Case#: Case 4, Sex: Female, Age:34

DiseaseAssertion: STGD

FamilyInfo: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: Text mentions BCVA 20/100 in both eyes later became 20/240. Bilateral atrophic-appearing foveal lesions associated with yellowish-white fundus flecks at the posterior pole. Subnormal scotopic and photopic responses. Subretinal fibrosis in left eye. Hypofluorescence due to hyperplasia of RPE in left eye.

CaseNotHPOs:n/a

CaseNotHPOFreeText: No ocular trauma.

Genotyping Method: genetic analysis

PreviouslyPublished: n/a

Variant: Variant is a heterozygous mutation given as NM_000350.3(ABCA4):c.3113C>T (p.Ala1038Val)

ClinVar: Variation ID: 7894

CAID: CA119135

SupplementalData: n/a

Case#: Case 2, Sex: Male, Age:20

DiseaseAssertion: STGD

FamilyInfo: n/a

CasePresentingHPOs: HP:0007663, HP:0007401

CaseHPOFreeText: Text mentions visual acuity of 20/32 in right eye and 20/50 in left eye but later degrades to 20/200 in both eyes. pigmented changes in macula associated with flecks. Area of subretinal fibrosis in right eye. Subnormal scotopic and photopic responses. Instable fixation in both eyes with low retinal mean sensitivity. Hypofluorescent central area corresponding to macular atrophy and corresponding to flecks. Atrophic areas, some with pigment, localized in the temporal sector of the left eye which have become areas of subretinal fibrosis.

CaseNotHPOs:n/a

CaseNotHPOFreeText: Anterior segment showed a healthy ocular adnexa, and specular, transparent and 'in situ' lens, absence of any ocular trauma.

Genotyping Method: genetic analysis

PreviouslyPublished: n/a

Variant: Variant is a homozygous mutation given as NM_000350.3(ABCA4):c.571-2A>T

ClinVar: Variation ID: 1048133

CAID: CA958800

SupplementalData: n/a

PMID:23341817

Gene: ABCA4

HGNC ID: 34

Case#: Case1, Sex:Female, Age:35

DiseaseAssertion: STGD

FamilyInfo: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: Clinical Notes: the patient reported an ocular trauma in the right eye, which required hospitalization and caused sudden loss of vision at the age of 9 years. In 1998, at our first observation, visual acuity was 20/1,000 in the right eye and 20/600 in the left eye.

CaseNotHPOs:n/a

CaseNotHPOFreeText: n/a

Genotyping Method: genetic analysis

PreviouslyPublished: n/a

Variant: Variant is a heterozygous mutation given as (N965S/G1961E); NM_000350.3(ABCA4):c.2894A>G (p.Asn965Ser) /NM_000350.3(ABCA4):c.5882G>A (p.Gly1961Glu)

ClinVar: Variation ID: 236096 / Variation ID: 7888

SupplementalData: n/a

Case#: Case 3, Sex: Male, Age:21

DiseaseAssertion: STGD

FamilyInfo: n/a

CasePresentingHPOs:

CaseHPOFreeText: Text mentions BCVA of 20/200 in both eyes. Pigmentary changes in macula associated with flecks, small inferior juxta-papillar area of subretinal fibrosis in right eye, left eye legion localized in posterior pole macula temporally. Instable fixation in right eye. Low retinal mean sensitivity in both eyes.

CaseNotHPOs:n/a

CaseNotHPOFreeText: Healthy ocular adnexa and specular transparent and 'in situ' lens. Visual acuity stable. Stable fixation in left eye.

Genotyping Method: genetic analysis

PreviouslyPublished: n/a

Variant: Variant is a heterozygous mutation given as NM_000350.3(ABCA4):c.3212C>T (p.Ser1071Leu) / NM_000350.3(ABCA4):c.667A>C (p.Lys223Gln) / NM_000350.3(ABCA4):c.3607G>A (p.Gly1203Arg)

ClinVar: Variation ID: 99208 / Variation ID: 845426/ Variation ID: 417989

SupplementalData: n/a

Case#: 25 year old Female, Sikh, India, Punjab

DiseaseAssertion: EORSD

FamilyInfo: Family history for other disease were negative

CasePresentingHPOs: HP:0007401, HP:0007913

CaseHPOFreeText: Macular atrophy, scar and pigment OU, plus midperipheral pigmentation OU

CaseNotHPOs: N/a

CaseNotHPOFreeText: N/a

Genotyping Method: BGISeq-500 2 x 100-bp paired-end module, Burrows-Wheeler Aligner and Genome Analysis Tooklit HaploptypeCaller

PreviouslyPublished: N/a

Variant: NM_000350.3(ABCA4):c.6729+5_6729+19del

ClinVar: 283573

CAID: CA501163

SupplementalData: Family reported never saw well and had poor vision and nystagmus before the age of one.

Case#: German/British, 76

DiseaseAssertion: EOSRD

FamilyInfo: Grandparents from Germany and the United Kingdom

CasePresentingHPOs: HP:0007401, HP:0007913

CaseHPOFreeText: Macular atrophy and pigmentation, peripheral pigmentation, early-onset severe retinal dystrophy

CaseNotHPOs: N/a

CaseNotHPOFreeText: N/a

Genotyping Method: BGISeq-500 2 x 100-bp paired-end module, Burrows-Wheeler Aligner and Genome Analysis Tooklit HaploptypeCaller

PreviouslyPublished: n/a

Variant: c.1622T>C, c.4326C>A, and c.3113C>T

ClinVar: 99067, 417991, 7894

CAID: CA226911, CA957653, CA119135

SupplementalData: The c.1622T>C variants and c.3133C>T are thought to be same gene copy

Case#: 39 Year Old Female, India Punjab

DiseaseAssertion: EORSD

FamilyInfo: Family history for other disease was negative, husband was first cousin and their son had normal vision

CasePresentingHPOs: HP:0007401, HP:0007913

CaseHPOFreeText: Macular atrophy and pigmentation, yellowish flecks

CaseNotHPOs: N/a

CaseNotHPOFreeText: N/a

Genotyping Method: BGISeq-500 2 x 100-bp paired-end module, Burrows-Wheeler Aligner and Genome Analysis Tooklit HaploptypeCaller

PreviouslyPublished: N/a

Variant: NM_000350.3(ABCA4):c.6729+5_6729+19del

ClinVar: 283573

CAID: CA501163

SupplementalData: Confirmed that she had never seen properly or normally, marked horizontal nystagmus and poor pupil reaction to light

PMID: 40465261

Gene: ABCA4

HGNC ID: 34

PMID: 33899203

Gene: ABCA4

HGNC ID: 34

Case#: Case1, Sex:Male, Age:19

DiseaseAssertion: STGD

FamilyInfo: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: Clinical Notes: Peripapillary sparing, discrete flecks; nummular atrophy. General notes: Panretinal cone dysfunction with preserved rod function was documented by ERG

CaseNotHPOs:n/a

CaseNotHPOFreeText: n/a

Genotyping Method: Whole exome sequencing data generation. Additional sequencing targeted amplification fo PRPH2 and ELOVL4 using PCR.

PreviouslyPublished: n/a

Variant: Variant 1 given as p.N965S; NM_000350.3(ABCA4):c.2894A>G (p.Asn965Ser). Variant 2 given as p.R2038W; NM_000350.3(ABCA4):c.6112C>T (p.Arg2038Trp)

ClinVar: Variation ID: 236096; Variation ID: 99430

CAID: CA958124; CA227368

SupplementalData: Proband variant information given in Table 1.

Case#: Case 6, Sex:Female, Age:34

DiseaseAssertion: STGD

FamilyInfo: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: Clinical Notes: Classic Stargardt. General notes: participant had classic features of STGD and field ERG showed abnormal cone responses with preserved rod function.

CaseNotHPOs:n/a

CaseNotHPOFreeText: n/a

Genotyping Method: Exome sequencing data generation. Additional sequencing targeted amplification fo PRPH2 and ELOVL4 using PCR.

PreviouslyPublished: n/a

Variant: ABCA4, NM_000350.3(ABCA4):c.2966T>C (p.Val989Ala)

ClinVar: Variation ID: 99180

SupplementalData: Proband variant information given in Table 1.

Case#: Case2, Sex:Female, Age:15

DiseaseAssertion: STGD

FamilyInfo: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: Clinical Notes: Few yellowish Flecks without autofluorescence. General notes: participant presented with atypical macular degeneration.

CaseNotHPOs:n/a

CaseNotHPOFreeText: n/a

Genotyping Method: Exome sequencing data generation. Additional sequencing targeted amplification fo PRPH2 and ELOVL4 using PCR.

PreviouslyPublished: n/a

Variant: Variant 1 given as p.G1961E; NM_000350.3:c.5882G>A p.(Gly1961Glu) . Variant 2 given as p.Q636X; NM_000350.3(ABCA4):c.1906C>T (p.Gln636Ter).

ClinVar: Variation ID: 7888 ; Variation ID: 265012

CAID: ; CA10588302

SupplementalData: Proband variant information given in Table 1.

PMID: 22863181

Gene: ABCA4

HGNC ID: 34

PMID:32043016

Gene: ABCA4

HGNC ID: 34

PMID: 26527198

Gene: ABCA4

HGNC ID: 34

PMID: 26527198

Gene: ABCA4

HGNCID: HGNC:34

Case#: 47-year-old female, sibling of patient 1.

DiseaseAssertion: Discordant STGD phenotype

FamilyInfo: The mother was found to harbour p.L541V/p.A1038V, and the father carried the p.R811C mutation; both of whom were asymptomatic with normal retinal examination (Fig. 1). ABCA4 screening detected three variants: two variants p.L541V and p.A1038V – commonly co-inherited in a complex allele in STGD (Maugeri et al. 2000) – and a third novel variant p.R881C (Fig. 1). Patient 1 had all three variants

CasePresentingHPOs: HP:0007401, HP:0025010, HP:0011507

CasePhenotypeFreeText: Patient 2 is the 47-year-old sister of patient 1. At initial examination in 1994, she reported a central scotoma. VA was 6/9 in both eyes with bilateral subtle foveal atrophy and perifoveal yellowish-white flecks (Fig. 1). By 2003, foveal atrophy had progressed with more perifoveal flecks (Fig. 1). In 2012, her VA was 6/12 bilaterally, but fundus findings remained stable (Fig. 1). AF imaging demonstrated a mottled signal within the central macula, optical coherence tomography showed outer retinal disruption confined to the central macula

CaseNotHPOs: N/A

CaseNotPhenotypeFreeText: N/A

CasePreviousTesting: The article mentions ABCA4 screen but does not go into detail. However, it does say,”(patient 2) harboured the complex allele (p.L541V/p.A1038V)”

GenotypingMethod: Again only mentioned ABCA4 screening without going into detail.

Variant: NM_000350.3:c.1621C>G and NM_000350.3(ABCA4):c.3113C>T

LegacyVariant: c.1621C>G (p.Leu541Val) and c.3113C>T(p.Ala1038Val)

CAID: CA341280463 and CA119135

gnomeAD: chr1-94063251-G-C and chr1-94043413-G-A

PreviouslyPublished: N/A

AdditionalInfo: Figure 1 provides information about the imaging of patients’ eyes that helps determine phenotype.

Case#: Female, age 44 years old

DiseaseAssertion: Discordant STGD phenotype

FamilyInfo: Information revolving the sister of this patient is given as well as they both have a discordant STGD phenotype. Additionally, it mentions that the parents each harboured a mutation but were asymptomatic/had normal examination results.

CasePresentingHPOs: HP:0001141, HP:0007401, HP:0030602

CaseHPOFreeText: At 23 central vision was deteriorating and patient had a VA of 6/36 in the right eye and 6/60 in the left. Through fundus photography, bilateral yellow/white flecks were found at the posterior pole. 12 years later, her VA was retested and it was 6/60 in both eyes. After autofluorescnece (AF) imaging was done, there was localized low signal at the macula found with abnromal foci. In 2008 her macular atrophy had enlarged and the flecks were less apparent.

CaseNotHPOs: N/a

CaseNotHPOFreeText: In this article there was not a phenotype presented that was normal.

CasePreviousTesting: It mentioned that there were two previously reported variants on the same allele detected in the siblings and one unique novel variant on the second allele for this patient. However, the testing they used was not listed, it just stated that the variants were found through sequencing. For this patient the variants were p.L541P/p.A1038V and p.R881C.

GenotypingMethod: Just mentioned sequencing and ABCA4 screening to look for two variants p.L541V and p.A1038V and a third novel variant p.R881C.

PreviouslyPublished: N/a

Variant: 1) NM_000350.3(ABCA4):c.1622T>C (p.Leu541Pro) 2) NM_000350.3(ABCA4):c.3113C>T (p.Ala1038Val) 3) N/a

ClinVar ID: 1) 99067 2) 7894 3) N/a

**CAID: ** 3) Because there was not a reference or alternate allele provided in this article I was unable to find a CAID for p.R881C.

gnomAD: 1) Highest minor allele frequency was 0.00017 (https://www.ncbi.nlm.nih.gov/clinvar/variation/99067/) 2) Highest minor allele frequency was 0.00188 (https://www.ncbi.nlm.nih.gov/clinvar/variation/7894/) 3) N/a

SupplementalData: Figure 1 had information regarding imaging and other testing done on the patient that is vital for phenotypic characterization. Also, it mentions a variant known as p.R881C, but was unable to find anything on ClinVar or gnomAD.

Case#: 80 yo M, siagonosed at 18 yo

DiseaseAssertion: Stargardt

FamilyInfo: one of his 2 sisters had same mutation to ABCA4

CasePresentingHPOs:,HP:0007663, HP:0008002

CaseHPOFreeText: RPE hyperplasia, atrophy of the inner and outer photoreceptor segments, the outer nuclear layer, and the outer plexiform layer, with scanty RPE cells in the macular area

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

Genotyping Method: N/A

PreviouslyPublished: none

Variant: G1961E

ClinVar: 7888

SupplementalData: See supplemental Material for further look at the probands Human Embryonic Stem Cell-derived Retinal Pigment Epithelium Transplantation

Case#: Female, 69yo, Puerto Rican

DiseaseAssertion: STDG1

FamilyInfo: Parents were first cousins (consanguinity), no other family history reported

CasePresentingHPOs: HP:0030603, HP:0007754, HP:0000512, HP:0008020, HP:0000603

CaseHPOFreeText: progressive vision loss, severe reduction in visual acuity (counting fingers at 5’ and 3’), bilateral central scotoma, extensive central macular atrophy, retinal pigment epithelium atrophy and pigment hyperplasia, multifocal retinal atrophy, central hypoautofluorescence with peripheral expansion, reduced macular thickness and volume on OCT, abnormal visual field (marked mean deviation)

CaseNotHPOs: HP:0000510

CaseNotHPOFreeText: normal rod response on full-field electroretinogram

Genotyping Method: Next-generation sequencing (Invitae Corporation, San Francisco, California)

PreviouslyPublished: N/A

Variant: NM_000350.3(ABCA4):c.5714+5G>A

ClinVar: ClinVarID:99403

CAID: N/A

SupplementalData: N/A

PMID: 36471740

Gene: ABCA4

HGNC ID: 34

PMID:31721179

Gene: ABCA4

HGNC ID: 34

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

PMID: 10634626 Gene: ABCA4 HGNCID: HGNC:34

Fifty-two unrelated French patients referred to the Eye University Clinic of Creteil for unilateral or bilateral exudative AMD due to any type of choroidal neovascularization (well-defined, occult, or vascularized pigment epithelium detachment) were included in this study.

SSCP analysis in a control population, obtained from 90 unrelated French individuals without any complaint of visual impairment. Our control group was not age- or sex-matched, and no ophthalmological examination was performed for these individuals.

MonDO:

Case: DiseaseAssertion: Age-related macular degeneration FamilyInfo: CasePresentingHPOs: CaseHPOFreeText: CaseNOTHPOs: CaseNOTHPOFreeText: CasePreviousTesting:

GenotypingMethod: entire coding sequence of the ABCR gene using a combination of single-strand conformation polymorphism (SSCP) and direct sequence analysis of each exon

Variant: "ABCR" (ABCA4), p.Ser2255ile

PMID: 35973334

Gene: ABCA4

HGNC ID: 34

PMID: 35973334

Gene: ABCA4

HGNC ID: 34

PMID: 30186147

Gene: ABCA4

HGNC ID: 34

Case#: 1 female, 12 years old.

DiseaseAssertion: bilateral stage 2B Coats disease. ABCA4 gene mutations were found upon genetic analysis but Stargardt disease was not diagnosed.

FamilyInfo: Single affected individual. Past medical history and family history was reported as normal. No additional information about family is provided in text.

CasePresentingHPOs: HP:0007663 - Reduced visual acuity, HP:0001147 - Retinal exudate, HP:0007763 - Retinal telangiectasia, HP:0025355 - Retinal arteriolar macroaneurysms, HP:0011505- Cystoid macular edema, HP:0020032 - Hyperreflective retinal dots on OCT, HP:0001045 - Vitiligo

CaseHPOFreeText: bilateral significant capillary nonperfusion noted mostly in the temporal retinal periphery together with light-bulb-like capillary dilations and staining of telangiectatic vessels. Mild intravitreal hemorrhage

CaseNotHPOs: HP:0012045 - Retinal flecks, HP:0025010 - Foveal atrophy, HP:0000603 - Central scotoma, HP:0000556 - Retinal dystrophy, HP:0000512 - Abnormal electroretinogram

CaseNotHPOFreeText: Relatively normal foveal architecture.

Genotyping Method: Genetic analysis was performed using Sanger sequencing for the NDP gene, which revealed no pathogenic variants. Exome sequencing was then used with the Illumina HiSeq 2500 platform, which identified two compound heterozygous variants in the ABCA4 gene. Lastly, no mutations were found in the TINF2 gene.

PreviouslyPublished: N/A

Variant: NM_000350.3(ABCA4):c.1373C>T (p.Arg458Cys), NM_000350.3(ABCA4):c.5882G>A (p.Gly1961Glu)

ClinVar: Variation ID: 7888 ( for p.Arg458Cys variant however I believe this is mislabeled for this variant NM_000350.3(ABCA4):c.5882G>A (p.Gly1961Glu), no variantion ID found for NM_000350.3(ABCA4):c.1373C>T (p.Arg458Cys)

CAID: N/A

SupplementalData: N/A

Case:RP3,03, male proband with first symptoms as 18 years old. DiseaseAssertion:RP19 FamilyInfo:Proband was born in a consangiuineous family of Moroccan origin. Parents were unaffected. InheritancePattern:AutosomalRecessive CasePresentingHPOs:HP:0007994,HP:0000510,HP:0100014 CaseHPOFreeText:Difficulty with dark adaptation, Fig 4B severe impairment of the entire visual field. Fig 4A Scotopic and photopic ERG traces were altered indicating rod and cone photoreceptor dysfunctions. Macular OCT showed relative preservation of the foveal structure. Epiretinal membrane formation was observed. CaseNOTHPOs:HP:0007667 CaseNOTHPOFreeText:absence of cystic spaces CasePreviousTesting: GenotypingMethod:Whole exome sequencing MultipleGeneVariants: compound heterozygous GeneName:ABCA4 Variant:NM_000350.3(ABCA4):c.5908C>T (p.Leu1970Phe) ClinVarID :7892 gnomAD:0.00362 GeneName:ABCA4 Variant:NM_000350.3(ABCA4):c.6148G>C (p.Val2050Leu) ClinVarID :7884 gnomAD:0.00308

PMID: PMC7883928

Gene: ABCA4

HGNC ID: 34

Case#: RP3.03, 23yo, 21yo on set, Moroccan

DiseaseAssertion: Retinitis Pigmentosa (RP19)

FamilyInfo: Born into a consanguineous family, parents are unaffected, has five unaffected siblings

CasePresentingHPOs: HP:0000505, HP:0007675, HP:0001133, HP:0007994, HP:0007843, HP:0000510, HP:0000580, HP:0007703

CaseHPOFreeText: Abnormal epiretinal membrane formation, Altered ERG traces, rod and cone photoreceptor dysfunctions, hyper fuorescence ring surrounding macula and peripheral retina, absence of cystic spaces

CaseNotHPOs: HP:0000551

CaseNotHPOFreeText: Central vision loss

Genotyping Method: Genomic DNA was extracted using QIAamp DND Blood Mini Kit, DNA underwent WES by BGI Tech Solutions, DNA was captured by MGIEasy Exome Capture V4 Probe Set, then Alligned using the Burrows-Wheeler Aligner and HaplotypeCaller of GAWK

PreviouslyPublished: CRB1, PDE6B

Variant: c.5908C>T, c.6148G>C

ClinVar: 7892, 7884

SupplementalData: Clinical data (table 1, figure 5), Genetic analysis (table 2), Patient Pedigree (figure 1.)

Case#: 43 year old woman II:2

DiseaseAssertion: Stargardt disease (STGD1)

FamilyInfo: none of family had co-existing systemic disorders, father carried variant, probands affected suster did not

CasePresentingHPOs:HP:0000007

CaseHPOFreeText: loss of ellipsoid zone, mascular dystrophy with features of bull's eye maculopathy,

CaseNotHPOs: na

CaseNotHPOFreeText: na

Genotyping Method: sanger sequencing

PreviouslyPublished: n/a

Variant: c.4685 T > C, p.(I1562T)

ClinVar: not found

CAID: not found

SupplementalData: probands affected sister did not carry the ABAA4 variant, indicating ABCA4 was not relevant to mascular dystrophy in family, CRX variant was also found

Case Annotation Template

Case#: Patient 40, female, Caucasian, onset at 2-3yo, Spain

DiseaseAssertion: STGD

FamilyInfo: Brother and Sister not affected showed heterozygous patterns of (p.His423Arg (c.1268A>G), IVS33+48 C>T) mutations. R1129L mutation heterozygous in the unaffected father; mutation not found in the unaffected mother. Patient has 4yo asymptomatic female child

CasePresentingHPOs: HP:0000505, HP: 0011463, HP:0030786, HP:0007641, HP:0007663, HP: 0000610, HP: 0007814, HP:0000007

CaseHPOFreeText: Macular yellow flecks, macular dystrophy

CaseNotHPOs: N/A

CaseNotHPOFreeText: Normal biomicroscopy

Genotyping Method: Conventional mutational screening on 77 STGD families and screened on the ABCR400 Microarray. Haplotype analyses, HR karyotypes, and MLPA were also performed.

PreviouslyPublished: N/A

Variant: p.Arg1129Leu (c.3386G>T)

CAID: CA227116

SupplementalData:N/A

PMID: 17277736

Gene: ABCA4

HGNC ID: 34

PMID: 35413457

Gene: ABCA4

HGNC ID: 34

Case#: Patient 1, male, Caucasian, onset at 20yo, USA

DiseaseAssertion: ABCA4

FamilyInfo: No family history of retinal disease.

CasePresentingHPOs: HP:0007677, HP:0030603, HP:0030500, HP:0030636, HP:0004328, HP:0012372

CaseHPOFreeText: Bilateral central vision loss, progressive decline in visual acuity (20/60 both eyes), foveomacular vitelliform lesions with fluid accumulation, optical gap lesions progressing to cavitated appearance after fluid resorption, thinning and abnormal reflectivity of photoreceptor layers, near-infrared autofluorescence abnormalities in lesion-adjacent regions

CaseNotHPOs: HP:0000510, HP:0000511

CaseNotHPOFreeText: No generalized rod or cone dysfunction on full-field electroretinogram, EOG findings not consistent with bestrophinopathy (Arden ratio 1.62)

Genotyping Method: Exome sequencing

PreviouslyPublished: None

Variant: NM_000350.3(ABCA4):c.5882G>A (p.Gly1961Glu), NM_000350.3(ABCA4):c.4139C>T (p.Pro1380Leu)

ClinVar: ClinVarID:7888, ClinVarID:7904

CAID: N/A

SupplementalData: N/A

PMID: 20149343

Gene: ABCA4

HGNC ID: 34

PMID: 10612508

Gene: ABCA4

HGNC ID: 34

Case#: Patient 4, Female, Caucasian, 33yo

DiseaseAssertion: STGD1

FamilyInfo: One of eight siblings; four affected. Disease segregates with ABCA4 variants consistent with autosomal recessive inheritance. Parents are deceased and can't be tested.

CasePresentingHPOs: HP:0007663, HP:0007754, HP:0025147, HP:0007924, HP:0011507

CaseHPOFreeText: gradual decline in visual acuity over 9 years, BCVA 20/300 OU, bilateral beaten-bronze appearance of the macula, numerous perimacular yellow flecks, fluorescein angiography showing hyperfluorescence in the posterior pole and dark choroid in the periphery

CaseNotHPOs: N/A

CaseNotHPOFreeText: absence of central hypofluorescence on fluorescein angiography (present in affected siblings but not this patient)

Genotyping Method: SSCP analysis; Taq Dyedeoxy Terminator Cycle Sequencing kit

PreviouslyPublished: N/A

Variant: NM_000350.3(ABCA4):c.2588G>C (p.Gly863Ala), NM_000350.3(ABCA4):c.161G>A (p.Cys54Tyr)

ClinVar: ClinVarID:7879, ClinVarID:99065

CAID: N/A

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

Case#: Male, 60

DiseaseAssertion: Stargardt disease

FamilyInfo: Possible macular degeneration in father

CasePresentingHPOs: HP:0007401, HP:0025010

CaseHPOFreeText: Vision was 20/40 in the right eye and 20/20 in the left eye. Dilated examination revealed scattered subretinal yellow flecks and macular atrophy bilaterally. The flecks were hyperautofluorescent. Fluorescein angiography showed obscuration of background choroidal fluorescence and window defects associated with the atrophy. Optical coherence tomography showed foveal atrophy and hyperreflective deposits at the level of the retinal pigment epithelium.

CaseNotHPOs: N/A

CaseNotHPOFreeText: Anterior segment examination was unremarkable. Normal cone and rod responses.

CasePreviousTesting: Target enrichment and next-generation sequencing were performed.

GenotypingMethod: N/A

PreviouslyPublished: N/A

Variant: Variant 1: NM_000350.3:c.5461-10T>C Variant 2: NM_000350.3:c.5603A>T

ClinVar: Variant 1: 92870 Variant 2: 99390

gnomAD: N/A

SupplementalData: Figure 1 shows fundus photographs (A and B), fundus autofluorescence (C and D), fluorescein angiography (E and F), near-infrared reflectance imaging (G), and an optical coherence tomography scan (H).

Case #: Male, 60 years old

DiseaseAssertion: He was diagnosed with late-onset Stargardts disease.

FamilyInfo: Has a family history with his father possibly having macular degeneration.

CasePresentingHPOs: HP:0007401, HP:0025010, HP:0012045 (sub-retinal/yellow), HP:0030602

CaseHPOFreeText: Proband presents with blurry vision (right eye) from over the past two years, with the right eye having 20/40 vision, while the left was 20/20. In addition to this, through dilation scattered subretinal yellow flecks and macular atrophy bilaterally, were revealed. The flecks were hyperautofluorescent. Obscuration of background choroidal fluorescence and window defects were also found. As well as foveal atrophy and hyperreflective deposits (RPE).

CaseNotHPOs: None found

CaseNotHPOFreeText: No abnormalities in the anterior segment examination. Through a full-field electroretinogram, normal rod and cone responses were found.

Genotyping Method: The genotyping was done through the use of target enrichment and next-generation sequencing.

PreviouslyPublished: N/a

Variant: 1) NM_000350.3(ABCA4):c.5461-10T>C 2) NM_000350.3(ABCA4):c.5603A>T (p.Asn1868Ile)

ClinVar: 1) 92870 2) 99390

CAID: N/a

gnomAD: 1) Highest minor allele frequency was 0.00031 (https://www.ncbi.nlm.nih.gov/clinvar/variation/92870/) 2) Highest minor allele frequency was 0.05787 (https://www.ncbi.nlm.nih.gov/clinvar/variation/99390/)

SupplementalData: I was able to find a variant (NM_000350.3(ABCA4):c.[5461-10T>C;5603A>T]) that addresses both of the variants. Also, Fig.1 shows the phenotype of the proband through tests.

PMID: 41063816 Gene:ABCA4 HGNC:34

PMID: 41063816

Gene: ABCA4

HGNC ID: 34

PMID: 18334942

Gene: ABCA4

HGNC ID: 34

Case#: patient 33, male, Spanish

DiseaseAssertion: STGD

FamilyInfo: Figure 1. Both parents and two siblings of the proband were heterozygous for ABCA4 c.5413A>G allele. Sister affected despite heterozygosity.

CasePresentingHPOs: HP:0007663, HP:0030786, HP:0007722

CaseHPOFreeText: myopia, astigmatism, opafication of posterior pole of lens, hyperpigmentation, a few central yellowish flecks, shallow peripheral scotomas in both eyes, full-field ERG response showed slightly reduced—but still within the normal range—amplitudes for rod, mixed cone-rod, cone single flash, and cone flicker, respectively.

CasePreviousTesting: n/a

GenotypingMethod: microarray

PreviouslyPublished: 11385708, 12442277

Variant: ABCA4 p.Asn1805Asp (c.5413A>G)

ClinVar: 99373 https://www.ncbi.nlm.nih.gov/clinvar/variation/99373/?term=%22ABCA4%22%5BGENE%5D+AND+%22p.Asn1805Asp%22%5BVARNAME%5D+AND+%22(c.5413A%3EG)%22%5BVARNAME%5D

gnomAD: 0.000009292 https://gnomad.broadinstitute.org/variant/1-94014590-T-C?dataset=gnomad_r4

PMID: 18334942

Gene: ABCA4

HGNCID: 34

Case#: patient 26, female, Spanish

DiseaseAssertion: early onset RP

FamilyInfo: Figure 1. One brother homozygous for ABCA4 c.5413A.G allele, parents and one brother heterozygous for ABCA4 c.5413A>G allele. All three brothers and father carriers of p.Cys948Tyr allele on the CRB1 gene. Mother heterozygous for p. Trp822ter (c.2465G>A)

CasePresentingHPOs: HP:0000662, HP:0001133, HP:0007663,

CaseHPOFreeText: hyperopia, astigmatism, nystagmus, roundish pigments distributed across entire retina including peripheral retina, posterior pole, and macular region, filiform constriction on retinal vessels.

CasePreviousTesting: N/A

GenotypingMethod: Microarray

PreviouslyPublished: 11385708, 12442277

Variant: ABCA4 p.Asn1805Asp (c.5413A>G)

ClinVar: 99373 https://www.ncbi.nlm.nih.gov/clinvar/variation/99373/?term=%22ABCA4%22%5BGENE%5D+AND+%22p.Asn1805Asp%22%5BVARNAME%5D+AND+%22(c.5413A%3EG)%22%5BVARNAME%5D

gnomAD: 0.000009292 https://gnomad.broadinstitute.org/variant/1-94014590-T-C?dataset=gnomad_r4

PMID: 41458191 Gene: ABCA4 HGNC: 34

PMID: 25375877

Gene: ABCA4, RPGR

HGNC ID: 34, 10295

PMID: 28611652

Gene: ABCA4

HGNC ID: 34

PMID: 36833411

Gene: ABCA4

HGNC ID: 34

Case#: Case 3, male, onset at 24yo, Italy

DiseaseAssertion: STGD1

FamilyInfo: third-degree consanguineous parents; both parents healthy heterozygous carriers of the ABCA4 variant

CasePresentingHPOs: HP:0000529, HP:0007754, HP:0000518

CaseHPOFreeText: progressive deterioration of vision at age 24. Bilateral macular dystrophy and diffuse lens opacities on ophthalmologic examination. OCT, ERG, and VEP consistent with Stargardt maculopathy.

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

Genotyping Method: NGS (custom enrichment panel), Illumina NextSeq550; variant confirmed by Sanger sequencing.

PreviouslyPublished: n/a

Variant: NM_000350.3(ABCA4):c.2828G>A (p.Arg943Gln), homozygous; rs1801581

ClinVar: Variation ID: 7913

CAID: n/a

SupplementalData: n/a

PMID: 29765157

Gene: ABCA4

HGNC ID: 34

Case#: 1 male, 24 years old, from consanguineous parents, Somali ancestry.

DiseaseAssertion: ABCA4-related retinopathy Stargardt disease

FamilyInfo: Single affected individual consanguineous parents, Somali ancestry. No additional information about family is provided in text.

CasePresentingHPOs: HP:0000572- reduced central vision, HP:0001102- Angioid streaks, HP:0007980- retinal pigment epithelium atrophy, HP:0007401- Macular atrophy, HP:0000630- Abnormal retinal arterial/arteriolar morphology

CaseHPOFreeText: Presents with reduced central vision, Fundus autofluorescence (FAF) showed angioid streaks, reduced signal in the central macula indicative of retinal pigment epithelium atrophy. Electrophysiological testing showed severe macular dysfunction with generalized retinal involvement.

CaseNotHPOs: HP:0200070- Peripheral retinal atrophy

CaseNotHPOFreeText: Peripheral retina appears unaffected after ultra-widefield FAF imaging

Genotyping Method: PCR-amplification and Sanger sequencing of ABCA4 on Exon 42, Stargardt/Macular dystrophy SmartPanel v5; Molecular Vision Laboratory, Hillsboro, Oregon tested DNA for mutations which confirmed findings of ABCA4, with no additional pathogenic mutations found.

PreviouslyPublished: PMID: 22261738, 1 male, 24 years old, from consanguineous parents, Somali ancestry presenting with reduced vision.

Variant: NM_000350.3(ABCA4):c.5882G>A (p.Gly1961Glu)

ClinVar: Variation ID: 7888

CAID: N/A

SupplementalData: N/A

PMID: 34008801

Gene: ABCA4

HGNC ID: 34

PMID: 34008801

Gene: ABCA4

HGNC ID: 34

PMID: 34008801

Gene: ABCA4

HGNC ID: 34

PMID: 28118664

Gene: ABCA4

HGNC ID: 34

Case#: 19 year old woman

DiseaseAssertion: Stargardt disease (STGD)

FamilyInfo: no family history of ocular disease

CasePresentingHPOs:HP:0025158

CaseHPOFreeText:20/25 in the right eye and 20/25-1 in the left eye, small irregular perifoveal lesions of both increased and decreased autofluorescence

CaseNotHPOs:na

CaseNotHPOFreeText:na

Genotyping Method: next gen sequencing

PreviouslyPublished: na

Variant: c.6079C > T, p.(Leu2027Phe) c.4139C > T, p.(Pro1380Leu)

ClinVar: not found not found

CAID: not found not found

SupplementalData: “black shadow” in the right eye after getting hit by a volley ball

PMID:39917552

Gene: ABCA4

HGNC ID: 34

PMID: 10874631

Gene: ABCA4

HGNC ID: 34

Case#: patient 34, female

DiseaseAssertion: RP19

FamilyInfo: paternal first cousin with STGD, healthy father heterozygous for 1938-1 G>A splice mutation, mother homozygous for normal allele

CasePresentingHPOs: HP:0000662, HP:0007663, HP:0007737, HP:0001133

CaseHPOFreeText: choriocapillaris atrophy, severe concentric reduction of the visual field, abrogation of rod function

Genotyping Method: PRISMTM Ready Reaction Sequencing Kit on an automatic fluorometric DNA sequencer

PreviouslyPublished: N/A

Variant: NM_000350.3(ABCA4):c.1938-1G>A

ClinVar: 99106 https://www.ncbi.nlm.nih.gov/clinvar/variation/99106/?term=%22ABCA4%22%5BGENE%5D+AND+%22(c.1938-1G%3EA)%22%5BVARNAME%5D

gnomAD: 0.000002488 https://gnomad.broadinstitute.org/variant/1-94060760-C-T?dataset=gnomad_r4

PMID: 10874631

Gene: ABCA4

HGNC ID: 34

Case#: patient 34, female

DiseaseAssertion: STGD

FamilyInfo: paternal first cousin with RP19, healthy father heterozygous for 1938-1 G>A splice mutation

CasePresentingHPOs: HP:0007663, HP:0000608, HP:0000603,

CaseHPOFreeText: yellowish flecks

Genotyping Method: PRISMTM Ready Reaction Sequencing Kit on an automatic fluorometric DNA sequencer

PreviouslyPublished: N/A

Variant: NM_000350.3(ABCA4):c.1938-1G>A

ClinVar: 99106 https://www.ncbi.nlm.nih.gov/clinvar/variation/99106/?term=%22ABCA4%22%5BGENE%5D+AND+%22(c.1938-1G%3EA)%22%5BVARNAME%5D

gnomAD: 0.000002488 https://gnomad.broadinstitute.org/variant/1-94060760-C-T?dataset=gnomad_r4

PMID: 22661473

Gene: ABCA4

HGNCID: HGNC:34

Stage I disease was characterized by central macular atrophy with parafoveal or perifoveal flecks. Where flecks were more numerous and extended anterior to the vascular arcades and/or nasal to the optic disc, then patients were classified as having stage II disease. Although partial resorption of flecks may be present in this stage, more complete resorption of flecks was indicative of stage III disease with choriocapillaris atrophy also within the macula. Widespread RPE and chorioretinal atrophy throughout the fundus defined stage IV disease.27 Based on this classification system, the patients in our study were subdivided into 2 groups, that is those with milder disease (stage I or II) and those with more severe disease (stage III or IV) phenotypes.

Case#: Male, Family #1, Patient #1, II:1 in pedigree

DiseaseAssertion: Hypomorphic Stargardt disease

FamilyInfo: Paternal female cousin also has hypomorphic Stargardt disease and both of them carry the complex allele p.[L541P; A1038V] and p.N1868I. Additionally, their paternal aunt was diagnosed with Stargardt disease. This information can be found on Fig.1.

CasePresentingHPOs: HP:0000622, HP:0025010

CaseHPOFreeText: This proband developed blurred vision at age 30. The foveal atrophy affects the left eye. In the first visit at 33.9 years old patient presents with 20/25-3 Snellen VA OD, 20/70-2 Snellen VA OS, 0.16 LogMAR VA OD, 0.58 LogMAR VA OS, and stage 1. In the last visit at age 40.7, the patient had a 20/40-2 Snellen VA OD, a 10/80-1 Snellen VA OS, 0.34 LogMAR VA OD, 0.92 LogMAR VA OS, and was now in stage 2. In a Goldmann Visual Field test, they found central scotomas II4e; mild-moderate constriction II2e.

CaseNotHPOs: N/a

CaseNotHPOFreeText: The proband maintained some relative foveolar sparing in his right eye and had a BCVAs of 20/4022 (test done at 40 years old).

Genotyping Method: Genetic testing was performed at Columbia University. It was not stated which method this proband underwent, so the genetic testing could have been one of the following: "The entire ABCA4 gene locus was sequenced in 17 patients; the ABCA4 gene, including all exons and intron/exon boundaries were sequenced in 4 patients. In the remaining 6 cases representing family members, only targeted testing was performed."

PreviouslyPublished: N/a

**Variant: ** M1) NM_000350.3(ABCA4):c.5603A>T M2) NM_000350.3(ABCA4):c.1622T>C (p.Leu541Pro)

ClinVar: M1) 99390 M2) 99067

CAID: N/a

gnomAD: M1) The highest minor allele frequency was 0.05787 (https://www.ncbi.nlm.nih.gov/clinvar/variation/99390/) M2) The highest minor allele frequency was 0.00017 (https://www.ncbi.nlm.nih.gov/clinvar/variation/99067/)

SupplementalData: Table 1. provided patient information for those with p.N1868I ABCA4 Stargardt disease and the associated ABCA4 mutations. Fig.1. shows the pedigrees of the families. Fig.3. shows Macular SD-OCT line profiles for some of the patients. Table 2. describes the onset/symptoms of the patients with p.N1868I ABCA4 Stargardt Disease. Table 3. shows Visual Acuity and Stage at Baseline and Most Recent Follow-up in Patients With p.N1868I ABCA4 Stargardt Disease. Fig.4. shows BCVA better eye vs Duration since first examination for the patients. Table 4. shows clinical findings in the patients.

Case#: Female, 6 years old, presenting with vision loss and behavioral changes.

Disease Assertion: After testing she was diagnosed with Stargardt disease

FamilyInfo: No family history of vision loss in childhood

CasePresentingHPOs: HP:0000572, HP:0000708, HP:0007988, HP:0008001, HP:0030609

CaseHPOFreeText: Showed changes in behavior through increased reliance on parents, and "Over the past six months, she had become increasingly emotional, anxious, frustrated, with difficulty concentrating on simple tasks". Additionally, beyond just the visual loss, she presented with 20/200 OU on her visual acuity test, as well as 1/14 Ishihara color plates with either eye. She also would overlook the top of objects, showed retinal arteriolar narrowing, had degeneration in the ellipsoid zone, and multiple hyperreflective granular deposits.

CaseNotHPOs: HP:0000648, HP:0000486, HP:0000639, HP:0000613, HP:0001336, HP:0011145 (just seizures in general, this was the closest I could find)

CaseNotHPOFreeText: Beyond the HPOs above, she also demonstrated a lack of seizures and had no other neurologic dysfunction. Additionally, she demonstrated brisk pupillary responses without paradoxical pupillary constriction to darkness. She also had normal results for the slip lamp biomicroscopy and tonometry.

CasePreviousTesting: Previously tested for myoclonus, seizures, and neurologic dysfunction with no history of any (did not describe the testing methods for such).

Genotyping Method: Although the genetic testing came up negative in relation to neuronal ceroid lipofuscinosis and the mutations associated, Stargardt disease was confirmed through whole genome sequencing. This revealed "compound heterozygosity for 2 pathogenic variants in the ABCA4 gene (c.3007 C > T p.Q1003X and c768 G > T PV256 = )".

Previously Published: n/a

Variant: NM_000350.3(ABCA4):c.3007C>T (p.Gln1003Ter) & NM_000350.3(ABCA4):c.768G>T (p.Val256=)

ClinVarID: 4538557 & 99505

CAID: n/a

gnomAD: For the first ID the data for this one was absent from gnomAD (https://www.ncbi.nlm.nih.gov/clinvar/variation/4538557/?term=%22NM_000350.3(ABCA4)%3Ac.3007C%3ET+(p.Gln1003Ter)%22%5BVARNAME%5D). While the other ID had the minor allele frequency of 0.00009 (highest compared to others available) (https://www.ncbi.nlm.nih.gov/clinvar/variation/99505/?term=%22NM_000350.3(ABCA4)%3Ac.768G%3ET%22%5BVARNAME%5D+AND+%22(p.Val256%3D)%22%5BVARNAME%5D)

Supplemental Data: Introduction was section in this article that discusses symptoms present as well as the re-diagnosis of Stargardt after the initial incorrect diagnosis of Batten disease. Additionally, Fig.1, Fig.2, and Fig.3 showed some of the phenotypes that appeared with this patient's condition.

PMID: 35112029

Gene: ABCA4

HGNCID: HGNC:34

Case#:case 1 II:4

DiseaseAssertion: Stargardt disease (STGD1)

FamilyInfo: mother has identical phenotype as proband, dad and sister asymptomatic, brother was symptomatic at 8 years old, other brother symptomatic at 15 years old.

CasePresentingHPOs: HP:0000007

CaseHPOFreeText: at age 50, with central visual imparement in right eye, 20/40 right, 20/20 left, linear and branching hyperautofluorescent subretinal deposits and extrafoveal RPE atrophy in both eyes,

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

Genotyping Method:

PreviouslyPublished: n/a

Variant: c.6031_6044delins18M/p.(Ile2003LeufsTer41)

ClinVar: not found

CAID: not found

SupplementalData:

PMID: 32627976

Gene: ABCA4

HGNC ID: 34

PMID: 22060670

Gene: ABCA4

HGNC ID: 34

PMID: 25922843 Gene: ABCA4 HGNCID: HGNC:34

PMID: 28726568

Gene: ABCA4

HGNC ID: 34

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

Case#: 11 year old female

DiseaseAssertion: Stargardt’s Disease

ParentalTesting: She was the product of an uncomplicated pregnancy born to a healthy Filipino mother and Italian/Irish father with no known family history of ocular disease. The mother and father were asymptomatic but not examined. Segregation analyses showed that both parents are asymptomatic carriers.

CasePresentingHPOs: HP:0007754, HP:0011462, HP:0008035

CasePhenotypeFreeText: The ABCA4 gene, when mutated, results in a spectrum of retinal degeneration, including Stargardt macular dystrophy, fundus flavimaculatus, autosomal recessive retinitis pigmentosa, and cone-rod dystrophy (1). Over 800 disease-associated ABCA4 gene mutations have been reported.

CaseNotHPOs: N/A

CaseNotPhenotypeFreeText: N/A

CasePreviousTesting: The proband underwent a full consultative ophthalmic examination at the Ocular Genetics Clinic at Wills Eye Hospital, including visual acuity, slit-lamp, and dilated fundus examination. Fundus autofluorescence and spectral-domain optical coherence tomography (Spectralis; Heidelberg Engineering), Goldmann visual field (Octopus 900 perimeter; Haag-Streit International), and intravenous fluorescein angiography were obtained. Full-field electroretinogram (Espion; Diagnosys LLC) and multifocal electroretinogram (Veris V.6.4.3; EDI Inc.) were performed in accordance with the International Society of Clinical Electrophysiology and Vision standards. Best-corrected visual acuity was 20/125 in the right eye and 20/200 in the left eye. The patient demonstrated eccentric fixation. Pupillary responses were normal. Slit-lamp examination was normal. Fundus examination revealed healthy optic nerves and retinal blood vessels, bilateral macular geographic pigmentary stippling with subretinal flecks in and around this area, and a blunted internal limiting membrane reflex (Fig. 1). Peripheral retina was normal.

GenotypingMethod: Genotyping microarray chips for ABCA4 can identify >98% of the most common mutations. In this report, we describe 2 novel ABCA4 variants in a patient with Stargardt disease. Bioinformatic and in silico analysis of the functional consequences of these variants provided compelling evidence for pathogenicity.

Variant: c.850_857delATTCAAGA and c.6184_6187delGTCT

CAID: CA10604079 and CA10604078

MultipleGeneVariants: N/A

PreviouslyPublished: N/A

AdditionalInfo: Bioinformatic assessment of the c.850_857delATTCAAGA mutation showed that it resulted in a truncated 317 amino acid polypeptide, devoid of several essential domains of the ABCA4 transporter. The c.6184_6187delGTCT mutation led to a premature stop codon at the C-terminal end of the protein, resulting in a loss of a total of 161 amino acid residues. Although less than 7% of the protein was absent, the important VFVNFA motif, present within the last 30 amino acids of the NBD2 domain, was deleted (Fig. 2). This motif is known to be critical to ABCA4 protein function, is highly conserved among members of the ABCA transporter subfamily, and has also been linked to Tangier disease in the ABCA1 protein (9). Removal of this motif in ABCA4 leads to a loss of retinal stimulated ATPase in vitro and energy transduction of the transporter (9, 10). Protein modeling predicted a loss of an essential β-sheet, which significantly altered its structure. The NBD domains are sites of ATP hydrolysis that provide energy for transport of R-PE through rod outer segment membranes. Enzymatic studies suggest that the NBD2 domain in particular provides energy necessary for translocation of retinal derivatives generated in the visual cycle. The structural changes in NBD2 would affect ABCA4 transporter’s ability to transport retinoids, leading to accumulation of cytotoxic lipofuscin in RPE cells and ultimately photoreceptor cell death.

PMID: 24020726

Gene: ABCA4

HGNC ID: 34

PMID: 28050124

Gene: ABCA4

HGNC ID: 34

PMID: 40948369

Gene: ABCA4

HGNC ID: 34

PMID: 40401218

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:328843395

Gene: ABCA4

HGNC ID: 34

PMID: 31819343

Gene: ABCA4

HGNC ID: 34

PMID: 28600779

Gene: ABCA4

HGNCID: HGNC:34

MonDO:

Case: 16N-0520, Male, Saudi Arabia, 1 yo

DiseaseAssertion:

FamilyInfo: Consanguineous parents, positive family history

CasePresentingHPOs: HP:0000618, HP:0000648 (Blindness, Optic atrophy)

CaseHPOFreeText: Coloboma of eye

GenotypingMethod: WES, analysis of Vision Panel, constituent genes are described in PMID 26112015.

SupplementalData: Supplemental table

Variant: ABCA4:NM_000350:exon49:c.6764G>T:p.S2255I

CAID: CA202970

gnomAD: 0.4845 (gnomAD v4.0.0, Grpmax Filtered AF African/African-American) https://gnomad.broadinstitute.org/variant/1-93996161-C-A?dataset=gnomad_r4

VariantEvidence: Authors classified as VOUS. But later downgraded to LB in PMID 31130284.

PMID: 34513887

Gene: ABCA4

HGNC ID: 34

PMID: 34440443

Gene: ABCA4

Disease: Retinal Dystrophies

Case#: Patient 9, female, Mexican, symptoms onset 6 yrs. ago, Mexico City

DiseaseAssertion: IRD

FamilyInfo: parents are non-sanguineous and asymptomatic, they also denied any history related to ocular diseases. Information disclosed that the mother had one stillbirth and three miscarriages, but denied any related diseases/health issues to this child.

CasePresentingHPOs: HP:00305, HP:00080, HP:0000493, HP:0025586, HP:0030329, HP:0012713

CaseHPOFreeText: Proband presented with light sensitivity as well as adaptation difficulties when going from dark-to-light. Right eye was 20/200 and left eye was 20/160 from the visual acuity test. Macular bull's eye appearance. Subnormal rod and cone responses. Peripapillary sparing retina.

CaseNotHPOs: HP:0007737, HP:0000750, HP:0000510

CaseNotHPOFreeText: No afferent pupillary defect. No anomalies in anterior segment.

Genotyping Method: QIAamp DNA Blood Kit was used to extract gDNA and quantification/purity of the sample was found using a NanoDrop 2000 spectrophotometer. 293 genes were sequenced. gDNA was sequenced via Illumina technology. Following, certain sequences were additionally analyzed against a reference genome in order to identify changes and interpret.

PreviouslyPublished: n/a

Variant: NM_000350.3(ABCA4):c.4926C>G (p.Ser1642Arg), NM_000350.3(ABCA4):c.5044_5058del (p.Val1682_Val1686del)

ClinVar: 99332, 99340

CAID: n/a

SupplementalData: Phenotype data in results section as well as figures 1, 2, and 3 showing phenotypic testing results.

PMID: 34679498

Gene: ABCA4

HGNC ID: 34

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

PMID: 24444108

Gene: ABCA4

HGNC ID: 34

PMID: 41201214

Gene: ABCA4

HGNC ID: 34

PMID: 33909047

Gene: ABCA4

HGNCID: HGNC:34

PMID: 20163366

Gene: ABCA4

HGNC ID: 34

PMID: 11594993

Gene: ABCA4

HGNC: 34

PMID: 24509150

Gene: ABCA4

HGNC ID: 34

PMID:31836589

Gene: ABCA4

HGNC ID: 34

Analysis of ABCA4 variants in 150 families with Stargardt disease. Most of which were of northern or central European ancestry. For comparison, 220 racially matched individuals with no personal history or known family history of STGD served as controls (Anderson et al. 1995; Allikmets et al. 1997b).

PMID: 9973280

Gene: ABCA4

HGNCID: HGNC:34

GenotypingMethod: combined SSCP and heteroduplex analyses of all 50 exons of ABCA4, Sanger sequencing

Pedigree AR417: onset at 8 years 2 segregations, 2 out of 3 offspring affected by STGD, parents and grandmother unaffected Variant: G1961E, A1038V CAID: CA119132, CA119135)

Pedigree AR427: onset at 12 years 1 segregation, 1 out of 2 offspring affected by STGD, parents unaffected Variant: G1961E, C75G CAID: CA119132, CA226985

Pedigree AR370: onset at 13 years 1 segregation, 1 out of 3 offspring affected by STGD, parents and grandparents unaffected Variant: G1961E, C1490Y CAID: CA119132, CA227198

Pedigree AR 218: onset at 14 years family history of AMD, was first reported by Anderson et al. [1995] Variant: G1961E, 2160+1G>C CAID: CA119132, CA226984

Pedigree AR 373: onset at 19 years 2 segregations, 2 out of 3 offspring affected by STGD, parents and grandparents unaffected Variant: G1961E, 4253+5G>T CAID: CA119132, CA227174

Pedigree AR 274: onset at 20 years 1 segregation, 1 out of 4 siblings affected by STGD, parents and grandparents unaffected Variant: G1961E, A1038V CAID: CA119132, CA119135

PMID:39398711

Gene: ABCA4

HGNC ID: 34

Case Annotation Template

Case#: 19-year-old male

DiseaseAssertion: Stargardt disease 1 (STGD1)

FamilyInfo: No family history of eye disease reported. Autosomal recessive inheritance consistent with STGD1. Homozygous ABCA4 variant identified.

CasePresentingHPOs: DecreasedCentralVA, MacularAtrophy, MacularFlecks, PeripapillarySparing, OpticNervePallor

CaseHPOFreeText: Five-year history of progressive bilateral central vision loss, worse at near. Alternating exotropia measuring 16 prism diopters in all gazes OU. Best corrected visual acuity 20/200 OU. Fundus examination revealed pigment deposition and macular mottling. Fundus autofluorescence showed central decreased autofluorescence surrounded by increased autofluorescence. Fluorescein angiography demonstrated dark choroid. OCT showed loss of the central ellipsoid zone with hyperreflective deposits. Multifocal ERG demonstrated significant functional loss.

CaseNotHPOs: NightBlindness

CaseNotHPOFreeText: Patient denied nyctalopia, photophobia, or flashes. Color vision normal on Ishihara testing.

Genotyping Method: Genotyping Method: Next-generation sequencing (NGS) with deletion/duplication analysis (Invitae Corporation).

PreviouslyPublished: N/A

Variant: ABCA4 c.52C>T (p.Arg18Trp)

ClinVar: ClinVarID:7899

CAID: N/A

SupplementalData: N/A