VCV000007899.45 - ClinVar

NM_000350.3(ABCA4):c.52C>T (p.Arg18Trp)

Germline

Classification

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

Pathogenic

8 out of 11 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.[52C>T;5603A>T]

Identifiers

NM_000350.3(ABCA4):c.52C>T (p.Arg18Trp)

Variation ID: 7899 Accession: VCV000007899.45

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1p22.1 1: 94120994 (GRCh38) [ NCBI UCSC ] 1: 94586550 (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	Apr 20, 2025	Mar 5, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_000350.3:c.52C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000341.2:p.Arg18Trp	missense
NM_001425324.1:c.52C>T	NP_001412253.1:p.Arg18Trp	missense
NC_000001.11:g.94120994G>A
NC_000001.10:g.94586550G>A
NG_009073.1:g.5156C>T
NG_009073.2:g.5154C>T
	P78363:p.Arg18Trp

... more HGVS ... less HGVS

Protein change

R18W

Other names

Canonical SPDI

NC_000001.11:94120993: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.

0.00040 (A)

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

The Genome Aggregation Database (gnomAD) 0.00005

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015

1000 Genomes Project 0.00040

1000 Genomes Project 30x 0.00062

Links

UniProtKB: P78363#VAR_008398 OMIM: 601691.0021 dbSNP: rs121909205 ClinGen: CA227296 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	4045	4425

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 (2)	criteria provided, multiple submitters, no conflicts	Apr 8, 2021	RCV000008356.17
not provided	Pathogenic (6)	criteria provided, multiple submitters, no conflicts	Mar 5, 2025	RCV000085719.51
Retinal dystrophy	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	May 9, 2019	RCV001075717.11
Stargardt disease 3	Pathogenic (1)	no assertion criteria provided	-	RCV004558241.2

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 (Sep 28, 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: SCV000701766.3 First in ClinVar: Jan 20, 2017 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: 2 Zygosity: Single Heterozygote Sex: mixed
Pathogenic (Jun 01, 2021) 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: SCV001745932.23 First in ClinVar: Jul 10, 2021 Last updated: Apr 20, 2025	Number of individuals with the variant: 1
Pathogenic (May 09, 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: SCV001241345.1 First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020 Comment: My Retina Tracker patient
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: SCV001573651.1 First in ClinVar: May 10, 2021 Last updated: May 10, 2021	Publications: PubMed (6) PubMed: 29925512‚ 29854428‚ 28118664‚ 23755871‚ 23096905‚ 9503029 Comment: The ABCA4 c.52C>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.52C>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, PM1, PP1, PM3-S. Based on this evidence we have classified this variant as Pathogenic. (less)
Pathogenic (Jan 01, 2017) 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: SCV000281792.3 First in ClinVar: Dec 07, 2016 Last updated: Dec 28, 2024	Publications: PubMed (10) PubMed: 28118664‚ 9503029‚ 23755871‚ 29555955‚ 30204727‚ 31589614‚ 29925512‚ 35119454‚ 35260635‚ 36460718
Pathogenic (Nov 08, 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: SCV001402755.6 First in ClinVar: Jul 16, 2020 Last updated: Feb 25, 2025	Publications: PubMed (4) PubMed: 23096905‚ 23755871‚ 29854428‚ 29925512 Comment: This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 18 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 18 of the ABCA4 protein (p.Arg18Trp). This variant is present in population databases (rs121909205, gnomAD 0.003%). This missense change has been observed in individuals with Stargardt disease and retinal disease (PMID: 23096905, 23755871, 29854428, 29925512). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 7899). 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%. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Mar 05, 2025) 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: SCV001796097.6 First in ClinVar: Aug 21, 2021 Last updated: Mar 16, 2025	Comment: Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more) Not observed at significant frequency in large population cohorts (gnomAD); 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: 9503029, 28044389, 10090887, 23755871, 28118664, 27014590, 31589614, 30204727, 29925512, 29555955, 37734845, 35120629, 35119454, 35260635, 36460718, 34906470, 38219857, 38309476, 39162841, 38369462) (less)
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: SCV001447330.2 First in ClinVar: Nov 28, 2020 Last updated: Apr 13, 2025	Clinical Features: Macular degeneration (present) , Macular dystrophy (present) Sex: female
Pathogenic (Feb 15, 1998) N Not contributing to aggregate classification	no assertion criteria provided Method: literature only	STARGARDT DISEASE 1 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000028564.2 First in ClinVar: Apr 04, 2013 Last updated: Jan 20, 2017	Publications: PubMed (1) PubMed: 9503029 Comment on evidence: In 2 patients with Stargardt disease (STGD1; 248200), Gerber et al. (1998) identified a homozygous C-to-T transition at nucleotide 52 in the ABCA4 gene, resulting … (more) In 2 patients with Stargardt disease (STGD1; 248200), Gerber et al. (1998) identified a homozygous C-to-T transition at nucleotide 52 in the ABCA4 gene, resulting in an arg18-to-trp substitution. (less)
Pathogenic (-) N Not contributing to aggregate classification	no assertion criteria provided Method: research	Stargardt disease 3 (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Ophthalmo-Genetics Lab, Instituto de Oftalmologia Conde de Valenciana Accession: SCV005046923.2 First in ClinVar: Jun 09, 2024 Last updated: Apr 13, 2025	Publications: PubMed (1) PubMed: 38369462 Zygosity: Compound Heterozygote Sex: female
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: SCV000117859.1 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.52C>T
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Comment:

The ABCA4 c.52C>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, PM1, PP1, 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 18 of the ABCA4 protein (p.Arg18Trp). This variant is present in population databases (rs121909205, gnomAD 0.003%). This missense change has been observed in individuals with Stargardt disease and retinal disease (PMID: 23096905, 23755871, 29854428, 29925512). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 7899). 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%. For these reasons, this variant has been classified as Pathogenic.

Comment:

Not observed at significant frequency in large population cohorts (gnomAD); 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: 9503029, 28044389, 10090887, 23755871, 28118664, 27014590, 31589614, 30204727, 29925512, 29555955, 37734845, 35120629, 35119454, 35260635, 36460718, 34906470, 38219857, 38309476, 39162841, 38369462)

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
ABCA4 variant screening in a Turkish cohort with Stargardt disease.	Sinim Kahraman N	Ophthalmic genetics	2024	PMID: 38369462
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
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
CLINICAL CHARACTERIZATION OF STARGARDT DISEASE PATIENTS WITH THE p.N1868I ABCA4 MUTATION.	Collison FT	Retina (Philadelphia, Pa.)	2019	PMID: 30204727
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
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
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
Outcome of ABCA4 disease-associated alleles in autosomal recessive retinal dystrophies: retrospective analysis in 420 Spanish families.	Riveiro-Alvarez R	Ophthalmology	2013	PMID: 23755871
Clinical and molecular genetic study of 12 Italian families with autosomal recessive Stargardt disease.	Oldani M	Genetics and molecular research : GMR	2012	PMID: 23096905
Complete exon-intron structure of the retina-specific ATP binding transporter gene (ABCR) allows the identification of novel mutations underlying Stargardt disease.	Gerber S	Genomics	1998	PMID: 9503029
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ABCA4	-	-	-	-
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Text-mined citations for rs121909205 ...

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 May 03, 2025

ClinVar Genomic variation as it relates to human health

NM_000350.3(ABCA4):c.52C>T (p.Arg18Trp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs121909205 ...