VCV000092867.61 - ClinVar

NM_000350.3(ABCA4):c.3322C>T (p.Arg1108Cys)

Germline

Classification

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

Pathogenic/Likely pathogenic

15 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_000350.3(ABCA4):c.[3322C>T;6320G>A]

Identifiers

NM_000350.3(ABCA4):c.3322C>T (p.Arg1108Cys)

Variation ID: 92867 Accession: VCV000092867.61

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1p22.1 1: 94042767 (GRCh38) [ NCBI UCSC ] 1: 94508323 (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	Dec 23, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000350.3:c.3322C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000341.2:p.Arg1108Cys	missense
NM_001425324.1:c.3100C>T	NP_001412253.1:p.Arg1034Cys	missense
NC_000001.11:g.94042767G>A
NC_000001.10:g.94508323G>A
NG_009073.1:g.83383C>T
NG_009073.2:g.83381C>T
	P78363:p.Arg1108Cys

... more HGVS ... less HGVS

Protein change

R1108C, R1034C

Other names

Canonical SPDI

NC_000001.11:94042766:G:A

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 (A)

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

Trans-Omics for Precision Medicine (TOPMed) 0.00012

The Genome Aggregation Database (gnomAD) 0.00019

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008

Exome Aggregation Consortium (ExAC) 0.00012

1000 Genomes Project 0.00060

The Genome Aggregation Database (gnomAD), exomes 0.00012

The Genome Aggregation Database (gnomAD), exomes 0.00020

1000 Genomes Project 30x 0.00047

Links

ClinGen: CA220683 UniProtKB: P78363#VAR_012562 dbSNP: rs61750120 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.
Severe early-childhood-onset retinal dystrophy	Pathogenic/Likely pathogenic (5)	criteria provided, multiple submitters, no conflicts	Oct 9, 2024	RCV000150052.20
not provided	Pathogenic (8)	criteria provided, multiple submitters, no conflicts	Dec 18, 2024	RCV000078665.54
Stargardt disease	Pathogenic (2)	criteria provided, single submitter	Oct 1, 2024	RCV001002834.10
Age related macular degeneration 2	Likely pathogenic (1)	criteria provided, single submitter	Jan 1, 2016	RCV001195927.10
Retinal dystrophy	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Aug 16, 2019	RCV001074904.11
ABCA4-related disorder	Pathogenic (1)	no assertion criteria provided	Jun 19, 2024	RCV004537308.2
Age related macular degeneration 2 Cone-rod dystrophy 3 Retinitis pigmentosa 19 Severe early-childhood-onset retinal dystrophy	Pathogenic (1)	criteria provided, single submitter	May 28, 2024	RCV002490678.9
Inborn genetic diseases	Pathogenic (1)	criteria provided, single submitter	Dec 23, 2024	RCV005338078.1

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.
Pathogenic (Jan 17, 2020) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Severe early-childhood-onset retinal dystrophy Affected status: yes Allele origin: unknown	Baylor Genetics Accession: SCV001521355.1 First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021	Comment: This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].

Pathogenic (May 26, 2023) 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: SCV000490375.3 First in ClinVar: Feb 02, 2015 Last updated: Jun 10, 2023	Comment: Published functional studies demonstrate a damaging, temperature-sensitive processing effect on the ABCA4 protein (Sabirzhanova et al., 2015); In silico analysis, which includes protein predictors and … (more) Published functional studies demonstrate a damaging, temperature-sensitive processing effect on the ABCA4 protein (Sabirzhanova et al., 2015); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 11379881, 19074458, 24713488, 11702214, 26354092, 23757202, 11527935, 11726554, 11328725, 29555955, 28118664, 28559085, 32531858, 25283059, 16917483, 23918662, 9781034, 10958763, 26103963, 16703556, 30337596, 30653986, 31456290, 32845050, 32467599, 31589614, 32619608, 32037395, 33732702, 35119454, 35656873, 34216551, 9973280, 29925512, 26092729) (less)

Pathogenic (Oct 09, 2024) 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: SCV005398876.1 First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024	Publications: PubMed (2) PubMed: 31522899‚ 33129279 Comment: Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more) Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Stargardt disease 1 (MIM#248200) and other inherited retinal diseases (OMIM). (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 cystine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v4) <0.01 for a recessive condition (313 heterozygotes, 0 homozygotes). (SP) 0309 - Multiple alternative amino acid changes at the same position have been observed in gnomAD (v4) (highest allele count: 75 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The variant has previously been observed in multiple individuals with Stargardt disease (ClinVar, PMID: 33129279). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)

Pathogenic (Dec 18, 2024) 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: SCV001224349.6 First in ClinVar: Apr 15, 2020 Last updated: Feb 25, 2025	Publications: PubMed (6) PubMed: 10958763‚ 11379881‚ 16703556‚ 26103963‚ 30337596‚ 26092729 Comment: This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1108 of the ABCA4 protein … (more) This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1108 of the ABCA4 protein (p.Arg1108Cys). This variant is present in population databases (rs61750120, gnomAD 0.02%). This missense change has been observed in individual(s) with Stargardt disease and retinitis pigmentosa (PMID: 10958763, 11379881, 16703556, 26103963, 30337596). 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: 92867). 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) indicates that this missense variant is expected to disrupt ABCA4 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ABCA4 function (PMID: 26092729). For these reasons, this variant has been classified as Pathogenic. (less)

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: SCV000281865.2 First in ClinVar: Dec 07, 2016 Last updated: Dec 07, 2016	Publications: PubMed (5) PubMed: 28118664‚ 19074458‚ 24713488‚ 25283059‚ 26092729 Indication for testing: Stargardt disease 1 Zygosity: Single Heterozygote

Pathogenic (Aug 16, 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: SCV001240508.1 First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020 Comment: My Retina Tracker patient

Likely pathogenic (Jan 01, 2016) 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: SCV001366351.2 First in ClinVar: Jul 06, 2020 Last updated: Jul 06, 2020	Comment: This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PM2,PM3,PM5,PP3,PP5.

Pathogenic (Oct 05, 2021) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Severe early-childhood-onset retinal dystrophy Affected status: yes Allele origin: maternal	Laboratory of Medical Genetics, National & Kapodistrian University of Athens Accession: SCV001976835.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021	Comment: PM1, PM2, PM5, PP3, PP5

Likely pathogenic (Jan 01, 2019) 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: SCV005072474.1 First in ClinVar: Dec 28, 2024 Last updated: Dec 28, 2024	Publications: PubMed (26) PubMed: 9781034‚ 16703556‚ 19074458‚ 24713488‚ 25283059‚ 26092729‚ 28559085‚ 29555955‚ 30337596‚ 31589614‚ 29925512‚ 30653986‚ 32845050‚ 32619608‚ 32467599‚ 31964843‚ 32307445‚ 31456290‚ 32531858‚ 32037395‚ 34216551‚ 33732702‚ 35119454‚ 35656873‚ 36460718‚ 35076026

Pathogenic (Oct 01, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Stargardt disease Affected status: yes Allele origin: inherited	Lab De Baere, Eye and Developmental Genetics Lab, Ghent University Accession: SCV005620039.1 First in ClinVar: Jun 22, 2025 Last updated: Jun 22, 2025	Comment: ACMG/AMP guidelines: PM2, PS4, PM5, PS3, PM3_PS Number of individuals with the variant: 1

Pathogenic (May 28, 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: SCV002791285.2 First in ClinVar: Dec 31, 2022 Last updated: Jan 25, 2025

Pathogenic (Dec 29, 2015) 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: SCV000110524.9 First in ClinVar: Jan 17, 2014 Last updated: Apr 13, 2025	Publications: PubMed (3) PubMed: 10958763‚ 11379881‚ 9781034 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: 4 Zygosity: Single Heterozygote Sex: mixed

Pathogenic (Sep 15, 2021) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV001905555.2 First in ClinVar: Sep 26, 2021 Last updated: Apr 13, 2025	Clinical Features: Cone-rod dystrophy (present) Sex: male

Pathogenic (Dec 23, 2024) C Contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV006001285.1 First in ClinVar: Apr 28, 2025 Last updated: Apr 28, 2025	Publications: PubMed (5) PubMed: 10958763‚ 24713488‚ 26092729‚ 26103963‚ 30337596 Comment: The c.3322C>T (p.R1108C) alteration is located in exon 22 (coding exon 22) of the ABCA4 gene. This alteration results from a C to T substitution … (more) The c.3322C>T (p.R1108C) alteration is located in exon 22 (coding exon 22) of the ABCA4 gene. This alteration results from a C to T substitution at nucleotide position 3322, causing the arginine (R) at amino acid position 1108 to be replaced by a cysteine (C). Based on data from gnomAD, the T allele has an overall frequency of 0.0127% (36/282728) total alleles studied. The highest observed frequency was 0.0201% (26/129052) of European (non-Finnish) alleles. This variant has been identified in the homozygous state and/or in conjunction with other ABCA4 variants in multiple individuals with features consistent with ABCA4-related retinal dystrophy; in at least one instance, the variants were identified in trans (Rivera, 2000; Bertelsen, 2014; Boulanger-Scemama, 2015; Ezquerra-Inchausti, 2018). This amino acid position is highly conserved in available vertebrate species. In an assay testing ABCA4 function, this variant showed a functionally abnormal result (Sabirzhanova, 2015). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. (less)

Pathogenic (Apr 01, 2024) 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: SCV001249465.31 First in ClinVar: May 09, 2020 Last updated: Jun 22, 2025	Comment: ABCA4: PM3:Very Strong, PM2, PM5, PP3, PS3:Supporting Number of individuals with the variant: 5

Pathogenic (Jun 23, 2019) N Not contributing to aggregate classification	no assertion criteria provided Method: research	Stargardt disease Affected status: yes Allele origin: inherited	Sharon lab, Hadassah-Hebrew University Medical Center Accession: SCV001160852.1 First in ClinVar: Feb 16, 2020 Last updated: Feb 16, 2020

Pathogenic (-) N Not contributing to aggregate classification	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001920815.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021

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: SCV005047001.1 First in ClinVar: Jun 09, 2024 Last updated: Jun 09, 2024	Publications: PubMed (1) PubMed: 29854428

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: SCV001958523.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021

Pathogenic (Jun 19, 2024) N Not contributing to aggregate classification	no assertion criteria provided Method: clinical testing	ABCA4-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004741972.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: The ABCA4 c.3322C>T variant is predicted to result in the amino acid substitution p.Arg1108Cys. This variant has been reported many times in the compound heterozygous … (more) The ABCA4 c.3322C>T variant is predicted to result in the amino acid substitution p.Arg1108Cys. This variant has been reported many times in the compound heterozygous state in individuals with Stargardt disease (see for examples Rozet et al. 1998. PubMed ID: 9781034; Bertelsen et al. 2014. PubMed ID: 24713488; Duncker et al. 2015. PubMed ID: 25283059; Zhu et al. 2021. PubMed ID: 33732702). This variant is reported in 0.020% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant has been classified as pathogenic by the majority of ClinVar submitters (https://www.ncbi.nlm.nih.gov/clinvar/variation/92867/). Given the evidence, we interpret this variant as pathogenic. (less)

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: SCV000117707.1 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.3322C>T

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Comment:

Published functional studies demonstrate a damaging, temperature-sensitive processing effect on the ABCA4 protein (Sabirzhanova et al., 2015); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 11379881, 19074458, 24713488, 11702214, 26354092, 23757202, 11527935, 11726554, 11328725, 29555955, 28118664, 28559085, 32531858, 25283059, 16917483, 23918662, 9781034, 10958763, 26103963, 16703556, 30337596, 30653986, 31456290, 32845050, 32467599, 31589614, 32619608, 32037395, 33732702, 35119454, 35656873, 34216551, 9973280, 29925512, 26092729)

Comment:

Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Stargardt disease 1 (MIM#248200) and other inherited retinal diseases (OMIM). (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 cystine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v4) <0.01 for a recessive condition (313 heterozygotes, 0 homozygotes). (SP) 0309 - Multiple alternative amino acid changes at the same position have been observed in gnomAD (v4) (highest allele count: 75 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The variant has previously been observed in multiple individuals with Stargardt disease (ClinVar, PMID: 33129279). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Comment:

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1108 of the ABCA4 protein (p.Arg1108Cys). This variant is present in population databases (rs61750120, gnomAD 0.02%). This missense change has been observed in individual(s) with Stargardt disease and retinitis pigmentosa (PMID: 10958763, 11379881, 16703556, 26103963, 30337596). 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: 92867). 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) indicates that this missense variant is expected to disrupt ABCA4 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ABCA4 function (PMID: 26092729). For these reasons, this variant has been classified as Pathogenic.

Comment:

The c.3322C>T (p.R1108C) alteration is located in exon 22 (coding exon 22) of the ABCA4 gene. This alteration results from a C to T substitution at nucleotide position 3322, causing the arginine (R) at amino acid position 1108 to be replaced by a cysteine (C). Based on data from gnomAD, the T allele has an overall frequency of 0.0127% (36/282728) total alleles studied. The highest observed frequency was 0.0201% (26/129052) of European (non-Finnish) alleles. This variant has been identified in the homozygous state and/or in conjunction with other ABCA4 variants in multiple individuals with features consistent with ABCA4-related retinal dystrophy; in at least one instance, the variants were identified in trans (Rivera, 2000; Bertelsen, 2014; Boulanger-Scemama, 2015; Ezquerra-Inchausti, 2018). This amino acid position is highly conserved in available vertebrate species. In an assay testing ABCA4 function, this variant showed a functionally abnormal result (Sabirzhanova, 2015). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.

Comment:

The ABCA4 c.3322C>T variant is predicted to result in the amino acid substitution p.Arg1108Cys. This variant has been reported many times in the compound heterozygous state in individuals with Stargardt disease (see for examples Rozet et al. 1998. PubMed ID: 9781034; Bertelsen et al. 2014. PubMed ID: 24713488; Duncker et al. 2015. PubMed ID: 25283059; Zhu et al. 2021. PubMed ID: 33732702). This variant is reported in 0.020% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant has been classified as pathogenic by the majority of ClinVar submitters (https://www.ncbi.nlm.nih.gov/clinvar/variation/92867/). Given the evidence, we interpret this variant 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 epidemiology of inherited retinal diseases in a large patient cohort followed at a single center in Italy.	Karali M	Scientific reports	2022	PMID: 36460718
Panel-based next-generation sequencing identifies novel mutations in Bulgarian patients with inherited retinal dystrophies.	Kamenarova K	Molecular genetics & genomic medicine	2022	PMID: 35656873
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
Targeted long-read sequencing identifies missing disease-causing variation.	Miller DE	American journal of human genetics	2021	PMID: 34216551
Identification of Four Novel Variants and Determination of Genotype-Phenotype Correlations for ABCA4 Variants Associated With Inherited Retinal Degenerations.	Zhu Q	Frontiers in cell and developmental biology	2021	PMID: 33732702
Novel variants of ABCA4 in Han Chinese families with Stargardt disease.	Hu FY	BMC medical genetics	2020	PMID: 33129279
Functional analysis and classification of homozygous and hypomorphic ABCA4 variants associated with Stargardt macular degeneration.	Curtis SB	Human mutation	2020	PMID: 32845050
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
Copy-number variation contributes 9% of pathogenicity in the inherited retinal degenerations.	Zampaglione E	Genetics in medicine : official journal of the American College of Medical Genetics	2020	PMID: 32037395
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
The Oculome Panel Test: Next-Generation Sequencing to Diagnose a Diverse Range of Genetic Developmental Eye Disorders.	Patel A	Ophthalmology	2019	PMID: 30653986
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
A new approach based on targeted pooled DNA sequencing identifies novel mutations in patients with Inherited Retinal Dystrophies.	Ezquerra-Inchausti M	Scientific reports	2018	PMID: 30337596
Mutation Spectrum of the ABCA4 Gene in a Greek Cohort with Stargardt Disease: Identification of Novel Mutations and Evidence of Three Prevalent Mutated Alleles.	Smaragda K	Journal of ophthalmology	2018	PMID: 29854428
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
Next-generation sequencing applied to a large French cone and cone-rod dystrophy cohort: mutation spectrum and new genotype-phenotype correlation.	Boulanger-Scemama E	Orphanet journal of rare diseases	2015	PMID: 26103963
Rescuing Trafficking Mutants of the ATP-binding Cassette Protein, ABCA4, with Small Molecule Correctors as a Treatment for Stargardt Eye Disease.	Sabirzhanova I	The Journal of biological chemistry	2015	PMID: 26092729
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
ABCA4 disease progression and a proposed strategy for gene therapy.	Cideciyan AV	Human molecular genetics	2009	PMID: 19074458
Occurrence of full-thickness macular hole complicating Stargardt disease with ABCR mutation.	Sodi A	European journal of ophthalmology	2006	PMID: 16703556
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
A comprehensive survey of sequence variation in the ABCA4 (ABCR) gene in Stargardt disease and age-related macular degeneration.	Rivera A	American journal of human genetics	2000	PMID: 10958763
Spectrum of ABCR gene mutations in autosomal recessive macular dystrophies.	Rozet JM	European journal of human genetics : EJHG	1998	PMID: 9781034
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ABCA4	-	-	-	-
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Text-mined citations for rs61750120 ...

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Record last updated Jul 05, 2025

ClinVar Genomic variation as it relates to human health

NM_000350.3(ABCA4):c.3322C>T (p.Arg1108Cys)

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Conditions - Germline

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Citations for germline classification of this variant

Text-mined citations for rs61750120 ...