ClinVar Genomic variation as it relates to human health
NM_000350.3(ABCA4):c.4539+1G>T
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.4539+1G>T
Variation ID: 99294 Accession: VCV000099294.9
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p22.1 1: 94029444 (GRCh38) [ NCBI UCSC ] 1: 94495000 (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 Sep 27, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000350.3:c.4539+1G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice donor NC_000001.11:g.94029444C>A NC_000001.10:g.94495000C>A NG_009073.2:g.96704G>T - Protein change
- Other names
- IVS30DS, G-T, +1
- Canonical SPDI
- NC_000001.11:94029443:C: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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Allele frequency
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The frequency of the allele represented by this VCV record.
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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
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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
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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
Help
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 (1) |
no assertion criteria provided
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Mar 1, 1998 | RCV000008343.5 | |
Pathogenic (1) |
no assertion criteria provided
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Mar 1, 1998 | RCV000008344.6 | |
Pathogenic (4) |
criteria provided, single submitter
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Sep 27, 2023 | RCV000085647.7 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 1, 2021 | RCV001723666.3 |
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
(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 Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV001950195.1
First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
Comment:
The c.4539+1G>T 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 c.4539+1G>T 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: PVS1, PM2, PM3-P. Based on this evidence we have classified this variant as Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab. (less)
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Pathogenic
(Sep 27, 2023)
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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: SCV003523416.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This sequence change affects a donor splice site in intron 30 of the ABCA4 gene. It is expected to disrupt RNA splicing. Variants that disrupt … (more)
This sequence change affects a donor splice site in intron 30 of the ABCA4 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ABCA4 are known to be pathogenic (PMID: 10958761, 24938718, 25312043, 26780318). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with Stargardt disease, cone-rod dystrophy, or retinitis pigmentosa (PMID: 9466990). 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: 99294). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(-)
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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: SCV001919335.1 First in ClinVar: Sep 25, 2021 Last updated: Sep 25, 2021 |
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Pathogenic
(Mar 01, 1998)
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no assertion criteria provided
Method: literature only
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RETINITIS PIGMENTOSA 19
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000028551.4
First in ClinVar: Apr 04, 2013 Last updated: Jul 16, 2023 |
Comment on evidence:
Ophthalmologic and molecular genetic studies were performed by Cremers et al. (1998) in a consanguineous family with individuals showing either retinitis pigmentosa (RP19; 601718) or … (more)
Ophthalmologic and molecular genetic studies were performed by Cremers et al. (1998) in a consanguineous family with individuals showing either retinitis pigmentosa (RP19; 601718) or cone-rod dystrophy (CORD3; 604116). Assuming pseudodominant (recessive) inheritance of allelic defects, linkage analysis positioned the causal gene at 1p21-p13 (lod score = 4.22), a genomic segment that harbors the ABCA4 gene involved in Stargardt disease and age-related macular degeneration. In 4 RP patients in this family they found homozygosity for a 5-prime splice site mutation, IVS30+1G-T. The 5 patients with CORD in this family were compound heterozygotes for the IVS30+1G-T mutation and a 5-prime splice site mutation in intron 40: IVS40+5G-A (601691.0010). Both splice site mutations were found heterozygously in 2 unrelated STGD patients (in whom the second mutation was either a missense mutation or unknown), but not in 100 control individuals. Since no Stargardt patient had been reported to carry 2 ABCR null alleles and the RP phenotype was more severe than the STGD phenotype, Cremers et al. (1998) hypothesized that the intron 30 splice site mutation represented a true null allele. Since the intron 30 mutation was found heterozygously in the CORD patients, the intron 40 mutation probably rendered the exon 40 5-prime splice site partially functional. These results showed that mutations in the ABCR gene result not only in STGD and ARMD, but also in autosomal recessive RP and CORD. (less)
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Pathogenic
(Mar 01, 1998)
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no assertion criteria provided
Method: literature only
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CONE-ROD DYSTROPHY 3
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000028552.4
First in ClinVar: Apr 04, 2013 Last updated: Jul 16, 2023 |
Comment on evidence:
Ophthalmologic and molecular genetic studies were performed by Cremers et al. (1998) in a consanguineous family with individuals showing either retinitis pigmentosa (RP19; 601718) or … (more)
Ophthalmologic and molecular genetic studies were performed by Cremers et al. (1998) in a consanguineous family with individuals showing either retinitis pigmentosa (RP19; 601718) or cone-rod dystrophy (CORD3; 604116). Assuming pseudodominant (recessive) inheritance of allelic defects, linkage analysis positioned the causal gene at 1p21-p13 (lod score = 4.22), a genomic segment that harbors the ABCA4 gene involved in Stargardt disease and age-related macular degeneration. In 4 RP patients in this family they found homozygosity for a 5-prime splice site mutation, IVS30+1G-T. The 5 patients with CORD in this family were compound heterozygotes for the IVS30+1G-T mutation and a 5-prime splice site mutation in intron 40: IVS40+5G-A (601691.0010). Both splice site mutations were found heterozygously in 2 unrelated STGD patients (in whom the second mutation was either a missense mutation or unknown), but not in 100 control individuals. Since no Stargardt patient had been reported to carry 2 ABCR null alleles and the RP phenotype was more severe than the STGD phenotype, Cremers et al. (1998) hypothesized that the intron 30 splice site mutation represented a true null allele. Since the intron 30 mutation was found heterozygously in the CORD patients, the intron 40 mutation probably rendered the exon 40 5-prime splice site partially functional. These results showed that mutations in the ABCR gene result not only in STGD and ARMD, but also in autosomal recessive RP and CORD. (less)
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Pathogenic
(-)
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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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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: SCV001952336.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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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: SCV000117786.1
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.4539%2B1G>T
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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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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 |
Screening of ABCA4 Gene in a Chinese Cohort With Stargardt Disease or Cone-Rod Dystrophy With a Report on 85 Novel Mutations. | Jiang F | Investigative ophthalmology & visual science | 2016 | PMID: 26780318 |
Clinical and molecular characteristics of childhood-onset Stargardt disease. | Fujinami K | Ophthalmology | 2015 | PMID: 25312043 |
Mutations of 60 known causative genes in 157 families with retinitis pigmentosa based on exome sequencing. | Xu Y | Human genetics | 2014 | PMID: 24938718 |
Splicing in action: assessing disease causing sequence changes. | Baralle D | Journal of medical genetics | 2005 | PMID: 16199547 |
Mutations in the ABCA4 (ABCR) gene are the major cause of autosomal recessive cone-rod dystrophy. | Maugeri A | American journal of human genetics | 2000 | PMID: 10958761 |
Autosomal recessive retinitis pigmentosa and cone-rod dystrophy caused by splice site mutations in the Stargardt's disease gene ABCR. | Cremers FP | Human molecular genetics | 1998 | PMID: 9466990 |
Text-mined citations for rs61751388 ...
HelpRecord last updated Mar 30, 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.