The ABCA4 c.4577C>T variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PS3, PM2, PP3, PP5. Based on this evidence we have classified this variant as Likely Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000350.3(ABCA4):c.4577C>T (p.Thr1526Met)
Germline
Classification
Help
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.
(14)
Help
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.
Pathogenic/Likely pathogenic
14
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000350.3(ABCA4):c.4577C>T (p.Thr1526Met)
Variation ID: 99303 Accession: VCV000099303.22
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 1p22.1 1: 94025011 (GRCh38) [ NCBI UCSC ] 1: 94490567 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Jun 9, 2024 Jan 29, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000350.3:c.4577C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000341.2:p.Thr1526Met missense NM_001425324.1:c.4355C>T NP_001412253.1:p.Thr1452Met missense NC_000001.11:g.94025011G>A NC_000001.10:g.94490567G>A NG_009073.1:g.101139C>T NG_009073.2:g.101137C>T P78363:p.Thr1526Met - Protein change
- T1526M, T1452M
- Other names
- -
- Canonical SPDI
- NC_000001.11:94025010:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD), exomes 0.00005
Trans-Omics for Precision Medicine (TOPMed) 0.00009
Exome Aggregation Consortium (ExAC) 0.00003
The Genome Aggregation Database (gnomAD) 0.00016
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
|||
| ABCA4 | - | - |
GRCh38 GRCh37 |
3758 | 4112 | |
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. |
|---|---|---|---|---|
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Jan 29, 2024 | RCV000085656.15 | |
| Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Mar 30, 2023 | RCV000177509.8 | |
| Likely pathogenic (2) |
no assertion criteria provided
|
Jan 23, 2015 | RCV000210286.4 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Oct 31, 2017 | RCV000623715.2 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Aug 2, 2019 | RCV001075849.2 | |
| Pathogenic (1) |
no assertion criteria provided
|
Jun 23, 2019 | RCV001002827.1 | |
| Pathogenic (1) |
no assertion criteria provided
|
- | RCV001542561.2 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Feb 12, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000229390.5
First in ClinVar: Jun 28, 2015 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
|
|
|
Pathogenic
(Aug 02, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Retinal dystrophy
Affected status: yes
Allele origin:
germline
|
Blueprint Genetics
Accession: SCV001241488.1
First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020
Comment:
My Retina Tracker patient
|
|
|
|
Likely pathogenic
(Apr 08, 2021)
|
criteria provided, single submitter
Method: research
|
Severe early-childhood-onset retinal dystrophy
Affected status: yes
Allele origin:
germline
|
Ocular Genomics Institute, Massachusetts Eye and Ear
Accession: SCV001573618.1
First in ClinVar: May 10, 2021 Last updated: May 10, 2021 |
Comment:
The ABCA4 c.4577C>T variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we … (more)
The ABCA4 c.4577C>T variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PS3, PM2, PP3, PP5. Based on this evidence we have classified this variant as Likely Pathogenic. (less)
|
|
|
Likely pathogenic
(Oct 31, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: yes
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000742931.3
First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023 |
Number of individuals with the variant: 1
Sex: female
Ethnicity/Population group: Caucasian/Irish/Italian/Native American/Cherokee
|
|
|
Pathogenic
(Jan 07, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000511899.5
First in ClinVar: Mar 08, 2017 Last updated: Jan 15, 2023 |
Comment:
Published functional studies demonstrate reduced basal ATPase activity and almost absent retinal-stimulated activity (Sun et al., 2000); In silico analysis supports that this missense variant … (more)
Published functional studies demonstrate reduced basal ATPase activity and almost absent retinal-stimulated activity (Sun et al., 2000); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30653986, 34240658, 34758253, 32467599, 11527935, 21558428, 23918662, 11702214, 11726554, 23755871, 19265867, 21911583, 14517951, 9973280, 26551331, 23982839, 23143460, 30337596, 29925512, 28559085, 31456290, 32581362, 31618761, 32845068, 33301772, 32037395, 35119454, 35409265, 11017087, 19074458, 25082885) (less)
|
|
|
Pathogenic
(Jan 29, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001200444.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 1526 of the ABCA4 protein (p.Thr1526Met). … (more)
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 1526 of the ABCA4 protein (p.Thr1526Met). This variant is present in population databases (rs61750152, gnomAD 0.01%). This missense change has been observed in individuals with Stargardt disease or cone-rod dystrophy and Stargardt disease in at least one family and has been observed in unrelated individuals affected with Stargardt disease or cone-rod dystrophy (PMID: 9973280, 19074458). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 99303). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ABCA4 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ABCA4 function (PMID: 11017087). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Mar 30, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Severe early-childhood-onset retinal dystrophy
Affected status: yes
Allele origin:
germline
|
Molecular Genetics, Royal Melbourne Hospital
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002503703.2
First in ClinVar: Apr 28, 2022 Last updated: Apr 15, 2024 |
Comment:
This sequence change is predicted to replace threonine with methionine at codon 1526 of the ABCA4 protein, p.(Thr1526Met). The threonine residue is moderately conserved (100 … (more)
This sequence change is predicted to replace threonine with methionine at codon 1526 of the ABCA4 protein, p.(Thr1526Met). The threonine residue is moderately conserved (100 vertebrates, UCSC), and in the extracellular domain. There is a moderate physicochemical difference between threonine and methionine. The variant is present in a large population cohort at a frequency of 0.006%, which is consistent with recessive disease (rs61750152, 18/282,882 alleles, 0 homozygotes in gnomAD v2.1.1). Multiple Stargardt disease/ABCA4 retinopathy cases are compound heterozygous with a second pathogenic variant or homozygous (PMID: 9973280, 19074458, 28446513), and at least two affected segregations in a single family have been reported for the variant (PMID: 19074458). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (7/7 algorithms). Based on the classification scheme RMH ACMG Guidelines v1.1.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PM2, PP1, PP3. (less)
|
|
|
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: SCV000598981.1
First in ClinVar: Jun 28, 2015 Last updated: Jun 28, 2015 |
Number of individuals with the variant: 1
Sex: female
Ethnicity/Population group: European
|
|
|
Pathogenic
(Jun 23, 2019)
|
no assertion criteria provided
Method: research
|
Stargardt disease
Affected status: yes
Allele origin:
inherited
|
Sharon lab, Hadassah-Hebrew University Medical Center
Accession: SCV001160844.1
First in ClinVar: Feb 16, 2020 Last updated: Feb 16, 2020 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
Age related macular degeneration 2
Affected status: yes
Allele origin:
germline
|
Genomics England Pilot Project, Genomics England
Accession: SCV001760051.1
First in ClinVar: Jul 27, 2021 Last updated: Jul 27, 2021 |
|
|
|
Likely pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
Retinitis pigmentosa 19
Affected status: yes
Allele origin:
germline
|
Genomics England Pilot Project, Genomics England
Accession: SCV001760052.1
First in ClinVar: Jul 27, 2021 Last updated: Jul 27, 2021 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: research
|
Severe early-childhood-onset retinal dystrophy
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Ophthalmo-Genetics Lab, Instituto de Oftalmologia Conde de Valenciana
Accession: SCV005047021.1
First in ClinVar: Jun 09, 2024 Last updated: Jun 09, 2024 |
|
|
|
Likely pathogenic
(Jan 23, 2015)
|
no assertion criteria provided
Method: clinical testing
|
Retinitis pigmentosa 19
Affected status: yes
Allele origin:
germline
|
Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals
Accession: SCV000259076.1
First in ClinVar: Mar 25, 2016 Last updated: Mar 25, 2016 |
|
|
|
not provided
(-)
|
no classification provided
Method: not provided
|
not provided
Affected status: not provided
Allele origin:
not provided
|
Retina International
Accession: SCV000117796.1
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.4577C>T
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| click to load more click to collapse | |||||
Comment:
Comment:
Published functional studies demonstrate reduced basal ATPase activity and almost absent retinal-stimulated activity (Sun et al., 2000); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30653986, 34240658, 34758253, 32467599, 11527935, 21558428, 23918662, 11702214, 11726554, 23755871, 19265867, 21911583, 14517951, 9973280, 26551331, 23982839, 23143460, 30337596, 29925512, 28559085, 31456290, 32581362, 31618761, 32845068, 33301772, 32037395, 35119454, 35409265, 11017087, 19074458, 25082885)
Comment:
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 1526 of the ABCA4 protein (p.Thr1526Met). This variant is present in population databases (rs61750152, gnomAD 0.01%). This missense change has been observed in individuals with Stargardt disease or cone-rod dystrophy and Stargardt disease in at least one family and has been observed in unrelated individuals affected with Stargardt disease or cone-rod dystrophy (PMID: 9973280, 19074458). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 99303). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ABCA4 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ABCA4 function (PMID: 11017087). For these reasons, this variant has been classified as Pathogenic.
Comment:
This sequence change is predicted to replace threonine with methionine at codon 1526 of the ABCA4 protein, p.(Thr1526Met). The threonine residue is moderately conserved (100 vertebrates, UCSC), and in the extracellular domain. There is a moderate physicochemical difference between threonine and methionine. The variant is present in a large population cohort at a frequency of 0.006%, which is consistent with recessive disease (rs61750152, 18/282,882 alleles, 0 homozygotes in gnomAD v2.1.1). Multiple Stargardt disease/ABCA4 retinopathy cases are compound heterozygous with a second pathogenic variant or homozygous (PMID: 9973280, 19074458, 28446513), and at least two affected segregations in a single family have been reported for the variant (PMID: 19074458). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (7/7 algorithms). Based on the classification scheme RMH ACMG Guidelines v1.1.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PM2, PP1, PP3.
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. |
Comment:
The ABCA4 c.4577C>T variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PS3, PM2, PP3, PP5. Based on this evidence we have classified this variant as Likely Pathogenic.
Comment:
Published functional studies demonstrate reduced basal ATPase activity and almost absent retinal-stimulated activity (Sun et al., 2000); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30653986, 34240658, 34758253, 32467599, 11527935, 21558428, 23918662, 11702214, 11726554, 23755871, 19265867, 21911583, 14517951, 9973280, 26551331, 23982839, 23143460, 30337596, 29925512, 28559085, 31456290, 32581362, 31618761, 32845068, 33301772, 32037395, 35119454, 35409265, 11017087, 19074458, 25082885)
Comment:
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 1526 of the ABCA4 protein (p.Thr1526Met). This variant is present in population databases (rs61750152, gnomAD 0.01%). This missense change has been observed in individuals with Stargardt disease or cone-rod dystrophy and Stargardt disease in at least one family and has been observed in unrelated individuals affected with Stargardt disease or cone-rod dystrophy (PMID: 9973280, 19074458). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 99303). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ABCA4 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ABCA4 function (PMID: 11017087). For these reasons, this variant has been classified as Pathogenic.
Comment:
This sequence change is predicted to replace threonine with methionine at codon 1526 of the ABCA4 protein, p.(Thr1526Met). The threonine residue is moderately conserved (100 vertebrates, UCSC), and in the extracellular domain. There is a moderate physicochemical difference between threonine and methionine. The variant is present in a large population cohort at a frequency of 0.006%, which is consistent with recessive disease (rs61750152, 18/282,882 alleles, 0 homozygotes in gnomAD v2.1.1). Multiple Stargardt disease/ABCA4 retinopathy cases are compound heterozygous with a second pathogenic variant or homozygous (PMID: 9973280, 19074458, 28446513), and at least two affected segregations in a single family have been reported for the variant (PMID: 19074458). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (7/7 algorithms). Based on the classification scheme RMH ACMG Guidelines v1.1.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PM2, PP1, PP3.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Clinically Focused Molecular Investigation of 1000 Consecutive Families with Inherited Retinal Disease. | Stone EM | Ophthalmology | 2017 | PMID: 28559085 |
| 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 |
| The Effect on Retinal Structure and Function of 15 Specific ABCA4 Mutations: A Detailed Examination of 82 Hemizygous Patients. | Fakin A | Investigative ophthalmology & visual science | 2016 | PMID: 27820952 |
| Whole Genome Sequencing Increases Molecular Diagnostic Yield Compared with Current Diagnostic Testing for Inherited Retinal Disease. | Ellingford JM | Ophthalmology | 2016 | PMID: 26872967 |
| ABCA4 disease progression and a proposed strategy for gene therapy. | Cideciyan AV | Human molecular genetics | 2009 | PMID: 19074458 |
| Biochemical defects in ABCR protein variants associated with human retinopathies. | Sun H | Nature genetics | 2000 | PMID: 11017087 |
| Genotype/Phenotype analysis of a photoreceptor-specific ATP-binding cassette transporter gene, ABCR, in Stargardt disease. | Lewis RA | American journal of human genetics | 1999 | PMID: 9973280 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ABCA4 | - | - | - | - |
Text-mined citations for rs61750152 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Nov 10, 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.