VCV000099300.29 - ClinVar

NM_000350.3(ABCA4):c.454C>T (p.Arg152Ter)

Germline

Classification

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

Pathogenic/Likely pathogenic

9 out of 10 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.454C>T (p.Arg152Ter)

Variation ID: 99300 Accession: VCV000099300.29

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1p22.1 1: 94103131 (GRCh38) [ NCBI UCSC ] 1: 94568687 (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	Jul 13, 2025	Dec 24, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000350.3:c.454C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000341.2:p.Arg152Ter	nonsense
NM_001425324.1:c.454C>T	NP_001412253.1:p.Arg152Ter	nonsense
NC_000001.11:g.94103131G>A
NC_000001.10:g.94568687G>A
NG_009073.1:g.23019C>T
NG_009073.2:g.23017C>T

... more HGVS ... less HGVS

Protein change

R152*

Other names

Canonical SPDI

NC_000001.11:94103130: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

The Genome Aggregation Database (gnomAD) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00002

Links

ClinGen: CA227213 dbSNP: rs62646861 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	4062	4447

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 (5)	criteria provided, multiple submitters, no conflicts	Dec 24, 2024	RCV000085653.25
Retinal dystrophy	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Apr 24, 2019	RCV001075709.3
Severe early-childhood-onset retinal dystrophy	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jan 30, 2021	RCV000408527.3
Cone-rod dystrophy 3	Pathogenic (1)	criteria provided, single submitter	Dec 29, 2021	RCV002272126.2

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.
Likely pathogenic (Jan 30, 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: germline	Institute of Medical Molecular Genetics, University of Zurich Accession: SCV001548060.1 First in ClinVar: Mar 28, 2021 Last updated: Mar 28, 2021	Publications: PubMed (1) PubMed: 33546218 Test name: long-range PCR Platform type: next-gen sequencing Platform name: MiSeq Method: long-range PCR

Pathogenic (Mar 21, 2024) 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: SCV005326972.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: Frequently reported together with p.(V2050L) on the same allele (in cis) representing a complex allele [p.(R152); p.(V2050L)] in individuals of central European ancestry (PMID: 26593885); … (more) Frequently reported together with p.(V2050L) on the same allele (in cis) representing a complex allele [p.(R152); p.(V2050L)] in individuals of central European ancestry (PMID: 26593885); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 26047050, 32619608, 31429209, 33301772, 19074458, 22328824, 29555955, 28118664, 10509673, 29925512, 30653986, 10486215, 35119454, 23695285, 26593885) (less)

Pathogenic (Dec 24, 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: SCV001419360.6 First in ClinVar: Jul 16, 2020 Last updated: Feb 25, 2025	Publications: PubMed (6) PubMed: 10958761‚ 24938718‚ 25312043‚ 26780318‚ 19074458‚ 23695285 Comment: This sequence change creates a premature translational stop signal (p.Arg152) in the ABCA4 gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Arg152) in the ABCA4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ABCA4 are known to be pathogenic (PMID: 10958761, 24938718, 25312043, 26780318). This variant is present in population databases (rs62646861, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with Stargardt disease (PMID: 19074458, 23695285). ClinVar contains an entry for this variant (Variation ID: 99300). For these reasons, this variant has been classified as Pathogenic. (less)

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: SCV000281807.2 First in ClinVar: Dec 07, 2016 Last updated: Dec 07, 2016	Publications: PubMed (7) PubMed: 28118664‚ 10509673‚ 19074458‚ 23695285‚ 22328824‚ 26047050‚ 25525159 Indication for testing: Stargardt disease 1 Zygosity: Single Heterozygote

Pathogenic (Apr 24, 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: SCV001241337.1 First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020 Comment: My Retina Tracker patient

Pathogenic (Dec 29, 2021) 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	Genetics and Molecular Pathology, SA Pathology Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002556378.2 First in ClinVar: Aug 08, 2022 Last updated: Dec 17, 2022

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: SCV005070949.1 First in ClinVar: Dec 28, 2024 Last updated: Dec 28, 2024	Publications: PubMed (19) PubMed: 10509673‚ 10486215‚ 19074458‚ 22328824‚ 23695285‚ 26593885‚ 26047050‚ 25525159‚ 28118664‚ 29555955‚ 29925512‚ 30653986‚ 32619608‚ 31964843‚ 31429209‚ 31980526‚ 32307445‚ 33301772‚ 35119454

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: SCV001446681.2 First in ClinVar: Nov 28, 2020 Last updated: Apr 13, 2025	Clinical Features: Rod-cone dystrophy (present) , Cone-rod dystrophy (present) Sex: male

Pathogenic (Jan 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: SCV004704289.14 First in ClinVar: Mar 10, 2024 Last updated: Jul 13, 2025	Comment: ABCA4: PM3:Very Strong, PVS1, PM2 Number of individuals with the variant: 2

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: SCV000117793.1 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.454C>T

Comment:

Frequently reported together with p.(V2050L) on the same allele (in cis) representing a complex allele [p.(R152*); p.(V2050L)] in individuals of central European ancestry (PMID: 26593885); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 26047050, 32619608, 31429209, 33301772, 19074458, 22328824, 29555955, 28118664, 10509673, 29925512, 30653986, 10486215, 35119454, 23695285, 26593885)

Comment:

This sequence change creates a premature translational stop signal (p.Arg152*) in the ABCA4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ABCA4 are known to be pathogenic (PMID: 10958761, 24938718, 25312043, 26780318). This variant is present in population databases (rs62646861, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with Stargardt disease (PMID: 19074458, 23695285). ClinVar contains an entry for this variant (Variation ID: 99300). For these reasons, this variant has been classified as Pathogenic.

Germline Functional Evidence

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

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
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
Long-Range PCR-Based NGS Applications to Diagnose Mendelian Retinal Diseases.	Maggi J	International journal of molecular sciences	2021	PMID: 33546218
Clinical and genetic analysis of the ABCA4 gene associated retinal dystrophy in a large Chinese cohort.	Sun Z	Experimental eye research	2021	PMID: 33301772
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
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
Precision medicine integrating whole-genome sequencing, comprehensive metabolomics, and advanced imaging.	Hou YC	Proceedings of the National Academy of Sciences of the United States of America	2020	PMID: 31980526
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
Inherited retinal disease in Norway - a characterization of current clinical and genetic knowledge.	Holtan JP	Acta ophthalmologica	2020	PMID: 31429209
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
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
Screening of ABCA4 Gene in a Chinese Cohort With Stargardt Disease or Cone-Rod Dystrophy With a Report on 85 Novel Mutations.	Jiang F	Investigative ophthalmology & visual science	2016	PMID: 26780318
Next-generation sequencing of ABCA4: High frequency of complex alleles and novel mutations in patients with retinal dystrophies from Central Europe.	Ścieżyńska A	Experimental eye research	2016	PMID: 26593885
Comprehensive Molecular Diagnosis of a Large Chinese Leber Congenital Amaurosis Cohort.	Wang H	Investigative ophthalmology & visual science	2015	PMID: 26047050
RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease.	Xiong HY	Science (New York, N.Y.)	2015	PMID: 25525159
Clinical and molecular characteristics of childhood-onset Stargardt disease.	Fujinami K	Ophthalmology	2015	PMID: 25312043
Mutations of 60 known causative genes in 157 families with retinitis pigmentosa based on exome sequencing.	Xu Y	Human genetics	2014	PMID: 24938718
Stargardt disease: towards developing a model to predict phenotype.	Heathfield L	European journal of human genetics : EJHG	2013	PMID: 23695285
Stargardt macular dystrophy: common ABCA4 mutations in South Africa--establishment of a rapid genetic test and relating risk to patients.	Roberts LJ	Molecular vision	2012	PMID: 22328824
ABCA4 disease progression and a proposed strategy for gene therapy.	Cideciyan AV	Human molecular genetics	2009	PMID: 19074458
Mutations in the ABCA4 (ABCR) gene are the major cause of autosomal recessive cone-rod dystrophy.	Maugeri A	American journal of human genetics	2000	PMID: 10958761
A novel ABCR nonsense mutation responsible for late-onset fundus flavimaculatus.	Souied EH	Investigative ophthalmology & visual science	1999	PMID: 10509673
The ABCR gene in recessive and dominant Stargardt diseases: a genetic pathway in macular degeneration.	Zhang K	Genomics	1999	PMID: 10486215
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Text-mined citations for rs62646861 ...

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 Jul 13, 2025

ClinVar Genomic variation as it relates to human health

NM_000350.3(ABCA4):c.454C>T (p.Arg152Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs62646861 ...