ClinVar Genomic variation as it relates to human health
NM_000350.3(ABCA4):c.2588G>C (p.Gly863Ala)
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
- NM_000350.2(ABCA4):c.[2588G>C;3289A>T]
- NM_000350.2(ABCA4):c.[2588G>C;5153T>G]
- NM_000350.3(ABCA4):c.[2588G>C;5603A>T]
- Identifiers
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NM_000350.3(ABCA4):c.2588G>C (p.Gly863Ala)
Variation ID: 7879 Accession: VCV000007879.80
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p22.1 1: 94051698 (GRCh38) [ NCBI UCSC ] 1: 94517254 (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 Apr 20, 2024 Mar 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000350.3:c.2588G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000341.2:p.Gly863Ala missense NM_001425324.1:c.2366G>C NP_001412253.1:p.Gly789Ala missense NC_000001.11:g.94051698C>G NC_000001.10:g.94517254C>G NG_009073.1:g.74452G>C NG_009073.2:g.74450G>C P78363:p.Gly863Ala - Protein change
- G863A, G789A
- Other names
- -
- Canonical SPDI
- NC_000001.11:94051697:C:G
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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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0.00120 (G)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00394
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00523
1000 Genomes Project 0.00120
1000 Genomes Project 30x 0.00141
The Genome Aggregation Database (gnomAD) 0.00445
Exome Aggregation Consortium (ExAC) 0.00507
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 |
3701 | 4056 |
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 (8) |
criteria provided, multiple submitters, no conflicts
|
Jan 31, 2023 | RCV000008328.29 | |
Likely pathogenic (2) |
criteria provided, single submitter
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Oct 23, 2015 | RCV000008329.16 | |
Pathogenic/Likely pathogenic/Pathogenic, low penetrance (12) |
criteria provided, multiple submitters, no conflicts
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Mar 1, 2024 | RCV000085494.52 | |
no classifications from unflagged records (1) |
no classifications from unflagged records
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Jan 2, 2024 | RCV000415097.11 | |
Pathogenic (3) |
criteria provided, single submitter
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Aug 9, 2019 | RCV000505063.11 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 11, 2014 | RCV000623365.13 | |
Pathogenic (1) |
no assertion criteria provided
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Apr 1, 2018 | RCV000787768.9 | |
Pathogenic (3) |
criteria provided, single submitter
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Apr 1, 2021 | RCV000787487.13 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Aug 24, 2022 | RCV000787486.13 | |
Likely pathogenic (2) |
no assertion criteria provided
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Oct 4, 2021 | RCV001198385.13 | |
not provided (1) |
no classification provided
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- | RCV001535670.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 7, 2023 | RCV003224856.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 18, 2024 | RCV003407302.5 | |
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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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Pathogenic
(Jan 01, 2016)
|
criteria provided, single submitter
Method: clinical testing
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Severe early-childhood-onset retinal dystrophy
Affected status: yes
Allele origin:
germline
|
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg
Accession: SCV000281847.2
First in ClinVar: Dec 07, 2016 Last updated: Jan 20, 2017 |
Indication for testing: Stargardt disease 1
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Pathogenic
(May 18, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000226568.5
First in ClinVar: Jun 28, 2015 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 15
Sex: mixed
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Pathogenic
(Apr 10, 2018)
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criteria provided, single submitter
Method: clinical testing
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Stargardt disease
(Autosomal recessive inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000711736.1
First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
Comment:
The p.Gly863Ala variant in ABCA4 has been reported in >25 individuals with Starg ardt disease in compound heterozygous state with a second ABCA4 variant (Allikme … (more)
The p.Gly863Ala variant in ABCA4 has been reported in >25 individuals with Starg ardt disease in compound heterozygous state with a second ABCA4 variant (Allikme ts 1997, Maugeri 1999, Zhang 1999, Heathfield 2013), and segregated with disease in 3 affected relatives in one family (Zhang 1999). Available evidence suggests that p.Gly863Ala is a mild variant and causes disease when there is a severe va riant on the other allele. This variant has also been identified in 0.79% (998/1 26588) of European chromosomes by the Genome Aggregation Consortium (gnomAD, htt p://gnomad.broadinstitute.org; dbSNP rs76157638). This frequency is consistent w ith the p.Gly863Ala variant being one of the most common ABCA4 variants in patie nts with Stargardt disease in the European population. This variant was demonstr ated to cause aberrant splicing and lead to deletion of the glycine residue at p osition 863 (p.Gly863del) in half of the transcripts from this allele and the mi ssense p.Gly863Ala change in the other half in patient cells (Maugeri 1999). Bot h of these variants had impaired protein activity in in vitro studies (Maugeri 1 999, Sun 2000, Suarez 2002). In summary, this variant meets our criteria to be c lassified as pathogenic for Stargardt disease in an autosomal recessive manner b ased upon its co-occurrence in trans with other pathogenic variants in patients and functional evidence. ACMG/AMP Criteria applied: PM3_Very Strong, PS3_Moderat e, PP1. (less)
Number of individuals with the variant: 4
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Pathogenic
(Aug 09, 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: SCV001241506.1
First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020 |
|
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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
(Unknown mechanism)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001447808.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Macular degeneration (present)
Sex: male
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Pathogenic
(May 27, 2022)
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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: SCV001135352.2
First in ClinVar: Jan 09, 2020 Last updated: Jun 05, 2022 |
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Pathogenic
(Aug 24, 2022)
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criteria provided, single submitter
Method: clinical testing
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Stargardt disease
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002572288.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
Variant summary: ABCA4 c.2588G>C (p.Gly863Ala) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging … (more)
Variant summary: ABCA4 c.2588G>C (p.Gly863Ala) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Three predict the variant weakens a canonical 3' acceptor site and three predict the variant creates a 3' acceptor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (e.g. Maugeri_1999). The variant produces a mixture of two different transcripts, one where the use of a cryptic 3' acceptor site causes a 3bp deletion (resulting in deletion of Gly863), and the other unaffected by splicing (resulting in Gly863Ala). The variant allele was found at a frequency of 0.0044 in 251244 control chromosomes, predominantly at a frequency of 0.008 within the Non-Finnish European subpopulation in the gnomAD database, including 6 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 6-fold of the estimated maximal expected allele frequency for a pathogenic variant in ABCA4 causing Stargardt Disease phenotype (0.0014), suggesting that the variant may be a benign polymorphism found primarily in populations of Non-Finnish European origin. However, c.2588G>C has been reported in the literature in the compound heterozygous state in many individuals affected with Stargardt Disease, including in at least one family where it segregated with the disease phenotype (e.g. Maugeri_1999, Zhang_1999, Heathfield_2013, Weisschuh_2020). It has been proposed that c.2588G>C is a mild founder variant in the western European population, which causes Stargardt Disease only in combination with a severe pathogenic variant on the second allele (e.g. Maugeri_1999). Several publications report experimental evidence evaluating an impact on protein function and have found that both Gly863del and Gly863Ala reduce ATPase activity and that Glu863Ala severely impairs interaction with 11-cis-retinal (e.g. Sun_2000, Suarez_2002, Biswas-Fiss_2012). Many submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and the overwhelming majority classified the variant as either pathogenic (n= 14) or likely pathogenic (n=6). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Jul 20, 2020)
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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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Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002556399.2
First in ClinVar: Aug 08, 2022 Last updated: Dec 17, 2022 |
Comment:
Although common this variant has been reported in the compound-heterozygous state in several individuals and families affected with Stargardt disease and retinitis pigmentosa (PMID: 10612508, … (more)
Although common this variant has been reported in the compound-heterozygous state in several individuals and families affected with Stargardt disease and retinitis pigmentosa (PMID: 10612508, 10634594, 10090887, 12192456, 9054934, 23695285, 26247787, 25097241, 28041643). However, studies suggest that this is a mild variant that may only cause disease when in combination with a severe, pathogenic ABCA4 variant (PMID: 10090887). ClinVar contains an entry for this variant (Variation ID: 7879). Experimental studies have shown that this variant results in the production of two transcripts: one that lacks glycine 863 and the other with the Gly863Ala missense change (PMID: 10090887). Additional functional studies have shown that this missense change affects nucleotide hydrolysis and reduces the interaction of ABCA4 with 11-cis-retinal (PMID: 11919200, 23144455, 11017087). In summary, this variant is reported to cause autosomal recessive Stargardt disease and retinitis pigmentosa. However, as this variant is associated with a lower penetrance than other pathogenic alleles in the ABCA4 gene, and as it may not result in disease in the homozygous state, it has been classified as Pathogenic (low penetrance). (less)
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Pathogenic
(Jan 31, 2023)
|
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: SCV001440306.3
First in ClinVar: Oct 31, 2020 Last updated: Mar 04, 2023 |
Comment:
This variant was identified together with NM_000350.3:c.1622T>C, NM_000350.3:c.3113C>T, NM_000350.3:c.5693G>A and NM_000350.3:c.1411G>A Criteria applied: PM3_VSTR, PS3_MOD, PM5, PP1
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Pathogenic
(Jun 28, 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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Revvity Omics, Revvity
Accession: SCV002019744.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
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Pathogenic
(Mar 01, 2024)
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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: SCV001245777.20
First in ClinVar: May 12, 2020 Last updated: Apr 15, 2024 |
Comment:
ABCA4: PM3:Very Strong, PM2:Supporting, PP3, PS3:Supporting
Number of individuals with the variant: 32
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Pathogenic
(Sep 11, 2014)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000742856.5
First in ClinVar: Apr 15, 2018 Last updated: Apr 20, 2024 |
Comment:
The c.2588G>C (p.G863A) alteration is located in exon 17 (coding exon 17) of the ABCA4 gene. This alteration results from a G to C substitution … (more)
The c.2588G>C (p.G863A) alteration is located in exon 17 (coding exon 17) of the ABCA4 gene. This alteration results from a G to C substitution at nucleotide position 2588, causing the glycine (G) at amino acid position 863 to be replaced by an alanine (A). The heterozygous missense change is somewhat rare in population databases:_x000D_ Based on data from the NHLBI Exome Sequencing Project (ESP), the ABCA4 c.2588G>C alteration was observed in 68 among 13006 total alleles studied (0.52%). The alteration was observed in the 1000 Genomes Project in 1 among 2098 total alleles studied (0.05%). Based on data from the Genome Aggregation Database (gnomAD), the c.2588G>C alteration was observed among 0.43% (1202/276994) of total alleles studied, having been observed in 0.79% (998/126588) European (non-Finnish) alleles. Rare missense alleles commonly exhibit a deleterious effect on protein function (Kryukov, 2007; Tennessen, 2012; please note that some variants may appear to be rare due to ethnic underrepresentation in the database)._x000D_ _x000D_ IF USED, PULL THESE INTO REFERENCES:_x000D_ Kryukov GV, et al. (2007) Am J Hum Genet 80:727-739. Tennessen JA, et al. (2012) Science 337(64):64-69. The alteration has been observed in affected individuals: _x000D_ The c.2588G>C alteration has been observed in multiple individuals with retinal dystrophy (Maugeri. 2002). It one of the highest frequency autosomal recessive disease mutation in European populations (Maugeri. 2002). The alteration is conserved throughout evolution:_x000D_ The p.G863 amino acid is completetly conserved in available vertebrate species. Functional analysis reveals a damaging effect of the amino acid alteration: _x000D_ Functional analysis demonstrated that the p.G863A alteration significantly decreased the rates of nucleotide hydrolysis as well as the binding affinities of the protein (Suárez, 2002) In silico prediction is conflicting:_x000D_ The p.G863A alteration is predicted to be benign by Polyphen and deleterious by SIFT in silico analyses. Based on the available evidence, this alteration is classified as pathogenic. (less)
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Likely pathogenic
(Oct 23, 2015)
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criteria provided, single submitter
Method: clinical testing
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Cone-rod dystrophy 3
Affected status: no
Allele origin:
germline
|
Knight Diagnostic Laboratories, Oregon Health and Sciences University
Study: CSER-NextGen
Accession: SCV000538010.2 First in ClinVar: Apr 03, 2017 Last updated: Jul 22, 2023 |
Comment:
he c.2588G>C (p.Gly863Ala) missense variant has been reported in several individuals with Stargardt disease (Maugeri A et al., 1999) as well as advanced cone and … (more)
he c.2588G>C (p.Gly863Ala) missense variant has been reported in several individuals with Stargardt disease (Maugeri A et al., 1999) as well as advanced cone and rod dysfunction (Gerth et al. 2002). It has been seen in trans with other known pathogenic variants in the ABCA4 gene of affected individuals (Heathfield L et al. 2013). In addition, in vitro studies showed that the function of this variant is highly attenuated (Biswas-Fiss et al. 2012). The frequency of this variant in the population databases is lower than the disease allele frequency for the disease and the ancestral amino acid is conserved throughout evolution. Together, the c.2588G>C (p.Gly863Ala) missense variant meets our criteria for Likely Pathogenic (less)
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Pathogenic
(Apr 01, 2021)
|
criteria provided, single submitter
Method: curation
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Retinitis pigmentosa
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV001950198.1
First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
Comment:
The p.Gly863Ala 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.Gly863Ala 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, PM2, PM3, PP1, PP3. 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
(Dec 20, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Severe early-childhood-onset retinal dystrophy
Affected status: yes
Allele origin:
germline
|
MGZ Medical Genetics Center
Accession: SCV002581194.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 |
Number of individuals with the variant: 1
Sex: female
|
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Pathogenic
(May 06, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Severe early-childhood-onset retinal dystrophy
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002769539.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with retinal dystrophy, Stargardt disease 1 (MIM#248200) and cone-rod dystrophy (MIM#604116). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Affected siblings can have variable age of onset and severity of disease (PMID:31522899). 0200 - Variant is predicted to result in a missense amino acid change from glycine to alanine. This variant also leads to aberrant splicing resulting in the in-frame deletion of this residue (p.(Gly863del)) in approximately 50% of transcripts (PMID:10090887). (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2, European subpopulation) <0.01 for a recessive condition (1200 heterozygotes, 7 homozygotes). (SP) 0309 - An alternative amino acid change p.(Gly863Glu) at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated Nucleotide Binding Domain 1 (NBD1) (PMID: 11444963). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The frequently reported p.[Gly863Ala, Gly863del] variant has strong evidence supporting pathogenicity when in cis with p.(Asn1868Ile) and in trans with a second pathogenic variant. This variant is unlikely to be disease-causing on its own, however the complex allele is fully penetrant and is associated with mild to moderate disease with variable phenotype, depending on the variant on the opposite allele (ClinVar, PMID:9054934, 28044389, 28446513, 32278709). (SP) 0901 - This variant has strong evidence for segregation with disease. This variant segregates with disease, in a compound heterozygous state with a second pathogenic allele, in at least 5 families in the literature (PMID: 10612508, 31522899). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. This variant leads to reduced protein expression, ATP-binding affinity, and ATP hydrolysis in in vitro studies (PMID: 11017087, 11919200). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Pathogenic
(Apr 12, 2022)
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criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000321344.10
First in ClinVar: Oct 09, 2016 Last updated: Mar 04, 2023 |
Comment:
Most common allele among individuals with Stargardt disease in Northern Europe, representing roughly 20-30% of disease associated alleles (Maugeri et al., 1999).; RNA studies demonstrated … (more)
Most common allele among individuals with Stargardt disease in Northern Europe, representing roughly 20-30% of disease associated alleles (Maugeri et al., 1999).; RNA studies demonstrated that the c.2588 G>C nucleotide change results in the utilization of an alternate splice site, which could produce an abnormal protein lacking the Gly863 residue (aka p.G863del) (Maugeri et al., 1999); Published functional studies demonstrate that G863A has minimal effect on ATP hydrolysis, but significantly reduces interaction of the nucleotide binding domain 1 of the ABCA4 protein with 11-cis-retinal (Biswas-Fiss et al., 2012); One study proposes G863A exhibits pathogenicity only when observed in cis with the common N1868I variant (Zernant et al., 2017); This variant is associated with the following publications: (PMID: 25082885, 25884411, 25346251, 25444351, 25712131, 25922843, 25097241, 9054934, 28446513, 28248825, 27939946, 28044389, 30643219, 30609409, 30718709, 30215852, 28559085, 32845050, 31456290, 25283059, 24082139, 24154662, 25333069, 11017087, 20981092, 22264887, 12192456, 11919200, 25363634, 23144455, 10612508, 23695285, 24713488, 25681002, 28327576, 26247787, 10090887, 28041643, 28341476, 29555955, 3002862, 29310964, 29431110, 29162642, 30563929, 29925512, 32467599, 31980526, 32036094, 32581362, 34426522, 34570182, 32619608, 32913387, 32815999, 32037395, 11527935) (less)
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Pathogenic
(Mar 07, 2023)
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criteria provided, single submitter
Method: clinical testing
|
Retinitis pigmentosa 19
Affected status: yes
Allele origin:
unknown
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV003921105.1
First in ClinVar: May 06, 2023 Last updated: May 06, 2023 |
Comment:
This variant was identified together with NM_000350.3:c.2828G>A._x000D_ Criteria applied: PM3_VSTR, PS3_MOD, PM5, PP1, PP3
|
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Pathogenic, low penetrance
(Jan 31, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV001211627.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 863 of the ABCA4 protein (p.Gly863Ala). … (more)
This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 863 of the ABCA4 protein (p.Gly863Ala). This variant is present in population databases (rs76157638, gnomAD 0.8%), including at least one homozygous and/or hemizygous individual. This variant has been reported in the compound-heterozygous state in several individuals and families affected with Stargardt disease and retinitis pigmentosa (PMID: 10612508, 10634594, 10090887, 12192456, 9054934, 23695285, 26247787, 25097241, 28041643). However, studies suggest that this is a mild variant that may only cause disease when in combination with a severe, pathogenic ABCA4 variant (PMID: 10090887). ClinVar contains an entry for this variant (Variation ID: 7879). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this variant results in the production of two transcripts: one that lacks glycine 863 and the other with the Gly863Ala missense change (PMID: 10090887). Additional functional studies have shown that this missense change affects nucleotide hydrolysis and reduces the interaction of ABCA4 with 11-cis-retinal (PMID: 11919200, 23144455, 11017087). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, this variant is reported to cause autosomal recessive Stargardt disease and retinitis pigmentosa. However, as this variant is associated with a lower penetrance than other pathogenic alleles in the ABCA4 gene, and as it may not result in disease in the homozygous state, it has been classified as Pathogenic (low penetrance). (less)
|
|
Likely pathogenic
(Nov 03, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001156938.3
First in ClinVar: Feb 10, 2020 Last updated: Feb 20, 2024 |
Comment:
The ABCA4 c.2588G>C; p.Gly863Ala variant (rs76157638) is reported in the medical literature in individuals with ABCA4-related diseases in the homozygous or compound heterozygous state (Bertelsen … (more)
The ABCA4 c.2588G>C; p.Gly863Ala variant (rs76157638) is reported in the medical literature in individuals with ABCA4-related diseases in the homozygous or compound heterozygous state (Bertelsen 2014, Birtel 2018, Duncker 2015, Khan 2018, Zernant 2017). The variant is reported as pathogenic or likely pathogenic by several sources in the ClinVar database (Variation ID: 7879) but is also listed in the European (non-Finnish) population with an allele frequency of 0.8% (1012/1209076 alleles, including 7 homozygotes) in the Genome Aggregation Database. This variant has been described as a European founder variant and is implicated as a mild pathogenic variant (Maugeri 1999, Zernant 2017). The glycine at this position is highly conserved but computational analyses (SIFT: Damaging, PolyPhen-2: Benign) predict conflicting effects of this variant on protein structure/function. However, the variant has also been shown to cause an alternative splice removing one amino acid (Maugeri 1999). Considering available information, this variant is classified as likely pathogenic but may result in a milder clinical phenotype. References: Bertelsen M et al. Generalized choriocapillaris dystrophy, a distinct phenotype in the spectrum of ABCA4-associated retinopathies. Invest Ophthalmol Vis Sci. 2014 Apr 29;55(4):2766-76. Birtel J et al. Clinical and genetic characteristics of 251 consecutive patients with macular and cone/cone-rod dystrophy. Sci Rep. 2018 Mar 19;8(1):4824. Duncker T et al. Quantitative fundus autofluorescence distinguishes ABCA4-associated and non-ABCA4-associated bull's-eye maculopathy. Ophthalmology. 2015 Feb;122(2):345-55. Khan KN et al. Early Patterns of Macular Degeneration in ABCA4-Associated Retinopathy. Ophthalmology. 2018 May;125(5):735-746. Maugeri A et al. The 2588G-->C mutation in the ABCR gene is a mild frequent founder mutation in the Western European population and allows the classification of ABCR mutations in patients with Stargardt disease. Am J Hum Genet. 1999 Apr;64(4):1024-35. Zernant J et al. Frequent hypomorphic alleles account for a significant fraction of ABCA4 disease and distinguish it from age-related macular degeneration. J Med Genet. 2017 Jun;54(6):404-412. (less)
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|
Pathogenic
(Jan 18, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
ABCA4-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004113554.2
First in ClinVar: Nov 20, 2023 Last updated: Mar 16, 2024 |
Comment:
The ABCA4 c.2588G>C variant is predicted to result in the amino acid substitution p.Gly863Ala. This variant is also predicted to alter splicing based on available … (more)
The ABCA4 c.2588G>C variant is predicted to result in the amino acid substitution p.Gly863Ala. This variant is also predicted to alter splicing based on available splicing prediction programs (Alamut Visual Plus v1.6.1). This variant is the first nucleotide of exon 17 and a functional study using RT-PCR analysis confirmed that this variant results in a mixture of predicted proteins either lacking one amino acid (p.Gly863del) or carrying the p.Gly863Ala substitution (Maugeri et al. 1999. PubMed ID: 10090887). This variant is reported in 0.78% of alleles in individuals of European (Non-Finnish) descent in gnomAD, including 7 homozygous individuals, which is evidence that this variant does not cause disease in the homozygous state. Several studies have supported that this variant is mild and only causes Stargardt disease (STGD) when in trans (on the opposite chromosome) with a severe ABCA4 pathogenic variant (Maugeri et al. 1999. PubMed ID: 10090887; Allikmets et al. 1997. PubMed ID: 9054934; Papaioannou et al. 2000. PubMed ID: 10634594; Suárez et al. 2002. PubMed ID: 11919200). This variant has also been found in cis (on the same chromosome) with another pathogenic variant (c.6088C>T, p.Arg2030*) in two siblings, who carried another pathogenic variant in trans (Song et al. 2015. PubMed ID: 26247787). Functional studies demonstrated that this variant results in a decrease of both basal and retinal-stimulated ATPase activity (Sun et al. 2000. PubMed ID: 11017087). This variant is interpreted as pathogenic. (less)
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|
Likely pathogenic
(Jan 01, 2015)
|
no assertion criteria provided
Method: research
|
Retinal dystrophy
Affected status: yes
Allele origin:
unknown
|
NIHR Bioresource Rare Diseases, University of Cambridge
Accession: SCV000598951.1
First in ClinVar: Sep 09, 2017 Last updated: Sep 09, 2017 |
Observation 1:
Number of individuals with the variant: 1
Sex: female
Ethnicity/Population group: European
Observation 2:
Number of individuals with the variant: 1
Sex: male
Ethnicity/Population group: European
|
|
Likely pathogenic
(Jan 01, 2015)
|
no assertion criteria provided
Method: research
|
None
Affected status: yes
Allele origin:
unknown
|
NIHR Bioresource Rare Diseases, University of Cambridge
Accession: SCV000598952.1
First in ClinVar: Jan 20, 2017 Last updated: Jan 20, 2017 |
Observation 1:
Number of individuals with the variant: 1
Sex: male
Ethnicity/Population group: European
Observation 2:
Number of individuals with the variant: 1
Sex: female
Ethnicity/Population group: European
|
|
Pathogenic
(Apr 01, 2018)
|
no assertion criteria provided
Method: research
|
Stargardt disease
Affected status: yes
Allele origin:
unknown
|
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet
Study: VeluxRD
Accession: SCV000926452.2 First in ClinVar: Jul 21, 2019 Last updated: Sep 03, 2023 |
|
|
Pathogenic
(Apr 01, 2018)
|
no assertion criteria provided
Method: research
|
Retinitis pigmentosa
Affected status: yes
Allele origin:
unknown
|
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet
Study: VeluxRD
Accession: SCV000926453.2 First in ClinVar: Jul 21, 2019 Last updated: Sep 03, 2023 |
|
|
Pathogenic
(Apr 01, 2018)
|
no assertion criteria provided
Method: research
|
Cone-rod dystrophy
Affected status: yes
Allele origin:
unknown
|
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet
Study: VeluxRD
Accession: SCV000926773.2 First in ClinVar: Jul 21, 2019 Last updated: Sep 03, 2023 |
|
|
Pathogenic
(Apr 01, 2018)
|
no assertion criteria provided
Method: research
|
Retinal dystrophy
Affected status: yes
Allele origin:
unknown
|
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet
Study: VeluxRD
Accession: SCV000926779.2 First in ClinVar: Jul 21, 2019 Last updated: Sep 03, 2023 |
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001969328.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
|
|
Pathogenic
(Jul 01, 2008)
|
no assertion criteria provided
Method: literature only
|
CONE-ROD DYSTROPHY 3
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000028537.3
First in ClinVar: Apr 04, 2013 Last updated: Jul 16, 2023 |
Comment on evidence:
In affected members of 3 families with Stargardt macular dystrophy (STGD1; 248200), Allikmets et al. (1997) found a 2588G-C transversion of the ABCR gene, predicting … (more)
In affected members of 3 families with Stargardt macular dystrophy (STGD1; 248200), Allikmets et al. (1997) found a 2588G-C transversion of the ABCR gene, predicting a gly863-to-ala (G863A) substitution. In 40 western European patients with STGD, Maugeri et al. (1999) found 19 novel mutations in the ABCR gene. The 2588G-C transversion, identified in 15 (37.5%) patients, showed linkage disequilibrium with a rare 2828G-A polymorphism (R943Q; 601691.0035) in exon 19, suggesting a founder effect. The guanine at position 2588 is part of the 3-prime splice site of exon 17. Analysis of the lymphoblastoid cell mRNA of 2 STGD patients with the 2588G-C mutation showed that the resulting mutant ABCR proteins either lack gly863 or contain the missense mutation gly863 to ala. Maugeri et al. (1999) hypothesized that the 2588G-C alteration is a mild mutation that causes STGD only in combination with a severe ABCR mutation. This was supported by the fact that the accompanying ABCR mutation in at least 5 of the 8 STGD patients was null (severe) and that a combination of 2 mild mutations had not been observed among 68 STGD patients. The 2588G-C mutation is present in 1 of every 35 western Europeans, a rate higher than that of the most frequent severe autosomal recessive mutation, delta-F508, in the CFTR gene in cystic fibrosis (602421.0001). Given an STGD incidence of 1 in 10,000, homozygosity for the 2588G-C mutation or compound heterozygosity for this and other mild ABCR mutations probably does not result in an STGD phenotype. Maugeri et al. (2002) studied 2,343 unrelated random control individuals from 11 European countries and 241 control individuals from the U.S. and found a carrier frequency of the 2588G-C mutation of 1 out of 54 and 1 out of 121, respectively. In Europe, an increasing gradient was observed from southwest (carrier frequency in Portugal: 0 out of 199) to northeast (carrier frequency in Sweden: 1 out of 18). Haplotype analysis in 16 families with STGD (12 Dutch, 3 German, and 1 of Swedish origin) segregating the 2588G-C mutation showed 4 intragenic SNPs invariably present in all disease chromosomes and sharing of the same allele for several microsatellite markers flanking the ABCA4 locus in most of the disease chromosomes. These results indicated a single origin of the 2588G-C mutation, which was estimated to have occurred between 2,400 and 3,000 years ago. This study confirmed the 2588G-C mutation as one of the most frequent autosomal recessive disease mutations in the European population, with an origin somewhere in the north-northeastern parts of Europe. Maugeri et al. (2002) raised the possibility of a carrier advantage due to some unknown function of ABCA4 in nonocular tissues. The high carrier frequency of the 2588C allele in Sweden of 1 out of 18 was in striking contrast with the incidence of STGD, which apparently is not higher in that country than in the rest of Europe, and therefore supported the hypothesis that this mutation represents a mild allele which is not disease causing in homozygous state. By enzyme-kinetic studies of mutations in the nucleotide-binding domain-1 (NBD1) of the ABCA4 gene, Suarez et al. (2002) showed that the G863Q mutation had a significant attenuation of the rate of nucleotide hydrolysis and nucleotide binding affinity compared to wildtype protein and the mild R943Q mutation. Aberrant or modified splicing patterns of genes are causative for many human diseases. Hiller et al. (2004) described widespread occurrence of alternative splicing at NAGNAG acceptors. Hiller et al. (2006) reported a genomewide screen for single-nucleotide polymorphisms (SNPs) that affect such tandem acceptors. From 121 SNPs identified, they extracted 64 SNPs that most likely affect alternative NAGNAG splicing. They demonstrated that the NAGNAG motif is necessary and sufficient for this type of alternative splicing. Since 28% of the NAGNAG SNPs occurred in known disease genes, they represented preferred candidates for functional analysis. As an example of the disease relevance of a NAGNAG SNP, they cited the ABCA4 gene and the mutation described by Maugeri et al. (1999): a NAGNAG mutation (2588G/C, changing the acceptor site TAGGAG to TAGCAG) that has a high frequency in patients with STGD1. By experimental analysis of the splice patterns of 2 patients with STGD who carried the mutation and 1 control individual, they found that only the alleles with the TAGCAG produce 2 splice forms. The study of Hiller et al. (2006) would predict exactly this outcome of the mutation. In an 18.5-year-old female with cone dystrophy (CORD3; 604116), in whom information on rod function was unavailable, Kitiratschky et al. (2008) identified compound heterozygosity for the G863A mutation and a splice site mutation (601690.0030). The patient, who had onset of disease at 18 years of age, had increased glare sensitivity and normal night vision, atrophy of RPE at the macula, central scotoma, and decreased cone response on electroretinography (ERG); information was unavailable on her color vision or on ERG rod function. Family members were not available for study. (less)
|
|
Pathogenic
(Jul 01, 2008)
|
no assertion criteria provided
Method: literature only
|
STARGARDT DISEASE 1
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000028536.3
First in ClinVar: Apr 04, 2013 Last updated: Jul 16, 2023 |
Comment on evidence:
In affected members of 3 families with Stargardt macular dystrophy (STGD1; 248200), Allikmets et al. (1997) found a 2588G-C transversion of the ABCR gene, predicting … (more)
In affected members of 3 families with Stargardt macular dystrophy (STGD1; 248200), Allikmets et al. (1997) found a 2588G-C transversion of the ABCR gene, predicting a gly863-to-ala (G863A) substitution. In 40 western European patients with STGD, Maugeri et al. (1999) found 19 novel mutations in the ABCR gene. The 2588G-C transversion, identified in 15 (37.5%) patients, showed linkage disequilibrium with a rare 2828G-A polymorphism (R943Q; 601691.0035) in exon 19, suggesting a founder effect. The guanine at position 2588 is part of the 3-prime splice site of exon 17. Analysis of the lymphoblastoid cell mRNA of 2 STGD patients with the 2588G-C mutation showed that the resulting mutant ABCR proteins either lack gly863 or contain the missense mutation gly863 to ala. Maugeri et al. (1999) hypothesized that the 2588G-C alteration is a mild mutation that causes STGD only in combination with a severe ABCR mutation. This was supported by the fact that the accompanying ABCR mutation in at least 5 of the 8 STGD patients was null (severe) and that a combination of 2 mild mutations had not been observed among 68 STGD patients. The 2588G-C mutation is present in 1 of every 35 western Europeans, a rate higher than that of the most frequent severe autosomal recessive mutation, delta-F508, in the CFTR gene in cystic fibrosis (602421.0001). Given an STGD incidence of 1 in 10,000, homozygosity for the 2588G-C mutation or compound heterozygosity for this and other mild ABCR mutations probably does not result in an STGD phenotype. Maugeri et al. (2002) studied 2,343 unrelated random control individuals from 11 European countries and 241 control individuals from the U.S. and found a carrier frequency of the 2588G-C mutation of 1 out of 54 and 1 out of 121, respectively. In Europe, an increasing gradient was observed from southwest (carrier frequency in Portugal: 0 out of 199) to northeast (carrier frequency in Sweden: 1 out of 18). Haplotype analysis in 16 families with STGD (12 Dutch, 3 German, and 1 of Swedish origin) segregating the 2588G-C mutation showed 4 intragenic SNPs invariably present in all disease chromosomes and sharing of the same allele for several microsatellite markers flanking the ABCA4 locus in most of the disease chromosomes. These results indicated a single origin of the 2588G-C mutation, which was estimated to have occurred between 2,400 and 3,000 years ago. This study confirmed the 2588G-C mutation as one of the most frequent autosomal recessive disease mutations in the European population, with an origin somewhere in the north-northeastern parts of Europe. Maugeri et al. (2002) raised the possibility of a carrier advantage due to some unknown function of ABCA4 in nonocular tissues. The high carrier frequency of the 2588C allele in Sweden of 1 out of 18 was in striking contrast with the incidence of STGD, which apparently is not higher in that country than in the rest of Europe, and therefore supported the hypothesis that this mutation represents a mild allele which is not disease causing in homozygous state. By enzyme-kinetic studies of mutations in the nucleotide-binding domain-1 (NBD1) of the ABCA4 gene, Suarez et al. (2002) showed that the G863Q mutation had a significant attenuation of the rate of nucleotide hydrolysis and nucleotide binding affinity compared to wildtype protein and the mild R943Q mutation. Aberrant or modified splicing patterns of genes are causative for many human diseases. Hiller et al. (2004) described widespread occurrence of alternative splicing at NAGNAG acceptors. Hiller et al. (2006) reported a genomewide screen for single-nucleotide polymorphisms (SNPs) that affect such tandem acceptors. From 121 SNPs identified, they extracted 64 SNPs that most likely affect alternative NAGNAG splicing. They demonstrated that the NAGNAG motif is necessary and sufficient for this type of alternative splicing. Since 28% of the NAGNAG SNPs occurred in known disease genes, they represented preferred candidates for functional analysis. As an example of the disease relevance of a NAGNAG SNP, they cited the ABCA4 gene and the mutation described by Maugeri et al. (1999): a NAGNAG mutation (2588G/C, changing the acceptor site TAGGAG to TAGCAG) that has a high frequency in patients with STGD1. By experimental analysis of the splice patterns of 2 patients with STGD who carried the mutation and 1 control individual, they found that only the alleles with the TAGCAG produce 2 splice forms. The study of Hiller et al. (2006) would predict exactly this outcome of the mutation. In an 18.5-year-old female with cone dystrophy (CORD3; 604116), in whom information on rod function was unavailable, Kitiratschky et al. (2008) identified compound heterozygosity for the G863A mutation and a splice site mutation (601690.0030). The patient, who had onset of disease at 18 years of age, had increased glare sensitivity and normal night vision, atrophy of RPE at the macula, central scotoma, and decreased cone response on electroretinography (ERG); information was unavailable on her color vision or on ERG rod function. Family members were not available for study. (less)
|
|
Likely pathogenic
(Jun 23, 2019)
|
no assertion criteria provided
Method: research
|
Retinitis pigmentosa
Affected status: yes
Allele origin:
inherited
|
Sharon lab, Hadassah-Hebrew University Medical Center
Accession: SCV001160859.1
First in ClinVar: Feb 17, 2020 Last updated: Feb 17, 2020 |
|
|
Likely pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001739756.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
|
|
Likely pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001926098.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
|
|
Likely pathogenic
(Oct 04, 2021)
|
no assertion criteria provided
Method: clinical testing
|
Age related macular degeneration 2
Affected status: yes
Allele origin:
germline
|
Clinical Genetics Laboratory, University Hospital Schleswig-Holstein
Accession: SCV002029211.1
First in ClinVar: Dec 04, 2021 Last updated: Dec 04, 2021 |
|
|
Likely pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
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: SCV001954981.2 First in ClinVar: Oct 02, 2021 Last updated: Dec 25, 2021 |
|
|
not provided
(-)
|
no classification provided
Method: not provided
|
not provided
Affected status: not provided
Allele origin:
not provided
|
Retina International
Accession: SCV000117631.1
First in ClinVar: Feb 20, 2014 Last updated: Feb 20, 2014 |
|
|
not provided
(-)
|
no classification provided
Method: phenotyping only
|
Cone-rod dystrophy 3
Retinitis pigmentosa 19 Retinitis pigmentosa 19 Age-related macular degeneration
Affected status: yes
Allele origin:
unknown
|
GenomeConnect - Invitae Patient Insights Network
Accession: SCV001749733.1
First in ClinVar: Jul 18, 2021 Last updated: Jul 18, 2021 |
Comment:
Variant interpreted as Pathogenic and reported on 02-21-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report … (more)
Variant interpreted as Pathogenic and reported on 02-21-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. (less)
Clinical Features:
Abnormality of vision (present) , Myopia (present) , Abnormal retinal morphology (present) , Abnormal intestine morphology (present) , Pregnancy history (present)
Indication for testing: Diagnostic
Age: 50-59 years
Sex: female
Testing laboratory: Invitae
Date variant was reported to submitter: 2020-02-21
Testing laboratory interpretation: Pathogenic
|
|
Uncertain significance
(Nov 28, 2013)
|
Flagged submission
flagged submission
Method: clinical testing
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
|
Abnormal macular morphology
Peripheral neuropathy
Affected status: yes
Allele origin:
unknown
|
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV000492965.1
First in ClinVar: Jan 13, 2017 Last updated: Jan 13, 2017 |
|
|
Uncertain significance
(Jan 01, 2016)
|
Flagged submission
flagged submission
Method: clinical testing
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
|
Age related macular degeneration 2
Affected status: yes
Allele origin:
unknown
|
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001369306.2
First in ClinVar: Jul 06, 2020 Last updated: Jul 06, 2020 |
Comment:
This variant was classified as: Uncertain significance.
|
|
click to load more click to collapse | |||||
Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more |
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: SCV000281847.2
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|
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
---|---|---|---|---|
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 |
Genetic architecture of inherited retinal degeneration in Germany: A large cohort study from a single diagnostic center over a 9-year period. | Weisschuh N | Human mutation | 2020 | PMID: 32531858 |
Clinical spectrum, genetic complexity and therapeutic approaches for retinal disease caused by ABCA4 mutations. | Cremers FPM | Progress in retinal and eye research | 2020 | PMID: 32278709 |
Highly Variable Disease Courses in Siblings with Stargardt Disease. | Valkenburg D | Ophthalmology | 2019 | PMID: 31522899 |
Molecular genetic analysis using targeted NGS analysis of 677 individuals with retinal dystrophy. | Jespersgaard C | Scientific reports | 2019 | PMID: 30718709 |
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 |
In Silico Functional Meta-Analysis of 5,962 ABCA4 Variants in 3,928 Retinal Dystrophy Cases. | Cornelis SS | Human mutation | 2017 | PMID: 28044389 |
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 |
Cone and rod loss in Stargardt disease revealed by adaptive optics scanning light ophthalmoscopy. | Song H | JAMA ophthalmology | 2015 | PMID: 26247787 |
Quantitative fundus autofluorescence distinguishes ABCA4-associated and non-ABCA4-associated bull's-eye maculopathy. | Duncker T | Ophthalmology | 2015 | PMID: 25283059 |
Disease variants in genomes of 44 centenarians. | Freudenberg-Hua Y | Molecular genetics & genomic medicine | 2014 | PMID: 25333069 |
Dependable and efficient clinical utility of target capture-based deep sequencing in molecular diagnosis of retinitis pigmentosa. | Wang J | Investigative ophthalmology & visual science | 2014 | PMID: 25097241 |
Molecular diagnostic testing by eyeGENE: analysis of patients with hereditary retinal dystrophy phenotypes involving central vision loss. | Alapati A | Investigative ophthalmology & visual science | 2014 | PMID: 25082885 |
Generalized choriocapillaris dystrophy, a distinct phenotype in the spectrum of ABCA4-associated retinopathies. | Bertelsen M | Investigative ophthalmology & visual science | 2014 | PMID: 24713488 |
Next generation sequencing-based molecular diagnosis of retinitis pigmentosa: identification of a novel genotype-phenotype correlation and clinical refinements. | Wang F | Human genetics | 2014 | PMID: 24154662 |
Personalized genomic disease risk of volunteers. | Gonzalez-Garay ML | Proceedings of the National Academy of Sciences of the United States of America | 2013 | PMID: 24082139 |
Stargardt disease: towards developing a model to predict phenotype. | Heathfield L | European journal of human genetics : EJHG | 2013 | PMID: 23695285 |
Retinoid binding properties of nucleotide binding domain 1 of the Stargardt disease-associated ATP binding cassette (ABC) transporter, ABCA4. | Biswas-Fiss EE | The Journal of biological chemistry | 2012 | PMID: 23144455 |
Clinical course, genetic etiology, and visual outcome in cone and cone-rod dystrophy. | Thiadens AA | Ophthalmology | 2012 | PMID: 22264887 |
A map of human genome variation from population-scale sequencing. | 1000 Genomes Project Consortium | Nature | 2010 | PMID: 20981092 |
Frequency of ABCA4 mutations in 278 Spanish controls: an insight into the prevalence of autosomal recessive Stargardt disease. | Riveiro-Alvarez R | The British journal of ophthalmology | 2009 | PMID: 18977788 |
ABCA4 gene analysis in patients with autosomal recessive cone and cone rod dystrophies. | Kitiratschky VB | European journal of human genetics : EJHG | 2008 | PMID: 18285826 |
Single-nucleotide polymorphisms in NAGNAG acceptors are highly predictive for variations of alternative splicing. | Hiller M | American journal of human genetics | 2006 | PMID: 16400609 |
Widespread occurrence of alternative splicing at NAGNAG acceptors contributes to proteome plasticity. | Hiller M | Nature genetics | 2004 | PMID: 15516930 |
Phenotypes of 16 Stargardt macular dystrophy/fundus flavimaculatus patients with known ABCA4 mutations and evaluation of genotype-phenotype correlation. | Gerth C | Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie | 2002 | PMID: 12192456 |
Phenotypic spectrum of autosomal recessive cone-rod dystrophies caused by mutations in the ABCA4 (ABCR) gene. | Klevering BJ | Investigative ophthalmology & visual science | 2002 | PMID: 12037008 |
The ABCA4 2588G>C Stargardt mutation: single origin and increasing frequency from South-West to North-East Europe. | Maugeri A | European journal of human genetics : EJHG | 2002 | PMID: 11973624 |
Biochemical defects in retina-specific human ATP binding cassette transporter nucleotide binding domain 1 mutants associated with macular degeneration. | Suárez T | The Journal of biological chemistry | 2002 | PMID: 11919200 |
Nucleotide binding domain 1 of the human retinal ABC transporter functions as a general ribonucleotidase. | Biswas EE | Biochemistry | 2001 | PMID: 11444963 |
Biochemical defects in ABCR protein variants associated with human retinopathies. | Sun H | Nature genetics | 2000 | PMID: 11017087 |
Further evidence for an association of ABCR alleles with age-related macular degeneration. The International ABCR Screening Consortium. | Allikmets R | American journal of human genetics | 2000 | PMID: 10880298 |
An analysis of ABCR mutations in British patients with recessive retinal dystrophies. | Papaioannou M | Investigative ophthalmology & visual science | 2000 | PMID: 10634594 |
The 2588G-->C mutation in the ABCR gene is a mild frequent founder mutation in the Western European population and allows the classification of ABCR mutations in patients with Stargardt disease. | Maugeri A | American journal of human genetics | 1999 | PMID: 10090887 |
A photoreceptor cell-specific ATP-binding transporter gene (ABCR) is mutated in recessive Stargardt macular dystrophy. | Allikmets R | Nature genetics | 1997 | PMID: 9054934 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ABCA4 | - | - | - | - |
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Text-mined citations for rs76157638 ...
HelpRecord last updated Apr 20, 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.