ClinVar Genomic variation as it relates to human health
NM_000350.3(ABCA4):c.4773+3A>G
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.4773+3A>G
Variation ID: 236122 Accession: VCV000236122.41
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p22.1 1: 94021843 (GRCh38) [ NCBI UCSC ] 1: 94487399 (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 Dec 7, 2016 Oct 8, 2024 Jan 5, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000350.3:c.4773+3A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NC_000001.11:g.94021843T>C NC_000001.10:g.94487399T>C NG_009073.1:g.104307A>G NG_009073.2:g.104305A>G NG_082117.1:g.1198T>C - Protein change
- Other names
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- Canonical SPDI
- NC_000001.11:94021842:T:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- sequence_variant_affecting_splicing Sequence Ontology [SO:1000071]
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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) 0.00002
The Genome Aggregation Database (gnomAD) 0.00004
The Genome Aggregation Database (gnomAD), exomes 0.00007
Exome Aggregation Consortium (ExAC) 0.00012
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
Help
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 |
3750 | 4104 | |
LOC126805793 | - | - | - | GRCh38 | - | 215 |
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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Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Feb 18, 2022 | RCV000408554.4 | |
Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Jan 5, 2024 | RCV000425309.35 | |
Pathogenic (2) |
criteria provided, single submitter
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May 21, 2019 | RCV000787761.4 |
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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Pathogenic
(Jan 01, 2016)
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criteria provided, single submitter
Method: clinical testing, in vitro
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Severe early-childhood-onset retinal dystrophy
Affected status: yes
Allele origin:
germline,
unknown
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Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg
Accession: SCV000281905.2
First in ClinVar: Dec 07, 2016 Last updated: Dec 07, 2016 |
Observation 1:
Indication for testing: Stargardt disease 1
Observation 2:
Method: Minigene assay.
Result:
Effect of most common transcripts: Several isoforms: skipping of exon 33, or 34, or both. Alternative isoform with deletion of 9 bp of exon 33. Use of alternative acceptor in exon 33. Probable effect at the RNA and protein level: r.4668_4773del; p.Y1557Afs*18 / r.4774_4848del; p.G1592_K1616del / exon 33 and 34 dele
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Pathogenic
(Sep 03, 2015)
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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: SCV000511900.4
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
Comment:
The c.4773+3 A>G splice site variant in the ABCA4 gene has been previously reported in association with Stargardt disease (Duno et al., 2012; Jonsson et … (more)
The c.4773+3 A>G splice site variant in the ABCA4 gene has been previously reported in association with Stargardt disease (Duno et al., 2012; Jonsson et al., 2013; Braun et al., 2013). This variant is predicted to destroy the canonical splice donor site in intron 33. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. The c.4773+3 A>G variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. (less)
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Pathogenic
(May 21, 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: SCV001241368.1
First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020
Comment:
My Retina Tracker patient
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Pathogenic
(Oct 23, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001446942.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Cone-rod dystrophy (present) , Macular dystrophy (present)
Sex: male
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Pathogenic
(Feb 18, 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:
paternal
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV002102455.1
First in ClinVar: Mar 05, 2022 Last updated: Mar 05, 2022 |
Comment:
_x000D_ Criteria applied: PM3_VSTR, PS3, PM2_SUP
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Pathogenic
(Sep 28, 2020)
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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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Revvity Omics, Revvity
Accession: SCV002019710.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 05, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001227047.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change falls in intron 33 of the ABCA4 gene. It does not directly change the encoded amino acid sequence of the ABCA4 protein. … (more)
This sequence change falls in intron 33 of the ABCA4 gene. It does not directly change the encoded amino acid sequence of the ABCA4 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs759672616, gnomAD 0.02%). This variant has been observed in individual(s) with clinical features of ABCA4-related conditions (PMID: 23443024, 23918662, 29555955, 30718709). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 236122). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 28118664, 29162642). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jan 01, 2020)
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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: SCV001248239.25
First in ClinVar: May 12, 2020 Last updated: Oct 08, 2024 |
Number of individuals with the variant: 1
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Uncertain significance
(Apr 01, 2018)
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no assertion criteria provided
Method: research
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Retinal dystrophy
Affected status: yes
Allele origin:
unknown
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Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet
Study: VeluxRD
Accession: SCV000926766.2 First in ClinVar: Jul 21, 2019 Last updated: Sep 03, 2023 |
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Germline Functional Evidence
Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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sequence_variant_affecting_splicing
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Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg
Accession: SCV000281905.2
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Molecular genetic analysis using targeted NGS analysis of 677 individuals with retinal dystrophy. | Jespersgaard C | Scientific reports | 2019 | PMID: 30718709 |
Clinical and genetic characteristics of 251 consecutive patients with macular and cone/cone-rod dystrophy. | Birtel J | Scientific reports | 2018 | PMID: 29555955 |
ABCA4 midigenes reveal the full splice spectrum of all reported noncanonical splice site variants in Stargardt disease. | Sangermano R | Genome research | 2018 | PMID: 29162642 |
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 |
Non-exomic and synonymous variants in ABCA4 are an important cause of Stargardt disease. | Braun TA | Human molecular genetics | 2013 | PMID: 23918662 |
Novel mutations in CRB1 and ABCA4 genes cause Leber congenital amaurosis and Stargardt disease in a Swedish family. | Jonsson F | European journal of human genetics : EJHG | 2013 | PMID: 23443024 |
Phenotypic and genetic spectrum of Danish patients with ABCA4-related retinopathy. | Duno M | Ophthalmic genetics | 2012 | PMID: 22229821 |
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
Text-mined citations for rs759672616 ...
HelpRecord last updated Oct 13, 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.