Variant summary: ABCA4 c.5381C>A (p.Ala1794Asp) results in a non-conservative amino acid change located in the ABC-2 type transporter, transmembrane domain (IPR013525) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251442 control chromosomes. c.5381C>A has been reported in the literature in multiple compound heterozygous individuals affected with Retinitis Pigmentosa and other forms of retinopathy (Maugeri_1999, Carss_2017, Birtel_2018, Salles_2018, Lynn_2023). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 29555955, 28041643, 36672815, 10090887, 30093795). ClinVar contains an entry for this variant (Variation ID: 99371). Based on the evidence outlined above, the variant was classified as pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000350.3(ABCA4):c.5381C>A (p.Ala1794Asp)
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.
(10)
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
10
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.5381C>A (p.Ala1794Asp)
Variation ID: 99371 Accession: VCV000099371.15
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 1p22.1 1: 94014622 (GRCh38) [ NCBI UCSC ] 1: 94480178 (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 Oct 26, 2024 Aug 21, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000350.3:c.5381C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000341.2:p.Ala1794Asp missense NM_001425324.1:c.5159C>A NP_001412253.1:p.Ala1720Asp missense NC_000001.11:g.94014622G>T NC_000001.10:g.94480178G>T NG_009073.1:g.111528C>A NG_009073.2:g.111526C>A P78363:p.Ala1794Asp - Protein change
- A1794D, A1720D
- Other names
- -
- Canonical SPDI
- NC_000001.11:94014621:G:T
-
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.
-
Trans-Omics for Precision Medicine (TOPMed) 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
The Genome Aggregation Database (gnomAD) 0.00003
- 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 |
3763 | 4118 | |
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, single submitter
|
Jan 14, 2024 | RCV000085725.18 | |
| Pathogenic (2) |
criteria provided, single submitter
|
Aug 16, 2019 | RCV000504739.11 | |
| Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Jan 30, 2021 | RCV000677343.12 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Aug 21, 2024 | RCV004767070.1 |
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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|---|---|---|---|---|---|
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Pathogenic
(May 28, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Severe early-childhood-onset retinal dystrophy
Affected status: unknown
Allele origin:
unknown
|
Mendelics
Accession: SCV001135332.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
|
|
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Pathogenic
(Aug 16, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Retinal dystrophy
Affected status: yes
Allele origin:
germline
|
Blueprint Genetics
Accession: SCV001239245.1
First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020
Comment:
My Retina Tracker patient
|
|
|
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Pathogenic
(Aug 21, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Retinitis pigmentosa
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV005380457.1
First in ClinVar: Oct 26, 2024 Last updated: Oct 26, 2024 |
Comment:
Variant summary: ABCA4 c.5381C>A (p.Ala1794Asp) results in a non-conservative amino acid change located in the ABC-2 type transporter, transmembrane domain (IPR013525) of the encoded protein … (more)
Variant summary: ABCA4 c.5381C>A (p.Ala1794Asp) results in a non-conservative amino acid change located in the ABC-2 type transporter, transmembrane domain (IPR013525) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251442 control chromosomes. c.5381C>A has been reported in the literature in multiple compound heterozygous individuals affected with Retinitis Pigmentosa and other forms of retinopathy (Maugeri_1999, Carss_2017, Birtel_2018, Salles_2018, Lynn_2023). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 29555955, 28041643, 36672815, 10090887, 30093795). ClinVar contains an entry for this variant (Variation ID: 99371). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Likely pathogenic
(Jan 30, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Severe early-childhood-onset retinal dystrophy
Affected status: yes
Allele origin:
germline
|
Institute of Medical Molecular Genetics, University of Zurich
Accession: SCV001548043.1
First in ClinVar: Mar 28, 2021 Last updated: Mar 28, 2021 |
Method: long-range PCR
|
|
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Pathogenic
(Jan 14, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001222426.4
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 1794 of the ABCA4 protein … (more)
This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 1794 of the ABCA4 protein (p.Ala1794Asp). This variant is present in population databases (rs61751406, gnomAD 0.004%). This missense change has been observed in individual(s) with ABCA4-related retinal diseases (PMID: 29555955, 30093795; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 99371). 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%. This variant disrupts the p.Ala1794 amino acid residue in ABCA4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 29847635; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
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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: SCV001955999.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
|
|
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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: SCV001968021.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
|
|
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Likely pathogenic
(Jan 12, 2017)
|
no assertion criteria provided
Method: research
|
Severe early-childhood-onset retinal dystrophy
(Autosomal recessive inheritance)
Affected status: no, yes
Allele origin:
inherited
|
Human Molecular Genetics Laboratory, Federal University of Parana
Additional submitter:
Pele Pequeno Principe Research Institute, Faculdades Pequeno Principe
Accession: SCV000598613.1
First in ClinVar: Aug 20, 2018 Last updated: Aug 20, 2018 |
Comment:
We suggest likely pathogenic clinical significance based on the following rationale: - Multiple lines of computational evidence support a deleterious effect (ACMG/AMP guidelines: PP3) - … (more)
We suggest likely pathogenic clinical significance based on the following rationale: - Multiple lines of computational evidence support a deleterious effect (ACMG/AMP guidelines: PP3) - Co-segregation with disease in multiple affected family members (ACMG/AMP guidelines: PP1) - Almost absent in population databases (ACMG/AMP guidelines: PM2; absent from 1000genomes, 3/121412 in EXaC) - Literature data also show that this allele is present in Stargardt patients' ABCA4 genotypes. (less)
Observation 1:
Number of individuals with the variant: 5
Number of families with the variant: 1
Clinical Features:
Macular degeneration (present) , Retinal Flecks (present)
Comment on evidence:
On our research, we carried out the genetic analysis of a Brazilian family with four affected siblings displaying a characteristic fundus changes of Stargardt disease … (more)
On our research, we carried out the genetic analysis of a Brazilian family with four affected siblings displaying a characteristic fundus changes of Stargardt disease 1 (early-onset STGD1) and intrafamilial phenotypic variability, including one additional affected second-degree relative presenting late onset of disease. We found the second-degree relative homozygous for this variant. Interestangly, the four sister were heterozygous for this variant and 5 unaffected relatives are carriers. Coding sequence variants were annotated with prediction of their impact on gene function and consequently on disease susceptibility in silico algorithms (SIFT, PolyPhen-2, MutationTaster, Mutation Assessor, and FATHMM). All four sisters were heterozygotes for nine candidate variants (in the RDH11 gene, CERKL gene, TLR4 gene, TLR3 gene, GUCA1B gene, CRX3 gene, and 3 in the ABCA4 gene), of all only this variant and a variant in the RDH11 gene were predicted to be pathogenic by four of the five algorithms. We screened the family for these candidate variants using Sanger sequencing. We proposed a possible digenic inheritance pattern through the combination of variants in the ABCA4 and RDH11 genes as the causative mutations of STGD1. The cosegregation analysis performed for variants in ABCA4 and RDH11 gene confirmed the possibility of our hypothesis. (less)
Method: Ion Ampliseq Exome RDY, Hi-Q chemistry
Observation 2:
Number of individuals with the variant: 5
Comment on evidence:
On our research, we carried out the genetic analysis of a Brazilian family with four affected siblings displaying a characteristic fundus changes of Stargardt disease … (more)
On our research, we carried out the genetic analysis of a Brazilian family with four affected siblings displaying a characteristic fundus changes of Stargardt disease 1 (early-onset STGD1) and intrafamilial phenotypic variability, including one additional affected second-degree relative presenting late onset of disease. We found the second-degree relative homozygous for this variant. Interestangly, the four sister were heterozygous for this variant and 5 unaffected relatives are carriers. Coding sequence variants were annotated with prediction of their impact on gene function and consequently on disease susceptibility in silico algorithms (SIFT, PolyPhen-2, MutationTaster, Mutation Assessor, and FATHMM). All four sisters were heterozygotes for nine candidate variants (in the RDH11 gene, CERKL gene, TLR4 gene, TLR3 gene, GUCA1B gene, CRX3 gene, and 3 in the ABCA4 gene), of all only this variant and a variant in the RDH11 gene were predicted to be pathogenic by four of the five algorithms. We screened the family for these candidate variants using Sanger sequencing. We proposed a possible digenic inheritance pattern through the combination of variants in the ABCA4 and RDH11 genes as the causative mutations of STGD1. The cosegregation analysis performed for variants in ABCA4 and RDH11 gene confirmed the possibility of our hypothesis. (less)
Method: Ion Ampliseq Exome RDY, Hi-Q chemistry
|
|
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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: SCV000598995.1
First in ClinVar: Sep 09, 2017 Last updated: Sep 09, 2017 |
Number of individuals with the variant: 1
Sex: male
Ethnicity/Population group: European
|
|
|
not provided
(-)
|
no classification provided
Method: not provided
|
not provided
Affected status: not provided
Allele origin:
unknown
|
Retina International
Accession: SCV000117865.1
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.5381C>A
|
|
Comment:
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 1794 of the ABCA4 protein (p.Ala1794Asp). This variant is present in population databases (rs61751406, gnomAD 0.004%). This missense change has been observed in individual(s) with ABCA4-related retinal diseases (PMID: 29555955, 30093795; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 99371). 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%. This variant disrupts the p.Ala1794 amino acid residue in ABCA4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 29847635; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Comment:
We suggest likely pathogenic clinical significance based on the following rationale: - Multiple lines of computational evidence support a deleterious effect (ACMG/AMP guidelines: PP3) - Co-segregation with disease in multiple affected family members (ACMG/AMP guidelines: PP1) - Almost absent in population databases (ACMG/AMP guidelines: PM2; absent from 1000genomes, 3/121412 in EXaC) - Literature data also show that this allele is present in Stargardt patients' ABCA4 genotypes.
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:
Variant summary: ABCA4 c.5381C>A (p.Ala1794Asp) results in a non-conservative amino acid change located in the ABC-2 type transporter, transmembrane domain (IPR013525) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251442 control chromosomes. c.5381C>A has been reported in the literature in multiple compound heterozygous individuals affected with Retinitis Pigmentosa and other forms of retinopathy (Maugeri_1999, Carss_2017, Birtel_2018, Salles_2018, Lynn_2023). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 29555955, 28041643, 36672815, 10090887, 30093795). ClinVar contains an entry for this variant (Variation ID: 99371). Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 1794 of the ABCA4 protein (p.Ala1794Asp). This variant is present in population databases (rs61751406, gnomAD 0.004%). This missense change has been observed in individual(s) with ABCA4-related retinal diseases (PMID: 29555955, 30093795; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 99371). 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%. This variant disrupts the p.Ala1794 amino acid residue in ABCA4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 29847635; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Comment:
We suggest likely pathogenic clinical significance based on the following rationale: - Multiple lines of computational evidence support a deleterious effect (ACMG/AMP guidelines: PP3) - Co-segregation with disease in multiple affected family members (ACMG/AMP guidelines: PP1) - Almost absent in population databases (ACMG/AMP guidelines: PM2; absent from 1000genomes, 3/121412 in EXaC) - Literature data also show that this allele is present in Stargardt patients' ABCA4 genotypes.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Genetic Diagnosis for 64 Patients with Inherited Retinal Disease. | Lynn J | Genes | 2022 | PMID: 36672815 |
| Long-Range PCR-Based NGS Applications to Diagnose Mendelian Retinal Diseases. | Maggi J | International journal of molecular sciences | 2021 | PMID: 33546218 |
| Variants in the ABCA4 gene in a Brazilian population with Stargardt disease. | Salles MV | Molecular vision | 2018 | PMID: 30093795 |
| Correlating the Expression and Functional Activity of ABCA4 Disease Variants With the Phenotype of Patients With Stargardt Disease. | Garces F | Investigative ophthalmology & visual science | 2018 | PMID: 29847635 |
| Clinical and genetic characteristics of 251 consecutive patients with macular and cone/cone-rod dystrophy. | Birtel J | Scientific reports | 2018 | PMID: 29555955 |
| 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 | PMC5270621 |
| 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 |
| Next generation sequencing based identification of disease-associated mutations in Swiss patients with retinal dystrophies. | Tiwari A | Scientific reports | 2016 | PMC4926080 |
| Mutations in the ABCA4 (ABCR) gene are the major cause of autosomal recessive cone-rod dystrophy. | Maugeri A | American journal of human genetics | 2000 | PMC1287897 |
| 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 |
Text-mined citations for rs61751406 ...
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 30, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.