ClinVar Genomic variation as it relates to human health
NM_000350.3(ABCA4):c.4594G>A (p.Asp1532Asn)
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.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000350.3(ABCA4):c.4594G>A (p.Asp1532Asn)
Variation ID: 99304 Accession: VCV000099304.19
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p22.1 1: 94024994 (GRCh38) [ NCBI UCSC ] 1: 94490550 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Feb 14, 2024 Jan 29, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000350.3:c.4594G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000341.2:p.Asp1532Asn missense NM_001425324.1:c.4372G>A NP_001412253.1:p.Asp1458Asn missense NC_000001.11:g.94024994C>T NC_000001.10:g.94490550C>T NG_009073.1:g.101156G>A NG_009073.2:g.101154G>A P78363:p.Asp1532Asn - Protein change
- D1532N, D1458N
- Other names
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- Canonical SPDI
- NC_000001.11:94024993:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe 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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00005
The Genome Aggregation Database (gnomAD) 0.00006
Exome Aggregation Consortium (ExAC) 0.00009
The Genome Aggregation Database (gnomAD), exomes 0.00011
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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ABCA4 | - | - |
GRCh38 GRCh37 |
3711 | 4068 |
Conditions - Germline
Condition
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Jan 29, 2024 | RCV000085657.15 | |
Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Aug 1, 2023 | RCV000177510.5 | |
Likely pathogenic (1) |
no assertion criteria provided
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Jun 23, 2019 | RCV001002826.2 | |
Pathogenic (1) |
criteria provided, single submitter
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May 27, 2019 | RCV001074286.3 | |
not provided (1) |
no classification provided
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- | RCV001535669.2 | |
Pathogenic (1) |
criteria provided, single submitter
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May 30, 2023 | RCV003235039.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 10, 2023 | RCV004529890.1 |
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
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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. |
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Pathogenic
(May 27, 2019)
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criteria provided, single submitter
Method: clinical testing
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Retinal dystrophy
Affected status: yes
Allele origin:
germline
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Blueprint Genetics
Accession: SCV001239859.1
First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020
Comment:
My Retina Tracker patient
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Pathogenic
(May 24, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001769717.4
First in ClinVar: Aug 07, 2021 Last updated: Jun 24, 2023 |
Comment:
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: 28118664, … (more)
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: 28118664, 9973280, 19217903, 22589445, 30055151, 29925512, 28559085, 29343940, 32013026, 31456290, 31589614, 32037395, 24409374, 33505770, 11726554) (less)
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Pathogenic
(May 30, 2023)
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criteria provided, single submitter
Method: clinical testing
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Retinitis pigmentosa
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003934465.1
First in ClinVar: Jun 24, 2023 Last updated: Jun 24, 2023 |
Comment:
Variant summary: ABCA4 c.4594G>A (p.Asp1532Asn) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging … (more)
Variant summary: ABCA4 c.4594G>A (p.Asp1532Asn) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 251478 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in ABCA4 causing Retinitis Pigmentosa (0.00011 vs 0.0014), allowing no conclusion about variant significance. c.4594G>A has been reported in the literature in multiple individuals affected with Stargardt disease and bull's eye maculopathy (examples: Lewis_1999, Shroyer_2001, Cella_2009, Giani_2012, Verdina_2014). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 11726554, 19217903 , 22589445, 24409374 , 9973280 ). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Jul 10, 2023)
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criteria provided, single submitter
Method: clinical testing
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ABCA4-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004118321.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The ABCA4 c.4594G>A variant is predicted to result in the amino acid substitution p.Asp1532Asn. This variant has previously been reported to be causative for autosomal … (more)
The ABCA4 c.4594G>A variant is predicted to result in the amino acid substitution p.Asp1532Asn. This variant has previously been reported to be causative for autosomal recessive Stargardt disease (see for example - Gomes et al. 2009. PubMed ID: 19324865; Lewis et al. 1999. PubMed ID: 9973280; Schulz et al. 2017. PubMed ID: 28118664). This variant is reported in 0.21% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-94490550-C-T). This variant is interpreted as pathogenic. (less)
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Likely pathogenic
(Jan 01, 2016)
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criteria provided, single submitter
Method: clinical testing
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Severe early-childhood-onset retinal dystrophy
Affected status: yes
Allele origin:
germline
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Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg
Accession: SCV000281897.2
First in ClinVar: Dec 07, 2016 Last updated: Dec 07, 2016 |
Indication for testing: Stargardt disease 1
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Pathogenic
(Feb 24, 2015)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000229391.5
First in ClinVar: Jun 28, 2015 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Likely pathogenic
(Aug 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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Severe early-childhood-onset retinal dystrophy
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
unknown
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV004032319.1
First in ClinVar: Sep 09, 2023 Last updated: Sep 09, 2023 |
Comment:
Criteria applied: PS4,PM2_SUP,PP3
Clinical Features:
Visual field defect (present) , Macular dystrophy (present) , Abnormality of vision (present)
Sex: male
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Pathogenic
(Jan 29, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001201993.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 1532 of the ABCA4 protein … (more)
This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 1532 of the ABCA4 protein (p.Asp1532Asn). This variant is present in population databases (rs62642574, gnomAD 0.2%). This missense change has been observed in individual(s) with Stargardt disease (PMID: 9973280, 11726554, 19217903, 22589445, 24409374, 29925512; Invitae). 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: 99304). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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)
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Likely pathogenic
(Jun 23, 2019)
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no assertion criteria provided
Method: research
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Maculopathy
Affected status: yes
Allele origin:
inherited
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Sharon lab, Hadassah-Hebrew University Medical Center
Accession: SCV001160843.1
First in ClinVar: Feb 16, 2020 Last updated: Feb 16, 2020 |
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not provided
(-)
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no classification provided
Method: not provided
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not provided
Affected status: not provided
Allele origin:
not provided
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Retina International
Accession: SCV000117797.1
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.4594G>A
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not provided
(-)
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no classification provided
Method: phenotyping only
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Cone-rod dystrophy 3
Retinitis pigmentosa 19 Retinitis pigmentosa 19 Age-related macular degeneration
Affected status: yes
Allele origin:
unknown
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GenomeConnect - Invitae Patient Insights Network
Accession: SCV001749732.1
First in ClinVar: Jul 18, 2021 Last updated: Jul 18, 2021 |
Comment:
Variant interpreted as Pathogenic and reported on 02-21-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report … (more)
Variant interpreted as Pathogenic and reported on 02-21-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. (less)
Clinical Features:
Abnormality of vision (present) , Myopia (present) , Abnormal retinal morphology (present) , Abnormal intestine morphology (present) , Pregnancy history (present)
Indication for testing: Diagnostic
Age: 50-59 years
Sex: female
Testing laboratory: Invitae
Date variant was reported to submitter: 2020-02-21
Testing laboratory interpretation: Pathogenic
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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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 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 |
Functional Analysis of Retinal Flecks in Stargardt Disease. | Verdina T | Journal of clinical & experimental ophthalmology | 2012 | PMID: 24409374 |
The dark atrophy with indocyanine green angiography in Stargardt disease. | Giani A | Investigative ophthalmology & visual science | 2012 | PMID: 22589445 |
G1961E mutant allele in the Stargardt disease gene ABCA4 causes bull's eye maculopathy. | Cella W | Experimental eye research | 2009 | PMID: 19217903 |
Cosegregation and functional analysis of mutant ABCR (ABCA4) alleles in families that manifest both Stargardt disease and age-related macular degeneration. | Shroyer NF | Human molecular genetics | 2001 | PMID: 11726554 |
Genotype/Phenotype analysis of a photoreceptor-specific ATP-binding cassette transporter gene, ABCR, in Stargardt disease. | Lewis RA | American journal of human genetics | 1999 | PMID: 9973280 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ABCA4 | - | - | - | - |
Text-mined citations for rs62642574 ...
HelpRecord last updated May 19, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.