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: 9973280, 31589614, 29854428, 28044389, 28118664, 24409374, 19265867, 18854780, 28365912, 18652558, 25097154, 22076985, 21873672, 19324865)
ClinVar Genomic variation as it relates to human health
NM_000350.3(ABCA4):c.5087G>A (p.Ser1696Asn)
Germline
Classification
Help
criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.
Pathogenic/Likely pathogenic
6 out of 7 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.
7
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000350.3(ABCA4):c.5087G>A (p.Ser1696Asn)
Variation ID: 99344 Accession: VCV000099344.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p22.1 1: 94019691 (GRCh38) [ NCBI UCSC ] 1: 94485247 (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 Oct 25, 2025 Dec 31, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000350.3:c.5087G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000341.2:p.Ser1696Asn missense NM_001425324.1:c.4865G>A NP_001412253.1:p.Ser1622Asn missense NC_000001.11:g.94019691C>T NC_000001.10:g.94485247C>T NG_009073.1:g.106459G>A NG_009073.2:g.106457G>A P78363:p.Ser1696Asn - Protein change
- S1696N, S1622N
- Other names
- -
- Canonical SPDI
- NC_000001.11:94019690:C:T
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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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The Genome Aggregation Database (gnomAD) 0.00003
Trans-Omics for Precision Medicine (TOPMed) 0.00003
- 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 |
4138 | 4535 | |
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/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Aug 22, 2024 | RCV000085697.10 | |
| Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Dec 31, 2024 | RCV000408469.3 | |
| Likely pathogenic (1) |
criteria provided, single submitter
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Jan 27, 2024 | RCV002490743.2 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Jan 1, 2020 | RCV004815120.1 |
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. |
Expand all rows
Collapse all rows
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
(Jan 01, 2016)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Severe early-childhood-onset retinal dystrophy |
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg
Accession: SCV000281912.2
First in ClinVar: Dec 07, 2016 Last updated: Dec 07, 2016 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Indication for testing: Stargardt disease 1
Zygosity: Single Heterozygote
|
|
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Likely pathogenic
(Nov 20, 2020)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Not Provided |
GeneDx
Accession: SCV001786187.1
First in ClinVar: Aug 14, 2021 Last updated: Aug 14, 2021 |
Comment:
show
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: 9973280, 31589614, 29854428, 28044389, 28118664, 24409374, 19265867, 18854780, 28365912, 18652558, 25097154, 22076985, 21873672, 19324865) (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Likely pathogenic
(Jan 01, 2020)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Retinal dystrophy |
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg
Accession: SCV005071282.1
First in ClinVar: Dec 28, 2024 Last updated: Dec 28, 2024 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Likely pathogenic
(Jan 27, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
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. |
Fulgent Genetics, Fulgent Genetics
Accession: SCV002788206.2
First in ClinVar: Dec 31, 2022 Last updated: Jan 25, 2025 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
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Pathogenic
(Aug 22, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001380885.6
First in ClinVar: Jul 16, 2020 Last updated: Feb 25, 2025 |
Comment:
show
This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 1696 of the ABCA4 protein (p.Ser1696Asn). This variant is present in population databases (rs61750564, gnomAD 0.02%). This missense change has been observed in individuals with Stargardt disease (PMID: 18854780, 20128570, 24409374, 29854428). ClinVar contains an entry for this variant (Variation ID: 99344). 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%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Likely pathogenic
(Dec 31, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Severe early-childhood-onset retinal dystrophy |
3billion
Accession: SCV006584807.1
First in ClinVar: Oct 25, 2025 Last updated: Oct 25, 2025 |
Comment:
show
The variant is observed at an extremely low frequency in the gnomAD v4.1.0 dataset (total allele frequency: 0.002%). Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.69 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.96 (>=0.6, sensitivity 0.72 and precision 0.9)]. The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000099344 /PMID: 9973280). Different missense changes at the same codon (p.Ser1696Arg, p.Ser1696Gly, p.Ser1696Thr) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000438099, VCV002821867, VCV002822370 /PMID: 23982839, 33090715). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Method: exome sequencing
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|
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not provided
(-)
N
Not contributing to aggregate classification
|
no classification provided
|
not provided |
Retina International
Accession: SCV000117837.1
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.5087G>A
|
Observation: 1
Collection method: not provided
Allele origin: not provided
Affected status: not provided
Observation 1
Collection method: not provided
Allele origin: not provided
Affected status: not provided
|
|
Comment:
Comment:
This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 1696 of the ABCA4 protein (p.Ser1696Asn). This variant is present in population databases (rs61750564, gnomAD 0.02%). This missense change has been observed in individuals with Stargardt disease (PMID: 18854780, 20128570, 24409374, 29854428). ClinVar contains an entry for this variant (Variation ID: 99344). 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%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic.
Comment:
The variant is observed at an extremely low frequency in the gnomAD v4.1.0 dataset (total allele frequency: 0.002%). Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.69 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.96 (>=0.6, sensitivity 0.72 and precision 0.9)]. The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000099344 /PMID: 9973280). Different missense changes at the same codon (p.Ser1696Arg, p.Ser1696Gly, p.Ser1696Thr) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000438099, VCV002821867, VCV002822370 /PMID: 23982839, 33090715). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.
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 |
| Genetic characteristics of 234 Italian patients with macular and cone/cone-rod dystrophy. | Falsini B | Scientific reports | 2022 | PMID: 35260635 |
| Functional Characterization of ABCA4 Missense Variants Linked to Stargardt Macular Degeneration. | Garces FA | International journal of molecular sciences | 2020 | PMID: 33375396 |
| 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 |
| 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 |
| 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 |
| 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 |
| ABCA4 gene screening by next-generation sequencing in a British cohort. | Fujinami K | Investigative ophthalmology & visual science | 2013 | PMID: 23982839 |
| Functional Analysis of Retinal Flecks in Stargardt Disease. | Verdina T | Journal of clinical & experimental ophthalmology | 2012 | PMID: 24409374 |
| Different patterns of fundus autofluorescence related to ABCA4 gene mutations in Stargardt disease. | Sodi A | Ophthalmic surgery, lasers & imaging : the official journal of the International Society for Imaging in the Eye | 2010 | PMID: 20128570 |
| Peripapillary atrophy in Stargardt disease. | Hwang JC | Retina (Philadelphia, Pa.) | 2009 | PMID: 18854780 |
| 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 |
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Text-mined citations for rs61750564 ...
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 Oct 26, 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.