The heterozygous p.Arg2030Ter variant in ABCA4 was identified by our study, in the compound heterozygous state along with a pathogenic variant (ClinVar Variation ID: 7898), in one individual with retinal dystrophy. This individual also carried a pathogenic variant (ClinVar Variation ID: 7898); however, the phase of these variants is unknown at this time. The p.Arg2030Ter variant in ABCA4 has been previously reported in at least six unrelated individuals with autosomal recessive ABCA4-related retinopathy (PMID: 25312043, PMID: 30718709, PMID: 16546111, PMID: 28947085, PMID: 25544989) and segregated with disease in 6 affected relatives from 2 families (PMID: 16546111, PMID: 25544989), but has been identified in 0.01% (4/30616) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs61751383). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. Of the six unrelated affected individuals previously reported (PMID: 25312043, PMID: 30718709, PMID: 16546111, PMID: 28947085, PMID: 25544989), two were homozygotes (PMID: 30718709, PMID: 16546111), two were compound heterozygotes who carried pathogenic or likely pathogenic variants in trans (PMID: 25544989, ClinVar Variation ID: 99114; PMID: 28947085, ClinVar Variation ID: 236128), and two were compound heterozygotes who carried pathogenic variants with unknown phase (PMID: 25312043, ClinVar Variation ID: 99108, 30218), which increases the likelihood that the p.Arg2030Ter variant is pathogenic. This variant has also been reported in ClinVar (Variation ID: 7907) and has been interpreted as pathogenic or likely pathogenic by multiple submitters. This nonsense variant leads to a premature termination codon at position 2030, which is predicted to lead to a truncated or absent protein. Loss of function of the ABCA4 gene is an established disease mechanism in autosomal recessive ABCA4-related retinopathy. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive ABCA4-related retinopathy. ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PM3_VeryStrong, PP1_Strong (Richards 2015).
ClinVar Genomic variation as it relates to human health
NM_000350.3(ABCA4):c.6088C>T (p.Arg2030Ter)
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.
(21)
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
21
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.6088C>T (p.Arg2030Ter)
Variation ID: 7907 Accession: VCV000007907.28
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 1p22.1 1: 94005500 (GRCh38) [ NCBI UCSC ] 1: 94471056 (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 Nov 24, 2024 Dec 1, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000350.3:c.6088C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000341.2:p.Arg2030Ter nonsense NM_001425324.1:c.5866C>T NP_001412253.1:p.Arg1956Ter nonsense NC_000001.11:g.94005500G>A NC_000001.10:g.94471056G>A NG_009073.1:g.120650C>T NG_009073.2:g.120648C>T - Protein change
- R2030*, R1956*
- Other names
-
NM_000350.3(ABCA4):c.6088C>T
p.Arg2030Ter
NP_000341.2:p.(Arg2030Ter)
- Canonical SPDI
- NC_000001.11:94005499:G:A
-
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.
-
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 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 |
3759 | 4113 | |
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 (1) |
no assertion criteria provided
|
May 1, 2006 | RCV000008365.5 | |
| Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Dec 1, 2023 | RCV000085786.15 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Oct 1, 2023 | RCV000504794.5 | |
| Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Jun 22, 2023 | RCV000505162.5 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Jul 24, 2023 | RCV000787773.5 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Mar 3, 2022 | RCV000763437.4 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
- | RCV001542555.3 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Feb 14, 2023 | RCV003447472.2 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jan 25, 2023 | RCV002512903.3 | |
| Pathogenic (1) |
no assertion criteria provided
|
Aug 29, 2024 | RCV004528093.2 |
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. |
|
|---|---|---|---|---|---|
|
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: SCV001135326.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
|
|
|
Pathogenic
(Mar 07, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Retinal dystrophy
Affected status: yes
Allele origin:
germline
|
Blueprint Genetics
Accession: SCV001241286.1
First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020
Comment:
My Retina Tracker patient
|
|
|
|
Pathogenic
(Oct 25, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Stargardt disease
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001983385.2
First in ClinVar: Oct 30, 2021 Last updated: May 27, 2023 |
Clinical Features:
Macular degeneration (present) , Macular atrophy (present) , Macular dystrophy (present)
|
|
|
Pathogenic
(Mar 03, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Age related macular degeneration 2
Severe early-childhood-onset retinal dystrophy Retinitis pigmentosa 19 Cone-rod dystrophy 3
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000894204.2
First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022 |
|
|
|
Pathogenic
(Oct 01, 2023)
|
criteria provided, single submitter
Method: research
|
Retinal dystrophy
Affected status: yes
Allele origin:
germline
|
Dept Of Ophthalmology, Nagoya University
Accession: SCV004706448.1
First in ClinVar: Mar 10, 2024 Last updated: Mar 10, 2024 |
|
|
|
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: SCV001548077.1
First in ClinVar: Mar 28, 2021 Last updated: Mar 28, 2021 |
Method: long-range PCR
|
|
|
Likely pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Retinitis pigmentosa 19
Affected status: yes
Allele origin:
germline
|
Genomics England Pilot Project, Genomics England
Accession: SCV001760043.1
First in ClinVar: Jul 27, 2021 Last updated: Jul 27, 2021 |
|
|
|
Pathogenic
(Jan 25, 2023)
|
criteria provided, single submitter
Method: curation
|
ABCA4-related retinopathy
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
|
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV003761278.1
First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023 |
Comment:
The heterozygous p.Arg2030Ter variant in ABCA4 was identified by our study, in the compound heterozygous state along with a pathogenic variant (ClinVar Variation ID: 7898), … (more)
The heterozygous p.Arg2030Ter variant in ABCA4 was identified by our study, in the compound heterozygous state along with a pathogenic variant (ClinVar Variation ID: 7898), in one individual with retinal dystrophy. This individual also carried a pathogenic variant (ClinVar Variation ID: 7898); however, the phase of these variants is unknown at this time. The p.Arg2030Ter variant in ABCA4 has been previously reported in at least six unrelated individuals with autosomal recessive ABCA4-related retinopathy (PMID: 25312043, PMID: 30718709, PMID: 16546111, PMID: 28947085, PMID: 25544989) and segregated with disease in 6 affected relatives from 2 families (PMID: 16546111, PMID: 25544989), but has been identified in 0.01% (4/30616) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs61751383). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. Of the six unrelated affected individuals previously reported (PMID: 25312043, PMID: 30718709, PMID: 16546111, PMID: 28947085, PMID: 25544989), two were homozygotes (PMID: 30718709, PMID: 16546111), two were compound heterozygotes who carried pathogenic or likely pathogenic variants in trans (PMID: 25544989, ClinVar Variation ID: 99114; PMID: 28947085, ClinVar Variation ID: 236128), and two were compound heterozygotes who carried pathogenic variants with unknown phase (PMID: 25312043, ClinVar Variation ID: 99108, 30218), which increases the likelihood that the p.Arg2030Ter variant is pathogenic. This variant has also been reported in ClinVar (Variation ID: 7907) and has been interpreted as pathogenic or likely pathogenic by multiple submitters. This nonsense variant leads to a premature termination codon at position 2030, which is predicted to lead to a truncated or absent protein. Loss of function of the ABCA4 gene is an established disease mechanism in autosomal recessive ABCA4-related retinopathy. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive ABCA4-related retinopathy. ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PM3_VeryStrong, PP1_Strong (Richards 2015). (less)
|
|
|
Pathogenic
(Mar 24, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000490381.2
First in ClinVar: Feb 20, 2014 Last updated: Apr 01, 2023 |
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of … (more)
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25544989, 26551331, 9973280, 28947085, 29186038, 25525159, 33090715, 35119454, 32619608, 29641573, 23755871, 22589445, 34758253, 30093795, 26780318, 33691693, 33301772, 26247787, 29925512) (less)
|
|
|
Pathogenic
(Jul 24, 2023)
|
criteria provided, single submitter
Method: research
|
Stargardt disease
Affected status: yes
Allele origin:
germline
|
Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel
Accession: SCV004030355.1
First in ClinVar: Sep 03, 2023 Last updated: Sep 03, 2023
Comment:
This variant was classified as Pathogenic based on ACMG criteria: PS4, PM2, PP5.
|
Comment:
Clinical significance based on ACMG v2.0
Number of individuals with the variant: 1
Sex: male
Geographic origin: Portugal
|
|
|
Pathogenic
(Feb 14, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Leber congenital amaurosis 14
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004175776.1
First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023 |
|
|
|
Pathogenic
(Dec 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001222421.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg2030*) in the ABCA4 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Arg2030*) in the ABCA4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ABCA4 are known to be pathogenic (PMID: 10958761, 24938718, 25312043, 26780318). This variant is present in population databases (rs61751383, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with ABCA4-related retinal diseases (PMID: 25544989, 28947085). ClinVar contains an entry for this variant (Variation ID: 7907). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Jun 22, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Severe early-childhood-onset retinal dystrophy
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV005400977.1
First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024 |
Comment:
The stop gained variant c.6088C>T(p.Arg2030Ter) in ABCA4 gene has been observed in homozygous or compound heterozygous state in multiple individual(s) with ABCA4-related retinal diseases (Tanaka … (more)
The stop gained variant c.6088C>T(p.Arg2030Ter) in ABCA4 gene has been observed in homozygous or compound heterozygous state in multiple individual(s) with ABCA4-related retinal diseases (Tanaka et. al., 2018; González-del Pozo et. al., 2014, Singh HP, et al., 2006). The (p.Arg2030Ter) variant is reported with 0.003% allele frequency in gnomAD Exomes. This variant has been reported to the ClinVar database as Likely Pathogenic / Pathogenic (multiple submitters). The nucleotide change c.6088C>T in ABCA4 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Loss-of-function variants in ABCA4 are known to be pathogenic (Jiang et. al., 2016). This variant is predicted to cause loss of normal protein function through protein truncation. For these reasons, this variant has been classified as Pathogenic. (less)
Clinical Features:
Abnormality of the eye (present)
|
|
|
Pathogenic
(Jan 01, 2015)
|
no assertion criteria provided
Method: research
|
None
Affected status: yes
Allele origin:
unknown
|
NIHR Bioresource Rare Diseases, University of Cambridge
Accession: SCV000599006.1
First in ClinVar: Sep 09, 2017 Last updated: Sep 09, 2017 |
Number of individuals with the variant: 1
Sex: male
Ethnicity/Population group: European
|
|
|
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: SCV000599007.1
First in ClinVar: Sep 09, 2017 Last updated: Sep 09, 2017 |
Number of individuals with the variant: 1
Sex: female
Ethnicity/Population group: European
|
|
|
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: SCV000926778.2 First in ClinVar: Jul 21, 2019 Last updated: Sep 03, 2023 |
|
|
|
Pathogenic
(May 01, 2006)
|
no assertion criteria provided
Method: literature only
|
RETINAL DYSTROPHY, EARLY-ONSET SEVERE
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000028573.3
First in ClinVar: Apr 04, 2013 Last updated: Jul 16, 2023 |
Comment on evidence:
In 3 brothers, born of consanguineous Indian parents, with early-onset severe retinal dystrophy (see 248200), Singh et al. (2006) identified homozygosity for a 6088C-T transition … (more)
In 3 brothers, born of consanguineous Indian parents, with early-onset severe retinal dystrophy (see 248200), Singh et al. (2006) identified homozygosity for a 6088C-T transition in exon 44 of the ABCA4 gene, resulting in an arg2030-to-ter substitution. The parents and an unaffected sib were heterozygous for the mutation, which was not found in 100 normal controls. (less)
|
|
|
Pathogenic
(Aug 29, 2024)
|
no assertion criteria provided
Method: clinical testing
|
ABCA4-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004104692.2
First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024 |
Comment:
The ABCA4 c.6088C>T variant is predicted to result in premature protein termination (p.Arg2030*). This variant has been reported many times in individuals with Stargardt disease … (more)
The ABCA4 c.6088C>T variant is predicted to result in premature protein termination (p.Arg2030*). This variant has been reported many times in individuals with Stargardt disease (see for examples Lewis et al. 1999. PubMed ID: 9973280; Pozo et al. 2014. PubMed ID: 25544989; Table S4 in Jiang et al. 2016. PubMed ID: 26780318; Table S2 in Del Pozo-Valero et al. 2022. PubMed ID: 35119454). This variant is reported in 0.013% of alleles in individuals of South Asian descent in gnomAD. Nonsense variants in ABCA4 are expected to be pathogenic. Given the evidence, we interpret c.6088C>T (p.Arg2030*) as pathogenic. (less)
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001923531.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
|
|
|
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: SCV001954312.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
|
|
|
not provided
(-)
|
no classification provided
Method: not provided
|
not provided
Affected status: not provided
Allele origin:
not provided
|
Retina International
Accession: SCV000117928.1
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.6088C>T
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Comment:
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25544989, 26551331, 9973280, 28947085, 29186038, 25525159, 33090715, 35119454, 32619608, 29641573, 23755871, 22589445, 34758253, 30093795, 26780318, 33691693, 33301772, 26247787, 29925512)
Comment:
Clinical significance based on ACMG v2.0
Comment:
This sequence change creates a premature translational stop signal (p.Arg2030*) in the ABCA4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ABCA4 are known to be pathogenic (PMID: 10958761, 24938718, 25312043, 26780318). This variant is present in population databases (rs61751383, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with ABCA4-related retinal diseases (PMID: 25544989, 28947085). ClinVar contains an entry for this variant (Variation ID: 7907). For these reasons, this variant has been classified as Pathogenic.
Comment:
The stop gained variant c.6088C>T(p.Arg2030Ter) in ABCA4 gene has been observed in homozygous or compound heterozygous state in multiple individual(s) with ABCA4-related retinal diseases (Tanaka et. al., 2018; González-del Pozo et. al., 2014, Singh HP, et al., 2006). The (p.Arg2030Ter) variant is reported with 0.003% allele frequency in gnomAD Exomes. This variant has been reported to the ClinVar database as Likely Pathogenic / Pathogenic (multiple submitters). The nucleotide change c.6088C>T in ABCA4 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Loss-of-function variants in ABCA4 are known to be pathogenic (Jiang et. al., 2016). This variant is predicted to cause loss of normal protein function through protein truncation. For these reasons, this variant has been classified as Pathogenic.
Comment:
The ABCA4 c.6088C>T variant is predicted to result in premature protein termination (p.Arg2030*). This variant has been reported many times in individuals with Stargardt disease (see for examples Lewis et al. 1999. PubMed ID: 9973280; Pozo et al. 2014. PubMed ID: 25544989; Table S4 in Jiang et al. 2016. PubMed ID: 26780318; Table S2 in Del Pozo-Valero et al. 2022. PubMed ID: 35119454). This variant is reported in 0.013% of alleles in individuals of South Asian descent in gnomAD. Nonsense variants in ABCA4 are expected to be pathogenic. Given the evidence, we interpret c.6088C>T (p.Arg2030*) as pathogenic.
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:
The heterozygous p.Arg2030Ter variant in ABCA4 was identified by our study, in the compound heterozygous state along with a pathogenic variant (ClinVar Variation ID: 7898), in one individual with retinal dystrophy. This individual also carried a pathogenic variant (ClinVar Variation ID: 7898); however, the phase of these variants is unknown at this time. The p.Arg2030Ter variant in ABCA4 has been previously reported in at least six unrelated individuals with autosomal recessive ABCA4-related retinopathy (PMID: 25312043, PMID: 30718709, PMID: 16546111, PMID: 28947085, PMID: 25544989) and segregated with disease in 6 affected relatives from 2 families (PMID: 16546111, PMID: 25544989), but has been identified in 0.01% (4/30616) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs61751383). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. Of the six unrelated affected individuals previously reported (PMID: 25312043, PMID: 30718709, PMID: 16546111, PMID: 28947085, PMID: 25544989), two were homozygotes (PMID: 30718709, PMID: 16546111), two were compound heterozygotes who carried pathogenic or likely pathogenic variants in trans (PMID: 25544989, ClinVar Variation ID: 99114; PMID: 28947085, ClinVar Variation ID: 236128), and two were compound heterozygotes who carried pathogenic variants with unknown phase (PMID: 25312043, ClinVar Variation ID: 99108, 30218), which increases the likelihood that the p.Arg2030Ter variant is pathogenic. This variant has also been reported in ClinVar (Variation ID: 7907) and has been interpreted as pathogenic or likely pathogenic by multiple submitters. This nonsense variant leads to a premature termination codon at position 2030, which is predicted to lead to a truncated or absent protein. Loss of function of the ABCA4 gene is an established disease mechanism in autosomal recessive ABCA4-related retinopathy. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive ABCA4-related retinopathy. ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PM3_VeryStrong, PP1_Strong (Richards 2015).
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25544989, 26551331, 9973280, 28947085, 29186038, 25525159, 33090715, 35119454, 32619608, 29641573, 23755871, 22589445, 34758253, 30093795, 26780318, 33691693, 33301772, 26247787, 29925512)
Comment:
Clinical significance based on ACMG v2.0
Comment:
This sequence change creates a premature translational stop signal (p.Arg2030*) in the ABCA4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ABCA4 are known to be pathogenic (PMID: 10958761, 24938718, 25312043, 26780318). This variant is present in population databases (rs61751383, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with ABCA4-related retinal diseases (PMID: 25544989, 28947085). ClinVar contains an entry for this variant (Variation ID: 7907). For these reasons, this variant has been classified as Pathogenic.
Comment:
The stop gained variant c.6088C>T(p.Arg2030Ter) in ABCA4 gene has been observed in homozygous or compound heterozygous state in multiple individual(s) with ABCA4-related retinal diseases (Tanaka et. al., 2018; González-del Pozo et. al., 2014, Singh HP, et al., 2006). The (p.Arg2030Ter) variant is reported with 0.003% allele frequency in gnomAD Exomes. This variant has been reported to the ClinVar database as Likely Pathogenic / Pathogenic (multiple submitters). The nucleotide change c.6088C>T in ABCA4 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Loss-of-function variants in ABCA4 are known to be pathogenic (Jiang et. al., 2016). This variant is predicted to cause loss of normal protein function through protein truncation. For these reasons, this variant has been classified as Pathogenic.
Comment:
The ABCA4 c.6088C>T variant is predicted to result in premature protein termination (p.Arg2030*). This variant has been reported many times in individuals with Stargardt disease (see for examples Lewis et al. 1999. PubMed ID: 9973280; Pozo et al. 2014. PubMed ID: 25544989; Table S4 in Jiang et al. 2016. PubMed ID: 26780318; Table S2 in Del Pozo-Valero et al. 2022. PubMed ID: 35119454). This variant is reported in 0.013% of alleles in individuals of South Asian descent in gnomAD. Nonsense variants in ABCA4 are expected to be pathogenic. Given the evidence, we interpret c.6088C>T (p.Arg2030*) as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| The first genetic landscape of inherited retinal dystrophies in Portuguese patients identifies recurrent homozygous mutations as a frequent cause of pathogenesis. | Peter VG | PNAS nexus | 2023 | PMID: 36909829 |
| 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 |
| The Rapid-Onset Chorioretinopathy Phenotype of ABCA4 Disease. | Tanaka K | Ophthalmology | 2018 | PMID: 28947085 |
| Screening of ABCA4 Gene in a Chinese Cohort With Stargardt Disease or Cone-Rod Dystrophy With a Report on 85 Novel Mutations. | Jiang F | Investigative ophthalmology & visual science | 2016 | PMID: 26780318 |
| Clinical and molecular characteristics of childhood-onset Stargardt disease. | Fujinami K | Ophthalmology | 2015 | PMID: 25312043 |
| Exome sequencing reveals novel and recurrent mutations with clinical significance in inherited retinal dystrophies. | González-del Pozo M | PloS one | 2014 | PMID: 25544989 |
| Mutations of 60 known causative genes in 157 families with retinitis pigmentosa based on exome sequencing. | Xu Y | Human genetics | 2014 | PMID: 24938718 |
| Homozygous null mutations in the ABCA4 gene in two families with autosomal recessive retinal dystrophy. | Singh HP | American journal of ophthalmology | 2006 | PMID: 16546111 |
| Mutations in the ABCA4 (ABCR) gene are the major cause of autosomal recessive cone-rod dystrophy. | Maugeri A | American journal of human genetics | 2000 | PMID: 10958761 |
| 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 rs61751383 ...
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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.