This variant was identified as compound heterozygous with NM_000350.3:c.666_678del.
ClinVar Genomic variation as it relates to human health
NM_000350.3(ABCA4):c.286A>G (p.Asn96Asp)
Germline
Classification
Help
criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.
Pathogenic/Likely pathogenic
7 out of 11 submissions contributed to this classification
Help
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.
11
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000350.3(ABCA4):c.286A>G (p.Asn96Asp)
Variation ID: 99166 Accession: VCV000099166.45
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p22.1 1: 94111454 (GRCh38) [ NCBI UCSC ] 1: 94577010 (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 May 25, 2025 Jan 6, 2025 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000350.3:c.286A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000341.2:p.Asn96Asp missense NM_001425324.1:c.286A>G NP_001412253.1:p.Asn96Asp missense NC_000001.11:g.94111454T>C NC_000001.10:g.94577010T>C NG_009073.1:g.14696A>G NG_009073.2:g.14694A>G P78363:p.Asn96Asp - Protein change
- N96D
- Other names
- -
- Canonical SPDI
- NC_000001.11:94111453:T:C
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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
Help
The frequency of the allele represented by this VCV record.
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Trans-Omics for Precision Medicine (TOPMed) 0.00001
Exome Aggregation Consortium (ExAC) 0.00003
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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 |
4046 | 4426 | |
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. |
|---|---|---|---|---|
| Pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Jan 6, 2025 | RCV000085515.38 | |
| Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jul 2, 2021 | RCV000986376.4 | |
| Likely pathogenic (1) |
criteria provided, single submitter
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Jan 1, 2020 | RCV004815092.1 | |
| Pathogenic (1) |
criteria provided, single submitter
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May 16, 2024 | RCV005025150.1 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Likely pathogenic
(Jul 02, 2021)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Severe early-childhood-onset retinal dystrophy
Affected status: yes
Allele origin:
unknown
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001950068.1
First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
Comment:
This variant was identified as compound heterozygous with NM_000350.3:c.666_678del.
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Pathogenic
(May 06, 2021)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
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Severe early-childhood-onset retinal dystrophy
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002767212.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with retinal dystrophy, Stargardt disease 1 (MIM#248200) and cone-rod dystrophy (MIM#604116). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Affected siblings can have variable age of onset and severity of disease (PMID:31522899). 0200 - Variant is predicted to result in a missense amino acid change from asparagine to aspartic acid. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v3) (3 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change p.(Asn96His) at the same position has been observed in gnomAD (v3) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has previously been reported in both the homozygous and compound heterozygous state in at least 10 individuals with Stargardt disease (ClinVar; PMID: 19365591; 25444351; 30093795; 29625472; 30060493). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Likely pathogenic
(Jan 01, 2020)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
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Retinal dystrophy
Affected status: yes
Allele origin:
germline
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Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg
Accession: SCV005071327.1
First in ClinVar: Dec 28, 2024 Last updated: Dec 28, 2024 |
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Pathogenic
(May 16, 2024)
C
Contributing to aggregate classification
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criteria provided, single submitter
Method: clinical testing
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Age related macular degeneration 2
Severe early-childhood-onset retinal dystrophy Retinitis pigmentosa 19 Cone-rod dystrophy 3
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
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Fulgent Genetics, Fulgent Genetics
Accession: SCV005656541.1
First in ClinVar: Jan 25, 2025 Last updated: Jan 25, 2025 |
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Pathogenic
(Jan 06, 2025)
C
Contributing to aggregate classification
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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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001222272.6
First in ClinVar: Apr 15, 2020 Last updated: Feb 25, 2025 |
Comment:
This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 96 of the ABCA4 protein … (more)
This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 96 of the ABCA4 protein (p.Asn96Asp). This variant is present in population databases (rs61748529, gnomAD 0.003%). This missense change has been observed in individuals with Stargardt disease (PMID: 19365591, 28355279, 29925512, 30060493, 30093795). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 99166). 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)
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Pathogenic
(May 28, 2019)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
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Severe early-childhood-onset retinal dystrophy
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV001135366.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Pathogenic
(Feb 01, 2018)
C
Contributing to aggregate classification
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001247763.30
First in ClinVar: May 09, 2020 Last updated: May 25, 2025 |
Number of individuals with the variant: 1
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Likely pathogenic
(-)
N
Not contributing to aggregate classification
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV002034591.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021 |
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Likely pathogenic
(-)
N
Not contributing to aggregate classification
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001808415.1 First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 2021 |
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Likely pathogenic
(-)
N
Not contributing to aggregate classification
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001958650.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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not provided
(-)
N
Not contributing to aggregate classification
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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: SCV000117652.1
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.286A>G
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| click to load more submissions click to collapse | |||||
Comment:
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with retinal dystrophy, Stargardt disease 1 (MIM#248200) and cone-rod dystrophy (MIM#604116). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Affected siblings can have variable age of onset and severity of disease (PMID:31522899). 0200 - Variant is predicted to result in a missense amino acid change from asparagine to aspartic acid. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v3) (3 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change p.(Asn96His) at the same position has been observed in gnomAD (v3) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has previously been reported in both the homozygous and compound heterozygous state in at least 10 individuals with Stargardt disease (ClinVar; PMID: 19365591; 25444351; 30093795; 29625472; 30060493). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 96 of the ABCA4 protein (p.Asn96Asp). This variant is present in population databases (rs61748529, gnomAD 0.003%). This missense change has been observed in individuals with Stargardt disease (PMID: 19365591, 28355279, 29925512, 30060493, 30093795). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 99166). 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.
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:
This variant was identified as compound heterozygous with NM_000350.3:c.666_678del.
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with retinal dystrophy, Stargardt disease 1 (MIM#248200) and cone-rod dystrophy (MIM#604116). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Affected siblings can have variable age of onset and severity of disease (PMID:31522899). 0200 - Variant is predicted to result in a missense amino acid change from asparagine to aspartic acid. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v3) (3 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change p.(Asn96His) at the same position has been observed in gnomAD (v3) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has previously been reported in both the homozygous and compound heterozygous state in at least 10 individuals with Stargardt disease (ClinVar; PMID: 19365591; 25444351; 30093795; 29625472; 30060493). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 96 of the ABCA4 protein (p.Asn96Asp). This variant is present in population databases (rs61748529, gnomAD 0.003%). This missense change has been observed in individuals with Stargardt disease (PMID: 19365591, 28355279, 29925512, 30060493, 30093795). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 99166). 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.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Genetic epidemiology of inherited retinal diseases in a large patient cohort followed at a single center in Italy. | Karali M | Scientific reports | 2022 | PMID: 36460718 |
| 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 |
| Functional analysis and classification of homozygous and hypomorphic ABCA4 variants associated with Stargardt macular degeneration. | Curtis SB | Human mutation | 2020 | PMID: 32845050 |
| Genotype-Phenotype Correlations in a Spanish Cohort of 506 Families With Biallelic ABCA4 Pathogenic Variants. | Del Pozo-Valero M | American journal of ophthalmology | 2020 | PMID: 32619608 |
| 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 |
| Inherited retinal disease in Norway - a characterization of current clinical and genetic knowledge. | Holtan JP | Acta ophthalmologica | 2020 | PMID: 31429209 |
| Highly Variable Disease Courses in Siblings with Stargardt Disease. | Valkenburg D | Ophthalmology | 2019 | PMID: 31522899 |
| 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 |
| Variants in the ABCA4 gene in a Brazilian population with Stargardt disease. | Salles MV | Molecular vision | 2018 | PMID: 30093795 |
| 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 |
| Visual Cortex Activation in Patients With Stargardt Disease. | Melillo P | Investigative ophthalmology & visual science | 2018 | PMID: 29625472 |
| Highly sensitive measurements of disease progression in rare disorders: Developing and validating a multimodal model of retinal degeneration in Stargardt disease. | Lambertus S | PloS one | 2017 | PMID: 28355279 |
| Early-onset stargardt disease: phenotypic and genotypic characteristics. | Lambertus S | Ophthalmology | 2015 | PMID: 25444351 |
| Quantitative fundus autofluorescence distinguishes ABCA4-associated and non-ABCA4-associated bull's-eye maculopathy. | Duncker T | Ophthalmology | 2015 | PMID: 25283059 |
| ABCA4 mutations in Portuguese Stargardt patients: identification of new mutations and their phenotypic analysis. | Maia-Lopes S | Molecular vision | 2009 | PMID: 19365591 |
| An analysis of ABCR mutations in British patients with recessive retinal dystrophies. | Papaioannou M | Investigative ophthalmology & visual science | 2000 | PMID: 10634594 |
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Text-mined citations for rs61748529 ...
HelpThese 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 25, 2025
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.