ClinVar Genomic variation as it relates to human health
NM_000350.3(ABCA4):c.3758C>T (p.Thr1253Met)
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.
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.
Uncertain significance(3); Benign(1); Likely benign(2)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000350.3(ABCA4):c.3758C>T (p.Thr1253Met)
Variation ID: 99239 Accession: VCV000099239.16
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p22.1 1: 94037200 (GRCh38) [ NCBI UCSC ] 1: 94502756 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Mar 16, 2024 Jan 28, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000350.3:c.3758C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000341.2:p.Thr1253Met missense NM_001425324.1:c.3536C>T NP_001412253.1:p.Thr1179Met missense NC_000001.11:g.94037200G>A NC_000001.10:g.94502756G>A NG_009073.1:g.88950C>T NG_009073.2:g.88948C>T NG_082118.1:g.669G>A P78363:p.Thr1253Met - Protein change
- T1253M, T1179M
- Other names
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- Canonical SPDI
- NC_000001.11:94037199:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00024
Trans-Omics for Precision Medicine (TOPMed) 0.00025
Exome Aggregation Consortium (ExAC) 0.00031
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00031
The Genome Aggregation Database (gnomAD), exomes 0.00043
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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ABCA4 | - | - |
GRCh38 GRCh37 |
3711 | 4068 | |
LOC126805794 | - | - | - | GRCh38 | - | 120 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Benign/Likely benign (4) |
criteria provided, multiple submitters, no conflicts
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Jan 28, 2024 | RCV000085592.10 | |
Uncertain significance (2) |
no assertion criteria provided
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Jan 6, 2020 | RCV000408481.4 | |
Uncertain significance (1) |
criteria provided, single submitter
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May 9, 2019 | RCV001075720.2 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Jun 30, 2021 | RCV001101851.5 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jun 12, 2023 | RCV003317087.1 |
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
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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
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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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Uncertain significance
(Apr 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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ABCA4-Related Disorders
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001258492.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Likely benign
(Feb 01, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000968530.3
First in ClinVar: Aug 26, 2019 Last updated: Mar 04, 2023 |
Comment:
This variant is associated with the following publications: (PMID: 25082829, 11726554, 26593885, 22661473, 23755871, 11385708, 19217903, 22076985, 28118664, 29925512, 31589614)
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Uncertain significance
(Jun 12, 2023)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004020573.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
Variant summary: ABCA4 c.3758C>T (p.Thr1253Met) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging … (more)
Variant summary: ABCA4 c.3758C>T (p.Thr1253Met) results in a non-conservative amino acid change in 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 0.00043 in 251346 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than estimated for a pathogenic variant in ABCA4 causing Retinitis Pigmentosa (0.00043 vs 0.0014), allowing no conclusion about variant significance. c.3758C>T has been reported in the literature as a non-informative genotype in cis with a different variant in the ABCA4 gene in cohorts with multifactorial age-related macular degeneration (AMD); bulls-eye maculopathy; inherited retinal disease and/or Stargardt disease (example, Shroyer_2001, Michaelides_2007, Zampaglione_2020, Sciezynska_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Retinitis Pigmentosa or ABCA4-related opthalmological disorders. 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: 18024811, 26593885, 11726554, 32037395). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (benign/likely benign, n=2; VUS, n=3). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. (less)
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Uncertain significance
(May 09, 2019)
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criteria provided, single submitter
Method: clinical testing
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Retinal dystrophy
Affected status: yes
Allele origin:
germline
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Blueprint Genetics
Accession: SCV001241348.1
First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020
Comment:
My Retina Tracker patient
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Benign
(Jan 28, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001732414.4
First in ClinVar: Jun 15, 2021 Last updated: Feb 14, 2024 |
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Likely benign
(Jun 30, 2021)
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criteria provided, single submitter
Method: clinical testing
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ABCA4-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004744363.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
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Uncertain significance
(Jan 06, 2020)
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no assertion criteria provided
Method: curation
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Severe early-childhood-onset retinal dystrophy
Affected status: unknown
Allele origin:
germline
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Reproductive Health Research and Development, BGI Genomics
Accession: SCV001142301.1
First in ClinVar: Jan 13, 2020 Last updated: Jan 13, 2020 |
Comment:
NM_000350.2:c.3758C>T in the ABCA4 gene has an allele frequency of 0.009 in Ashkenazi Jewish subpopulation in the gnomAD database. This variant has been reported previously … (more)
NM_000350.2:c.3758C>T in the ABCA4 gene has an allele frequency of 0.009 in Ashkenazi Jewish subpopulation in the gnomAD database. This variant has been reported previously in individuals with fundus flavimaculatus or retinal disorders (PMID: 11385708, 23755871). Riveiro-Alvarez reported a patient with autosomal recessive Retinal Dystrophies habors c.[3758C>T; 5582G>A];[3943C>T] (PMID: 23755871). In addition, Cella et al. reported T1253M compound heterozygous with G1961E in a bull's eye maculopathy patient (PMID: 19217903). Pathogenic computational verdict because pathogenic predictions from DANN, DEOGEN2, EIGEN, FATHMM-MKL, M-CAP, MVP, MutationAssessor, MutationTaster, REVEL and SIFT. We interpret it as variant of uncertain significance (VUS). ACMG/AMP criteria applied: PM3; PP3, PP4. (less)
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001552360.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The ABCA4 p.Thr1253Met variant was identified in 6 of 1414 proband chromosomes (frequency: 0.0042) from individuals or families with ABCA4-related conditions (Stargardt disease 1, autosomal … (more)
The ABCA4 p.Thr1253Met variant was identified in 6 of 1414 proband chromosomes (frequency: 0.0042) from individuals or families with ABCA4-related conditions (Stargardt disease 1, autosomal recessive retinitis pigmentosa, cone-rod dystrophy), however this variant has often been found in cis with the pathogenic p.G1961E variant, therefore it is unclear how this variant contributes to disease (Burke_2012_PMID:22661473; Shroyer_2001_PMID:11726554; Rosenberg_2007_PMID:17982420; Valverde_2005_PMID:16917483; Cella_2009_PMID:19217903; Riveiro-Alvarez_2013_PMID:23755871). The variant was identified in dbSNP (ID: rs61752424) and ClinVar (classified as likely benign by GeneDx, likely pathogenic by Institute of Human Genetics University Regensburg for Stargardt disease 1 and uncertain significance by Reproductive Health Research and Development BGI Genomics). The variant was identified in control databases in 113 of 282758 chromosomes (1 homozygous) at a frequency of 0.0003996 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Ashkenazi Jewish in 93 of 10358 chromosomes (freq: 0.008979), European (non-Finnish) in 18 of 129090 chromosomes (freq: 0.000139) and South Asian in 2 of 30614 chromosomes (freq: 0.000065), but was not observed in the African, Latino, East Asian, European (Finnish), or Other populations. The p.Thr1253 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. (less)
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not provided
(-)
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no classification provided
Method: not provided
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not provided
Affected status: not provided
Allele origin:
unknown
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Retina International
Accession: SCV000117730.1
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.3758C>T
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Likely pathogenic
(Jan 01, 2016)
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Flagged submission
flagged submission
Method: clinical testing
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
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Severe early-childhood-onset retinal dystrophy
Affected status: yes
Allele origin:
germline
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Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg
Accession: SCV000281872.2
First in ClinVar: Dec 07, 2016 Last updated: Dec 07, 2016 |
Indication for testing: Stargardt disease 1
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Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more |
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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Copy-number variation contributes 9% of pathogenicity in the inherited retinal degenerations. | Zampaglione E | Genetics in medicine : official journal of the American College of Medical Genetics | 2020 | PMID: 32037395 |
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 of ABCA4: High frequency of complex alleles and novel mutations in patients with retinal dystrophies from Central Europe. | Ścieżyńska A | Experimental eye research | 2016 | PMID: 26593885 |
Outcome of ABCA4 disease-associated alleles in autosomal recessive retinal dystrophies: retrospective analysis in 420 Spanish families. | Riveiro-Alvarez R | Ophthalmology | 2013 | PMID: 23755871 |
Retinal phenotypes in patients homozygous for the G1961E mutation in the ABCA4 gene. | Burke TR | Investigative ophthalmology & visual science | 2012 | PMID: 22661473 |
Transition zones between healthy and diseased retina in choroideremia (CHM) and Stargardt disease (STGD) as compared to retinitis pigmentosa (RP). | Lazow MA | Investigative ophthalmology & visual science | 2011 | PMID: 22076985 |
Quantification of peripapillary sparing and macular involvement in Stargardt disease (STGD1). | Burke TR | Investigative ophthalmology & visual science | 2011 | PMID: 21873672 |
G1961E mutant allele in the Stargardt disease gene ABCA4 causes bull's eye maculopathy. | Cella W | Experimental eye research | 2009 | PMID: 19217903 |
ABCA4 mutations and discordant ABCA4 alleles in patients and siblings with bull's-eye maculopathy. | Michaelides M | The British journal of ophthalmology | 2007 | PMID: 18024811 |
Cosegregation and functional analysis of mutant ABCR (ABCA4) alleles in families that manifest both Stargardt disease and age-related macular degeneration. | Shroyer NF | Human molecular genetics | 2001 | PMID: 11726554 |
Spectrum of ABCA4 (ABCR) gene mutations in Spanish patients with autosomal recessive macular dystrophies. | Paloma E | Human mutation | 2001 | PMID: 11385708 |
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Text-mined citations for rs61752424 ...
HelpRecord last updated May 27, 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.