In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 19243736, 25444351, 26720470, 14517951, 17982420, 20398653, 25681002, 23953153, 20029649, 29555955, 28118664, 29925512, 33706644)
ClinVar Genomic variation as it relates to human health
NM_000350.3(ABCA4):c.656G>C (p.Arg219Thr)
Germline
Classification
Help
criteria provided, conflicting classifications. Learn more about how ClinVar calculates review status.
Conflicting classifications of pathogenicity
Pathogenic(1); Uncertain significance(4)
Pathogenic(1); Uncertain significance(4)
5 out of 8 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.
8
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000350.3(ABCA4):c.656G>C (p.Arg219Thr)
Variation ID: 99470 Accession: VCV000099470.50
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 1p22.1 1: 94098906 (GRCh38) [ NCBI UCSC ] 1: 94564462 (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 Jan 11, 2026 Jan 6, 2025 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000350.3:c.656G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000341.2:p.Arg219Thr missense NM_001425324.1:c.656G>C NP_001412253.1:p.Arg219Thr missense NC_000001.11:g.94098906C>G NC_000001.10:g.94564462C>G NG_009073.1:g.27244G>C NG_009073.2:g.27242G>C - Protein change
- R219T
- Other names
- -
- Canonical SPDI
- NC_000001.11:94098905:C:G
-
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.
-
0.00020 (T)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00003
Exome Aggregation Consortium (ExAC) 0.00004
- 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 |
4134 | 4531 | |
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. |
|---|---|---|---|---|
| Uncertain significance (6) |
criteria provided, multiple submitters, no conflicts
|
Jan 6, 2025 | RCV000085831.46 | |
| Conflicting classifications of pathogenicity (2) |
criteria provided, conflicting classifications
|
Jan 1, 2023 | RCV001073757.5 |
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. |
Expand all rows
Collapse all rows
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. |
|
|---|---|---|---|---|---|
|
Uncertain significance
(Nov 29, 2017)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Retinal dystrophy |
Blueprint Genetics
Accession: SCV001239317.1
First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020
Comment:
My Retina Tracker patient
|
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Uncertain significance
(Sep 12, 2022)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Not Provided |
GeneDx
Accession: SCV000321331.9
First in ClinVar: Oct 09, 2016 Last updated: Mar 04, 2023 |
Comment:
show
In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 19243736, 25444351, 26720470, 14517951, 17982420, 20398653, 25681002, 23953153, 20029649, 29555955, 28118664, 29925512, 33706644) (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Uncertain significance
(Jan 06, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001403273.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 25, 2025 |
Comment:
show
This sequence change replaces arginine, which is basic and polar, with threonine, which is neutral and polar, at codon 219 of the ABCA4 protein (p.Arg219Thr). This variant is present in population databases (rs61748537, gnomAD 0.009%). This missense change has been observed in individual(s) with clinical features of ABCA4-related conditions (PMID: 19243736, 25444351, 26720470, 28118664, 29555955, 35120629). ClinVar contains an entry for this variant (Variation ID: 99470). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ABCA4 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Uncertain significance
(Jun 01, 2017)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
CeGaT Center for Human Genetics Tuebingen
Accession: SCV000608486.41
First in ClinVar: Oct 30, 2017 Last updated: Jan 11, 2026 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Jan 01, 2023)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Retinal dystrophy |
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg
Accession: SCV000281809.3
First in ClinVar: Dec 07, 2016 Last updated: Dec 28, 2024 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Uncertain significance
(-)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
not provided |
Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001979242.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Uncertain significance
(-)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
not provided |
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: SCV001979936.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
not provided
(-)
N
Not contributing to aggregate classification
|
no classification provided
|
not provided |
Retina International
Accession: SCV000117974.1
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.656G>C
|
Observation: 1
Collection method: not provided
Allele origin: not provided
Affected status: not provided
Observation 1
Collection method: not provided
Allele origin: not provided
Affected status: not provided
|
|
Comment:
Comment:
This sequence change replaces arginine, which is basic and polar, with threonine, which is neutral and polar, at codon 219 of the ABCA4 protein (p.Arg219Thr). This variant is present in population databases (rs61748537, gnomAD 0.009%). This missense change has been observed in individual(s) with clinical features of ABCA4-related conditions (PMID: 19243736, 25444351, 26720470, 28118664, 29555955, 35120629). ClinVar contains an entry for this variant (Variation ID: 99470). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ABCA4 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Personalized genetic counseling for Stargardt disease: Offspring risk estimates based on variant severity. | Cornelis SS | American journal of human genetics | 2022 | PMID: 35120629 |
| Peripheral pigmented lesions in ABCA4-associated retinopathy. | Al-Ani HH | Ophthalmic genetics | 2021 | PMID: 33706644 |
| 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 |
| Worldwide carrier frequency and genetic prevalence of autosomal recessive inherited retinal diseases. | Hanany M | Proceedings of the National Academy of Sciences of the United States of America | 2020 | PMID: 31964843 |
| Prevalence of mutations in inherited retinal diseases: A comparison between the United States and India. | Yohe S | Molecular genetics & genomic medicine | 2020 | PMID: 31816670 |
| Detailed genetic characteristics of an international large cohort of patients with Stargardt disease: ProgStar study report 8. | Fujinami K | The British journal of ophthalmology | 2019 | PMID: 29925512 |
| 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 | PMID: 28118664 |
| Monoallelic ABCA4 Mutations Appear Insufficient to Cause Retinopathy: A Quantitative Autofluorescence Study. | Müller PL | Investigative ophthalmology & visual science | 2015 | PMID: 26720470 |
| Early-onset stargardt disease: phenotypic and genotypic characteristics. | Lambertus S | Ophthalmology | 2015 | PMID: 25444351 |
| Lipofuscin- and melanin-related fundus autofluorescence in patients with ABCA4-associated retinal dystrophies. | Kellner S | American journal of ophthalmology | 2009 | PMID: 19243736 |
| Genotyping microarray (gene chip) for the ABCR (ABCA4) gene. | Jaakson K | Human mutation | 2003 | PMID: 14517951 |
| click to load more citations click to collapse | ||||
Text-mined citations for rs61748537 ...
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 Jan 11, 2026
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.