The W1408R pathogenic variant in the ABCA4 gene has been reported previously in autosomal recessive Stargardt disease in affected individuals when in trans with another pathogenic variant (Lewis et al., 1999). The W1408R variant has been reported on the same allele (in cis) with the R1640W variant in families with Stargardt disease, and in a family presenting with both Stargardt disease and retinitis pigmentosa, when in trans with another pathogenic variant (Valverde et al, 2006; Shroyer et al, 2001). Shroyer et al. (2001) showed very little protein from cells transfected with the W1408R and R1640W variants in cis; however, proteins bearing only the W1408R or the R1640W variants appear to have mild or moderate defects in expression or stability. Sun et al. (2000) showed the W1408R variant had reduced basal ATPase activity compared to wild-type. The W1408R variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The W1408R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. We interpret W1408R as a pathogenic variant.
ClinVar Genomic variation as it relates to human health
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- Interpretation:
-
Pathogenic, other
- Review status:
- criteria provided, multiple submitters, no conflicts
- Submissions:
- 8 (Most recent: Apr 26, 2021)
- Last evaluated:
- Apr 8, 2021
- Accession:
- VCV000099260.6
- Variation ID:
- 99260
- Description:
- single nucleotide variant
Help
NM_000350.3(ABCA4):c.4222T>C (p.Trp1408Arg)
- Allele ID
- 105149
- Variant type
- single nucleotide variant
- Variant length
- 1 bp
- Cytogenetic location
- 1p22.1
- Genomic location
- 1: 94031027 (GRCh38) GRCh38 UCSC
- 1: 94496583 (GRCh37) GRCh37 UCSC
- HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNC_000001.10:g.94496583A>G NC_000001.11:g.94031027A>G NG_009073.1:g.95123T>C NM_000350.3:c.4222T>C MANE Select NP_000341.2:p.Trp1408Arg missense P78363:p.Trp1408Arg - Protein change
- W1408R
- Other names
- -
- Canonical SPDI
- NC_000001.11:94031026:A:G
- Functional consequence
- -
- Global minor allele frequency (GMAF)
- -
- Allele frequency
- The Genome Aggregation Database (gnomAD), exomes 0.00002
- Exome Aggregation Consortium (ExAC) 0.00001
- Links
- ClinGen: CA227166
- UniProtKB: P78363#VAR_008446
- dbSNP: rs61750135
- Varsome
Help
Aggregate interpretations per condition
| Interpreted condition | Interpretation | Number of submissions | Review status | Last evaluated | Variation/condition record |
|---|---|---|---|---|---|
| Pathogenic, other | 4 | criteria provided, multiple submitters, no conflicts | Jun 24, 2020 | RCV000085613.5 | |
| Pathogenic | 2 | criteria provided, multiple submitters, no conflicts | Apr 8, 2021 | RCV000408501.2 | |
| Pathogenic | 2 | criteria provided, single submitter | Jun 16, 2019 | RCV000210333.2 |
Submitted interpretations and evidence
Help| Interpretation (Last evaluated) |
Review status (Assertion criteria) |
Condition (Inheritance) |
Submitter | Supporting information
(See all) |
|---|---|---|---|---|
|
Pathogenic
(Jan 01, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Stargardt disease 1
Allele origin:
germline
|
Institute of Human Genetics, Univ. Regensburg,Univ. Regensburg
Accession: SCV000281881.2
Submitted: (May 25, 2016) |
|
|
other
(Aug 31, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Allele origin:
germline
|
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics
Accession: SCV000339313.4
Submitted: (Sep 19, 2018) |
|
|
Pathogenic
(Oct 04, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Allele origin:
germline
|
GeneDx
Accession: SCV000321350.6
Submitted: (Jan 29, 2019) |
Comment:
The W1408R pathogenic variant in the ABCA4 gene has been reported previously in autosomal recessive Stargardt disease in affected individuals when in trans with another … (more)
The W1408R pathogenic variant in the ABCA4 gene has been reported previously in autosomal recessive Stargardt disease in affected individuals when in trans with another pathogenic variant (Lewis et al., 1999). The W1408R variant has been reported on the same allele (in cis) with the R1640W variant in families with Stargardt disease, and in a family presenting with both Stargardt disease and retinitis pigmentosa, when in trans with another pathogenic variant (Valverde et al, 2006; Shroyer et al, 2001). Shroyer et al. (2001) showed very little protein from cells transfected with the W1408R and R1640W variants in cis; however, proteins bearing only the W1408R or the R1640W variants appear to have mild or moderate defects in expression or stability. Sun et al. (2000) showed the W1408R variant had reduced basal ATPase activity compared to wild-type. The W1408R variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The W1408R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. We interpret W1408R as a pathogenic variant. (less)
|
|
Pathogenic
(Jun 16, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Retinal dystrophy
Allele origin:
germline
|
Blueprint Genetics
Accession: SCV001239107.1
Submitted: (Oct 15, 2019)
Comment:
My Retina Tracker patient
|
|
|
Pathogenic
(Jun 24, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Allele origin:
germline
|
Invitae
Accession: SCV001230608.2
Submitted: (Jan 07, 2021) |
Comment:
This sequence change replaces tryptophan with arginine at codon 1408 of the ABCA4 protein (p.Trp1408Arg). The tryptophan residue is highly conserved and there is a … (more)
This sequence change replaces tryptophan with arginine at codon 1408 of the ABCA4 protein (p.Trp1408Arg). The tryptophan residue is highly conserved and there is a moderate physicochemical difference between tryptophan and arginine. This variant is present in population databases (rs61750135, ExAC 0.002%). This variant has been observed in individual(s) with ABCA4-related conditions. While this variant is commonly found in cis with the variant p.Arg1640Trp, it has also been observed without p.Arg1640Trp in affected individuals (PMID: 9973280, 29925512). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from p.Arg1640Trp (PMID: 28559085). ClinVar contains an entry for this variant (Variation ID: 99260). This variant has been reported to affect ABCA4 protein function (PMID: 11687513, 11017087). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
Pathogenic
(Apr 08, 2021)
|
criteria provided, single submitter
Method: research
|
Stargardt disease 1
Allele origin:
germline
|
Ocular Genomics Institute, Massachusetts Eye and Ear
Accession: SCV001573565.1
Submitted: (Apr 26, 2021) |
Comment:
The ABCA4 c.4222T>C 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.4222T>C 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: PM2, PP3, PS3, PM1, PM3-S. Based on this evidence we have classified this variant as Pathogenic. (less)
|
|
Pathogenic
(Jan 30, 2015)
|
no assertion criteria provided
Method: clinical testing
|
Retinal dystrophy
Allele origin:
germline
|
Centre for Genomic Medicine, Manchester,Central Manchester University Hospitals
Accession: SCV000259104.1
Submitted: (Jan 21, 2016) |
|
|
not provided
(-)
|
no assertion provided
Method: not provided
|
not provided
Allele origin:
not provided
|
Retina International
Accession: SCV000117752.1
Submitted: (Dec 20, 2012)
Comment:
http://phencode.bx.psu.edu/cgi-bin/phencode/phencode?build=hg19&id=RISN_ABCR:c.4222T>C
|
Functional evidence
Help| 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 this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Detailed genetic characteristics of an international large cohort of patients with Stargardt disease: ProgStar study report 8. | Fujinami K | The British journal of ophthalmology | 2019 | PMID: 29925512 |
| Clinically Focused Molecular Investigation of 1000 Consecutive Families with Inherited Retinal Disease. | Stone EM | Ophthalmology | 2017 | PMID: 28559085 |
| 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 |
| Whole Genome Sequencing Increases Molecular Diagnostic Yield Compared with Current Diagnostic Testing for Inherited Retinal Disease. | Ellingford JM | Ophthalmology | 2016 | PMID: 26872967 |
| Molecular diagnostic testing by eyeGENE: analysis of patients with hereditary retinal dystrophy phenotypes involving central vision loss. | Alapati A | Investigative ophthalmology & visual science | 2014 | PMID: 25082885 |
| Null missense ABCR (ABCA4) mutations in a family with stargardt disease and retinitis pigmentosa. | Shroyer NF | Investigative ophthalmology & visual science | 2001 | PMID: 11687513 |
| Biochemical defects in ABCR protein variants associated with human retinopathies. | Sun H | Nature genetics | 2000 | PMID: 11017087 |
| 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 | - | - | - | - |
Text-mined citations for rs61750135...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Sep 07, 2021