VCV000099428.68 - ClinVar

NM_000350.3(ABCA4):c.6089G>A (p.Arg2030Gln)

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Pathogenic/Likely pathogenic

14 out of 21 submissions contributed to this classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

This variant is part of a Haplotype

NM_000350.2(ABCA4):c.[1A>G;6089G>A]

Identifiers

NM_000350.3(ABCA4):c.6089G>A (p.Arg2030Gln)

Variation ID: 99428 Accession: VCV000099428.68

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1p22.1 1: 94005499 (GRCh38) [ NCBI UCSC ] 1: 94471055 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Feb 20, 2014	Jun 22, 2025	Jan 13, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_000350.3:c.6089G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000341.2:p.Arg2030Gln	missense
NM_001425324.1:c.5867G>A	NP_001412253.1:p.Arg1956Gln	missense
NC_000001.11:g.94005499C>T
NC_000001.10:g.94471055C>T
NG_009073.1:g.120651G>A
NG_009073.2:g.120649G>A
	P78363:p.Arg2030Gln

... more HGVS ... less HGVS

Protein change

R2030Q, R1956Q

Other names

Canonical SPDI

NC_000001.11:94005498:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00060 (T)

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD), exomes 0.00035

Exome Aggregation Consortium (ExAC) 0.00039

Trans-Omics for Precision Medicine (TOPMed) 0.00042

The Genome Aggregation Database (gnomAD) 0.00047

The Genome Aggregation Database (gnomAD) 0.00048

The Genome Aggregation Database (gnomAD), exomes 0.00048

1000 Genomes Project 0.00060

1000 Genomes Project 30x 0.00062

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00062

Links

ClinGen: CA227366 UniProtKB: P78363#VAR_008480 dbSNP: rs61750641 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
ABCA4		-	-	GRCh38 GRCh37	4050	4431

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not provided	Pathogenic/Likely pathogenic (9)	criteria provided, multiple submitters, no conflicts	Jan 13, 2025	RCV000085787.57
Severe early-childhood-onset retinal dystrophy	Pathogenic/Likely pathogenic (4)	criteria provided, multiple submitters, no conflicts	Jan 25, 2023	RCV000178545.13
Age related macular degeneration 2 Cone-rod dystrophy 3 Retinitis pigmentosa 19 Severe early-childhood-onset retinal dystrophy	Pathogenic (1)	criteria provided, single submitter	Apr 24, 2024	RCV000763436.5
Vitreoretinopathy	Pathogenic (1)	no assertion criteria provided	Apr 1, 2018	RCV000787516.3
Macular dystrophy	Pathogenic (1)	no assertion criteria provided	Apr 1, 2018	RCV000787517.3
Progressive cone dystrophy (without rod involvement)	Pathogenic (1)	no assertion criteria provided	Apr 1, 2018	RCV000787766.3
Retinal dystrophy	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jan 1, 2023	RCV001074874.4
Age related macular degeneration 2	Pathogenic (1)	criteria provided, single submitter	Nov 23, 2018	RCV001197157.3
ABCA4-related disorder	Pathogenic (1)	criteria provided, single submitter	Jun 6, 2023	RCV004529893.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely pathogenic (Jan 01, 2016) C Contributing to aggregate classification	criteria provided, single submitter (Schulz et al. (Invest Ophthalmol Vis Sci. 2017)) Method: clinical testing	Severe early-childhood-onset retinal dystrophy Affected status: yes Allele origin: germline	Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg Accession: SCV000281948.2 First in ClinVar: Dec 07, 2016 Last updated: Dec 07, 2016	Publications: PubMed (5) PubMed: 28118664‚ 9973280‚ 24713488‚ 25283059‚ 24265693 Indication for testing: Stargardt disease 1 Zygosity: Single Heterozygote

Pathogenic (Aug 08, 2019) C Contributing to aggregate classification	criteria provided, single submitter (Blueprint Genetics Variant Classification Scheme) Method: clinical testing	Retinal dystrophy Affected status: yes Allele origin: germline	Blueprint Genetics Accession: SCV001240478.1 First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020 Comment: My Retina Tracker patient

Pathogenic (Nov 23, 2018) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Age related macular degeneration 2 Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV001367793.2 First in ClinVar: Jul 04, 2020 Last updated: Jul 04, 2020	Comment: This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PM1,PP2,PP3,PP5.

Pathogenic (May 06, 2021) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Severe early-childhood-onset retinal dystrophy (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002767252.1 First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022	Publications: PubMed (9) PubMed: 11379881‚ 18854780‚ 23499370‚ 23953153‚ 28044389‚ 29925512‚ 30670881‚ 30718709‚ 31522899 Comment: Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as pathogenic. The following criteria are met: 0102 - Loss of function is a known … (more) Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as pathogenic. The following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Stargardt disease (MIM #248200), fundus flavimaculatus (MIM #248200), early-onset severe retinal dystrophy (MIM #248200) and retinitis pigmentosa 19 (MIM #601718). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 31522899). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v3) (72 heterozygotes, 1 homozygote). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated ABC transporter 2 domain (Pfam). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in more than 30 patients with Stargardt disease or ABCA4-related eye disease in the literature where a 2nd disease-causing variant was identified in trans (PMIDs: 30718709; 30670881; 29925512; 28044389; 23953153; 23499370; 18854780; 11379881). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)

Pathogenic (Jan 25, 2023) C Contributing to aggregate classification	criteria provided, single submitter (Classification criteria August 2017) Method: clinical testing	Severe early-childhood-onset retinal dystrophy (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München Accession: SCV004045779.1 First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023	Number of individuals with the variant: 1 Clinical Features: Macular degeneration (present)

Pathogenic (Jun 06, 2023) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	ABCA4-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004107331.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023	Comment: The ABCA4 c.6089G>A variant is predicted to result in the amino acid substitution p.Arg2030Gln. This variant has been reported many times as causative for retinal … (more) The ABCA4 c.6089G>A variant is predicted to result in the amino acid substitution p.Arg2030Gln. This variant has been reported many times as causative for retinal disorders (see for example Lewis et al. 1999. PubMed ID: 9973280; Duncker et al. 2015. PubMed ID: 25283059). This variant is reported in 0.062% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-94471055-C-T). This variant has been classified as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/99428/). This variant is interpreted as pathogenic. (less)

Pathogenic (Jun 28, 2023) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002018125.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024

Likely pathogenic (Jan 01, 2023) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Retinal dystrophy Affected status: yes Allele origin: germline	Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg Accession: SCV005071021.1 First in ClinVar: Dec 28, 2024 Last updated: Dec 28, 2024	Publications: PubMed (29) PubMed: 9973280‚ 24265693‚ 24713488‚ 25283059‚ 27596865‚ 28559085‚ 29555955‚ 30215852‚ 31589614‚ 29925512‚ 30718709‚ 30798147‚ 32845050‚ 32619608‚ 32467599‚ 31964843‚ 32307445‚ 32815999‚ 31456290‚ 32531858‚ 34647987‚ 34327195‚ 34426522‚ 33851411‚ 35119454‚ 35260635‚ 36460718‚ 35076026‚ 36672815

Pathogenic (May 04, 2022) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000329050.6 First in ClinVar: Dec 06, 2016 Last updated: Sep 16, 2024	Comment: Published functional studies demonstrate a mild damaging effect (PMID: 32845050); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more) Published functional studies demonstrate a mild damaging effect (PMID: 32845050); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27491360, 11527935, 18854780, 28559085, 30798147, 32531858, 34647987, 29925512, 25283059, 9973280, 11379881, 27596865, 27820952, 28044389, 28118664, 24713488, 24265693, 26103963, 29555955, 23891399, 30718709, 30215852, 31456290, 31589614, 32619608, 34327195, 34426522, 32815999, 33851411, 32467599, 35119454, 32845050) (less)

Pathogenic (Apr 24, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Age related macular degeneration 2 Severe early-childhood-onset retinal dystrophy Retinitis pigmentosa 19 Cone-rod dystrophy 3 Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: germline	Fulgent Genetics, Fulgent Genetics Accession: SCV000894203.3 First in ClinVar: Mar 31, 2019 Last updated: Jan 25, 2025	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30

Pathogenic (Mar 01, 2022) C Contributing to aggregate classification	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001247597.31 First in ClinVar: May 09, 2020 Last updated: Jun 22, 2025	Comment: ABCA4: PS1, PM2, PM3, PP3, PS3:Supporting Number of individuals with the variant: 5

Likely pathogenic (Jun 02, 2017) C Contributing to aggregate classification	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process) Method: clinical testing	Not Provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV000883316.1 First in ClinVar: Dec 15, 2018 Last updated: Dec 15, 2018	Comment: The ABCA4 c.6089G>A;p.Arg2030Gln variant has been published in several individuals with Stargardt disease and other ABVA4-related disorders (Bertelsen 2014, Cideciyan 2005, Duncker 2015, Jaakson 2003, … (more) The ABCA4 c.6089G>A;p.Arg2030Gln variant has been published in several individuals with Stargardt disease and other ABVA4-related disorders (Bertelsen 2014, Cideciyan 2005, Duncker 2015, Jaakson 2003, Lewis 1999, Webster 2001, Zhang 2015). However, the variant has also been published on the same allele as another pathogenic variant, p.Met1Val (Eisenberger 2013, Maia-Lopes 2009). The variant is listed in the ClinVar database (Variation ID: 99428) and the dbSNP variant database (rs61750641) with an allele frequency of 0.0615 percent (8/12998 alleles) in the Exome Variant Server and 0.03609 percent (100/277108 alleles) in the Genome Aggregation Database. The amino acid at this position is highly conserved across species, occurs in a transporter domain, and computational algorithms (PolyPhen2, SIFT) predict this variant is deleterious. Considering available information, this variant is classified as likely pathogenic. This variant would be causative for autosomal recessive Stargardt disease and other ABCA4-related disorders (OMIM#601691). References: Bertelsen M et al. Generalized choriocapillaris dystrophy, a distinct phenotype in the spectrum of ABCA4-associated retinopathies. Invest Ophthalmol Vis Sci. 2014 Apr 29;55(4):2766-76. Cideciyan AV et al. ABCA4-associated retinal degenerations spare structure and function of the human parapapillary retina. Invest Ophthalmol Vis Sci. 2005 Dec;46(12):4739-46. Duncker T et al. Quantitative fundus autofluorescence distinguishes ABCA4-associated and non-ABCA4-associated bull's-eye maculopathy. Ophthalmology. 2015 Feb;122(2):345-55. Eisenberger T et al. Increasing the yield in targeted next-generation sequencing by implicating CNV analysis, non-coding exons and the overall variant load: the example of retinal dystrophies. PLoS One. 2013 Nov 12;8(11):e78496. Jaakson K et al Genotyping microarray (gene chip) for the ABCR (ABCA4) gene. Hum Mutat. 2003 Nov;22(5):395-403. Lewis RA et al. Genotype/Phenotype analysis of a photoreceptor-specific ATP-binding cassette transporter gene, ABCR, in Stargardt disease. Am J Hum Genet. 1999 Feb;64(2):422-34. Maia-Lopes S et al. ABCA4 mutations in Portuguese Stargardt patients: identification of new mutations and their phenotypic analysis. Mol Vis. 2009;15:584-91. Webster AR et al. An analysis of allelic variation in the ABCA4 gene. Invest Ophthalmol Vis Sci. 2001 May;42(6):1179-89. Zhang Q et al. Next-generation sequencing-based molecular diagnosis of 35 Hispanic retinitis pigmentosa probands. Sci Rep. 2016 Sep 6;6:32792. (less)

Pathogenic (Jan 13, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001214008.6 First in ClinVar: Apr 15, 2020 Last updated: Feb 25, 2025	Publications: PubMed (2) PubMed: 22229821‚ 23143460 Comment: This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 2030 of the ABCA4 protein (p.Arg2030Gln). … (more) This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 2030 of the ABCA4 protein (p.Arg2030Gln). This variant is present in population databases (rs61750641, gnomAD 0.06%). This missense change has been observed in individual(s) with Stargardt disease (PMID: 22229821, 23143460). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 99428). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ABCA4 protein function. For these reasons, this variant has been classified as Pathogenic. (less)

Pathogenic (Aug 10, 2016) C Contributing to aggregate classification	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000230645.6 First in ClinVar: Jun 28, 2015 Last updated: Apr 13, 2025	Publications: PubMed (7) PubMed: 11328725‚ 11379881‚ 18854780‚ 23143460‚ 24713488‚ 25283059‚ 9973280 Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ABCA4 Number of individuals with the variant: 5 Zygosity: Single Heterozygote Sex: mixed

Pathogenic (Apr 01, 2018) N Not contributing to aggregate classification	no assertion criteria provided Method: research	Vitreoretinopathy Affected status: yes Allele origin: unknown	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet Study: VeluxRD Accession: SCV000926484.2 First in ClinVar: Jul 21, 2019 Last updated: Sep 03, 2023	Publications: PubMed (1) PubMed: 30718709

Pathogenic (Apr 01, 2018) N Not contributing to aggregate classification	no assertion criteria provided Method: research	Macular dystrophy Affected status: yes Allele origin: unknown	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet Study: VeluxRD Accession: SCV000926485.2 First in ClinVar: Jul 21, 2019 Last updated: Sep 03, 2023	Publications: PubMed (1) PubMed: 30718709

Pathogenic (Apr 01, 2018) N Not contributing to aggregate classification	no assertion criteria provided Method: research	Progressive cone dystrophy (without rod involvement) Affected status: yes Allele origin: unknown	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet Study: VeluxRD Accession: SCV000926771.2 First in ClinVar: Jul 21, 2019 Last updated: Sep 03, 2023	Publications: PubMed (1) PubMed: 30718709

Pathogenic (-) N Not contributing to aggregate classification	no assertion criteria provided Method: research	Severe early-childhood-onset retinal dystrophy (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Ophthalmo-Genetics Lab, Instituto de Oftalmologia Conde de Valenciana Accession: SCV005049261.1 First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024	Publications: PubMed (1) PubMed: 28044389

Likely pathogenic (-) N Not contributing to aggregate classification	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001955238.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021

Pathogenic (-) N Not contributing to aggregate classification	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001968124.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021

not provided (-) N Not contributing to aggregate classification	no classification provided Method: not provided	not provided Affected status: not provided Allele origin: unknown	Retina International Accession: SCV000117929.1 First in ClinVar: Feb 20, 2014 Last updated: Feb 20, 2014 Comment: http://phencode.bx.psu.edu/cgi-bin/phencode/phencode?build=hg19&id=RISN_ABCR:c.6089G>A

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Comment:

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as pathogenic. The following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Stargardt disease (MIM #248200), fundus flavimaculatus (MIM #248200), early-onset severe retinal dystrophy (MIM #248200) and retinitis pigmentosa 19 (MIM #601718). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 31522899). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v3) (72 heterozygotes, 1 homozygote). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated ABC transporter 2 domain (Pfam). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in more than 30 patients with Stargardt disease or ABCA4-related eye disease in the literature where a 2nd disease-causing variant was identified in trans (PMIDs: 30718709; 30670881; 29925512; 28044389; 23953153; 23499370; 18854780; 11379881). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Comment:

The ABCA4 c.6089G>A variant is predicted to result in the amino acid substitution p.Arg2030Gln. This variant has been reported many times as causative for retinal disorders (see for example Lewis et al. 1999. PubMed ID: 9973280; Duncker et al. 2015. PubMed ID: 25283059). This variant is reported in 0.062% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-94471055-C-T). This variant has been classified as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/99428/). This variant is interpreted as pathogenic.

Comment:

Published functional studies demonstrate a mild damaging effect (PMID: 32845050); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27491360, 11527935, 18854780, 28559085, 30798147, 32531858, 34647987, 29925512, 25283059, 9973280, 11379881, 27596865, 27820952, 28044389, 28118664, 24713488, 24265693, 26103963, 29555955, 23891399, 30718709, 30215852, 31456290, 31589614, 32619608, 34327195, 34426522, 32815999, 33851411, 32467599, 35119454, 32845050)

Comment:

The ABCA4 c.6089G>A;p.Arg2030Gln variant has been published in several individuals with Stargardt disease and other ABVA4-related disorders (Bertelsen 2014, Cideciyan 2005, Duncker 2015, Jaakson 2003, Lewis 1999, Webster 2001, Zhang 2015). However, the variant has also been published on the same allele as another pathogenic variant, p.Met1Val (Eisenberger 2013, Maia-Lopes 2009). The variant is listed in the ClinVar database (Variation ID: 99428) and the dbSNP variant database (rs61750641) with an allele frequency of 0.0615 percent (8/12998 alleles) in the Exome Variant Server and 0.03609 percent (100/277108 alleles) in the Genome Aggregation Database. The amino acid at this position is highly conserved across species, occurs in a transporter domain, and computational algorithms (PolyPhen2, SIFT) predict this variant is deleterious. Considering available information, this variant is classified as likely pathogenic. This variant would be causative for autosomal recessive Stargardt disease and other ABCA4-related disorders (OMIM#601691). References: Bertelsen M et al. Generalized choriocapillaris dystrophy, a distinct phenotype in the spectrum of ABCA4-associated retinopathies. Invest Ophthalmol Vis Sci. 2014 Apr 29;55(4):2766-76. Cideciyan AV et al. ABCA4-associated retinal degenerations spare structure and function of the human parapapillary retina. Invest Ophthalmol Vis Sci. 2005 Dec;46(12):4739-46. Duncker T et al. Quantitative fundus autofluorescence distinguishes ABCA4-associated and non-ABCA4-associated bull's-eye maculopathy. Ophthalmology. 2015 Feb;122(2):345-55. Eisenberger T et al. Increasing the yield in targeted next-generation sequencing by implicating CNV analysis, non-coding exons and the overall variant load: the example of retinal dystrophies. PLoS One. 2013 Nov 12;8(11):e78496. Jaakson K et al Genotyping microarray (gene chip) for the ABCR (ABCA4) gene. Hum Mutat. 2003 Nov;22(5):395-403. Lewis RA et al. Genotype/Phenotype analysis of a photoreceptor-specific ATP-binding cassette transporter gene, ABCR, in Stargardt disease. Am J Hum Genet. 1999 Feb;64(2):422-34. Maia-Lopes S et al. ABCA4 mutations in Portuguese Stargardt patients: identification of new mutations and their phenotypic analysis. Mol Vis. 2009;15:584-91. Webster AR et al. An analysis of allelic variation in the ABCA4 gene. Invest Ophthalmol Vis Sci. 2001 May;42(6):1179-89. Zhang Q et al. Next-generation sequencing-based molecular diagnosis of 35 Hispanic retinitis pigmentosa probands. Sci Rep. 2016 Sep 6;6:32792.

Comment:

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 2030 of the ABCA4 protein (p.Arg2030Gln). This variant is present in population databases (rs61750641, gnomAD 0.06%). This missense change has been observed in individual(s) with Stargardt disease (PMID: 22229821, 23143460). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 99428). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ABCA4 protein function. For these reasons, this variant has been classified as Pathogenic.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Genetic Diagnosis for 64 Patients with Inherited Retinal Disease.	Lynn J	Genes	2022	PMID: 36672815
Genetic epidemiology of inherited retinal diseases in a large patient cohort followed at a single center in Italy.	Karali M	Scientific reports	2022	PMID: 36460718
Genetic characteristics of 234 Italian patients with macular and cone/cone-rod dystrophy.	Falsini B	Scientific reports	2022	PMID: 35260635
Impact of Next Generation Sequencing in Unraveling the Genetics of 1036 Spanish Families With Inherited Macular Dystrophies.	Del Pozo-Valero M	Investigative ophthalmology & visual science	2022	PMID: 35119454
Photoreceptor degeneration in ABCA4-associated retinopathy and its genetic correlates.	Pfau M	JCI insight	2022	PMID: 35076026
Evaluating the Occurrence of Rare Variants in the Complement Factor H Gene in Patients With Early-Onset Drusen Maculopathy.	de Breuk A	JAMA ophthalmology	2021	PMID: 34647987
The genetic structure of the Turkish population reveals high levels of variation and admixture.	Kars ME	Proceedings of the National Academy of Sciences of the United States of America	2021	PMID: 34426522
Updating the Genetic Landscape of Inherited Retinal Dystrophies.	García Bohórquez B	Frontiers in cell and developmental biology	2021	PMID: 34327195
Molecular genetics of inherited retinal degenerations in Icelandic patients.	Thorsteinsson DA	Clinical genetics	2021	PMID: 33851411
Functional analysis and classification of homozygous and hypomorphic ABCA4 variants associated with Stargardt macular degeneration.	Curtis SB	Human mutation	2020	PMID: 32845050
Association of Sex With Frequent and Mild ABCA4 Alleles in Stargardt Disease.	Runhart EH	JAMA ophthalmology	2020	PMID: 32815999
Genotype-Phenotype Correlations in a Spanish Cohort of 506 Families With Biallelic ABCA4 Pathogenic Variants.	Del Pozo-Valero M	American journal of ophthalmology	2020	PMID: 32619608
Genetic architecture of inherited retinal degeneration in Germany: A large cohort study from a single diagnostic center over a 9-year period.	Weisschuh N	Human mutation	2020	PMID: 32531858
The genetic architecture of Stargardt macular dystrophy (STGD1): a longitudinal 40-year study in a genetic isolate.	Green JS	European journal of human genetics : EJHG	2020	PMID: 32467599
Resolving the dark matter of ABCA4 for 1054 Stargardt disease probands through integrated genomics and transcriptomics.	Khan M	Genetics in medicine : official journal of the American College of Medical Genetics	2020	PMID: 32307445
Worldwide carrier frequency and genetic prevalence of autosomal recessive inherited retinal diseases.	Hanany M	Proceedings of the National Academy of Sciences of the United States of America	2020	PMID: 31964843
A nationwide genetic analysis of inherited retinal diseases in Israel as assessed by the Israeli inherited retinal disease consortium (IIRDC).	Sharon D	Human mutation	2020	PMID: 31456290
Optimizing clinical exome design and parallel gene-testing for recessive genetic conditions in preconception carrier screening: Translational research genomic data from 14,125 exomes.	Capalbo A	PLoS genetics	2019	PMID: 31589614
Highly Variable Disease Courses in Siblings with Stargardt Disease.	Valkenburg D	Ophthalmology	2019	PMID: 31522899
Generation of two iPS cell lines (FRIMOi003-A and FRIMOi004-A) derived from Stargardt patients carrying ABCA4 compound heterozygous mutations.	Riera M	Stem cell research	2019	PMID: 30798147
Molecular genetic analysis using targeted NGS analysis of 677 individuals with retinal dystrophy.	Jespersgaard C	Scientific reports	2019	PMID: 30718709
ABCA4-associated disease as a model for missing heritability in autosomal recessive disorders: novel noncoding splice, cis-regulatory, structural, and recurrent hypomorphic variants.	Bauwens M	Genetics in medicine : official journal of the American College of Medical Genetics	2019	PMID: 30670881
Detailed genetic characteristics of an international large cohort of patients with Stargardt disease: ProgStar study report 8.	Fujinami K	The British journal of ophthalmology	2019	PMID: 29925512
Genetic screening for macular dystrophies in patients clinically diagnosed with dry age-related macular degeneration.	Kersten E	Clinical genetics	2018	PMID: 30215852
Clinical and genetic characteristics of 251 consecutive patients with macular and cone/cone-rod dystrophy.	Birtel J	Scientific reports	2018	PMID: 29555955
Clinically Focused Molecular Investigation of 1000 Consecutive Families with Inherited Retinal Disease.	Stone EM	Ophthalmology	2017	PMID: 28559085
Mutation Spectrum of the ABCA4 Gene in 335 Stargardt Disease Patients From a Multicenter German Cohort-Impact of Selected Deep Intronic Variants and Common SNPs.	Schulz HL	Investigative ophthalmology & visual science	2017	PMID: 28118664
In Silico Functional Meta-Analysis of 5,962 ABCA4 Variants in 3,928 Retinal Dystrophy Cases.	Cornelis SS	Human mutation	2017	PMID: 28044389
Next-generation sequencing-based molecular diagnosis of 35 Hispanic retinitis pigmentosa probands.	Zhang Q	Scientific reports	2016	PMID: 27596865
Quantitative fundus autofluorescence distinguishes ABCA4-associated and non-ABCA4-associated bull's-eye maculopathy.	Duncker T	Ophthalmology	2015	PMID: 25283059
Generalized choriocapillaris dystrophy, a distinct phenotype in the spectrum of ABCA4-associated retinopathies.	Bertelsen M	Investigative ophthalmology & visual science	2014	PMID: 24713488
Increasing the yield in targeted next-generation sequencing by implicating CNV analysis, non-coding exons and the overall variant load: the example of retinal dystrophies.	Eisenberger T	PloS one	2013	PMID: 24265693
Clinical and molecular analysis of Stargardt disease with preserved foveal structure and function.	Fujinami K	American journal of ophthalmology	2013	PMID: 23953153
A longitudinal study of stargardt disease: clinical and electrophysiologic assessment, progression, and genotype correlations.	Fujinami K	American journal of ophthalmology	2013	PMID: 23499370
Detection rate of pathogenic mutations in ABCA4 using direct sequencing: clinical and research implications.	Downes SM	Archives of ophthalmology (Chicago, Ill. : 1960)	2012	PMID: 23143460
Phenotypic and genetic spectrum of Danish patients with ABCA4-related retinopathy.	Duno M	Ophthalmic genetics	2012	PMID: 22229821
Peripapillary atrophy in Stargardt disease.	Hwang JC	Retina (Philadelphia, Pa.)	2009	PMID: 18854780
Late-onset Stargardt disease is associated with missense mutations that map outside known functional regions of ABCR (ABCA4).	Yatsenko AN	Human genetics	2001	PMID: 11379881
An analysis of allelic variation in the ABCA4 gene.	Webster AR	Investigative ophthalmology & visual science	2001	PMID: 11328725
Genotype/Phenotype analysis of a photoreceptor-specific ATP-binding cassette transporter gene, ABCR, in Stargardt disease.	Lewis RA	American journal of human genetics	1999	PMID: 9973280
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ABCA4	-	-	-	-
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Text-mined citations for rs61750641 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Jun 22, 2025

ClinVar Genomic variation as it relates to human health

NM_000350.3(ABCA4):c.6089G>A (p.Arg2030Gln)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs61750641 ...