ClinVar Genomic variation as it relates to human health
NM_000350.3(ABCA4):c.6658C>T (p.Gln2220Ter)
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.6658C>T (p.Gln2220Ter)
Variation ID: 99476 Accession: VCV000099476.33
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p22.1 1: 93997932 (GRCh38) [ NCBI UCSC ] 1: 94463488 (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 Nov 27, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000350.3:c.6658C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000341.2:p.Gln2220Ter nonsense NM_001425324.1:c.6436C>T NP_001412253.1:p.Gln2146Ter nonsense NC_000001.11:g.93997932G>A NC_000001.10:g.94463488G>A NG_009073.1:g.128218C>T NG_009073.2:g.128216C>T - Protein change
- Q2220*, Q2146*
- Other names
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- Canonical SPDI
- NC_000001.11:93997931:G: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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0.00020 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00000
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
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
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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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 |
3709 | 4065 |
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
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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 (3) |
criteria provided, multiple submitters, no conflicts
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Nov 27, 2023 | RCV000085837.9 | |
Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Oct 13, 2021 | RCV000408450.7 | |
Pathogenic (1) |
no assertion criteria provided
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Jan 1, 2015 | RCV000504742.1 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jan 3, 2022 | RCV001352970.4 | |
Pathogenic (1) |
criteria provided, single submitter
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May 4, 2023 | RCV003421986.4 |
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
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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
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Severe early-childhood-onset retinal dystrophy
Affected status: yes
Allele origin:
germline
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Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg
Accession: SCV000281963.2
First in ClinVar: Dec 07, 2016 Last updated: Dec 07, 2016 |
Indication for testing: Stargardt disease 1
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Likely pathogenic
(Jan 30, 2021)
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criteria provided, single submitter
Method: clinical testing
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Retinitis pigmentosa 19
Affected status: yes
Allele origin:
unknown
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Institute of Medical Molecular Genetics, University of Zurich
Accession: SCV001548047.1
First in ClinVar: Mar 28, 2021 Last updated: Mar 28, 2021 |
Method: long-range PCR
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Retinitis pigmentosa 19
Affected status: yes
Allele origin:
germline
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Genomics England Pilot Project, Genomics England
Accession: SCV001760041.1
First in ClinVar: Jul 31, 2021 Last updated: Jul 31, 2021 |
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Pathogenic
(Jan 03, 2022)
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criteria provided, single submitter
Method: clinical testing
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Retinitis pigmentosa 19
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002058761.1
First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022 |
Comment:
Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are … (more)
Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS).The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000099476, PMID:10958761). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000052, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Rod-cone dystrophy (present)
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Pathogenic
(Dec 20, 2022)
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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: SCV000680671.3
First in ClinVar: Feb 13, 2018 Last updated: Dec 31, 2022 |
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of … (more)
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 10958761, 25525159, 31429209, 34758253, 35456422, 22968130, 28341476, 28118664, 28041643, 32581362, 23134348) (less)
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Pathogenic
(May 04, 2023)
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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: SCV004116763.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The ABCA4 c.6658C>T variant is predicted to result in premature protein termination (p.Gln2220*). This variant has been reported as causative for autosomal recessive ABCA4-related retinal … (more)
The ABCA4 c.6658C>T variant is predicted to result in premature protein termination (p.Gln2220*). This variant has been reported as causative for autosomal recessive ABCA4-related retinal disorders (see for example Khan et al. 2012. PubMed ID: 23134348; Shanks et al. 2013. PubMed ID: 22968130; Supplement in Holtan et al. 2020. PubMed ID: 31429209). This variant is reported in 0.042% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-94463488-G-A). Nonsense variants in ABCA4 are expected to be pathogenic. Given all the evidence, we interpret c.6658C>T (p.Gln2220*) as pathogenic. (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Severe early-childhood-onset retinal dystrophy
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004171925.1
First in ClinVar: Dec 09, 2023 Last updated: Dec 09, 2023 |
Comment:
The stop gained c.6658C>T(p.Gln2220Ter) variant in ABCA4 gene has been reported in homozygous/compound heterozygous state in multiple patients affected with Retinal dystrophy or ABCA4 related … (more)
The stop gained c.6658C>T(p.Gln2220Ter) variant in ABCA4 gene has been reported in homozygous/compound heterozygous state in multiple patients affected with Retinal dystrophy or ABCA4 related disorders (Khan et. al., 2013; Maggi et. al., 2021; Shanks et. al., 2013). The p.Gln2220Ter variant has been observed in two affected male cousins in a family (Shanks et. al., 2013). The observed variant has been reported with alllele frequency of 0.005% in gnomAD exomes database. This variant has been reported to the ClinVar database as Likely Pathogenic / Pathogenic (multiple submitters). The nucleotide change c.6658C>T in ABCA4 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Nov 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: SCV001232973.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Gln2220*) in the ABCA4 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Gln2220*) in the ABCA4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ABCA4 are known to be pathogenic (PMID: 10958761, 24938718, 25312043, 26780318). This variant is present in population databases (rs61753046, gnomAD 0.04%). This premature translational stop signal has been observed in individuals with ABCA4-related retinal dystrophy (PMID: 22968130, 28041643, 28341476). ClinVar contains an entry for this variant (Variation ID: 99476). For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Feb 01, 2013)
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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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Arcensus
Accession: SCV002564564.1
First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022 |
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Pathogenic
(Oct 13, 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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Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002556925.2
First in ClinVar: Aug 08, 2022 Last updated: Dec 17, 2022 |
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Pathogenic
(Jan 01, 2015)
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no assertion criteria provided
Method: research
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None
Affected status: yes
Allele origin:
unknown
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NIHR Bioresource Rare Diseases, University of Cambridge
Accession: SCV000599020.1
First in ClinVar: Sep 08, 2017 Last updated: Sep 08, 2017 |
Observation 1:
Number of individuals with the variant: 1
Sex: male
Ethnicity/Population group: NA
Observation 2:
Number of individuals with the variant: 1
Sex: male
Ethnicity/Population group: South East Asian
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Pathogenic
(Jan 01, 2015)
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no assertion criteria provided
Method: research
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Cone-rod dystrophy
Affected status: yes
Allele origin:
unknown
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NIHR Bioresource Rare Diseases, University of Cambridge
Accession: SCV000599021.1
First in ClinVar: Sep 09, 2017 Last updated: Sep 09, 2017 |
Number of individuals with the variant: 1
Sex: male
Ethnicity/Population group: South East Asian
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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: SCV000117980.1
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.6658C>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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Long-Range PCR-Based NGS Applications to Diagnose Mendelian Retinal Diseases. | Maggi J | International journal of molecular sciences | 2021 | PMID: 33546218 |
Panel-Based Clinical Genetic Testing in 85 Children with Inherited Retinal Disease. | Taylor RL | Ophthalmology | 2017 | PMID: 28341476 |
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 |
Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease. | Carss KJ | American journal of human genetics | 2017 | PMID: 28041643 |
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 |
RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease. | Xiong HY | Science (New York, N.Y.) | 2015 | PMID: 25525159 |
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 |
Homozygosity mapping identifies genetic defects in four consanguineous families with retinal dystrophy from Pakistan. | Khan MI | Clinical genetics | 2013 | PMID: 23134348 |
Next-generation sequencing (NGS) as a diagnostic tool for retinal degeneration reveals a much higher detection rate in early-onset disease. | Shanks ME | European journal of human genetics : EJHG | 2013 | PMID: 22968130 |
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 |
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Text-mined citations for rs61753046 ...
HelpRecord last updated Apr 06, 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.