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

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

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

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:

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

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:

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

PMID: 17277736

Gene: ABCA4

HGNC ID: 34

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)

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

This variant was not evaluated.

This variant was not evaluated.

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)

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

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.

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.

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.

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

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

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

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

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

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

Case#:2, 29-year-old woman

DiseaseAssertion:NR

FamilyInfo:NR

CasePresentingHPOs:

CaseHPOFreeText:decreased ability to focus, increasing difficulty to adapt in the dark, normal visual acuity in both eyes (logMar BCVA OD/OS: 0.02), PERG responses were diminished in both eyes.

CaseNotHPOs:

CaseNotHPOFreeText:

Genotyping Method: ”Analysis of the ABCA4 gene”

PreviouslyPublished:No

Variant:NM_000350.3:c.1805G>A, NM_000350.3:c.6079C>T

ClinVar: 99085, 7882

CAID:CA226933, CA119129

SupplementalData:

PMID: 23949494 HGNC: 34 Gene: ABCA4 DiseaseAssertion: Stargardt Disease

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: 16917483

Gene: ABCA4

Disease: Stargardt

This paper was referenced by PMID: 23755871 as containing variant c.6410G>A (p.Cys2137Tyr), but this variant foes not appear to be in the text or tables

PMID: 34008801

Gene: ABCA4

HGNC ID: 34

PMID: 17562343 GeneName: ABCA4

Case#: Patient 13, 35yo

DiseaseAssertion: STGD

FamilyInfo: Family 8

CasePresentingHPOs:

CaseHPOFreeText: Visual acuity=0.017. OCT ft (μm)=163. MP (dB)=0. Fundus=3(extensive atrophic-appearing RPE changes). ERG=3(abnormal responses involving both rods and cones). mfERG=4(subnormal mfERG in the entire test field (0°–30°) plus pathologic Ganzfeld ERG).

CaseNotHPOs:

CaseNotHPOFreeText:

GenotypingMethod: PCR of coding regions, intron/exon boundaries, and 5′ and 3′ regions of ABCA4; Standard cycle-sequencing reactions with BigDye Terminator

PreviouslyPublished:

Variant: L541P; R1098C

CAID: CA226911;

SupplementalData: n/a

Case#:48-year old man, onset at 13-years old

DiseaseAssertion: STGD1

FamilyInfo: n/a

CasePresentingHPOs: HP:0003621, HP:0025147, HP:0011507, HP:0030329, HP:0030610, HP:0007722, HP:0007703, HP:0007663

CaseHPOFreeText: BCVA was 20/200 bilaterally and refractive error was OD: −1.50/+0.50 × 149° and OS: −1.50/+0.25 × 161°. Hyperautofluorescent transitional zone in each eye more pronounced in right eye. The left eye showed a complete defect of the RPE-Bruch membrane complex with herniation of the outer retina. Maximum horizontal diameter of this RPE-Bruch membrane complex defect was 266um.

CaseNotHPOs: HP:0000510, HP:0000548, HP:0007984

CaseNotHPOFreeText: No defect observed in the RPE and Bruch membrane in right eye. Patient had normal cone and rod responses on ERG

Genotyping Method: ABCR 600 micro-array chip

PreviouslyPublished: n/a

Variant: NM_000350.3(ABCA4):c.4216C>T (p.His1406Tyr), NM_000350.3(ABCA4):c.5882G>A (p.Gly1961Glu)

ClinVar: 99259, 7888

SupplementalData: n/a

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

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.

PMID: 41063816

Gene: ABCA4

HGNC ID: 34

Case#: Case 3, 39yo

DiseaseAssertion: BEM, RCD

FamilyInfo: n/a

CasePresentingHPOs:

CaseHPOFreeText: a ring of increased AF surrounding decreased foveal AF, visual acuity= 6/6, 6/6

CaseNotHPOs:

CaseNotHPOFreeText: acquired toxic aetiology

GenotypingMethod: The entire coding sequence (50 exons), including exon–intron boundaries, of the ABCA4 gene of each patient was screened using single‐stranded conformational polymorphism (SSCP) analysis and direct sequencing.

PreviouslyPublished: n/a

Variant: Val552Ile heterozygous

CAID: CA239745

SupplementalData: n/a

Case#: Family 1 proband, male, 6yo at onset, Chinese

DiseaseAssertion: CORD

FamilyInfo: heterozygous unaffected parents

CasePresentingHPOs: HP:0000613, HP:0000505, HP:0007401, HP:0012511, HP:0008043, HP:0000512

CaseHPOFreeText:  ERG responses from cones reduced, BVA=0.20/0.15

CaseNotHPOs:

CaseNotHPOFreeText:

PreviouslyPublished: n/a

Variant: c.[1957C>T];[4604dup] phase confirmed

ClinVar: n/a

CAID: CA645372205

SupplementalData:

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.

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#: Patient 24, male, Caucasian, onset at 50yo, Germany

DiseaseAssertion: STGD

FamilyInfo: co-segregation of variant in 2 family members (siblings) but they do not appear to be affected based on pedigree

CasePresentingHPOs: HP:0030528, HP:0000505, HP:0012508, HP:0001105, HP:0025148

CaseHPOFreeText: progressive paracentral scotoma OU, progressive visual impairment OU (blurry vision). BCVA: OD-0.1, OS-0.22. Tension: 13mmHg/14mmHg. FAF: bilateral hyperautofluorescent macular and peripapillary spots, few spots of paracentral retinal atrophy (foveal sparing). Autofluorescence and deposits (severity): deposits medium, atrophy low. OCT: hyperreflective spots, partially invading into the outer retina, partly confluent lesions of cRORA, foveal sparing, degenerative intraretinal fluid. Central macular thickness: 328µm/322µm. Macular volume: 9.31mm³/9.00mm³. mfERG: bilateral amplitudes in normal range, slight relative reduction in the paracentral areas. Fluorescein angiography: bilateral dark choroid, mild paracentral dye pooling in the late phase. Color vision: Inconspicuous. Clinical examination: pattern-like distribution of the lesions.

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

GenotypingMethod: WES, in-house RD-associated gene panel including 619 candidates and disease-associated genes

PreviouslyPublished: n/a

Variant: ABCA4 NM_000350.2 c.[6601_6602delAG] (p.Arg2201fs);[=], c.[4253+43G>A] p.Ile1377Hisfs3;[=]

CAID: CA227421; CA227172

SupplementalData: phenotype and segregation info in supplemental data (table s1, figure s1)

This variant was mentioned in reference to a previous publication. PMID: 23419329

PMID: 30204727

Gene: ABCA4

HGNC ID: 34

Case#: Female, family #5, Patient #20

DiseaseAssertion: STGD

FamilyInfo: Proband's sister presented with same clinical prognosis. Sister diagnosed with pattern dystrophy and photoaversion at age 57, with difficulty seeing at night. Sister has nuclear sclerotic and cortical cataracts in both eyes.

CasePresentingHPOs: HP:0000662, HP:0000603, HP:0000603, HP:0000493

CaseHPOFreeText: Proband presented with localized blur at age 62, (late onset) in her left eye. BVCA 20/20-3 and 20/20-2 at age 70. Also has macular lesions with stage 2 fundus flecks.

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

Genotyping Method: Genotyping performed at Columbia University, sequencing technology used is not disclosed.

PreviouslyPublished: n/a

Variant: p.N18681, IVS36:c.5196+1G>A

ClinVar: M2) 99067, M6) 99351

CAID: N/A

SupplementalData: Fig 1: Pedigree illustrating ABCA4 variants and the associated Stargardt phenotype for 5 families. Proband Labeled w/ white arrow for each family. Fig 2: retinal scan measuring melanin in 4 patients of family 2. Panel shows bull's-eye ring of RPE atropy. Fig 3: Macular SD-OCT line profile from b-scans. Reflectivity plotted against function of retinal depth. Table 1: table shows patients with p.N18681 variant, type of mutation, and pathogenicity class. Table 2: Patients, age on-set and first symptom

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).

PMID: 37628710

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

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

Annotating here since the full text is a PDF.

Case#: Family AR321 proband, US, 6yo at onset

DiseaseAssertion: Stargardt

FamilyInfo: proband and two other siblings are affected

CasePresentingHPOs: The essential and defining features of STGD were (1) pedigrees with at least one living affected individual compatible with autosomal recessive inheritance; (2) an ophthalmoscopically characteristic retinal disorder in families with both parents living; (3) bilateral central visual loss with both “beaten metal” elliptical foveal dystrophy and temporal pallor of the optic discs, documented by retinal color photography, with or without yellow-pigment epithelial flecks in the macular and/or retinal “near periphery”; and (4) the characteristic fluorescein angiographic feature of a dark choroid (Blacharski 1988).

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText: (1) evidence of autosomal dominant inheritance; (2) any history of night blindness, loss of peripheral vision, or "retinitis pigmentosa"; (3) cataracta complicata or cells in the vitreous; (4) substantially abnormal electroretinographic or electrooculographic responses; (5) no fluorescein angiography performed or no dark choroid documented; (6) neurological disease (including loss of cognition or seizures); 7) drug exposures (especially to antimalarial and agents known to cause crystalline retinopathies); or (8) any "atypical" maculopathies in which a unique diagnosis of STGD could not be established.

PreviouslyPublished: PMID: 8533764

Variant: c.3113C>T p.A1038V; c.1715G>C p.R572P . Heteroduplex and SSCP analyses were used to screen the 50 exons of ABCA4. Linkage analysis and haplotype analysis were previously performed

ClinVar: 99073

CAID: CA226919

SupplementalData: n/a

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

This variant is reported in Table S6, but only location, predictions, frequencies, etc are reported for it, not cases.

This variant is reported in Table S6, but only location, predictions, frequencies, etc are reported for it, not cases.

PMID: 36471740

Gene: ABCA4

HGNC ID: 34

Unable to find this variant in the text or supplementary even though Mastermind says it's in supplemental MOESM1

Case#: Patient 225, Female, age of onset 7 y.o, Poland

DiseaseAssertion: STGD-1

FamilyInfo: no given family information.

CasePresentingHPOs: HP:0007722, HP:0000608, HP:0025158

CaseHPOFreeText: RPE atrophy, macular degeneration, central hyper-autofluorescence in fundus autofluorescence

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a, non-proband identified HPO's mentioned, but not assignable to individual proband.

Genotyping Method: DNA isolated from peripheral blood from patients and relatives via MagNA Pure 24, samples screened with MIPs targeting 108 genes involved in pathogensis of IRD's. PCR completed on library, analysed with NGS fragment analysis kit.

PreviouslyPublished: yes

Variant: c.[1622T>C;3113C>T]

ClinVar: 99067, 7894

CAID: n/a

gnomeAD 0.0001266 allele frequency

SupplementalData: Fig1: List of families displaying pseudo-dominant inheritance. Fig2: Number of alleles for most common variants.

PMID:39967245

Gene: ABCA4

HGNC ID: 34

Case#:39 man

DiseaseAssertion:NA

FamilyInfo:NA

CasePresentingHPOs:Snellen in both eye, visual impairment with night blindnessisual acuity was 20/20Snellen in both eyes, with a minor correction for astig-matism. The anterior segment and intraocular pressurewere within normal limits. On fundus examination, dif-fuse fleck-like lesions were scattered both inside and out-side the arcades, while sharply demarcated areas ofmacular atrophy with foveal sparing, more pronouncedin the left eye, were visible.

CaseHPOFreeText:NA

CaseNotHPOs:NA

CaseNotHPOFreeText:

Genotyping Method:Next-Generation Sequencing (NGS), using theTruSight One Clinical Exome sequencing panel on anIllumina NexSeq500 platform, enriching for 4800 genesincluding ABCA4, CNGB3, ELOVL4, PROM1, and PRPH2

PreviouslyPublished:Under refernces?

Variant:WDR19 variants:the novel deletion at c.1777 + 1 within the donor splicingsite (class 4) and the rare c.1430 G>T variant causing theamino-acid substitution p.(Arg477Leu) (class 3) in the putative protein. Additionally, a heterozygous c.1793A>G(class 3) variant in the CDH23 gene was found, though it was deemed as not contributive to the patient’s clinical phenotype. All reported variants were confirmed throughSanger sequencing

ClinVar:NA

CAID:NA

SupplementalData:NA

Case#: Family 12 Proband, male, 43yo at onset, Portuguese

DiseaseAssertion: Stargardt

FamilyInfo: no affected family members in pedigree (Fig. 1)

CasePresentingHPOs: HP:0007663

CaseHPOFreeText: "The criteria for STGD phenotype included bilateral central vision loss and pigmentary macular lesions, normal caliber of retinal vessels, absence of pigmented bone spicules, and compatibility with recessive mode of inheritance." Moderate central retinal changes, decreased mfERG responses exclusively in the central 15 degrees

CaseNotHPOs:

CaseNotHPOFreeText:

PreviouslyPublished: n/a

Variant: p.Glu1574X; p.Val931Met. Several other polymorphisms also reported. ABCR400 gene chip microarray, DHPLC

ClinVar: 1460063

CAID: CA341283936

SupplementalData: n/a

Case#: Bryant Subject JB260, US

DiseaseAssertion: Stargardt

FamilyInfo:

CasePresentingHPOs: "Stargardt disease is a childhood-onset macular degeneration and is most commonly caused by mutations in ABCA4. Characteristic yellow flecks are typically seen under the macula during a fundus exam."

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

GenotypingMethod: WES; previously screened using arrayed primer extension (APEX) multigene panels for the relevant disease and no disease-causing variants had been identified; PCR and Sanger for verification

PreviouslyPublished: n/a

Variant: c.6119G>A p.Arg2040Gln; c.2879del p.Ala960Aspfs*17

CAID: CA232815

SupplementalData:

PMID:39215425

Gene: ABCA4

HGNC ID: 34

case27-year-old male, the brother of case 1

DiseaseAssertion: Table 1 The summary of the clinical assessment of IRD patients’ family in this research fro there down they did a whole pannel on the family

Pedigree one can be fore form the beggginnings of case presention section?

CasePresentingHPOs: Case 2, a 27-year-old male, the brother of case 1 had blurry vision which was not corrected with an eyeglass and inconveniences under bright light starting from 14 years ago. Case 2 also underwent a fundus examination after finding that case 1 was RP. In further examination of those patients and their family members found that case 1 was confirmed as RP and case 2

CaseHPOFreeText:NA

CaseNotHPOs:NA

CaseNotHPOFreeText:NA

Genotyping Method:NA

PreviouslyPublished:NA

Variant:NA

ClinVar:

CAID:NA

SupplementalData:NA

Inheritance pattern Autosomal Recessive

Case#: Patients were identified from the inherited retinal disease (IRD) database at UC San Diego (UCSD).

DiseaseAssertion: RP with macular edema

FamilyInfo:

CasePresentingHPOs:

CaseHPOFreeText: Dx of RP based on "a history of progressive peripheral vision loss or nyctalopia, and ocular examination findings of RP including bone spicule pigmentation, disc pallor and attenuated vessels and genetic confirmation."

CaseNotHPOs:

CaseNotHPOFreeText:

GenotypingMethod: Next-generation sequencing (NGS), exome sequencing, and/or targeted Sanger sequencing were the primary genetic testing approaches.

PreviouslyPublished: PMID:10206579 is referenced but it seems a reference to the variant and not the proband

Variant: c.6383A>G (p.His2128Arg); c.3G>T (p.Met1?). phase unknown

ClinVar: 99455

CAID: CA227399

SupplementalData: Variant is found in table S2

another patient with the 541 variant potentially not in cis with ala1038val. G1961E has been classified as pathogenic by the ABCA4 VCEP

another patient with the 541 variant potentially not in cis with ala1038val. F655C is path/LP in clinvar

Case#: Patient 13, 35yo

DiseaseAssertion: STGD

FamilyInfo: Family 8

CasePresentingHPOs:

CaseHPOFreeText: Visual acuity=0.017. OCT ft (μm)=163. MP (dB)=0. Fundus=3(extensive atrophic-appearing RPE changes). ERG=3(abnormal responses involving both rods and cones). mfERG=4(subnormal mfERG in the entire test field (0°–30°) plus pathologic Ganzfeld ERG).

CaseNotHPOs:

CaseNotHPOFreeText:

GenotypingMethod: PCR of coding regions, intron/exon boundaries, and 5′ and 3′ regions of ABCA4; Standard cycle-sequencing reactions with BigDye Terminator

PreviouslyPublished:

Variant: L541P; R1098C

CAID: CA226911;

SupplementalData: n/a

Case#: 4, 34 year old male

DiseaseAssertion: Stargardt Disease

FamilyInfo: NR

CasePresentingHPOs: NR

CaseHPOFreeText: NR

CaseNotHPOs:

CaseNotHPOFreeText: NR

Genotyping Method: Analyzing the ABCA4 gene

PreviouslyPublished: NR

Variant: 4469G>A

ClinVar: NR

CAID: NR

SupplementalData: NR

PMID: 23949494 HGNC: 34 Gene: ABCA4 DiseaseAssertion: Stargardt Disease

gnomad 0.0001 frequency

I don't understand what this means, but how I interepret it is if an homozygous STGD1 variant appears at a lower frequency that it is less severe.

I don't understand what this means, but how I interepret it is if an homozygous STGD1 variant appears at a lower frequency that it is less severe.

SupplementalData:

SupplementalData:

This variant was found in Patient 074752 in cis with a nonsense (c.6088C>T) and in trans with an intronic variant (c.4253+43G>A); neither of which has been curated yet by the ABCA4 VCEP

Not sure if this variant is c.1988G>A or c.1989G>A.

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