ClinVar Genomic variation as it relates to human health
NM_000350.3(ABCA4):c.5603A>T (p.Asn1868Ile)
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.
Likely pathogenic(2); Established risk allele(2); Uncertain significance(4); Benign(3); Likely benign(5)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000350.3(ABCA4):c.5603A>T (p.Asn1868Ile)
Variation ID: 99390 Accession: VCV000099390.45
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p22.1 1: 94010911 (GRCh38) [ NCBI UCSC ] 1: 94476467 (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 Mar 10, 2024 Mar 5, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000350.3:c.5603A>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000341.2:p.Asn1868Ile missense NC_000001.11:g.94010911T>A NC_000001.10:g.94476467T>A NG_009073.1:g.115239A>T P78363:p.Asn1868Ile - Protein change
- N1868I
- Other names
- p.N1868I:AAT>ATT
- Canonical SPDI
- NC_000001.11:94010910:T:A
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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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0.02077 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.04456
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.04775
1000 Genomes Project 0.02077
1000 Genomes Project 30x 0.02124
Trans-Omics for Precision Medicine (TOPMed) 0.03802
The Genome Aggregation Database (gnomAD) 0.04126
The Genome Aggregation Database (gnomAD), exomes 0.04255
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 | ||
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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. |
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ABCA4 | - | - |
GRCh38 GRCh37 |
3700 | 4057 |
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. |
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Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
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Dec 18, 2021 | RCV000085744.32 | |
Benign (1) |
criteria provided, multiple submitters, no conflicts
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May 20, 2014 | RCV000178424.16 | |
Likely benign (1) |
criteria provided, single submitter
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Jun 14, 2016 | RCV000293913.13 | |
Likely benign (1) |
criteria provided, single submitter
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Jun 14, 2016 | RCV000309306.13 | |
Likely benign (1) |
criteria provided, single submitter
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Jun 14, 2016 | RCV000348932.13 | |
Likely benign (1) |
criteria provided, single submitter
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Jun 14, 2016 | RCV000391356.13 | |
Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
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Jun 23, 2022 | RCV000721173.14 | |
Likely pathogenic (1) |
no assertion criteria provided
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Jun 23, 2019 | RCV001002812.9 | |
Likely benign (1) |
criteria provided, single submitter
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Apr 27, 2017 | RCV001097975.12 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jun 27, 2019 | RCV001197336.10 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 1, 2019 | RCV001262623.9 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Apr 1, 2021 | RCV001723669.10 | |
Established risk allele (1) |
criteria provided, single submitter
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Mar 5, 2024 | RCV003883462.1 | |
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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 benign
(Jun 14, 2016)
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criteria provided, single submitter
Method: clinical testing
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Macular Degeneration
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000359266.2
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
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Likely benign
(Jun 14, 2016)
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criteria provided, single submitter
Method: clinical testing
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Retinitis Pigmentosa, Recessive
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000359265.2
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
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Likely benign
(Jun 14, 2016)
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criteria provided, single submitter
Method: clinical testing
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Stargardt Disease, Recessive
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000359267.2
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
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Likely benign
(Jun 14, 2016)
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criteria provided, single submitter
Method: clinical testing
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Cone-Rod Dystrophy, Recessive
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000359264.2
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
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Benign
(May 20, 2014)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000230500.5
First in ClinVar: Jun 28, 2015 Last updated: Oct 02, 2016 |
Number of individuals with the variant: 1
Sex: mixed
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Uncertain significance
(May 28, 2019)
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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: SCV001135331.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Likely benign
(Apr 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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ABCA4-Related Disorders
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001254309.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
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Uncertain significance
(Jan 01, 2019)
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criteria provided, single submitter
Method: clinical testing
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Cone-rod dystrophy 3
Affected status: yes
Allele origin:
unknown
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001440560.1
First in ClinVar: Oct 31, 2020 Last updated: Oct 31, 2020 |
Comment:
This variant was identified as compound heterozygous.
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Uncertain significance
(Jun 27, 2019)
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criteria provided, single submitter
Method: clinical testing
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Age related macular degeneration 2
Affected status: yes
Allele origin:
unknown
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001368030.2
First in ClinVar: Jul 04, 2020 Last updated: Jul 04, 2020 |
Comment:
This variant was classified as: Uncertain significance. The available evidence favors the pathogenic nature of this variant, however the currently available data is insufficient to … (more)
This variant was classified as: Uncertain significance. The available evidence favors the pathogenic nature of this variant, however the currently available data is insufficient to conclusively support its pathogenic nature. Thus this variant is classified as Uncertain significance - favor pathogenic. The following ACMG criteria were applied in classifying this variant: PP2,PP3,BS1. (less)
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Likely pathogenic
(Jan 30, 2021)
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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 Medical Molecular Genetics, University of Zurich
Accession: SCV001548165.1
First in ClinVar: Mar 28, 2021 Last updated: Mar 28, 2021 |
Method: long-range PCR
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Likely pathogenic
(Apr 01, 2021)
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criteria provided, single submitter
Method: curation
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Retinitis pigmentosa
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Broad Institute Rare Disease Group, Broad Institute
Accession: SCV001950192.1
First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
Comment:
The p.Asn1868Ile variant in ABCA4 was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics … (more)
The p.Asn1868Ile variant in ABCA4 was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PS3, PM3, PM3, BP2. Based on this evidence we have classified this variant as Likely Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab. (less)
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Benign
(Dec 18, 2021)
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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: SCV001731765.2
First in ClinVar: Jun 15, 2021 Last updated: May 16, 2022 |
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Established risk allele
(Jun 23, 2022)
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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:
unknown
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV002549835.1
First in ClinVar: Jul 23, 2022 Last updated: Jul 23, 2022 |
Comment:
This variant was identified as compound heterozygous with NM_000350.3:c.67-2A>G
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Established risk allele
(Mar 05, 2024)
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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: SCV000303765.2
First in ClinVar: Oct 02, 2016 Last updated: Mar 10, 2024 |
Comment:
This variant is reported with a global allele frequency of 4.2% in gnomAD, with the highest population frequency being 6.6% in individuals of European (Non-Finnish) … (more)
This variant is reported with a global allele frequency of 4.2% in gnomAD, with the highest population frequency being 6.6% in individuals of European (Non-Finnish) descent, including hundreds of homozygous individuals. Allele frequencies this high are most often associated with variants that are considered benign for Mendelian disease. However, statistical analyses have shown that this variant is significantly enriched in Stargardt patient populations compared to controls (Webster et al. 2001. PubMed ID: 11328725; Aguirre-Lamban et al. 2011. PubMed ID: 21330655). Large cohort studies of individuals with only one known pathogenic variant in ABCA4 found that this c.5603A>T (p.Asn1868Ile) variant could explain ~50% of those missing heritability cases (Zernant et al. 2017. PubMed ID: 28446513; Bauwens et al. 2019. PubMed ID: 30670881). Despite the enrichment in the patient population, the very high allele frequency has been used to estimate that the penetrance of this variant is less than 5% (Runhart et al. 2018. PubMed ID: 29971439). Additionally, it has been demonstrated that patients who harbor this variant have a more mild phenotype and an average age of onset in the 4th decade compared to the typical juvenile-onset associated with ABCA4 disease (Zernant et al. 2017. PubMed ID: 28446513; Bauwens et al. 2019. PubMed ID: 30670881). Functional studies have shown that this variant causes a small but significant decrease in the ATPase activity (Sun et al. 2000. PubMed ID: 11017087) and a decrease in substrate binding ability (Garces et al. 2021. PubMed ID: 33375396). This variant has often been found in cis with other ABCA4 variants such as c.2588G>C, c.5461-10T>C, and many others; forming a complex allele which can modify the penetrance and severity of disease (Zernant et al. 2017. PubMed ID: 28446513; Bauwens et al. 2019. PubMed ID: 30670881). Given all the evidence, we interpret c.5603A>T (p.Asn1868Ile) as a risk variant for mild and late-onset disease when in trans with a severe variant. (less)
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Benign
(Jan 28, 2019)
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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: SCV000166748.12
First in ClinVar: Jun 23, 2014 Last updated: Mar 04, 2023 |
Comment:
The variant in the ABCA4 gene that is indicated below was identified in this patient and is not currently known to cause an ABCA4-related disorder. … (more)
The variant in the ABCA4 gene that is indicated below was identified in this patient and is not currently known to cause an ABCA4-related disorder. The variant is observed in 8,580/129,074 (6.65%) alleles from individuals of non-Finnish European background and in 11,928/282,712 (4.22%) global alleles, including 364 homozygous individuals, in large population cohorts (Lek et al., 2016). However, some publications theorize N1868I may cause hypomorphic retinal dystrophy only when in trans with a pathogenic ABCA4 variant (Zernant et al., 2017; Runhart et al., 2018). Individuals who had the N1868I variant in trans with another ABCA4 pathogenic variant were reported to have late-onset Stargardt disease (Zernant et al., 2017; Runhart et al,. 2018).; This variant is associated with the following publications: (PMID: 26780318, 21330655, 32845050, 28118664, 11328725, 28446513, 27775217, 24265693, 11017087, 29555955, 29971439, 23443024, 30204727, 30480703, 30480704, 29925512, 30670881, 30643219, 31618761, 31456290, 32467599, 32037395) (less)
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Uncertain significance
(Aug 01, 2018)
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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: SCV000493309.24
First in ClinVar: May 29, 2016 Last updated: Mar 10, 2024 |
Number of individuals with the variant: 6
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other
(Sep 10, 2018)
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no assertion criteria provided
Method: clinical testing
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Severe early-childhood-onset retinal dystrophy
Affected status: yes
Allele origin:
germline
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Molecular Vision Laboratory
Accession: SCV000852088.1
First in ClinVar: Nov 17, 2018 Last updated: Nov 17, 2018 |
Comment:
Asn1868Ile has been found to be associated with autosomal recessive Stargardt disease (STGD1). Its presence explained >40% of monoallelic ABCA4 carriers in two separate STGD1 … (more)
Asn1868Ile has been found to be associated with autosomal recessive Stargardt disease (STGD1). Its presence explained >40% of monoallelic ABCA4 carriers in two separate STGD1 cohorts. Penetrance was estimated to be less than 5% based on expected incidence of Asn1868Ile combinations with severe ABCA4 mutations and estimated prevalence of cases due to these combinations in a STGD1 cohort. (less)
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Likely pathogenic
(Jun 23, 2019)
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no assertion criteria provided
Method: research
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Stargardt disease
Affected status: yes
Allele origin:
inherited
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Sharon lab, Hadassah-Hebrew University Medical Center
Accession: SCV001160826.1
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: SCV000117885.1
First in ClinVar: Feb 20, 2014 Last updated: Feb 20, 2014 |
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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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Recommendations for risk allele evidence curation, classification, and reporting from the ClinGen Low Penetrance/Risk Allele Working Group. | Schmidt RJ | Genetics in medicine : official journal of the American College of Medical Genetics | 2024 | PMID: 38054408 |
The importance of automation in genetic diagnosis: Lessons from analyzing an inherited retinal degeneration cohort with the Mendelian Analysis Toolkit (MATK). | Zampaglione E | Genetics in medicine : official journal of the American College of Medical Genetics | 2022 | PMID: 34906470 |
Long-Range PCR-Based NGS Applications to Diagnose Mendelian Retinal Diseases. | Maggi J | International journal of molecular sciences | 2021 | PMID: 33546218 |
Penetrance of the ABCA4 p.Asn1868Ile Allele in Stargardt Disease. | Allikmets R | Investigative ophthalmology & visual science | 2018 | PMID: 30480703 |
The Common ABCA4 Variant p.Asn1868Ile Shows Nonpenetrance and Variable Expression of Stargardt Disease When Present in trans With Severe Variants. | Runhart EH | Investigative ophthalmology & visual science | 2018 | PMID: 29971439 |
Clinical and genetic characteristics of 251 consecutive patients with macular and cone/cone-rod dystrophy. | Birtel J | Scientific reports | 2018 | PMID: 29555955 |
Frequent hypomorphic alleles account for a significant fraction of ABCA4 disease and distinguish it from age-related macular degeneration. | Zernant J | Journal of medical genetics | 2017 | PMID: 28446513 |
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 |
Increasing the yield in targeted next-generation sequencing by implicating CNV analysis, non-coding exons and the overall variant load: the example of retinal dystrophies. | Eisenberger T | PloS one | 2013 | PMID: 24265693 |
Further associations between mutations and polymorphisms in the ABCA4 gene: clinical implication of allelic variants and their role as protector/risk factors. | Aguirre-Lamban J | Investigative ophthalmology & visual science | 2011 | PMID: 21330655 |
An analysis of allelic variation in the ABCA4 gene. | Webster AR | Investigative ophthalmology & visual science | 2001 | PMID: 11328725 |
Biochemical defects in ABCR protein variants associated with human retinopathies. | Sun H | Nature genetics | 2000 | PMID: 11017087 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ABCA4 | - | - | - | - |
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Text-mined citations for rs1801466 ...
HelpRecord last updated Mar 23, 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.