PMID: 41561667

Gene: ABCA4

HGNC ID: 34

Case#: patient 66, male, Italy

DiseaseAssertion: STGD

FamilyInfo: N/A

CasePresentingHPOs: HP:0000505, HP:0000551, HP:0000546

CaseHPOFreeText: best-corrected visual acuity (BCVA) was 20/400 in both eyes, mild myopia, both eyes were pseudophakic, extensive bilateral chorioretinal atrophy involving both the posterior pole and the peripheral retina, widespread mottled hypoautofluorescence in the mid-periphery, along with pronounced macular hypoautofluorescence, significant central retinal thinning, an enlarged foveal depression, outer retinal hyper-reflectivity associated with extensive atrophy of both the RPE and the underlying choroid, dense epiretinal membrane (ERM) was also identified in the right eye, large central hypofluorescent zone involving the macular region and extending beyond the vascular arcades

CasePreviousTesting: n/a

GenotypingMethod: Next-Generation Sequencing

PreviouslyPublished: n/a

Variant: c.1714C > T p. (Arg572∗)

ClinVar: 620085 https://www.ncbi.nlm.nih.gov/clinvar/variation/620085/?term=620085%5BVariation+ID%5D

gnomAD: 0.000001859 https://gnomad.broadinstitute.org/variant/1-94063158-G-A?dataset=gnomad_r4

Variant: c.2461T > A p. (Trp821Arg)

ClinVar: 99136 https://www.ncbi.nlm.nih.gov/clinvar/variation/99136/?term=99136%5BVariation+ID%5D

gnomAD: 0.000008054 https://gnomad.broadinstitute.org/variant/1-94055237-A-T?dataset=gnomad_r4

Variant: c.4417C>А p. (Leu1473Met)

ClinVar: 546600 https://www.ncbi.nlm.nih.gov/clinvar/variation/546600/?term=546600%5BVariation+ID%5D

gnomAD: 0.00005762 https://gnomad.broadinstitute.org/variant/1-94029567-G-T?dataset=gnomad_r4

PMID: 31618812

Gene: ABCA4

HGNCID: HGNC:34

Patients: a group of 31 Stargardt disease/fundus flavimaculatus patients (14 males, 17 females) with an established ABCA4 genotype, accumulated prospectively over an interval of 12 months at the outpatient service of the Institution, were included in this study.

MonDO: MONDO:0019353

CaseInfo: Case 11, Male, 12yo. Compound het c.5882G > A; p.Gly1961glu (Pathogenic in ClinVar); c.6764G > T,p.Ser2255Ile

DiseaseAssertion: Stargardt disease/fundus flavimaculatus

FamilyInfo: Not provided

CasePresentingHPOs: HP:0007769, HP:0000608, HP:0012045 (Peripheral retinal degeneration, Macular degeneration, Retinal flecks)

CaseHPOFreeText: cone-rod pattern of retinal dysfunction

GenotypingMethod: Mutation screening was performed by single-strand conformation polymorphism (SSCP) strategy of the whole coding region of ABCA4. Direct sequencing was also performed on siblings of probands and parents, when available, to confirm segregation of alleles.

MultipleGeneVariants: (1) GeneName: ABCA4

(1)Variant: c.5882G > A; p.Gly1961glu

(1) CAID: CA119132

(1) gnomAD: 0.01250 (gnomadv4.0.0, Grpmax Filtering AF, South Asian) https://gnomad.broadinstitute.org/variant/1-94008251-C-T?dataset=gnomad_r4

(2) GeneName: ABCA4

(2) Variant: c.6764G>T (p.Ser2255Ile)

(2) CAID: CA202970

(2) gnomAD: 0.4845 (gnomadv4.0.0, Grpmax Filtering AF, African/African-American) https://gnomad.broadinstitute.org/variant/1-93996161-C-A?dataset=gnomad_r4

Case#: Pt 13, 34yo, female

DiseaseAssertion: Stargardt

FamilyInfo: n/a

CasePresentingHPOs:

CaseHPOFreeText: stage 3 (resorbed flecks), logMAR acuity: OD=1.02 OS 1.06, FST Rod Blue Stimulus (dB) OD= −68.3, FST Cone Red stimulus (dB) OD=−23.3, FST Group 2 (elevated cone and normal rod FST thresholds)

CaseNotHPOs:

CaseNotHPOFreeText:

GenotypingMethod:

PreviouslyPublished:

Variant: p.Gly818Glu; p.Cys1488Arg

ClinVar: 99135

CAID: CA227000

SupplementalData: n/a

This variant was transfected into HEK 293 cells and appears to show reduced expression and ATP-binding capacity, but no quantities were provided

PMID: 11017087

Gene: ABCA4

Disease: retinopathies

PMID: 38540785

Gene: ABCA4

Disease: maculopathies

PMID: 24444108

Gene: ABCA4

HGNC ID: 34

PMID: 12192456

Gene: ABCA4

Disease: Stargardt macular dystrophy/fundus flavimaculatus

Case#: Garces Patient 4, Canada

DiseaseAssertion: mild STGD1

FamilyInfo:

CasePresentingHPOs:

CaseHPOFreeText: 30yo, VA=20/30, FC=Stage 2 (flecks throughout the posterior pole, anterior to the vascular arcades and nasal to the optic disc and relatively normal ERGs but with prolonged dark adaptation)

CaseNotHPOs:

CaseNotHPOFreeText:

GenotypingMethod: screened for mutations in the ABCA4, CNGB3, and ELOVL4 genes

PreviouslyPublished: n/a

Variant: c.213dupG/p.Ile73Asnfs*26; c.1654G>A/p.Val552Ile

CAID: CA239745

SupplementalData:

PMID: 41201214

Gene: ABCA4

HGNC ID: 34

PMID:36910710 Gene: ABCA4 HGNC: 34

Case#: Braun Family 3 Proband (from left to right, top to bottom of available pedigrees), female

DiseaseAssertion: Stargardt

FamilyInfo: Both parents are unaffected, but only mother has genotype information available since father is deceased. c.1622T>C (p.L541P) and c.3113C>T (p.A1038V) complex variants were maternally inherited.

CasePresentingHPOs:

CaseHPOFreeText: "five or more of the following features of ABCA4-associated retinal disease: decreased visual acuity before age 20, decreased visual acuity as the first visual symptom, symmetrical fundus findings, pisciform flecks, beaten metal macular atrophy, bulls-eye maculopathy, peripapillary sparing, vermillion fundus, masked choroid on fluorescein angiography, nummular pigment overlying extensive macular atrophy, central outer retinal atrophy on optical coherence tomography and central scotomas on Goldmann perimetry."

CaseNotHPOs:

CaseNotHPOFreeText:

GenotypingMethod: one plausible disease-causing mutation detected in ABCA4 after assessing the entire coding sequence and canonical retinal splice junctions with automated bidirectional Sanger sequencing using an ABI 3730 sequencer

PreviouslyPublished: n/a

Variant: c.5196+1137G>A; c.1622T>C (p.L541P) and c.3113C>T (p.A1038V) complex variant

ClinVar: 438100

CAID: CA26843511

SupplementalData: pedigree in fig s2

PMID: 29555955

Gene: ABCA4

Disease: macular and cone/cone-rod dystrophy

PMID: 24516651

Gene: ABCA4

Disease: Stargardt or CRD

This variant is well-known in exon 42, [M2]: c.5882G > A; p.(Gly1961Glu), rs1800553. The father of the affected patient was deceased; however, the mother was found to be homozygous for the wild type (WT) allele. According to the ACMG standards, M2 is likely pathogenic.

PMID: 33909047

Gene: ABCA4

HGNCID: HGNC:34

The effects of this variant on 11-cis-retinal interaction with the NBD1 was evaluated via fluorescence anisotropy. The binding of mutant G863A was significantly attenuated (Kd was ≥1.0 × 10−5 m) as indicated by the drastic right shift of the binding isotherm as well as its inability to achieve saturation in the presence of a high concentration of protein (Fig. 6A).

Patient 38 has this variant and also c.5882G>A p.(Gly1961Glu) (Supplement 4-supplementary table 1). Phase is unknown and more specific phenotype information is not provided.

clinical diagnosis of STGD1 was supported by the presence of ≥1 (likely) pathogenic ABCA4 variants with a follow-up data of ≥6 months on FAF imaging.

ATPase activity in COS7 cells showed decreased activity (68.1% of wild-type), indicating that this variant impacts protein function (PS3_Supporting; PMIDs). However, this is not a cell type that is counted for PS3 evidence by the ABCA4 VCEP.

PMID: 20163366

Gene: ABCA4

HGNC ID: 34

PMID: 10612508

Gene: ABCA4

Case#: Patient 2, 46-year-old female

DiseaseAssertion: STGD1

FamilyInfo: One of four affected siblings in a family consistent with autosomal recessive inheritance.

CasePresentingHPOs: HP:0000545 — Decreased visual acuity HP:0007754 — Macular atrophy HP:0030638 — Retinal flecks HP:0000512 — Abnormal fundus morphology

CaseHPOFreeText: Progressive visual decline since age 16. Best-corrected visual acuity 20/400 in both eyes. Fundus examination showed bilateral symmetrical central chorioretinal atrophy (~3 disc diameters) with prominent pigment deposits and numerous yellow flecks in the posterior pole. Fluorescein angiography demonstrated central hypofluorescence with surrounding hyperfluorescence and peripheral dark choroid.

CaseNotHPOs: Not reported

CaseNotHPOFreeText: Not reported

GenotypingMethod: PCR amplification and direct sequencing of ABCA4 after SSCP screening

PreviouslyPublished: Yes

Variant: NM_000350.2:c.2588G>C (p.Gly863Ala) NM_000350.2:c.161G>A (p.Cys54Tyr)

ClinVar: Not reported

CAID: Not reported

SupplementalData: Segregation and sequencing data shown in Figures 1 and 4

Case#: Patient 3, 37-year-old female

PMID: 10612508

DiseaseAssertion: STGD1

FamilyInfo: Affected sibling in autosomal recessive family.

CasePresentingHPOs: HP:0000545 — Decreased visual acuity HP:0007754 — Macular atrophy HP:0030638 — Retinal flecks HP:0000512 — Abnormal fundus morphology

CaseHPOFreeText: Gradual visual decline beginning at age 12. Visual acuity 20/400 in both eyes. Fundus examination revealed bilateral macular atrophy with pigment deposits and numerous yellow flecks in the posterior pole and midperiphery. Fluorescein angiography showed large hypofluorescent regions with surrounding hyperfluorescence and peripheral dark choroid.

CaseNotHPOs: Not reported

CaseNotHPOFreeText: Not reported

GenotypingMethod: PCR and direct sequencing of ABCA4

PreviouslyPublished: Yes

Variant: NM_000350.2:c.2588G>C (p.Gly863Ala) NM_000350.2:c.161G>A (p.Cys54Tyr)

ClinVar: Not reported

CAID: Not reported

SupplementalData: Segregation and sequencing data (Figures 1, 4)

Case#: OGI802_001554

DiseaseAssertion: IRD

FamilyInfo: n/a

CasePresentingHPOs:

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

GenotypingMethod: detection of CNVs on the panel-based NGS Genetic Eye Disease (GEDi) diagnostic test that involves sequencing the exons of all known IRD disease genes

PreviouslyPublished: n/a

Variant: c.1715G>C; c.5196+1137G>A

ClinVar: 99073

CAID: CA226919

SupplementalData: Table S2

PMID: 32037395

Gene: ABCA4

Disease: IRD

PMID: 36284460

Gene: ABCA4

Disease: inherited retinal diseases

This variant was not evaluated.

This variant was not evaluated.

This variant was not evaluated.

PMID: 35120629

Gene: ABCA4

Disease: Stargardt disease

PAPER USED TO SCORE PS4

PMID: 35120629

Gene: ABCA4

Disease: Stargardt disease

PAPER USED TO SCORE PS4

Case#:two cases from two additional families (case 3, 11 years and case 4, 11 years).

DiseaseAssertion: Stargardt’s Disease

FamilyInfo: NR

ParentalTesting: NR

CasePresentingHPOs: HP:0030500, HP:0011507

CasePhenotypeFreeText: LogMAR visual acuity for the right and left eye of cases 1–4 was 0.3 and 0.2, 0.1 and 0.1, 0.5 and 0.4, and 0.3 and 0.4, respectively. Gross disruption of the outer retinal layers at the macula in all cases; in two (cases 2 and 4), the presumed external limiting membrane (ELM) peak was broadened with the inner segment ellipsoid band (ISe) missing. Subtle white-yellowish fine dots at the macula and numerous white-yellowish flecks extending anterior to the arcade are shown in the colour fundus photograph of case 1. Autofluorescence (AF) imaging of case 1 detected well-defined dots with high signal at the central macula surrounded by a ring of increased signal and numerous foci with high or low signal extending to the peripheral retina. Case 2 also had subtle white-yellowish fine dots at the central macula and numerous white-yellowish flecks extending anterior to the arcade, both associated with high signal on AF imaging. In addition, case 3 had white-yellowish fine dots at the macula and numerous white-yellowish flecks extending to the periphery, both of which had high or low signal on AF imaging. Case 4 showed subtle fine macular dots mainly in a para-foveal location, which are well-defined on AF imaging.

CaseNotHPOs: HP:0007401, HP:0000505

CaseNotPhenotypeFreeText: Most cases with STGD have central macular atrophy with numerous more peripheral flecks (Michaelides et al. 2003). Given their relatively good visual acuity, it is likely that the central macular dots observed in our cases may be an early sign of macular dysfunction before the development of macular atrophy. Similar fine macular dots or a ‘mottled macula’ have also been reported in other inherited retinal diseases

CasePreviousTesting: The age of disease onset in cases 1–4, defined as either the age at which visual loss was first noted by the subject or in the asymptomatic subjects when abnormal retinal appearance was first detected, was 5, 7, 8, and 6 years old, respectively.

GenotypingMethod: After informed consent was obtained, blood samples were taken from probands of 2/3 families for ABCA4 screening. A full medical history was obtained, and a full ophthalmologic examination was performed in all cases. Mutation screening of ABCA4 was performed in two probands of the three families, and two likely disease-causing variants were identified in each case; c.768G > T, p.V256V (a previously reported splicing-altering synonymous variant) and c.4363T > C, p.C1455R (a missense variant) in case 1, and c.1906C > T, p.Q636* (a non-sense variant) and c.5461-10 T > C (a disease-associated intronic variant with uncertain effect) in case 3. A blood sample was not available in one proband (case 4).

Variant: NM_000350.3(ABCA4):c.1906C>T (p.Gln636Ter) and NM_000350.3:c.5461-10T>C

LegacyVariant: c.1906C>T (p.Gln636Ter) and c.5461-10T>C

ClinVar: 265012 and 92870

CAID: CA10588302 and CA220687

gnomeAD: 1:94528164 G / A and 1:94476951 A / G

MultipleGeneVariants:No

PreviouslyPublished: No

AdditionalInfo: Most symptoms/diagnoses are consistent with Stargardt’s Disease 3, however the probands in the study were younger in age, so many of the symptoms hadn’t progressed much. Also, all of the cases had decent visual acuity, which contradicts a symptom of Stargardt’s Disease 3. Similar fine macular dots or a ‘mottled macula’ have also been reported in other inherited retinal diseases, for example, in those caused by mutations in RDH5 or RPE65, both of which encode proteins with known function in the visual cycle. The thickening of the ELM may be an OCT abnormality that precedes atrophy in the early stages of STGD

Case#: two siblings (female) were from one consanguineous family (case 1, 11 years and case 2, 9 years)

DiseaseAssertion: Stargardt’s Disease

FamilyInfo: NR

ParentalTesting: NR

CasePresentingHPOs: HP:0030500, HP:0011507

CasePhenotypeFreeText: LogMAR visual acuity for the right and left eye of cases 1–4 was 0.3 and 0.2, 0.1 and 0.1, 0.5 and 0.4, and 0.3 and 0.4, respectively. Gross disruption of the outer retinal layers at the macula in all cases; in two (cases 2 and 4), the presumed external limiting membrane (ELM) peak was broadened with the inner segment ellipsoid band (ISe) missing. Subtle white-yellowish fine dots at the macula and numerous white-yellowish flecks extending anterior to the arcade are shown in the colour fundus photograph of case 1. Autofluorescence (AF) imaging of case 1 detected well-defined dots with high signal at the central macula surrounded by a ring of increased signal and numerous foci with high or low signal extending to the peripheral retina. Case 2 also had subtle white-yellowish fine dots at the central macula and numerous white-yellowish flecks extending anterior to the arcade, both associated with high signal on AF imaging. In addition, case 3 had white-yellowish fine dots at the macula and numerous white-yellowish flecks extending to the periphery, both of which had high or low signal on AF imaging. Case 4 showed subtle fine macular dots mainly in a para-foveal location, which are well-defined on AF imaging.

CaseNotHPOs: HP:0007401, HP:0000505

CaseNotPhenotypeFreeText: Most cases with STGD have central macular atrophy with numerous more peripheral flecks (Michaelides et al. 2003). Given their relatively good visual acuity, it is likely that the central macular dots observed in our cases may be an early sign of macular dysfunction before the development of macular atrophy. Similar fine macular dots or a ‘mottled macula’ have also been reported in other inherited retinal diseases

CasePreviousTesting: The age of disease onset in cases 1–4, defined as either the age at which visual loss was first noted by the subject or in the asymptomatic subjects when abnormal retinal appearance was first detected, was 5, 7, 8, and 6 years old, respectively.

GenotypingMethod: After informed consent was obtained, blood samples were taken from probands of 2/3 families for ABCA4 screening. A full medical history was obtained, and a full ophthalmologic examination was performed in all cases. Mutation screening of ABCA4 was performed in two probands of the three families, and two likely disease-causing variants were identified in each case; c.768G > T, p.V256V (a previously reported splicing-altering synonymous variant) and c.4363T > C, p.C1455R (a missense variant) in case 1, and c.1906C > T, p.Q636* (a non-sense variant) and c.5461-10 T > C (a disease-associated intronic variant with uncertain effect) in case 3. A blood sample was not available in one proband (case 4).

Variant: NM_000350.3(ABCA4):c.768G>T (p.Val256=) and NM_000350.3(ABCA4):c.4363T>C (p.Cys1455Arg)

LegacyVariant: c.768G>T (p.Val256=) and c.4363T>C (p.Cys1455Arg)

ClinVar: 99505 and 377404

CAID: CA227458 and CA957621

gnomeAD: 1:94564350 C / A and 1:94495177 A / G

MultipleGeneVariants:No

PreviouslyPublished: No

AdditionalInfo: Some symptoms/diagnoses are consistent with Stargardt’s Disease 3, however the probands in the study were younger in age, so many of the symptoms hadn’t progressed much. Also, all of the cases had decent visual acuity, which contradicts a symptom of Stargardt’s Disease 3.

Case#: Patient P28592/1,

DiseaseAssertion: STGD

FamilyInfo: n/a

CasePresentingHPOs:

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

GenotypingMethod: Custom 300-kb retinal resequencing chip. PCR amplification, DNA fragmentation, and chip hybridization. Hybridization signals were analyzed using Sequence pilot module seq-C mutation detection software (2009). This resequencing approach was validated by Sanger sequence technology.

PreviouslyPublished: n/a

Variant: c.635G>A p.(R212H); c.6445C>T p.(R2149X); c.6285T>C p.(D2095D)

CAID: CA285825

SupplementalData: n/a

This patient was later phenotypically characterized in more depth (PMID: 12037008)

PMID: 19352439

Gene: ABCA4

HGNC ID: 34

Case#: Patient #34, female, 61yo at baseline visit, "intermediate" age of onset

DiseaseAssertion: ABCA4-related retinopathy with secondary RPE atrophy

FamilyInfo: n/a

CasePresentingHPOs:

CaseHPOFreeText: Inclusion criteria were defined as 1) presence of at least one mutated allele in ABCA4 (NM_000350.2) in Sanger sequencing with multiplex ligation-dependent probe amplification analysis or next-generation sequencing 2) a compatible phenotype with flecks at the level of the RPE consistent with ABCA4 -related Stargardt disease 3) presence of RPE atrophy, and 4) serial examinations with an interval of at least 6 months. RPE atrophy to the end-stage (i.e., demarcated lesions with ≥90% darkness of the optic disc under short-wavelength excitation light, DDAF) that previously showed highest interreader agreement.7 The size of DDAF has to be at least 0.05 mm 2 (each single atrophic area in cases of multifocality), and the entire lesion must be completely visualized on the AF image at each visit to be advanced for analysis. Self-reported symptom onset into early-onset (≤10 years), intermediate-onset (11–44 years), and late-onset (≥45 years). ff-ERG based Category: Group 1 contained eyes with normal scotopic and photopic responses; Group 2, eyes with normal scotopic responses, but reduced (over 2 SDs) photopic B-wave and 30-Hz flicker amplitudes; and Group 3, eyes with impairment of both rod- and cone-driven responses. BCVA: OD=n/a, OS=1 [LogMAR] .

CaseNotHPOs:

CaseNotHPOFreeText: Insufficient pupil dilation, additional retinal pathology, previous retinal treatment, or other ocular comorbidities substantially affecting image quality led to exclusion from the study

GenotypingMethod: Sanger sequencing with multiplex ligation-dependent probe amplification analysis or next-generation sequencing

PreviouslyPublished: possible since Birtel is an author on this paper and the probands both have the same second variant as in PMID: 29555955

Variant: allele 1: c.3468C>G p.(Tyr1156*) allele 2: c.5059A>T p.(Ile1687Phe)

ClinVar: n/a

CAID: CA341290648

SupplementalData: The supplemental table linked here contains genotype and phenotype information.

Case#: Patient #32, male, 60yo at baseline visit, "late" age of onset

DiseaseAssertion: ABCA4-related retinopathy with secondary RPE atrophy

FamilyInfo: n/a

CasePresentingHPOs:

CaseHPOFreeText: Inclusion criteria were defined as 1) presence of at least one mutated allele in ABCA4 (NM_000350.2) in Sanger sequencing with multiplex ligation-dependent probe amplification analysis or next-generation sequencing 2) a compatible phenotype with flecks at the level of the RPE consistent with ABCA4 -related Stargardt disease 3) presence of RPE atrophy, and 4) serial examinations with an interval of at least 6 months. RPE atrophy to the end-stage (i.e., demarcated lesions with ≥90% darkness of the optic disc under short-wavelength excitation light, DDAF) that previously showed highest interreader agreement.7 The size of DDAF has to be at least 0.05 mm 2 (each single atrophic area in cases of multifocality), and the entire lesion must be completely visualized on the AF image at each visit to be advanced for analysis. Self-reported symptom onset into early-onset (≤10 years), intermediate-onset (11–44 years), and late-onset (≥45 years). ff-ERG based Category: Group 1 contained eyes with normal scotopic and photopic responses; Group 2, eyes with normal scotopic responses, but reduced (over 2 SDs) photopic B-wave and 30-Hz flicker amplitudes; and Group 3, eyes with impairment of both rod- and cone-driven responses. BCVA: OD=0, OS=0 [LogMAR] .

CaseNotHPOs:

CaseNotHPOFreeText: Insufficient pupil dilation, additional retinal pathology, previous retinal treatment, or other ocular comorbidities substantially affecting image quality led to exclusion from the study

GenotypingMethod: Sanger sequencing with multiplex ligation-dependent probe amplification analysis or next-generation sequencing

PreviouslyPublished: n/a

Variant: allele 1: c.52C>T/p.(Arg18Trp) // c.1715G>A/p.(Arg572Gln) // c.2828G>A/p.(Arg943Gln) allele 2: c.1588G>A/p.(Gly863Ala) // c.5603A>T/p.(Asn1868Ile)

ClinVar: 7900

CAID: CA226918

SupplementalData: The supplemental table linked here contains genotype and phenotype information.

Case#: Patient #33, female, 64yo at baseline visit, "late" age of onset

DiseaseAssertion: ABCA4-related retinopathy with secondary RPE atrophy

FamilyInfo:

CasePresentingHPOs:

CaseHPOFreeText: Inclusion criteria were defined as 1) presence of at least one mutated allele in ABCA4 (NM_000350.2) in Sanger sequencing with multiplex ligation-dependent probe amplification analysis or next-generation sequencing,9 2) a compatible phenotype with flecks at the level of the RPE consistent with ABCA4 -related Stargardt disease,9 3) presence of RPE atrophy, and 4) serial examinations with an interval of at least 6 months. RPE atrophy to the end-stage (i.e., demarcated lesions with ≥90% darkness of the optic disc under short-wavelength excitation light, DDAF) that previously showed highest interreader agreement.7 The size of DDAF has to be at least 0.05 mm 2 (each single atrophic area in cases of multifocality), and the entire lesion must be completely visualized on the AF image at each visit to be advanced for analysis. Self-reported symptom onset into early-onset (≤10 years), intermediate-onset (11–44 years), and late-onset (≥45 years). ff-ERG based Category: Group 1 contained eyes with normal scotopic and photopic responses; Group 2, eyes with normal scotopic responses, but reduced (over 2 SDs) photopic B-wave and 30-Hz flicker amplitudes; and Group 3, eyes with impairment of both rod- and cone-driven responses. BCVA: OD=0.4, OS=1.1 [LogMAR] .

CaseNotHPOs:

CaseNotHPOFreeText: Insufficient pupil dilation, additional retinal pathology, previous retinal treatment, or other ocular comorbidities substantially affecting image quality led to exclusion from the study

GenotypingMethod: Sanger sequencing with multiplex ligation-dependent probe amplification analysis or next-generation sequencing

PreviouslyPublished: possible since Birtel is an author on this paper and the probands both have the same second variant as in PMID: 29555955

Variant: allele 1: c.3468C>G p.(Tyr1156*) allele 2: c.5059A>T p.(Ile1687Phe); c.4297G>A p.(Val1433Ile)

ClinVar: n/a

CAID: CA341290648

SupplementalData: The supplemental table linked here contains genotype and phenotype information.

Case#: Patient #9, female, 23yo at onset, 32yo at report, German

DiseaseAssertion: macular dystrophy or cone-rod dystrophy

FamilyInfo: inheritance= sporadic. phase not confirmed, but no other affected family members and no parental consanguinity

CasePresentingHPOs:

CaseHPOFreeText: reduced visual acuity, erg scotopic= reduced, erg-photopic=reduced

CaseNotHPOs:

CaseNotHPOFreeText: syndromic retinal disease, age-related macular degeneration, central serous retinopathy, autoimmune retinopathy, retinal vascular disease, achromatopsia, X-linked retinoschisis, North Carolina macular dystrophy

CasePreviousTesting: n/a

GenotypingMethod: Sanger sequencing of ABCA4

PreviouslyPublished: n/a

Variant: c.1654G>A p.Val552Ile; c.4771G>A p.Gly1591Arg; c.1622T>C p.Leu541Pro; c.3113C>T p.Ala1038Val

CAID: CA239745

SupplementalData: Supplementary table 1

Supplementary table 4 contains this variant, but this table is for single variants found in a recessive gene. Thus, PM3 would not be able to be used and neither would PP4

Case#: Patient #42, female, 31yo at onset, German

DiseaseAssertion: macular dystrophy or cone-rod dystrophy

FamilyInfo: phase not confirmed, but assumed in case of parental consanguinity or if only siblings were affected

CasePresentingHPOs: HP:0012508

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText: syndromic retinal disease, age-related macular degeneration, central serous retinopathy, autoimmune retinopathy, retinal vascular disease, achromatopsia, X-linked retinoschisis, North Carolina macular dystrophy

PreviouslyPublished: n/a

Variant: c.3468C>G (p.Tyr1156Ter); c.5059A>T (p.Ile1687Phe) Sanger sequencing of ABCA4

ClinVar: n/a

CAID: CA341290648

SupplementalData: Supplementary table 1

PMID: 11594993

Gene: ABCA4

HGNC: 34

PMID: 29925512

Gene: ABCA4

Disease: Stargardt

This variant is found on pg 2 in proband 11019. Compound heterozygous for c.4532C>A, (p.Pro1511His). JHU institute (US). Said to have Stargardt based on the following criteria: "(1) patients (at least 6 years old) with at least two ABCA4 variants or one ABCA4 variant associated with a typical STGD1 phenotype and (2) presence of a well-defined atrophic lesion with/without flecks at the most recent visit of at least 300 µm in diameter (the total area of all lesions <12 mm2)." No additional details provided

This variant is found on pg 21 in proband 13047. Compound heterozygous for c.5882G>A p.Gly1961Glu. Said to have Stargardt based on the following criteria: "(1) patients (at least 6 years old) with at least two ABCA4 variants or one ABCA4 variant associated with a typical STGD1 phenotype and (2) presence of a well-defined atrophic lesion with/without flecks at the most recent visit of at least 300 µm in diameter (the total area of all lesions <12 mm2)." No additional details provided

PMID: 37774808

Gene: ABCA4

Disease: Stargardt

Case#: Patient#010046, Chinese, female, 28yo at onset

DiseaseAssertion: stargardt

FamilyInfo: n/a

CasePresentingHPOs: STGD1 diagnosis based on the following criteria: "a bilateral central vision defect; fundus displaying a beaten-bronze appearance and/or orange-yellow flecks in the retina from the macula to the midperiphery; fluorescein angiography presenting with a typical dark choroid; and normal to subnormal ERG results." stage 2( numerous yellow-whitish flecks throughout the posterior pole) BCVA=0.05/ 0.05

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

PreviouslyPublished: PMID: 26780318

Variant: p.P2097S; p.A1773V phase unknown

ClinVar: 2202780

CAID: CA341277622

SupplementalData: supplementary table S4 has phenotype information

Case#: Patient#010633, Chinese, female, 20yo at onset

DiseaseAssertion: stargardt

FamilyInfo: n/a

CasePresentingHPOs: STGD1 diagnosis based on the following criteria: "a bilateral central vision defect; fundus displaying a beaten-bronze appearance and/or orange-yellow flecks in the retina from the macula to the midperiphery; fluorescein angiography presenting with a typical dark choroid; and normal to subnormal ERG results." BCVA=0.05/ 0.05

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

PreviouslyPublished: n/a

Variant: p.P2097S; c.3468C>G p.(Tyr1156*) phase unknown

ClinVar: 2202780;

CAID: CA341277622;

SupplementalData: supplementary table S4 has phenotype information

PMID: 25712131

Gene: ABCA4

Disease: ABCA4-associated retinal degenerations

ATPase activity in HEK293 cells showed severely reduced basal ATPase activity, ∼30% of WT ABCA4, indicating that this variant impacts protein function (PS3_Supporting; PMIDs).

Autofluorescence and A2E production was measured in transgenic mice and showed loss of function of ABCA4 protein indicating that this variant impacts protein function (PS3; PMIDs).

Case#: Braun Family 4 Proband (from left to right, top to bottom of available pedigrees), male

DiseaseAssertion: Stargardt

FamilyInfo: Both parents are unaffected, but only mother has genotype information available since father is deceased. c.5196+1137G>A maternally inherited. c.1022-1035fs inferred to be inherited from the father since other siblings also have this variant. Proband has 1 affected sister with the same genotype, and 2 siblings that were unaffected heterozygotes

CasePresentingHPOs:

CaseHPOFreeText: "five or more of the following features of ABCA4-associated retinal disease: decreased visual acuity before age 20, decreased visual acuity as the first visual symptom, symmetrical fundus findings, pisciform flecks, beaten metal macular atrophy, bulls-eye maculopathy, peripapillary sparing, vermillion fundus, masked choroid on fluorescein angiography, nummular pigment overlying extensive macular atrophy, central outer retinal atrophy on optical coherence tomography and central scotomas on Goldmann perimetry."

CaseNotHPOs:

CaseNotHPOFreeText:

GenotypingMethod: one plausible disease-causing mutation detected in ABCA4 after assessing the entire coding sequence and canonical retinal splice junctions with automated bidirectional Sanger sequencing using an ABI 3730 sequencer

PreviouslyPublished: n/a

Variant: c.5196+1137G>A; c.1022-1035fs

ClinVar: 438100

CAID: CA26843511

SupplementalData: pedigree in fig s2

PMID: 23918662

Gene: ABCA4

Disease: Stargardt disease

PMID: 18977788

Gene: ABCA4

Disease: Stargardt disease

Case#: MD-0324 Proband,

DiseaseAssertion: STGD

FamilyInfo: Family MD-0324

CasePresentingHPOs:

CaseHPOFreeText: STGD diagnosed based on "bilateral central vision loss; fundus presenting with a beaten-bronze appearance and/or the presence of orange-yellow flecks in the retina from the posterior pole to the mid-periphery; fluorescein angiography showing typical dark choroid; and normal to subnormal electroretinogram (ERGs)."

CaseNotHPOs:

CaseNotHPOFreeText:

GenotypingMethod: Haplotype analysis, ABCR400, NGS

PreviouslyPublished: n/a

Variant:c.3386G>T p.Arg1129Leu; c.3G>A p.Met1Ile

ClinVar: n/a

CAID: CA341289040

SupplementalData: n/a

Case#: Family MD-0247 Proband, 12yo at onset

DiseaseAssertion: AR cone rod dystrophy

FamilyInfo:

CasePresentingHPOs:

CaseHPOFreeText: STGD diagnosed based on "bilateral central vision loss; fundus presenting with a beaten-bronze appearance and/or the presence of orange-yellow flecks in the retina from the posterior pole to the mid-periphery; fluorescein angiography showing typical dark choroid; and normal to subnormal electroretinogram (ERGs)." VA loss, VF loss, BCVA=0.05/0.1, cone-pattern on ERG

CaseNotHPOs:

CaseNotHPOFreeText:

PreviouslyPublished: Aguirre-Lamban et al. 2009 (8); PMID: 19959634

Variant: c.6410G>A (p.Cys2137Tyr); c.3386G>T (p.Arg1129Leu) found by ABCR400 + dHPLC + HRM

ClinVar: 2202779; 99224

CAID: CA341277358; CA227116

SupplementalData:

PMID: 23755871

Gene: ABCA4

Disease: Retinal Dystrophies

another case with 541 variant potentially not in cis with 1038

Paper is said to contain this variant based on LOVD entry, but this paper is not publicly available. Requested from library. Annotation on stable PDF. No individual phenotype provided

PMID: 29975949

Gene: ABCA4

Disease: Stargardt

This variant was listed in a supplemental table under "autosomal recessive variants" but there are no patient IDs to be able to know if the person who had this variant had another variant. There was also no phenotype information provided

Case#: 1 male, 6 years old, from Taiwanese and Korean decent.

DiseaseAssertion: ABCA4-related retinopathy Stargardt disease

FamilyInfo: Single affected individual. Paternal uncle presented with Stargart disease previously, and Taiwanese and Korean descent underwent genetic testing to identify two pathogenic variants in the ABCA4 gene. One of the variants found was the same ABCA4 variant from the originally affected individual. No additional family information is provided in text.

CasePresentingHPOs: HP:0000529 - progressive visual loss, HP:0025010 - Foveal atrophy, HP:0000603 - Central scotoma, HP:0007663 - Decreased visual acuity, HP:0030602 - Abnormal fundus autofluorescence imaging, HP:0007984 - ERG: Reduced dark-adapted b-wave amplitude, HP:0000512 - Abnormal electroretinogram, HP:0020032 - Hyperreflective retinal dots on OCT

CaseHPOFreeText: peripapillary sparing was observed on fundus autofluorescence imaging.

CaseNotHPOs: HP:0012045 - Retinal flecks

CaseNotHPOFreeText: N/A

Genotyping Method: Genetic testing was used and after sequencing two variants were found on the ABCA4 gene.

PreviouslyPublished: N/A

Variant: NM_000350.3(ABCA4):c.3523-2A>G

Variant: NM_000350.3(ABCA4):c.2249T>C (p.Leu750Pro)

ClinVar: Variation ID: 866764

ClinVar: Variation ID: 417984

CAID: N/A

SupplementalData: N/A

PMID: 24509150

Gene: ABCA4

HGNC ID: 34

Case#: Sporadic Patient #4, female, Chinese, 30yo at report

DiseaseAssertion: STGD

FamilyInfo: n/a, sporadic case

CasePresentingHPOs:

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

GenotypingMethod: WES with Sanger sequencing confirmation

PreviouslyPublished: no

Variant: c.4555delA p.(T1519Rfs*5); c.6397T>C p.(C2133R)

ClinVar: 2021273; 2733921

CAID: CA341277387; CA645372203

SupplementalData:

PMID: 33846575

Gene: ABCA4

Disease: Stargardt disease and retinitis pigmentosa

Case#: Patient female, 10y, ethnicity not reported

DiseaseAssertion: Stargardt disease (STGD1), early onset

FamilyInfo: autosomal recessive inheritance; co-segregation of variants in parents (each heterozygous). Pedigree shown in Figure 1A. One unaffected sibling reported.

CasePresentingHPOs: HP:0007663, HP:0007754, HP:0002587, HP:0030636, HP:0000548

CaseHPOFreeText: early-onset visual decline (age 7), symmetric disease in both eyes, hyperautofluorescent ring surrounding macular atrophy, lipofuscin accumulation, photoreceptor degeneration.

CaseNotHPOs: HP:0007707

CaseNotHPOFreeText: normal anterior segment on slit lamp exam; no external ocular abnormalities reported.

Genotyping Method: Sanger sequencing confirmation; variant identification likely via next-generation sequencing (not explicitly stated).

PreviouslyPublished: n/a

Variant: ABCA4 NM_000350.2: c.6817-713A>G; c.3259G>A (p.Glu1087Lys)

ClinVar: n/a

CAID: CA2837995439, CA227097

SupplementalData: phenotype and validation data in Figures 1–5 and Supplemental Figures S1–S5

Case#: Hwang Case 1, US, male, 55yo at report, 18yo at onset

DiseaseAssertion: Stargardt disease

FamilyInfo: Family history was not significant for ocular disease

CasePresentingHPOs: HP:0007663, HP:0500087, HP:0000603, HP:0000512

CaseHPOFreeText: BCVA of 20/350 OD and 20/200 OS. Spherical refractive error measured −3.5 OD and −2.0 OS. Posterior segment examination and autofluorescence imaging were significant for sharply demarcated central and peripapillary zones of atrophy and the absence of fleck lesions (Figure 1, A–D). Humphrey visual fields demonstrated bilateral central scotomas with eccentric fixation at the inferior border.

CaseNotHPOs:

CaseNotHPOFreeText:

GenotypingMethod: Genotyping was performed by the ABCR400 microarray followed by direct sequencing to confirm identified variants.

PreviouslyPublished: n/a

Variant: P1380L and IVS40 + 5G>A

ClinVar: 7904

CAID: CA129033

SupplementalData: n/a

Case#: Hwang Case 4, male, 52yo at report, 45yo at onset

DiseaseAssertion: Stargardt

FamilyInfo: Family history was not significant for ocular disease.

CasePresentingHPOs: HP:0000545

CaseHPOFreeText: declining vision OS, BCVA was 20/100 OD and 20/70 OS. Spherical refractive error measured −3.00 OD and −3.25 OS. Posterior segment examination was significant for central atrophy and classic peripheral pisciform flecks sparing the peripapillary regions OU (Figure 4, A and B). Autofluorescence imaging demonstrated inner atrophic flecks and outer hyperautofluorescent flecks. Moderate peripapillary hypoautofluorescence, but not atrophy, was present (Figure 4, C and D).

CaseNotHPOs: HP:0500087

CaseNotHPOFreeText:

GenotypingMethod: Genotyping was performed by the ABCR400 microarray followed by direct sequencing to confirm identified variants.

PreviouslyPublished: n/a

Variant: P1380L and S1696N

ClinVar: 7904

CAID: CA129033

SupplementalData: n/a

Case#: Hwang Case 1, US, male, 55yo at report, 18yo at onset

DiseaseAssertion: Stargardt disease

FamilyInfo: Family history was not significant for ocular disease

CasePresentingHPOs: HP:0007663, HP:0500087, HP:0000603, HP:0000512

CaseHPOFreeText: BCVA of 20/350 OD and 20/200 OS. Spherical refractive error measured −3.5 OD and −2.0 OS. Posterior segment examination and autofluorescence imaging were significant for sharply demarcated central and peripapillary zones of atrophy and the absence of fleck lesions (Figure 1, A–D). Humphrey visual fields demonstrated bilateral central scotomas with eccentric fixation at the inferior border.

CaseNotHPOs:

CaseNotHPOFreeText:

GenotypingMethod: Genotyping was performed by the ABCR400 microarray followed by direct sequencing to confirm identified variants.

PreviouslyPublished: n/a

Variant: P1380L and IVS40 + 5G>A

ClinVar: 7904

CAID: CA129033

SupplementalData: n/a

PMID: 17277736

Gene: ABCA4

HGNC ID: 34

PMID: 19028736

Gene: ABCA4

Disease: cone rod dystrophy

This variant is found in homozygosity in family MD-0084 in a previous publication (PMID: 23755871)

PMID: 31456290

Gene: ABCA4

HGNCID: HGNC:34

SupplementalData: as applicable Table S2. Variant found in cohort of 2,420 families including 3,413 individuals with inherited retinal diseases in Israel. Likely, this is the same family reported in PMID 29706639.

Total number of families: 1; phenotype/s: CRD; NM_000350.2:c.4895dup, p.(Asn1632Lysfs*14)

PMID: 19365591

Gene: ABCA4

Disease: Stargardt

Case#: Maia-Lopes Family 17 Proband 5137, Portuguese, 25yo at onset

DiseaseAssertion: STGD

FamilyInfo: Family 17

CasePresentingHPOs:

CaseHPOFreeText: moderate central fundus changes, vision: 3/10 / FC

CaseNotHPOs:

CaseNotHPOFreeText:

GenotypingMethod: ABCR400 microarray, dHPLC

PreviouslyPublished: n/a

Variant: ND / c.32T>C(1); ND/p.Leu11Pro

ClinVar: 99217

CAID: CA227106

SupplementalData: n/a

Case#: Family F23 Patient P26, 42yo

DiseaseAssertion: MD-C

FamilyInfo: family f23

CasePresentingHPOs:

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

GenotypingMethod: capture-based next-generation sequencing (NGS) testing

PreviouslyPublished: n/a

Variant: c.4555del(;)6119G>A genotype b (a patient harboring a severe/null variant and a missense or in-frame insertion/deletion variant)

CAID: CA232815

SupplementalData: table s2

This variant was found in 92 of the 670 alleles in this cohort (Supplement 4). Supplement 5 has the individuals listed with their genotypes, but only mentions variants that were classified as VUS/LP/P, so it is unknown which individuals specifically had this variant or which other variants they also had.

PMID: 33375396

Gene: ABCA4

Disease: Stargardt MD

When expressed in transfected HEK293T cells and quantified by Western blotting, this variant was in the range of 40%-52%. This variant has a basal ATPase activity of 63% ± 5% compared to WT (100%) and was categorized as class 2 (partial reduction in expression and basal ATPase activity that was modestly stimulated by N-Ret-PE) with a moderate/severe predicted severity.

This variant is listed for Stargardt DNAID#070982 in trans with c.4253+43G>A. No phenotype information provided. This genotype was also reported in PMID: 32619608 and the first author of that paper is listed under authorship for this paper. Cannot confirm this isn't the same individual

This variant is listed for Stargardt DNAID#067322 in trans with c.5603A>T p.(Asn1868Ile). No phenotype information provided.

This variant is listed for Stargardt DNAID#067322 in trans with c.5603A>T p.(Asn1868Ile). No phenotype information provided.

PMID: 32845068

Gene: ABCA4

Disease: Stargardt

PMID: 23982839

Gene: ABCA4

Disease: ABCA4-associated disease

PMID:31836589

Gene: ABCA4

HGNC ID: 34

Case#: Patient 19, female, age 16

DiseaseAssertion: STGD

FamilyInfo: diagnosis of autosomal recessive STGD based on the pedigree and clinical phenotype of fleck deposits with or without genetic testing

CasePresentingHPOs: HP:0000608, HP:0000007, HP:0030610, HP:0030500

CaseHPOFreeText: Macular degeneration. autosomal recessive, Photoreceptor outer segment loss on macular OCT, Yellow/white lesions of the macula

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

Genotyping Method: n/a

PreviouslyPublished: n/a

Variant: Allele 1: NM_000350.3:c.5714+5G>A Allele 2: NM_000350.3:c.4469G>A

ClinVar: Allele 1: NM_000350.3(ABCA4):c.5714+5G>A Allele 2: NM_000350.3(ABCA4):c.4469G>A (p.Cys1490Tyr)

CAID: Allele 1: CA227338 Allele 2: CA227198

SupplementalData: composite mask analysis shown in figure 3 for patient 19, show large areas of matched degeneration and isolated IS/OS loss

Case#: DNAID 072962/Pat272, male

DiseaseAssertion: STGD1

FamilyInfo: n/a

CasePresentingHPOs:

CaseHPOFreeText: "In classic STGD1, loss of central vision starts around the second decade of life, but both early- and late-onset subtypes have been extensively described." No patient-specific details provided

CaseNotHPOs:

CaseNotHPOFreeText:

GenotypingMethod: smMIPs sequencing of the complete ABCA4 locus

PreviouslyPublished: n/a

Variant: c.6416G>A (p.Arg2139Gln); c.6445C>T (p.Arg2149Ter)

CAID: CA956878

SupplementalData: tables s9 and s11

Case#: DNAID 072284/Pat191, female

DiseaseAssertion: STGD1

FamilyInfo: n/a

CasePresentingHPOs:

CaseHPOFreeText: "In classic STGD1, loss of central vision starts around the second decade of life, but both early- and late-onset subtypes have been extensively described." No patient-specific details provided

CaseNotHPOs:

CaseNotHPOFreeText:

GenotypingMethod: smMIPs sequencing of the complete ABCA4 locus

PreviouslyPublished: n/a

Variant: c.1519G>T (p.Asp507Tyr); c.4139C>T (p.Pro1380Leu) phase not confirmed

CAID: CA958508

SupplementalData: tables s9 and s11

Case#: 14-year-old, female, asian (Chinese) patient

DiseaseAssertion: ABCA-4 associated retinal dystrophy

FamilyInfo: The effect of the deep intronic variant on splicing was validated by a minigene assay in our previous study (Tian et al., 2022). Co-segregation analysis result exhibited that the variant c.1222C>T p.(Arg408Ter) came from the female parent, and the deep intronic variant c.2919-884G>T p.[Phe973LeufsTer3,=] from the male parent

ParentalTesting: Co-segregation analysis result exhibited that the variant c.1222C>T p.(Arg408Ter) came from the female parent, and the deep intronic variant c.2919-884G>T p.[Phe973LeufsTer3,=] from the male parent

CasePresentingHPOs: HP:0000556

CasePhenotypeFreeText: ABCA4-associated retinal dystrophy

CaseNotHPOs: NR

CaseNotPhenotypeFreeText: NR

CasePreviousTesting:NR

GenotypingMethod:

In the present study, we recruited a 14-year-old female patient diagnosed with ABCA4-RD. Biallelic variants were found in this patient, including the nonsense variant c.1222C>T p.(Arg408Ter) detected by Sanger sequencing and the deep intronic variant c.2919-884G>T p.[Phe973LeufsTer3,=] identified by next-generation sequencing.

We isolated peripheral blood mononuclear cells (PBMCs) from the patient’s peripheral venous blood and introduced three episomal plasmids containing transcription factors OCT4, SOX2, NANOG, LIN28, c-MYC, KLF4, and SV40LT into PBMCs. The reprogramming iPSC line, named BIOi003-A, showed stabilized morphology (Fig. 1A) and a normal karyotype in culture (Fig. 1B). Then, the endogenous expression of two pluripotent biomarkers, POU5F1 and NANOG, was detected (Table 2). The expression levels were compared with human embryonic stem cell line H1(hESC-H1) and mesenchymal stem cell line P3 (MSC-P3) by qRT-PCR (Fig. 1C). Surface markers SSEA4 and TRA-1–81 were analyzed by flow cytometry (Fig. 1D). the ABCA4 compound heterozygous variants c.(1222C>T;2919-884G>T) p.[Arg408Ter;Phe973LeufsTer3,=] were verified by Sanger sequencing (Fig. 1E). Furthermore, the teratoma assay exhibited the differentiation capacity of this iPSC line in vivo (Fig. 1F). Short tandem repeats (STR) analysis exhibited that the PBMCs and the iPSC line came from the same patient. PCR proved negative for mycoplasma contamination

Variant: NM_000350.3(ABCA4):c.1222C>T (p.Arg408Ter) and NM_000350.3(ABCA4):c.2919G>T (p.Leu973Phe)

LegacyVariant: c.1222C>T (p.Arg408Ter) and c.2919G>T (p.Leu973Phe)

ClinVar: 99035 and NR

CAID: CA179692 and CA341275270

gnomeAD: 1:94544895 G / A and NR

MultipleGeneVariants: No

PreviouslyPublished:No

AdditionalInfo: One patient was homozygous at the ABCA-4 gene, so there is information about both variants in one annotation because there is only one patient.

PMID: 35973334

Gene: ABCA4

HGNC ID: 34

Case#: Patient 23, Female

DiseaseAssertion: STGD

FamilyInfo: Not evaluated

CasePresentingHPOs: HP:0000609, HP:0012632, HP:0007906

CaseHPOFreeText: The patient also had a history of bilateral optic nerve hypoplasia, labile intraocular pressure (IOP), and ocular hypertension without glaucoma.

CaseNotHPOs: n/a

CaseNotHPOFreeText:n/a

Genotyping Method: Not listed

PreviouslyPublished: n/a

Variant: p.Arg2107Cys:c.6319C>T and p.Gly607Arg:c.1819G>A

ClinVar: 635988, 99087

CAID: CA956906, CA226936

SupplementalData: Phenotype shown in case report with continued treatment below

PMID: 28095140

Gene: ABCA4

Disease: macular dystrophy

Case#: Patient 37 yo, F, Eastern Asian, onset at 8yo (early onset), Heterozygous, AR inheritance patterns

DiseaseAssertion:Retinitis Pigmentosa (RP)

FamilyInfo: Two brothers with RP and father with poor vision at 30 yo but no formal diagnosis

CasePresentingHPOs: HP:0003581, HP:0007737, HP:0000510, HP:000133

CaseHPOFreeText: N/A

CaseNotHPOs: HP: 0000007, HP:0007663, HP:0000505, HP:0000662

CaseNotHPOFreeText: N/A

Genotyping Method: N/A

PreviouslyPublished: Panel of genes; RP1L1, RP-GRIP1, ABCA4, and GRM6

Variant: c.5501T>C p.(Met1019Ille)

ClinVar: 1481089

SupplementalData: see tables 1 and 2 for genetic variant panel

PMID: 20647261

Gene: ABCA4

Disease: retinal phenotypes ranging from Stargardt disease to retinitis pigmentosa

PMID: 11919200

Gene: ABCA4

Disease: MD

ATPase function of G863A mutant protein was reduced ∼3-fold as compared with NBD1wt, indicating ∼70% of inhibition of the ATPase activity (Fig. 3). TheVmax (ATPase) for G863A mutant was 128 pmol/min/mg and that of the wild-type NBD1 was 584 pmol/min/mg (Table II).

Case#: 1

DiseaseAssertion: stargardt disease originally but didn;t have fishtail flecks

FamilyInfo: both unaffected parents carrying heterozygous MFSD8 variants

CasePresentingHPOs:HP:0001272

CaseHPOFreeText:at 5 years old BCVA was measured at a Snellen equivalent at 0.13 in both eyes, at age 8, BCVA had decreased to 0.07 in both eyes, complete absence of all retinal responses on full‐field flash ERG, No fishtail flecks typical of Stargardt disease were observed

CaseNotHPOs: n/a

CaseNotHPOFreeText:n/a

Genotyping Method: HaloPlex target enrichment kit amplified and sequenced using illumina, then WES

PreviouslyPublished: n/a

Variant: c.3113C>T p.(Ala1038Val)

ClinVar: https://www.ncbi.nlm.nih.gov/clinvar/variation/7894/

SupplementalData: MFSD8 variants identified

ABCA4 variant revealed but not target of research and doesn't seem to amount to anything Variantc.3113C>T p.(Ala1038Val)

Case#: Family MD-0247/ARDM-247 Proband, 12yo at onset

DiseaseAssertion: AR cone rod dystrophy

FamilyInfo:

CasePresentingHPOs:

CaseHPOFreeText: STGD diagnosed based on "bilateral central vision loss; fundus presenting with a beaten-bronze appearance and/or the presence of orange-yellow flecks in the retina from the posterior pole to the mid-periphery; fluorescein angiography showing typical dark choroid; and normal to subnormal electroretinogram (ERGs)." VA loss, VF loss, BCVA=0.05/0.1, cone-pattern on ERG

CaseNotHPOs:

CaseNotHPOFreeText:

PreviouslyPublished: PMID: 19028736

Variant: c.6410G>A (p.Cys2137Tyr); c.3386G>T (p.Arg1129Leu) found by ABCR400 + dHPLC + HRM

ClinVar: 2202779

CAID: CA341277358

SupplementalData: n/a

This variant was found in 2 control alleles. No additional details

PMID: 10958763

Gene: ABCA4

Disease: Stargardt

Case#: STGD87, 10-14yo at onset, German

DiseaseAssertion: STGD

FamilyInfo: segregation in family

CasePresentingHPOs:

CaseHPOFreeText: "The diagnosis of STGD was based on the demonstration of bilateral impairment of central vision and the appearance of perimacular and/or peripheral yellow-white flecks, with or without atrophy of the central retinal-pigment epithelium and a normal or only mildly abnormal flash electroretinogram when recorded in early stages of the disease."

CaseNotHPOs:

CaseNotHPOFreeText:

GenotypingMethod: denaturing gradient gel electrophoresis, dHPLC, and SSCP analysis, PCR amplification of individual coding exons and flanking intron sequences, direct DNA sequencing

PreviouslyPublished: n/a

Variant: Q1750X; 2588G→C in trans "Correct segregation of disease alleles was demonstrated in all 39 cases in which family samples were available for study"

ClinVar: 7879

CAID: CA119128

SupplementalData: n/a

Case#: STGD47/164, 10-14yo at onset, German

DiseaseAssertion: STGD

FamilyInfo: segregation in family

CasePresentingHPOs:

CaseHPOFreeText: "The diagnosis of STGD was based on the demonstration of bilateral impairment of central vision and the appearance of perimacular and/or peripheral yellow-white flecks, with or without atrophy of the central retinal-pigment epithelium and a normal or only mildly abnormal flash electroretinogram when recorded in early stages of the disease."

CaseNotHPOs:

CaseNotHPOFreeText:

GenotypingMethod: denaturing gradient gel electrophoresis, dHPLC, and SSCP analysis, PCR amplification of individual coding exons and flanking intron sequences, direct DNA sequencing

PreviouslyPublished: n/a

Variant: IVS13+1G→A; 2588G→C in trans "Correct segregation of disease alleles was demonstrated in all 39 cases in which family samples were available for study"

ClinVar: 7879

CAID: CA119128

SupplementalData: n/a