VCV000099330.40 - ClinVar

NM_000350.3(ABCA4):c.4918C>T (p.Arg1640Trp)

Germline

Classification

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

Pathogenic/Likely pathogenic; other

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

Identifiers

NM_000350.3(ABCA4):c.4918C>T (p.Arg1640Trp)

Variation ID: 99330 Accession: VCV000099330.40

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1p22.1 1: 94021340 (GRCh38) [ NCBI UCSC ] 1: 94486896 (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 12, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_000350.3:c.4918C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000341.2:p.Arg1640Trp	missense
NM_001425324.1:c.4696C>T	NP_001412253.1:p.Arg1566Trp	missense
NC_000001.11:g.94021340G>A
NC_000001.10:g.94486896G>A
NG_009073.1:g.104810C>T
NG_009073.2:g.104808C>T
NG_082117.1:g.695G>A
	P78363:p.Arg1640Trp

... more HGVS ... less HGVS

Protein change

R1640W, R1566W

Other names

NP_000341.2:p.(Arg1640Trp)

Canonical SPDI

NC_000001.11:94021339: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.

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

Exome Aggregation Consortium (ExAC) 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00002

The Genome Aggregation Database (gnomAD) 0.00003

Links

ClinGen: CA227253 UniProtKB: P78363#VAR_008461 dbSNP: rs61751404 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
LOC126805793	-	-	-	GRCh38	-	234

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; other (6)	criteria provided, multiple submitters, no conflicts	Jan 12, 2025	RCV000085683.32
Retinal dystrophy	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Jan 1, 2022	RCV000210311.6
Severe early-childhood-onset retinal dystrophy	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Mar 30, 2023	RCV000408519.11
Leber congenital amaurosis	Likely pathogenic (1)	no assertion criteria provided	Jan 1, 2015	RCV000505114.3
Stargardt disease	Pathogenic (3)	criteria provided, single submitter	Jul 24, 2023	RCV000787504.4
Age related macular degeneration 2 Cone-rod dystrophy 3 Retinitis pigmentosa 19 Severe early-childhood-onset retinal dystrophy	Pathogenic (1)	criteria provided, single submitter	Aug 12, 2021	RCV002505017.2
ABCA4-related disorder	Pathogenic (1)	no assertion criteria provided	Aug 14, 2024	RCV004732674.1
Cone-rod dystrophy 3	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Nov 14, 2023	RCV004760372.3

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 (Oct 04, 2018) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000321353.7 First in ClinVar: Oct 09, 2016 Last updated: Apr 17, 2019	Comment: The R1640W pathogenic variant in the ABCA4 gene has been reported previously in autosomal recessive Stargardt disease in affected individuals when in the homozgyous state … (more) The R1640W pathogenic variant in the ABCA4 gene has been reported previously in autosomal recessive Stargardt disease in affected individuals when in the homozgyous state or when in trans with another pathogenic variant (Battu et al., 2015; Fujinami et al., 2013; Rozet et al., 1998). The R1640W variant has been reported on the same allele (in cis) with the W1408R variant in families with Stargardt disease, and in a family presenting with both Stargardt disease and retinitis pigmentosa, when in trans with another pathogenic variant (Valverde et al, 2006; Shroyer et al, 2001). Shroyer et al. (2001) showed very little protein from cells transfected with the W1408R and R1640W variants in cis; however, proteins bearing only the W1408R or the R1640W variants appear to have mild or moderate defects in expression or stability. The R1640W variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R1640W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. We interpret R1640W as a pathogenic variant. (less)

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: SCV001239246.1 First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020 Comment: My Retina Tracker patient

Pathogenic (Aug 12, 2021) 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 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002812456.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022

Pathogenic (Mar 30, 2023) 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: germline	Molecular Genetics, Royal Melbourne Hospital Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002503642.2 First in ClinVar: Apr 28, 2022 Last updated: Apr 15, 2024	Publications: PubMed (4) PubMed: 9781034‚ 10090887‚ 11687513‚ 21873672 Comment: This sequence change is predicted to replace arginine with tryptophan at codon 1640 of the ABCA4 protein, p.(Arg1640Trp). The arginine residue is highly conserved (100 … (more) This sequence change is predicted to replace arginine with tryptophan at codon 1640 of the ABCA4 protein, p.(Arg1640Trp). The arginine residue is highly conserved (100 vertebrates, UCSC), and there is a large physicochemical difference between arginine and tryptophan. The variant is present in a large population cohort at a frequency of 0.003%, consistent with recessive disease (rs61751404, 8/251,420 alleles, 0 homozygotes in gnomAD v2.1). The variant has been identified in the homozygous state and compound heterozygous with a second pathogenic allele in multiple Stargardt disease cases (PMID: 9781034, 10090887, 11687513, 21873672). The missense change causes reduced protein expression and ATPase activity in in vitro functional assays (PMID: 11687513). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (6/7 algorithms). A different missense change at the same amino acid residue (p.Arg1640Gln) determined to be pathogenic has been seen before (ClinVar ID: 99331). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_Strong, PM2, PM5, PS3_Supporting, PP3. (less)

Pathogenic (Jan 01, 2022) 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: SCV000281907.3 First in ClinVar: Dec 07, 2016 Last updated: Dec 28, 2024	Publications: PubMed (18) PubMed: 28118664‚ 9781034‚ 11687513‚ 25082885‚ 28041643‚ 28559085‚ 29555955‚ 31589614‚ 29925512‚ 31573552‚ 32619608‚ 31964843‚ 32307445‚ 31456290‚ 32531858‚ 32141364‚ 35119454‚ 36460718

Pathogenic (Feb 02, 2022) 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: SCV002558011.2 First in ClinVar: Aug 04, 2022 Last updated: Jul 23, 2024	Publications: PubMed (8) PubMed: 23769331‚ 25066811‚ 25922843‚ 29854428‚ 30060493‚ 30834176‚ 31522899‚ 31766579 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 1 (MIM#248200), cone-rod dystrophy 3 (MIM#604116), 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 tryptophan. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2) (8 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (8 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools and highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated ABC2_membrane_3 domain (Protein DataBank). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been identified in multiple individuals diagnosed with Stargardt disease (ClinVar, PMIDs: 23769331, 25066811, 25922843, 29854428, 30060493, 30834176, 31766579). (SP) 1102 - Strong phenotype match for this individual. (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 (Nov 14, 2023) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cone-rod dystrophy 3 Affected status: yes Allele origin: germline	3billion Accession: SCV005906326.1 First in ClinVar: Apr 13, 2025 Last updated: Apr 13, 2025	Publications: PubMed (3) PubMed: 10711710‚ 17325136‚ 9781034 Comment: The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.003%). Predicted Consequence/Location: Missense variant Functional studies provide … (more) The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.003%). Predicted Consequence/Location: Missense variant Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 17325136). In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.80 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.93 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000099330 /PMID: 9781034 /3billion dataset). A different missense change at the same codon (p.Arg1640Gln) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000099331 /PMID: 10711710 /3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less) Platform type: exome

Likely pathogenic (Oct 23, 2020) 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: SCV001447306.2 First in ClinVar: Nov 28, 2020 Last updated: Apr 13, 2025	Clinical Features: Cone-rod dystrophy (present) Sex: female

Pathogenic (Jul 24, 2023) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Stargardt disease Affected status: yes Allele origin: germline	Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel Accession: SCV004030316.2 First in ClinVar: Sep 03, 2023 Last updated: Apr 13, 2025 Comment: This variant was classified as Pathogenic based on ACMG criteria: PM1, PP2, PM2, PM5, PP3, PP5.	Publications: PubMed (1) PubMed: 36909829 Comment: Clinical significance based on ACMG v2.0 Number of individuals with the variant: 1 Sex: female Geographic origin: Portugal

Pathogenic (Mar 28, 2023) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cone-rod dystrophy 3 (Autosomal recessive inheritance) Affected status: yes Allele origin: paternal	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV005368459.2 First in ClinVar: Oct 13, 2024 Last updated: Apr 13, 2025	Comment: Criteria applied: PM3_VSTR,PM5,PS3_SUP,PM2_SUP,PP3 Clinical Features: Abnormality of the eye (present) , Retinal dystrophy (present) Sex: male

Pathogenic (Apr 08, 2021) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Severe early-childhood-onset retinal dystrophy Affected status: yes Allele origin: germline	Ocular Genomics Institute, Massachusetts Eye and Ear Accession: SCV001573564.1 First in ClinVar: May 10, 2021 Last updated: May 10, 2021	Publications: PubMed (13) PubMed: 30718709‚ 29925512‚ 28559085‚ 28118664‚ 28041643‚ 26872967‚ 26103963‚ 25082885‚ 23755871‚ 11687513‚ 11527935‚ 10711710‚ 9781034 Comment: The ABCA4 c.4918C>T variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we … (more) The ABCA4 c.4918C>T variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PM2, PP3, PS3, PM1, PM3-S. Based on this evidence we have classified this variant as Pathogenic. (less)

Pathogenic (Jan 12, 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: SCV001210838.6 First in ClinVar: Apr 15, 2020 Last updated: Feb 25, 2025	Publications: PubMed (10) PubMed: 9781034‚ 28041643‚ 28559085‚ 29925512‚ 11687513‚ 10711710‚ 11527935‚ 23755871‚ 26103963‚ 28118664 Comment: This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1640 of the ABCA4 protein … (more) This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1640 of the ABCA4 protein (p.Arg1640Trp). This variant is present in population databases (rs61751404, gnomAD 0.007%). This missense change has been observed in individuals with ABCA4-related conditions (PMID: 9781034, 28041643, 28559085, 29925512). ClinVar contains an entry for this variant (Variation ID: 99330). 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: 11687513). This variant disrupts the p.Arg1640 amino acid residue in ABCA4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10711710, 11527935, 23755871, 26103963, 28118664). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)

other Variant classified as "other reportable" ??? variant is clinically benign (not associated with disease) but is reported when observed (e.g. pseudodeficiency alleles). (Aug 31, 2017) 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: SCV000339315.5 First in ClinVar: Dec 06, 2016 Last updated: Apr 13, 2025	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: 1 Zygosity: Single Heterozygote Sex: mixed

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: SCV004702745.13 First in ClinVar: Mar 10, 2024 Last updated: Jun 22, 2025	Comment: ABCA4: PM3:Very Strong, PM2, PM5 Number of individuals with the variant: 3

Pathogenic (Jan 30, 2015) N Not contributing to aggregate classification	no assertion criteria provided Method: clinical testing	Retinal dystrophy Affected status: yes Allele origin: germline	Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals Accession: SCV000259103.1 First in ClinVar: Mar 25, 2016 Last updated: Mar 25, 2016	Publications: PubMed (1) PubMed: 26872967

Pathogenic (Apr 01, 2018) N Not contributing to aggregate classification	no assertion criteria provided Method: research	Stargardt disease Affected status: yes Allele origin: unknown	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet Study: VeluxRD Accession: SCV000926470.2 First in ClinVar: Jul 21, 2019 Last updated: Sep 03, 2023	Publications: PubMed (1) PubMed: 30718709

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: SCV001160839.1 First in ClinVar: Feb 16, 2020 Last updated: Feb 16, 2020

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: SCV005047039.1 First in ClinVar: Jun 09, 2024 Last updated: Jun 09, 2024	Publications: PubMed (1) PubMed: 23769331

Likely pathogenic (Jan 01, 2015) N Not contributing to aggregate classification	no assertion criteria provided Method: research	Leber congenital amaurosis Affected status: yes Allele origin: unknown	NIHR Bioresource Rare Diseases, University of Cambridge Accession: SCV000598986.2 First in ClinVar: Sep 09, 2017 Last updated: Apr 13, 2025	Publications: PubMed (2) PubMed: 28041643‚ 9781034 Number of individuals with the variant: 1 Sex: male Ethnicity/Population group: NA Platform type: Whole Exome Sequencing

Pathogenic (Aug 14, 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: SCV005362339.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: The ABCA4 c.4918C>T variant is predicted to result in the amino acid substitution p.Arg1640Trp. This variant has been reported many times to be causative for … (more) The ABCA4 c.4918C>T variant is predicted to result in the amino acid substitution p.Arg1640Trp. This variant has been reported many times to be causative for autosomal recessive Stargardt disease or macular and cone/cone-rod dystrophy (see for examples: Rozet et al. 1998. PubMed ID: 9781034; Alapati et al. 2014. PubMed ID: 25082885; Table S1, Birtel et al. 2018. PubMed ID: 29555955). This variant is reported in 0.0053% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted 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: not provided	Retina International Accession: SCV000117823.1 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.4918C>T

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Comment:

The R1640W pathogenic variant in the ABCA4 gene has been reported previously in autosomal recessive Stargardt disease in affected individuals when in the homozgyous state or when in trans with another pathogenic variant (Battu et al., 2015; Fujinami et al., 2013; Rozet et al., 1998). The R1640W variant has been reported on the same allele (in cis) with the W1408R variant in families with Stargardt disease, and in a family presenting with both Stargardt disease and retinitis pigmentosa, when in trans with another pathogenic variant (Valverde et al, 2006; Shroyer et al, 2001). Shroyer et al. (2001) showed very little protein from cells transfected with the W1408R and R1640W variants in cis; however, proteins bearing only the W1408R or the R1640W variants appear to have mild or moderate defects in expression or stability. The R1640W variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R1640W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. We interpret R1640W as a pathogenic variant.

Comment:

This sequence change is predicted to replace arginine with tryptophan at codon 1640 of the ABCA4 protein, p.(Arg1640Trp). The arginine residue is highly conserved (100 vertebrates, UCSC), and there is a large physicochemical difference between arginine and tryptophan. The variant is present in a large population cohort at a frequency of 0.003%, consistent with recessive disease (rs61751404, 8/251,420 alleles, 0 homozygotes in gnomAD v2.1). The variant has been identified in the homozygous state and compound heterozygous with a second pathogenic allele in multiple Stargardt disease cases (PMID: 9781034, 10090887, 11687513, 21873672). The missense change causes reduced protein expression and ATPase activity in in vitro functional assays (PMID: 11687513). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (6/7 algorithms). A different missense change at the same amino acid residue (p.Arg1640Gln) determined to be pathogenic has been seen before (ClinVar ID: 99331). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_Strong, PM2, PM5, PS3_Supporting, PP3.

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 1 (MIM#248200), cone-rod dystrophy 3 (MIM#604116), 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 tryptophan. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2) (8 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (8 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools and highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated ABC2_membrane_3 domain (Protein DataBank). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been identified in multiple individuals diagnosed with Stargardt disease (ClinVar, PMIDs: 23769331, 25066811, 25922843, 29854428, 30060493, 30834176, 31766579). (SP) 1102 - Strong phenotype match for this individual. (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:

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.003%). Predicted Consequence/Location: Missense variant Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 17325136). In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.80 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.93 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000099330 /PMID: 9781034 /3billion dataset). A different missense change at the same codon (p.Arg1640Gln) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000099331 /PMID: 10711710 /3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

The ABCA4 c.4918C>T variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PM2, PP3, PS3, PM1, PM3-S. Based on this evidence we have classified this variant as Pathogenic.

Comment:

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1640 of the ABCA4 protein (p.Arg1640Trp). This variant is present in population databases (rs61751404, gnomAD 0.007%). This missense change has been observed in individuals with ABCA4-related conditions (PMID: 9781034, 28041643, 28559085, 29925512). ClinVar contains an entry for this variant (Variation ID: 99330). 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: 11687513). This variant disrupts the p.Arg1640 amino acid residue in ABCA4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10711710, 11527935, 23755871, 26103963, 28118664). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

Comment:

The ABCA4 c.4918C>T variant is predicted to result in the amino acid substitution p.Arg1640Trp. This variant has been reported many times to be causative for autosomal recessive Stargardt disease or macular and cone/cone-rod dystrophy (see for examples: Rozet et al. 1998. PubMed ID: 9781034; Alapati et al. 2014. PubMed ID: 25082885; Table S1, Birtel et al. 2018. PubMed ID: 29555955). This variant is reported in 0.0053% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted 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
The first genetic landscape of inherited retinal dystrophies in Portuguese patients identifies recurrent homozygous mutations as a frequent cause of pathogenesis.	Peter VG	PNAS nexus	2023	PMID: 36909829
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
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
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
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
Genetic testing for inherited ocular conditions in a developing country.	Zanolli M	Ophthalmic genetics	2020	PMID: 32141364
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
Genetic Spectrum of ABCA4-Associated Retinal Degeneration in Poland.	Tracewska AM	Genes	2019	PMID: 31766579
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
[Phenotype-genotype correlations in patients with inherited retinal diseases with p.G1961E mutation in the ABCA4 gene].	Sheremet NL	Vestnik oftalmologii	2019	PMID: 31573552
Highly Variable Disease Courses in Siblings with Stargardt Disease.	Valkenburg D	Ophthalmology	2019	PMID: 31522899
Cross-Sectional and Longitudinal Assessment of the Ellipsoid Zone in Childhood-Onset Stargardt Disease.	Tanna P	Translational vision science & technology	2019	PMID: 30834176
Molecular genetic analysis using targeted NGS analysis of 677 individuals with retinal dystrophy.	Jespersgaard C	Scientific reports	2019	PMID: 30718709
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
Expanding the Mutation Spectrum in ABCA4: Sixty Novel Disease Causing Variants and Their Associated Phenotype in a Large French Stargardt Cohort.	Nassisi M	International journal of molecular sciences	2018	PMID: 30060493
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
Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease.	Carss KJ	American journal of human genetics	2017	PMID: 28041643
Whole Genome Sequencing Increases Molecular Diagnostic Yield Compared with Current Diagnostic Testing for Inherited Retinal Disease.	Ellingford JM	Ophthalmology	2016	PMID: 26872967
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
Identification of Novel Mutations in ABCA4 Gene: Clinical and Genetic Analysis of Indian Patients with Stargardt Disease.	Battu R	BioMed research international	2015	PMID: 25922843
Molecular diagnostic testing by eyeGENE: analysis of patients with hereditary retinal dystrophy phenotypes involving central vision loss.	Alapati A	Investigative ophthalmology & visual science	2014	PMID: 25082885
Genetic and clinical analysis of ABCA4-associated disease in African American patients.	Zernant J	Human mutation	2014	PMID: 25066811
The clinical effect of homozygous ABCA4 alleles in 18 patients.	Fujinami K	Ophthalmology	2013	PMID: 23769331
Outcome of ABCA4 disease-associated alleles in autosomal recessive retinal dystrophies: retrospective analysis in 420 Spanish families.	Riveiro-Alvarez R	Ophthalmology	2013	PMID: 23755871
Quantification of peripapillary sparing and macular involvement in Stargardt disease (STGD1).	Burke TR	Investigative ophthalmology & visual science	2011	PMID: 21873672
Spectrum of the ABCA4 gene mutations implicated in severe retinopathies in Spanish patients.	Valverde D	Investigative ophthalmology & visual science	2007	PMID: 17325136
Null missense ABCR (ABCA4) mutations in a family with stargardt disease and retinitis pigmentosa.	Shroyer NF	Investigative ophthalmology & visual science	2001	PMID: 11687513
Mutations in ABCR (ABCA4) in patients with Stargardt macular degeneration or cone-rod degeneration.	Briggs CE	Investigative ophthalmology & visual science	2001	PMID: 11527935
New ABCR mutations and clinical phenotype in Italian patients with Stargardt disease.	Simonelli F	Investigative ophthalmology & visual science	2000	PMID: 10711710
The 2588G-->C mutation in the ABCR gene is a mild frequent founder mutation in the Western European population and allows the classification of ABCR mutations in patients with Stargardt disease.	Maugeri A	American journal of human genetics	1999	PMID: 10090887
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 rs61751404 ...

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.4918C>T (p.Arg1640Trp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs61751404 ...