Criteria applied: PM3_VSTR,PM5,PM2_SUP,PP3; Identified as compund heterozygous with NM_000350.3:c.2012_2013del
ClinVar Genomic variation as it relates to human health
NM_000350.3(ABCA4):c.4919G>A (p.Arg1640Gln)
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.4919G>A (p.Arg1640Gln)
Variation ID: 99331 Accession: VCV000099331.45
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p22.1 1: 94021339 (GRCh38) [ NCBI UCSC ] 1: 94486895 (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 20, 2024 Aug 20, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000350.3:c.4919G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000341.2:p.Arg1640Gln missense NM_001425324.1:c.4697G>A NP_001412253.1:p.Arg1566Gln missense NC_000001.11:g.94021339C>T NC_000001.10:g.94486895C>T NG_009073.1:g.104811G>A NG_009073.2:g.104809G>A NG_082117.1:g.694C>T P78363:p.Arg1640Gln - Protein change
- R1640Q, R1566Q
- Other names
- -
- Canonical SPDI
- NC_000001.11:94021338:C:T
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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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00003
Exome Aggregation Consortium (ExAC) 0.00006
- 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 |
3759 | 4113 | |
| LOC126805793 | - | - | - | GRCh38 | - | 215 |
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 (5) |
criteria provided, multiple submitters, no conflicts
|
Jan 10, 2024 | RCV000085684.38 | |
| Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Aug 20, 2024 | RCV000321118.8 | |
| Pathogenic (2) |
criteria provided, single submitter
|
Apr 25, 2019 | RCV000504816.6 | |
| Pathogenic (2) |
no assertion criteria provided
|
Jun 23, 2019 | RCV000787505.3 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Apr 21, 2023 | RCV003223338.4 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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
(Apr 25, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Retinal dystrophy
Affected status: yes
Allele origin:
germline
|
Blueprint Genetics
Accession: SCV001239057.1
First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020
Comment:
My Retina Tracker patient
|
|
|
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Pathogenic
(Apr 21, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Cone-rod dystrophy 3
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV003918846.1
First in ClinVar: Apr 23, 2023 Last updated: Apr 23, 2023 |
Clinical Features:
Cone-rod dystrophy (present) , Macular degeneration (present) , Macular dystrophy (present)
|
|
|
Pathogenic
(Feb 01, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001334599.25
First in ClinVar: Jun 08, 2020 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Jan 01, 2016)
|
criteria provided, single submitter
Method: clinical testing, in vitro
|
Severe early-childhood-onset retinal dystrophy
Affected status: yes
Allele origin:
germline,
unknown
|
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg
Accession: SCV000281908.2
First in ClinVar: Dec 07, 2016 Last updated: Dec 07, 2016 |
Observation 1:
Indication for testing: Stargardt disease 1
Observation 2:
Method: Minigene assay.
Result:
Effect of most common transcripts: Normal isoform (but less than in wild type). Probable effect at the RNA and protein level: r.4849_4920del p.V1617_R1640del
|
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Pathogenic
(Oct 27, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000336550.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
|
|
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Pathogenic
(Aug 20, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Severe early-childhood-onset retinal dystrophy
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
unknown
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV005368317.1
First in ClinVar: Oct 13, 2024 Last updated: Oct 13, 2024 |
Comment:
Criteria applied: PM3_VSTR,PM5,PM2_SUP,PP3; Identified as compund heterozygous with NM_000350.3:c.2012_2013del
Clinical Features:
Fundus atrophy (present) , Cone-rod dystrophy (present)
Sex: female
|
|
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Likely pathogenic
(Jan 30, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Severe early-childhood-onset retinal dystrophy
Affected status: yes
Allele origin:
unknown
|
Institute of Medical Molecular Genetics, University of Zurich
Accession: SCV001548083.1
First in ClinVar: Mar 28, 2021 Last updated: Mar 28, 2021 |
Method: long-range PCR
|
|
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Pathogenic
(Dec 22, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000511902.5
First in ClinVar: Mar 08, 2017 Last updated: Mar 04, 2023 |
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate that the c.4919 G>A variant may … (more)
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate that the c.4919 G>A variant may have a negative effect on proper splicing (Schulz et al., 2017); This variant is associated with the following publications: (PMID: 26743751, 11527935, 11379881, 10711710, 23755871, 26377081, 26103963, 25082885, 19074458, 28118664, 28041643, 29925512, 31736247, 31456290, 30718709, 32581362, 31589614, 32037395) (less)
|
|
|
Pathogenic
(Jan 10, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001198188.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1640 of the ABCA4 protein (p.Arg1640Gln). … (more)
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1640 of the ABCA4 protein (p.Arg1640Gln). This variant is present in population databases (rs61751403, gnomAD 0.009%). This missense change has been observed in individuals with autosomal recessive ABCA4-related conditions (PMID: 10711710, 11527935, 23755871, 26103963). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 99331). 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%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
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Uncertain significance
(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: SCV000598987.2
First in ClinVar: Sep 09, 2017 Last updated: Sep 21, 2018 |
Number of individuals with the variant: 1
Sex: female
Ethnicity/Population group: European
|
|
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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: SCV000926471.2 First in ClinVar: Jul 21, 2019 Last updated: Sep 03, 2023 |
|
|
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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: SCV005047040.1
First in ClinVar: Jun 09, 2024 Last updated: Jun 09, 2024 |
|
|
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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: SCV001160838.1
First in ClinVar: Feb 16, 2020 Last updated: Feb 16, 2020 |
|
|
|
not provided
(-)
|
no classification provided
Method: not provided
|
not provided
Affected status: not provided
Allele origin:
not provided
|
Retina International
Accession: SCV000117824.1
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.4919G>A
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| click to load more click to collapse | |||||
Comment:
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate that the c.4919 G>A variant may have a negative effect on proper splicing (Schulz et al., 2017); This variant is associated with the following publications: (PMID: 26743751, 11527935, 11379881, 10711710, 23755871, 26377081, 26103963, 25082885, 19074458, 28118664, 28041643, 29925512, 31736247, 31456290, 30718709, 32581362, 31589614, 32037395)
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1640 of the ABCA4 protein (p.Arg1640Gln). This variant is present in population databases (rs61751403, gnomAD 0.009%). This missense change has been observed in individuals with autosomal recessive ABCA4-related conditions (PMID: 10711710, 11527935, 23755871, 26103963). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 99331). 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%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic.
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. |
|---|---|---|---|---|
|
sequence_variant_affecting_splicing
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Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg
Accession: SCV000281908.2
|
|
Comment:
Criteria applied: PM3_VSTR,PM5,PM2_SUP,PP3; Identified as compund heterozygous with NM_000350.3:c.2012_2013del
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate that the c.4919 G>A variant may have a negative effect on proper splicing (Schulz et al., 2017); This variant is associated with the following publications: (PMID: 26743751, 11527935, 11379881, 10711710, 23755871, 26377081, 26103963, 25082885, 19074458, 28118664, 28041643, 29925512, 31736247, 31456290, 30718709, 32581362, 31589614, 32037395)
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1640 of the ABCA4 protein (p.Arg1640Gln). This variant is present in population databases (rs61751403, gnomAD 0.009%). This missense change has been observed in individuals with autosomal recessive ABCA4-related conditions (PMID: 10711710, 11527935, 23755871, 26103963). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 99331). 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%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Long-Range PCR-Based NGS Applications to Diagnose Mendelian Retinal Diseases. | Maggi J | International journal of molecular sciences | 2021 | PMID: 33546218 |
| Molecular genetic analysis using targeted NGS analysis of 677 individuals with retinal dystrophy. | Jespersgaard C | Scientific reports | 2019 | PMID: 30718709 |
| 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 |
| Next-generation sequencing applied to a large French cone and cone-rod dystrophy cohort: mutation spectrum and new genotype-phenotype correlation. | Boulanger-Scemama E | Orphanet journal of rare diseases | 2015 | PMID: 26103963 |
| Outcome of ABCA4 disease-associated alleles in autosomal recessive retinal dystrophies: retrospective analysis in 420 Spanish families. | Riveiro-Alvarez R | Ophthalmology | 2013 | PMID: 23755871 |
| ABCA4 disease progression and a proposed strategy for gene therapy. | Cideciyan AV | Human molecular genetics | 2009 | PMID: 19074458 |
| Mutations in ABCR (ABCA4) in patients with Stargardt macular degeneration or cone-rod degeneration. | Briggs CE | Investigative ophthalmology & visual science | 2001 | PMID: 11527935 |
| New ABCR mutations and clinical phenotype in Italian patients with Stargardt disease. | Simonelli F | Investigative ophthalmology & visual science | 2000 | PMID: 10711710 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ABCA4 | - | - | - | - |
Text-mined citations for rs61751403 ...
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 25, 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.