The ABCA4 c.1804C>T variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PM1, PM2, PS3, PM3, PP3. Based on this evidence we have classified this variant as Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000350.3(ABCA4):c.1804C>T (p.Arg602Trp)
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.
(22)
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
22
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.1804C>T (p.Arg602Trp)
Variation ID: 99084 Accession: VCV000099084.33
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 1p22.1 1: 94062710 (GRCh38) [ NCBI UCSC ] 1: 94528266 (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 30, 2024 Jan 29, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000350.3:c.1804C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000341.2:p.Arg602Trp missense NM_001425324.1:c.1804C>T NP_001412253.1:p.Arg602Trp missense NC_000001.11:g.94062710G>A NC_000001.10:g.94528266G>A NG_009073.1:g.63440C>T NG_009073.2:g.63438C>T P78363:p.Arg602Trp - Protein change
- R602W
- Other names
-
NP_000341.2:p.(Arg602Trp)
- Canonical SPDI
- NC_000001.11:94062709: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) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00003
The Genome Aggregation Database (gnomAD), exomes 0.00004
Exome Aggregation Consortium (ExAC) 0.00005
- 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 (6) |
criteria provided, multiple submitters, no conflicts
|
Jan 29, 2024 | RCV000085428.20 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Mar 30, 2023 | RCV000408597.6 | |
| Pathogenic (2) |
criteria provided, single submitter
|
Aug 16, 2019 | RCV000504951.3 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Oct 12, 2018 | RCV000850520.1 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Jan 30, 2021 | RCV001353025.1 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
May 22, 2022 | RCV002250560.2 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Apr 1, 2021 | RCV001723664.3 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jul 24, 2023 | RCV003324506.2 | |
| Pathogenic (2) |
criteria provided, single submitter
|
Mar 5, 2022 | RCV001849310.5 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Mar 22, 2022 | RCV002498452.2 | |
| Pathogenic (1) |
no assertion criteria provided
|
- | RCV004558305.1 | |
| click to load more click to collapse | ||||
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
(Jan 01, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Severe early-childhood-onset retinal dystrophy
Affected status: yes
Allele origin:
germline
|
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg
Accession: SCV000281831.2
First in ClinVar: Dec 07, 2016 Last updated: Dec 07, 2016 |
Indication for testing: Stargardt disease 1
|
|
|
Pathogenic
(Oct 12, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Cone-rod dystrophy 3
Retinitis pigmentosa 19 Severe early-childhood-onset retinal dystrophy
Affected status: yes
Allele origin:
germline
|
Baylor Genetics
Accession: SCV000992724.1
First in ClinVar: Sep 21, 2019 Last updated: Sep 21, 2019 |
|
|
|
Pathogenic
(Aug 16, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Retinal dystrophy
Affected status: yes
Allele origin:
germline
|
Blueprint Genetics
Accession: SCV001240003.1
First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020
Comment:
My Retina Tracker patient
|
|
|
|
Pathogenic
(Apr 08, 2021)
|
criteria provided, single submitter
Method: research
|
Severe early-childhood-onset retinal dystrophy
Affected status: yes
Allele origin:
germline
|
Ocular Genomics Institute, Massachusetts Eye and Ear
Accession: SCV001573247.1
First in ClinVar: May 10, 2021 Last updated: May 10, 2021 |
Comment:
The ABCA4 c.1804C>T variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we … (more)
The ABCA4 c.1804C>T variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PM1, PM2, PS3, PM3, PP3. Based on this evidence we have classified this variant as Pathogenic. (less)
|
|
|
Pathogenic
(Apr 01, 2021)
|
criteria provided, single submitter
Method: curation
|
Retinitis pigmentosa
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV001950194.1
First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
Comment:
The p.Arg602Trp variant in ABCA4 was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics … (more)
The p.Arg602Trp variant in ABCA4 was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PM1, PM2, PS3, PM3, PP3. Based on this evidence we have classified this variant as Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab. (less)
|
|
|
Pathogenic
(Oct 17, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000701678.2
First in ClinVar: Dec 07, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
|
|
|
Pathogenic
(Oct 23, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001447936.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Cone-rod dystrophy (present)
Sex: male
|
|
|
Likely pathogenic
(Jan 30, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Cone-rod dystrophy 3
Affected status: yes
Allele origin:
unknown
|
Institute of Medical Molecular Genetics, University of Zurich
Accession: SCV001548136.1
First in ClinVar: Mar 28, 2021 Last updated: Mar 28, 2021 |
Method: long-range PCR
|
|
|
Pathogenic
(Mar 05, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
ABCA4-related disorder
Affected status: yes
Allele origin:
germline
|
DASA
Accession: SCV002107086.2
First in ClinVar: Mar 28, 2022 Last updated: Apr 02, 2022 |
Comment:
Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 16103129) - PS3.The c.1804C>T;p.(Arg602Trp) missense … (more)
Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 16103129) - PS3.The c.1804C>T;p.(Arg602Trp) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 99084; PMID: 28181551; 28118664; 28041643; 24444108; 23982839; 23755871; 9973280) - PS4. The variant is present at low allele frequencies population databases (rs61749409 – gnomAD 0.0004385%; ABraOM 0.001708 frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Arg602Trp) was detected in trans with a pathogenic variant (PMID: 28181551; PMID: 16103129; PMID: 24444108; PMID: 23982839; PMID: 23755871) - PM3. The variant co-segregated with disease in multiple affected family members (PMID: 16103129) - PP1. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic. (less)
Number of individuals with the variant: 1
Sex: male
Geographic origin: Brazil
|
|
|
Pathogenic
(May 22, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Retinitis pigmentosa 19
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002521184.1
First in ClinVar: Jun 03, 2022 Last updated: Jun 03, 2022 |
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.004%). In silico tool predictions suggest damaging effect … (more)
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.004%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.93; 3Cnet: 0.99). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000099084). The variant has been reported to be in trans with other pathogenic variant(s) as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 16103129). A different missense change at the same codon (p.Arg602Gln) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000099085). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Retinal dystrophy (present)
|
|
|
Pathogenic
(Mar 22, 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: SCV002809677.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
|
Pathogenic
(Nov 18, 2021)
|
criteria provided, single submitter
Method: research
|
Retinitis pigmentosa 19
(Autosomal recessive inheritance)
Affected status: yes, no
Allele origin:
unknown,
germline
|
Pangenia Genomics, Pangenia Inc.
Accession: SCV003925675.1
First in ClinVar: May 27, 2023 Last updated: May 27, 2023 |
Comment:
The ABCA4, c.1804C>T (p.Arg602Trp) variant is at extremely low frequency in population database. In vitro functional studies demonstrated that this variant results in protein mis-folding … (more)
The ABCA4, c.1804C>T (p.Arg602Trp) variant is at extremely low frequency in population database. In vitro functional studies demonstrated that this variant results in protein mis-folding and mis-localization [PMID: 16103129]. This variant has been observed in many individuals with autosomal recessive retinopathy, in homozygosity, or with another variant in ABCA4 gene, including null variants and missense variants [PMID: 16103129, 30093795, 9973280, 23755871, 32619608, 29186038]. This variant has been found to co-segregate with retinitis pigmentosa, Stargardt disease 1 or Cone-rod dystrophy in multiple families (PMID: 16103129, 23755871, 32619608, 29114839). Multiple lines of computational evidence support a deleterious effect on the gene/gene product (REVEL = 0.934). This variant has multiple submissions in ClinVar (Variation ID: 99084). (less)
Observation 1:
Ethnicity/Population group: Asian
Observation 2:
Ethnicity/Population group: Asian
|
|
|
Pathogenic
(Aug 08, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000321339.7
First in ClinVar: Oct 09, 2016 Last updated: Aug 18, 2023 |
Comment:
Published functional studies demonstrate a damaging effect suggestive of protein misfolding (Wiszniewski et al., 2005); In silico analysis supports that this missense variant has a … (more)
Published functional studies demonstrate a damaging effect suggestive of protein misfolding (Wiszniewski et al., 2005); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24444108, 31429209, 33706644, 28118664, 28041643, 28181551, 28947085, 28446513, 29186038, 23755871, 29641573, 29114839, 30093795, 28559085, 28838317, 32036094, 32581362, 32845050, 31216405, 34327195, 33781268, 31589614, 32619608, 33090715, 33301772, 33261146, 35657619, 35119454, 20696155, 25472526, 36338671, 22449572, 23982839, 34906470, 25910913, 9973280, 16103129, 23695285) (less)
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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: SCV004030271.1
First in ClinVar: Sep 03, 2023 Last updated: Sep 03, 2023
Comment:
This variant was classified as Pathogenic based on ACMG criteria: PS4, PM1, PP2, PM2, PM5, PP3, PP5.
|
Comment:
Clinical significance based on ACMG v2.0
Number of individuals with the variant: 1
Sex: female
Geographic origin: Portugal
|
|
|
Pathogenic
(Oct 15, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002019722.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Jan 29, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001223382.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 602 of the ABCA4 protein … (more)
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 602 of the ABCA4 protein (p.Arg602Trp). This variant is present in population databases (rs61749409, gnomAD 0.03%). This missense change has been observed in individuals with Stargardt disease and autosomal recessive retinitis pigmentosa (PMID: 16103129, 23755871). ClinVar contains an entry for this variant (Variation ID: 99084). 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%. Experimental studies have shown that this missense change affects ABCA4 function (PMID: 16103129). This variant disrupts the p.Arg602 amino acid residue in ABCA4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20696155, 22449572, 23982839, 25472526, 25910913). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Mar 30, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Severe early-childhood-onset retinal dystrophy
Affected status: yes
Allele origin:
germline
|
Molecular Genetics, Royal Melbourne Hospital
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002503795.2
First in ClinVar: Apr 28, 2022 Last updated: Apr 15, 2024 |
Comment:
This sequence change is predicted to replace arginine with tryptophan at codon 602 of the ABCA4 protein, p.(Arg602Trp). The arginine residue is moderately conserved (100 … (more)
This sequence change is predicted to replace arginine with tryptophan at codon 602 of the ABCA4 protein, p.(Arg602Trp). The arginine residue is moderately conserved (100 vertebrates, UCSC), and is present in the extracellular domain. There is a moderate physicochemical difference between arginine and tryptophan. The variant is present in a large population cohort 0.004%, which is consistent with recessive disease (rs61749409, 11/250,870 alleles, 0 homozygotes in gnomAD v2.1). It has been reported compound heterozygous with another pathogenic allele and homozygous most commonly in Stargardt disease cases, and also cases of cone-rod dystrophy and retinitis pigmentosa co-segregating with disease (PMID: 9973280, 16103129, 23695285). In vitro functional assays demonstrate that the missense substitution prevents correct localisation of the protein in to the rod outer segment, and perturbs ATPase activity (PMID: 16103129). Additionally, multiple lines of computational evidence predict a deleterious effect for the missense substitution (7/7 algorithms). Based on the classification scheme RMH ACMG Guidelines v1.1.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PM2, PS3_Supporting, PP1, PP3. (less)
|
|
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Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Age related macular degeneration 2
Cone-rod dystrophy 3 Severe early-childhood-onset retinal dystrophy Retinitis pigmentosa 19
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: yes
Allele origin:
germline
|
Juno Genomics, Hangzhou Juno Genomics, Inc
Accession: SCV005415992.1
First in ClinVar: Nov 30, 2024 Last updated: Nov 30, 2024 |
Comment:
PM2_Supporting+PM3_VeryStrong+PP1+PP3_Strong
|
|
|
Likely 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: SCV000598942.1
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
(-)
|
no assertion criteria provided
Method: research
|
Stargardt disease 3
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Ophthalmo-Genetics Lab, Instituto de Oftalmologia Conde de Valenciana
Accession: SCV005046937.1
First in ClinVar: Jun 09, 2024 Last updated: Jun 09, 2024 |
|
|
|
Pathogenic
(Sep 16, 2024)
|
no assertion criteria provided
Method: clinical testing
|
ABCA4-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV005367178.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
The ABCA4 c.1804C>T variant is predicted to result in the amino acid substitution p.Arg602Trp. This variant has been reported in multiple individuals with ABCA4-related retinal … (more)
The ABCA4 c.1804C>T variant is predicted to result in the amino acid substitution p.Arg602Trp. This variant has been reported in multiple individuals with ABCA4-related retinal disease (Lewis et al. 1999. PubMed ID: 9973280; Riveiro-Alvarez et al. 2013. PubMed ID: 23755871; Xin et al. 2015. PubMed ID: 26161775). Of note, this variant has been reported to cause mislocalized protein and results in an early disease onset and severe disease phenotype (Wiszniewski et al. 2005. PubMed ID: 16103129). This variant is reported in 0.027% of alleles in individuals of East Asian descent in gnomAD. This variant is interpreted as pathogenic. (less)
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|
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not provided
(-)
|
no classification provided
Method: not provided
|
not provided
Affected status: not provided
Allele origin:
not provided
|
Retina International
Accession: SCV000117565.1
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.1804C>T
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| click to load more click to collapse | |||||
Comment:
Comment:
The p.Arg602Trp variant in ABCA4 was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PM1, PM2, PS3, PM3, PP3. Based on this evidence we have classified this variant as Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab.
Comment:
Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 16103129) - PS3.The c.1804C>T;p.(Arg602Trp) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 99084; PMID: 28181551; 28118664; 28041643; 24444108; 23982839; 23755871; 9973280) - PS4. The variant is present at low allele frequencies population databases (rs61749409 – gnomAD 0.0004385%; ABraOM 0.001708 frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Arg602Trp) was detected in trans with a pathogenic variant (PMID: 28181551; PMID: 16103129; PMID: 24444108; PMID: 23982839; PMID: 23755871) - PM3. The variant co-segregated with disease in multiple affected family members (PMID: 16103129) - PP1. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic.
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.004%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.93; 3Cnet: 0.99). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000099084). The variant has been reported to be in trans with other pathogenic variant(s) as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 16103129). A different missense change at the same codon (p.Arg602Gln) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000099085). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
The ABCA4, c.1804C>T (p.Arg602Trp) variant is at extremely low frequency in population database. In vitro functional studies demonstrated that this variant results in protein mis-folding and mis-localization [PMID: 16103129]. This variant has been observed in many individuals with autosomal recessive retinopathy, in homozygosity, or with another variant in ABCA4 gene, including null variants and missense variants [PMID: 16103129, 30093795, 9973280, 23755871, 32619608, 29186038]. This variant has been found to co-segregate with retinitis pigmentosa, Stargardt disease 1 or Cone-rod dystrophy in multiple families (PMID: 16103129, 23755871, 32619608, 29114839). Multiple lines of computational evidence support a deleterious effect on the gene/gene product (REVEL = 0.934). This variant has multiple submissions in ClinVar (Variation ID: 99084).
Comment:
Published functional studies demonstrate a damaging effect suggestive of protein misfolding (Wiszniewski et al., 2005); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24444108, 31429209, 33706644, 28118664, 28041643, 28181551, 28947085, 28446513, 29186038, 23755871, 29641573, 29114839, 30093795, 28559085, 28838317, 32036094, 32581362, 32845050, 31216405, 34327195, 33781268, 31589614, 32619608, 33090715, 33301772, 33261146, 35657619, 35119454, 20696155, 25472526, 36338671, 22449572, 23982839, 34906470, 25910913, 9973280, 16103129, 23695285)
Comment:
Clinical significance based on ACMG v2.0
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 602 of the ABCA4 protein (p.Arg602Trp). This variant is present in population databases (rs61749409, gnomAD 0.03%). This missense change has been observed in individuals with Stargardt disease and autosomal recessive retinitis pigmentosa (PMID: 16103129, 23755871). ClinVar contains an entry for this variant (Variation ID: 99084). 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%. Experimental studies have shown that this missense change affects ABCA4 function (PMID: 16103129). This variant disrupts the p.Arg602 amino acid residue in ABCA4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20696155, 22449572, 23982839, 25472526, 25910913). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Comment:
This sequence change is predicted to replace arginine with tryptophan at codon 602 of the ABCA4 protein, p.(Arg602Trp). The arginine residue is moderately conserved (100 vertebrates, UCSC), and is present in the extracellular domain. There is a moderate physicochemical difference between arginine and tryptophan. The variant is present in a large population cohort 0.004%, which is consistent with recessive disease (rs61749409, 11/250,870 alleles, 0 homozygotes in gnomAD v2.1). It has been reported compound heterozygous with another pathogenic allele and homozygous most commonly in Stargardt disease cases, and also cases of cone-rod dystrophy and retinitis pigmentosa co-segregating with disease (PMID: 9973280, 16103129, 23695285). In vitro functional assays demonstrate that the missense substitution prevents correct localisation of the protein in to the rod outer segment, and perturbs ATPase activity (PMID: 16103129). Additionally, multiple lines of computational evidence predict a deleterious effect for the missense substitution (7/7 algorithms). Based on the classification scheme RMH ACMG Guidelines v1.1.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PM2, PS3_Supporting, PP1, PP3.
Comment:
PM2_Supporting+PM3_VeryStrong+PP1+PP3_Strong
Comment:
The ABCA4 c.1804C>T variant is predicted to result in the amino acid substitution p.Arg602Trp. This variant has been reported in multiple individuals with ABCA4-related retinal disease (Lewis et al. 1999. PubMed ID: 9973280; Riveiro-Alvarez et al. 2013. PubMed ID: 23755871; Xin et al. 2015. PubMed ID: 26161775). Of note, this variant has been reported to cause mislocalized protein and results in an early disease onset and severe disease phenotype (Wiszniewski et al. 2005. PubMed ID: 16103129). This variant is reported in 0.027% of alleles in individuals of East Asian descent in gnomAD. This variant is interpreted 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 ABCA4 c.1804C>T variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PM1, PM2, PS3, PM3, PP3. Based on this evidence we have classified this variant as Pathogenic.
Comment:
The p.Arg602Trp variant in ABCA4 was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PM1, PM2, PS3, PM3, PP3. Based on this evidence we have classified this variant as Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab.
Comment:
Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 16103129) - PS3.The c.1804C>T;p.(Arg602Trp) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 99084; PMID: 28181551; 28118664; 28041643; 24444108; 23982839; 23755871; 9973280) - PS4. The variant is present at low allele frequencies population databases (rs61749409 – gnomAD 0.0004385%; ABraOM 0.001708 frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Arg602Trp) was detected in trans with a pathogenic variant (PMID: 28181551; PMID: 16103129; PMID: 24444108; PMID: 23982839; PMID: 23755871) - PM3. The variant co-segregated with disease in multiple affected family members (PMID: 16103129) - PP1. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic.
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.004%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.93; 3Cnet: 0.99). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000099084). The variant has been reported to be in trans with other pathogenic variant(s) as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 16103129). A different missense change at the same codon (p.Arg602Gln) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000099085). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
The ABCA4, c.1804C>T (p.Arg602Trp) variant is at extremely low frequency in population database. In vitro functional studies demonstrated that this variant results in protein mis-folding and mis-localization [PMID: 16103129]. This variant has been observed in many individuals with autosomal recessive retinopathy, in homozygosity, or with another variant in ABCA4 gene, including null variants and missense variants [PMID: 16103129, 30093795, 9973280, 23755871, 32619608, 29186038]. This variant has been found to co-segregate with retinitis pigmentosa, Stargardt disease 1 or Cone-rod dystrophy in multiple families (PMID: 16103129, 23755871, 32619608, 29114839). Multiple lines of computational evidence support a deleterious effect on the gene/gene product (REVEL = 0.934). This variant has multiple submissions in ClinVar (Variation ID: 99084).
Comment:
Published functional studies demonstrate a damaging effect suggestive of protein misfolding (Wiszniewski et al., 2005); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24444108, 31429209, 33706644, 28118664, 28041643, 28181551, 28947085, 28446513, 29186038, 23755871, 29641573, 29114839, 30093795, 28559085, 28838317, 32036094, 32581362, 32845050, 31216405, 34327195, 33781268, 31589614, 32619608, 33090715, 33301772, 33261146, 35657619, 35119454, 20696155, 25472526, 36338671, 22449572, 23982839, 34906470, 25910913, 9973280, 16103129, 23695285)
Comment:
Clinical significance based on ACMG v2.0
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 602 of the ABCA4 protein (p.Arg602Trp). This variant is present in population databases (rs61749409, gnomAD 0.03%). This missense change has been observed in individuals with Stargardt disease and autosomal recessive retinitis pigmentosa (PMID: 16103129, 23755871). ClinVar contains an entry for this variant (Variation ID: 99084). 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%. Experimental studies have shown that this missense change affects ABCA4 function (PMID: 16103129). This variant disrupts the p.Arg602 amino acid residue in ABCA4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20696155, 22449572, 23982839, 25472526, 25910913). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Comment:
This sequence change is predicted to replace arginine with tryptophan at codon 602 of the ABCA4 protein, p.(Arg602Trp). The arginine residue is moderately conserved (100 vertebrates, UCSC), and is present in the extracellular domain. There is a moderate physicochemical difference between arginine and tryptophan. The variant is present in a large population cohort 0.004%, which is consistent with recessive disease (rs61749409, 11/250,870 alleles, 0 homozygotes in gnomAD v2.1). It has been reported compound heterozygous with another pathogenic allele and homozygous most commonly in Stargardt disease cases, and also cases of cone-rod dystrophy and retinitis pigmentosa co-segregating with disease (PMID: 9973280, 16103129, 23695285). In vitro functional assays demonstrate that the missense substitution prevents correct localisation of the protein in to the rod outer segment, and perturbs ATPase activity (PMID: 16103129). Additionally, multiple lines of computational evidence predict a deleterious effect for the missense substitution (7/7 algorithms). Based on the classification scheme RMH ACMG Guidelines v1.1.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PM2, PS3_Supporting, PP1, PP3.
Comment:
PM2_Supporting+PM3_VeryStrong+PP1+PP3_Strong
Comment:
The ABCA4 c.1804C>T variant is predicted to result in the amino acid substitution p.Arg602Trp. This variant has been reported in multiple individuals with ABCA4-related retinal disease (Lewis et al. 1999. PubMed ID: 9973280; Riveiro-Alvarez et al. 2013. PubMed ID: 23755871; Xin et al. 2015. PubMed ID: 26161775). Of note, this variant has been reported to cause mislocalized protein and results in an early disease onset and severe disease phenotype (Wiszniewski et al. 2005. PubMed ID: 16103129). This variant is reported in 0.027% of alleles in individuals of East Asian descent in gnomAD. This variant is interpreted 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 |
| The importance of automation in genetic diagnosis: Lessons from analyzing an inherited retinal degeneration cohort with the Mendelian Analysis Toolkit (MATK). | Zampaglione E | Genetics in medicine : official journal of the American College of Medical Genetics | 2022 | PMID: 34906470 |
| Long-Range PCR-Based NGS Applications to Diagnose Mendelian Retinal Diseases. | Maggi J | International journal of molecular sciences | 2021 | PMID: 33546218 |
| Genotypes Predispose Phenotypes-Clinical Features and Genetic Spectrum of ABCA4-Associated Retinal Dystrophies. | Sung YC | Genes | 2020 | PMID: 33261146 |
| Genotype-Phenotype Correlations in a Spanish Cohort of 506 Families With Biallelic ABCA4 Pathogenic Variants. | Del Pozo-Valero M | American journal of ophthalmology | 2020 | PMID: 32619608 |
| Variants in the ABCA4 gene in a Brazilian population with Stargardt disease. | Salles MV | Molecular vision | 2018 | PMID: 30093795 |
| Molecular Screening of 43 Brazilian Families Diagnosed with Leber Congenital Amaurosis or Early-Onset Severe Retinal Dystrophy. | Porto FBO | Genes | 2017 | PMID: 29186038 |
| Novel Complex ABCA4 Alleles in Brazilian Patients With Stargardt Disease: Genotype-Phenotype Correlation. | Salles MV | Investigative ophthalmology & visual science | 2017 | PMID: 29114839 |
| Whole exome sequencing using Ion Proton system enables reliable genetic diagnosis of inherited retinal dystrophies. | Riera M | Scientific reports | 2017 | PMID: 28181551 |
| 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 |
| Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease. | Carss KJ | American journal of human genetics | 2017 | PMID: 28041643 |
| High Diagnostic Yield of Whole Exome Sequencing in Participants With Retinal Dystrophies in a Clinical Ophthalmology Setting. | Lee K | American journal of ophthalmology | 2015 | PMID: 25910913 |
| Next-generation sequencing-based molecular diagnosis of 82 retinitis pigmentosa probands from Northern Ireland. | Zhao L | Human genetics | 2015 | PMID: 25472526 |
| Whole exome sequencing detects homozygosity for ABCA4 p.Arg602Trp missense mutation in a pediatric patient with rapidly progressive retinal dystrophy. | Ortube MC | BMC medical genetics | 2014 | PMID: 24444108 |
| ABCA4 gene screening by next-generation sequencing in a British cohort. | Fujinami K | Investigative ophthalmology & visual science | 2013 | PMID: 23982839 |
| Outcome of ABCA4 disease-associated alleles in autosomal recessive retinal dystrophies: retrospective analysis in 420 Spanish families. | Riveiro-Alvarez R | Ophthalmology | 2013 | PMID: 23755871 |
| Stargardt disease: towards developing a model to predict phenotype. | Heathfield L | European journal of human genetics : EJHG | 2013 | PMID: 23695285 |
| Clinical and genetic characteristics of late-onset Stargardt's disease. | Westeneng-van Haaften SC | Ophthalmology | 2012 | PMID: 22449572 |
| Loss of peripapillary sparing in non-group I Stargardt disease. | Burke TR | Experimental eye research | 2010 | PMID: 20696155 |
| ABCA4 mutations causing mislocalization are found frequently in patients with severe retinal dystrophies. | Wiszniewski W | Human molecular genetics | 2005 | PMID: 16103129 |
| 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 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ABCA4 | - | - | - | - |
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Text-mined citations for rs61749409 ...
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Record last updated Nov 30, 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.