frameshift variant in exon 48 of 50 that is predicted to trigger nonsense-mediated decay (or to truncate the C-terminal 4.4% of the protein product.

CaseAddInfo: The proband is the mother of a patient with a diagnosis of Stargardt disease. Her husband and brother-in-law have similarly been diagnosed with age-related macular degeneration between ages 55 and 70 years, but do not have an identified ABCA4 variant.

CasePMIDs: N/A

Case#: El-Haig_2014_Proband, female, age not specified, family origin reported to be Egyptian

CasePresentingHPOs: HP:0011463 (Childhood onset), HP:0000548 (Cone/cone-rod dystrophy), HP:0007787 (Posterior subcapsular cataract), HP:0010923 (Anterior subcapsular cataract), HP:0000505 (Visual impairment), HP:0007703 (Abnormality of retinal pigmentation), HP:0007843 (Attenuation of retinal blood vessels), HP:0000543 (Optic disc pallor)

CaseHPOFreeText: The proband and her affected family members have been diagnosed with cone-rod dystrophy, with the family showing an autosomal recessive mode of inheritance.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The proband and her family were initially genotyped by IROme, which generates a hybridization-based DNA library of the 64 most frequently mutated genes in retinal dystrophy, then analyzes it by high-throughput sequencing.

CaseMethod1: Next-generation sequencing panel

CaseMethod2: Sanger sequencing of ADAM9 exon 14 and flanking exon-intron junctions

CaseGenotypingMethod: The proband and her family were initially genotyped by IROme, which generates a hybridization-based DNA library of the 64 most frequently mutated genes in retinal dystrophy, then analyzes it by high-throughput sequencing. Sanger sequencing of ADAM9 exon 14 and flanking exon-intron junctions was then performed.

Variant: The proband harbors the NM_003816.3(ADAM9):c.1396-2A>G variant in the homozygous state.

ClinVar: 189795

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

VariantEvidence: NM_003816.3(ADAM9):c.1396-2A>G is a variant disrupting a canonical splice site in intron 13, which is predicted but not confirmed to disrupt mRNA splicing.

CaseAddInfo: The proband is from a consanguineous family and has two affected sons who are also homozygous for the variant, as well as five unaffected heterozygous family members.

CasePMIDs: N/A

SRF1186

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#: Parry_2009_Family_MOL0172_patient_IV:3, male, age not specified, family origin reported to be Tunisian Jewish

CasePresentingHPOs: HP:0410280 (Pediatric onset), HP:0007663 (Reduced visual acuity), HP:0007401 (Macular atrophy), HP:0000580 (Pigmentary retinopathy), HP:0007769 (Peripheral retinal degeneration), HP:0008323 (Abnormal light- and dark-adapted electroretinogram)

CaseHPOFreeText: The proband was diagnosed with cone-rod dystrophy, with family showing autosomal recessive mode of inheritance. Most affected members of the proband's family had white patches around the optic disc and in the posterior pole.

CaseNotHPOs: HP:0000639 (Nystagmus), HP:0000613 (Photophobia)

CaseNotHPOFreeText: N/A

CasePreviousTesting: The proband and his family have been initially genotyped by autozygosity mapping with both 10k and 250k Affymetrix SNP arrays and microsatellite markers.

CaseMethod1: Autozygosity mapping

CaseMethod2: Sanger sequencing

CaseGenotypingMethod: The proband and his family have been initially genotyped by autozygosity mapping with both 10k and 250k Affymetrix SNP arrays and microsatellite markers. Sanger sequencing of the ADAM9 locus then identified the variants.

Variant: The proband harbors the NM_003816.3(ADAM9):c.490C>T (p.Arg164Ter) variant in the homozygous state.

ClinVar: 6878

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

VariantEvidence: NM_003816.3(ADAM9):c.490C>T (p.Arg164Ter) is a nonsense variant in exon 6 of 21, and is therefore predicted to result in nonsense-mediated decay.

CaseAddInfo: The proband's family is known to be consanguineous, with the father being the mother's uncle (pedigree shown in Figure 2).

CasePMIDs: N/A

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

CasePresentingHPOs: N/A

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

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

CaseMethod2: Candidate gene sequencing

CaseGenotypingMethod: Sanger sequencing of the RPE65 locus

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

ClinVar: 750796

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

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

CaseAddInfo: N/A

CasePMIDs: N/A