Across a selection of literature, the ABCA4 c.71G>A (p.Arg24His) missense variant has been reported in a compound heterozygous state in five individuals with Stargardt disease (STGD) as well as in a heterozygous state in one individual (also with STGD) where a second variant was not identified (Lewis et al., 1999; Fujinami et al., 2013; Chacón-Camacho et al., 2013). Four of the compound heterozygous individuals belong to the same family and demonstrated segregation of the disease phenotype with the p.Arg24His variant. The p.Arg24His variant was absent from 440 control chromosomes and is reported at a frequency of 0.002091 in the East Asian population of the Exome Aggregation Consortium. Based on the evidence, the p.Arg24His variant is classified as likely pathogenic for ABCA4-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
ClinVar Genomic variation as it relates to human health
NM_000350.3(ABCA4):c.71G>A (p.Arg24His)
Germline
Classification
Help
criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.
Pathogenic/Likely pathogenic
8 out of 10 submissions contributed to this 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
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000350.3(ABCA4):c.71G>A (p.Arg24His)
Variation ID: 99498 Accession: VCV000099498.23
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 1p22.1 1: 94113062 (GRCh38) [ NCBI UCSC ] 1: 94578618 (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 Apr 13, 2025 Feb 5, 2025 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000350.3:c.71G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000341.2:p.Arg24His missense NM_001425324.1:c.71G>A NP_001412253.1:p.Arg24His missense NC_000001.11:g.94113062C>T NC_000001.10:g.94578618C>T NG_009073.1:g.13088G>A NG_009073.2:g.13086G>A P78363:p.Arg24His - Protein change
- R24H
- Other names
- -
- Canonical SPDI
- NC_000001.11:94113061:C: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.
-
0.00040 (T)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD) 0.00006
Trans-Omics for Precision Medicine (TOPMed) 0.00009
1000 Genomes Project 0.00040
The Genome Aggregation Database (gnomAD), exomes 0.00018
Exome Aggregation Consortium (ExAC) 0.00019
1000 Genomes Project 30x 0.00031
- 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 |
4045 | 4425 | |
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/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Nov 21, 2024 | RCV000085859.22 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Jul 31, 2017 | RCV000779009.13 | |
| Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Jul 23, 2019 | RCV001074842.10 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Dec 19, 2023 | RCV005252754.2 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Feb 5, 2025 | RCV005234985.1 | |
| Pathogenic (1) |
criteria provided, single submitter
|
- | RCV004796010.1 |
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. |
|
|---|---|---|---|---|---|
|
Likely pathogenic
(Jul 31, 2017)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
ABCA4-Related Disorders
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000915450.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
Across a selection of literature, the ABCA4 c.71G>A (p.Arg24His) missense variant has been reported in a compound heterozygous state in five individuals with Stargardt disease … (more)
Across a selection of literature, the ABCA4 c.71G>A (p.Arg24His) missense variant has been reported in a compound heterozygous state in five individuals with Stargardt disease (STGD) as well as in a heterozygous state in one individual (also with STGD) where a second variant was not identified (Lewis et al., 1999; Fujinami et al., 2013; Chacón-Camacho et al., 2013). Four of the compound heterozygous individuals belong to the same family and demonstrated segregation of the disease phenotype with the p.Arg24His variant. The p.Arg24His variant was absent from 440 control chromosomes and is reported at a frequency of 0.002091 in the East Asian population of the Exome Aggregation Consortium. Based on the evidence, the p.Arg24His variant is classified as likely pathogenic for ABCA4-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
|
|
|
Likely pathogenic
(Jun 30, 2020)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002020995.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Likely pathogenic
(Jan 01, 2016)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Retinal dystrophy
Affected status: yes
Allele origin:
germline
|
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg
Accession: SCV005070613.1
First in ClinVar: Dec 28, 2024 Last updated: Dec 28, 2024 |
|
|
|
Pathogenic
(Nov 21, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001212928.6
First in ClinVar: Apr 15, 2020 Last updated: Feb 25, 2025 |
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 24 of the ABCA4 protein (p.Arg24His). … (more)
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 24 of the ABCA4 protein (p.Arg24His). This variant is present in population databases (rs62645958, gnomAD 0.1%). This missense change has been observed in individuals with retinopathy (PMID: 9973280, 27820952, 31015497). ClinVar contains an entry for this variant (Variation ID: 99498). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ABCA4 protein function with a positive predictive value of 95%. This variant disrupts the p.Arg24 amino acid residue in ABCA4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15494742, 28559085, 29162642, 30093795). 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)
|
|
|
Likely pathogenic
(Feb 05, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Severe early-childhood-onset retinal dystrophy
Affected status: yes
Allele origin:
germline
|
SingHealth Duke-NUS Institute of Precision Medicine
Accession: SCV005881653.1
First in ClinVar: Mar 16, 2025 Last updated: Mar 16, 2025 |
Comment:
Variant is located in a mutational hotspot where >50% of variants are pathogenic (PM1) + Homozygous allele count is less than 0 in gnomAD exomes … (more)
Variant is located in a mutational hotspot where >50% of variants are pathogenic (PM1) + Homozygous allele count is less than 0 in gnomAD exomes and genomes (PM2). Other variant at this amino acid residue has been classified as pathogenic (PM5, p.Arg24Gly). REVEL score 0.811 (PP3_mod) (less)
|
|
|
Pathogenic
(Jul 23, 2019)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Retinal dystrophy
Affected status: yes
Allele origin:
germline
|
Blueprint Genetics
Accession: SCV001240443.1
First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020
Comment:
My Retina Tracker patient
|
|
|
|
Pathogenic
(-)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Age related macular degeneration 2
Cone-rod dystrophy 3 Severe early-childhood-onset retinal dystrophy Retinitis pigmentosa 19
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: yes
Allele origin:
germline
|
Juno Genomics, Hangzhou Juno Genomics, Inc
Accession: SCV005418514.1
First in ClinVar: Nov 30, 2024 Last updated: Nov 30, 2024 |
Comment:
PM2_Supporting+PP3_Moderate+PM3_Strong+PP1_Moderate+PP4
|
|
|
Pathogenic
(Dec 19, 2023)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Retinitis pigmentosa 19
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV005904925.1
First in ClinVar: Apr 13, 2025 Last updated: Apr 13, 2025 |
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.018%). Predicted Consequence/Location: Missense variant In silico tool … (more)
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.018%). Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.81 (>=0.6, sensitivity 0.68 and specificity 0.92)]. Same nucleotide change resulting in same amino acid change (ClinVar ID: VCV000099498 /PMID: 9973280)and different missense changes at the same codon (p.Arg24Cys, p.Arg24Gly / ClinVar ID: VCV000099497, VCV000857107 / PMID: 15494742) have been previously reported as pathogenic/likely pathogenic with strong evidence. The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 9973280). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
|
|
|
Likely pathogenic
(-)
N
Not contributing to aggregate classification
|
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: SCV001966739.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
|
|
|
not provided
(-)
N
Not contributing to aggregate classification
|
no classification provided
Method: not provided
|
not provided
Affected status: not provided
Allele origin:
not provided
|
Retina International
Accession: SCV000118002.1
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.71G>A
|
|
Comment:
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 24 of the ABCA4 protein (p.Arg24His). This variant is present in population databases (rs62645958, gnomAD 0.1%). This missense change has been observed in individuals with retinopathy (PMID: 9973280, 27820952, 31015497). ClinVar contains an entry for this variant (Variation ID: 99498). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ABCA4 protein function with a positive predictive value of 95%. This variant disrupts the p.Arg24 amino acid residue in ABCA4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15494742, 28559085, 29162642, 30093795). 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:
Variant is located in a mutational hotspot where >50% of variants are pathogenic (PM1) + Homozygous allele count is less than 0 in gnomAD exomes and genomes (PM2). Other variant at this amino acid residue has been classified as pathogenic (PM5, p.Arg24Gly). REVEL score 0.811 (PP3_mod)
Comment:
PM2_Supporting+PP3_Moderate+PM3_Strong+PP1_Moderate+PP4
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.018%). Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.81 (>=0.6, sensitivity 0.68 and specificity 0.92)]. Same nucleotide change resulting in same amino acid change (ClinVar ID: VCV000099498 /PMID: 9973280)and different missense changes at the same codon (p.Arg24Cys, p.Arg24Gly / ClinVar ID: VCV000099497, VCV000857107 / PMID: 15494742) have been previously reported as pathogenic/likely pathogenic with strong evidence. The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 9973280). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
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:
Across a selection of literature, the ABCA4 c.71G>A (p.Arg24His) missense variant has been reported in a compound heterozygous state in five individuals with Stargardt disease (STGD) as well as in a heterozygous state in one individual (also with STGD) where a second variant was not identified (Lewis et al., 1999; Fujinami et al., 2013; Chacón-Camacho et al., 2013). Four of the compound heterozygous individuals belong to the same family and demonstrated segregation of the disease phenotype with the p.Arg24His variant. The p.Arg24His variant was absent from 440 control chromosomes and is reported at a frequency of 0.002091 in the East Asian population of the Exome Aggregation Consortium. Based on the evidence, the p.Arg24His variant is classified as likely pathogenic for ABCA4-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 24 of the ABCA4 protein (p.Arg24His). This variant is present in population databases (rs62645958, gnomAD 0.1%). This missense change has been observed in individuals with retinopathy (PMID: 9973280, 27820952, 31015497). ClinVar contains an entry for this variant (Variation ID: 99498). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ABCA4 protein function with a positive predictive value of 95%. This variant disrupts the p.Arg24 amino acid residue in ABCA4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15494742, 28559085, 29162642, 30093795). 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:
Variant is located in a mutational hotspot where >50% of variants are pathogenic (PM1) + Homozygous allele count is less than 0 in gnomAD exomes and genomes (PM2). Other variant at this amino acid residue has been classified as pathogenic (PM5, p.Arg24Gly). REVEL score 0.811 (PP3_mod)
Comment:
PM2_Supporting+PP3_Moderate+PM3_Strong+PP1_Moderate+PP4
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.018%). Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.81 (>=0.6, sensitivity 0.68 and specificity 0.92)]. Same nucleotide change resulting in same amino acid change (ClinVar ID: VCV000099498 /PMID: 9973280)and different missense changes at the same codon (p.Arg24Cys, p.Arg24Gly / ClinVar ID: VCV000099497, VCV000857107 / PMID: 15494742) have been previously reported as pathogenic/likely pathogenic with strong evidence. The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 9973280). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
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 |
| The genetic structure of the Turkish population reveals high levels of variation and admixture. | Kars ME | Proceedings of the National Academy of Sciences of the United States of America | 2021 | PMID: 34426522 |
| Clinical and genetic analysis of the ABCA4 gene associated retinal dystrophy in a large Chinese cohort. | Sun Z | Experimental eye research | 2021 | PMID: 33301772 |
| Genotypes Predispose Phenotypes-Clinical Features and Genetic Spectrum of ABCA4-Associated Retinal Dystrophies. | Sung YC | Genes | 2020 | PMID: 33261146 |
| Resolving the dark matter of ABCA4 for 1054 Stargardt disease probands through integrated genomics and transcriptomics. | Khan M | Genetics in medicine : official journal of the American College of Medical Genetics | 2020 | PMID: 32307445 |
| Precision medicine integrating whole-genome sequencing, comprehensive metabolomics, and advanced imaging. | Hou YC | Proceedings of the National Academy of Sciences of the United States of America | 2020 | PMID: 31980526 |
| Inherited retinal disease in Norway - a characterization of current clinical and genetic knowledge. | Holtan JP | Acta ophthalmologica | 2020 | PMID: 31429209 |
| A Vietnamese human genetic variation database. | Le VS | Human mutation | 2019 | PMID: 31180159 |
| Multi-platform imaging in ABCA4-Associated Disease. | Chen L | Scientific reports | 2019 | PMID: 31015497 |
| Variants in the ABCA4 gene in a Brazilian population with Stargardt disease. | Salles MV | Molecular vision | 2018 | PMID: 30093795 |
| ABCA4 midigenes reveal the full splice spectrum of all reported noncanonical splice site variants in Stargardt disease. | Sangermano R | Genome research | 2018 | PMID: 29162642 |
| Clinically Focused Molecular Investigation of 1000 Consecutive Families with Inherited Retinal Disease. | Stone EM | Ophthalmology | 2017 | PMID: 28559085 |
| 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 |
| Clinical and molecular analysis of Stargardt disease with preserved foveal structure and function. | Fujinami K | American journal of ophthalmology | 2013 | PMID: 23953153 |
| ABCA4 mutational spectrum in Mexican patients with Stargardt disease: Identification of 12 novel mutations and evidence of a founder effect for the common p.A1773V mutation. | Chacón-Camacho OF | Experimental eye research | 2013 | PMID: 23419329 |
| Microarray-based mutation analysis of the ABCA4 (ABCR) gene in autosomal recessive cone-rod dystrophy and retinitis pigmentosa. | Klevering BJ | European journal of human genetics : EJHG | 2004 | PMID: 15494742 |
| 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 |
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Text-mined citations for rs62645958 ...
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 Apr 28, 2025
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.