ClinVar Genomic variation as it relates to human health
NM_000326.5(RLBP1):c.700C>T (p.Arg234Trp)
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000326.5(RLBP1):c.700C>T (p.Arg234Trp)
Variation ID: 13100 Accession: VCV000013100.19
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 15q26.1 15: 89210794 (GRCh38) [ NCBI UCSC ] 15: 89754025 (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 Apr 4, 2013 Mar 10, 2024 Oct 1, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000326.5:c.700C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000317.1:p.Arg234Trp missense NC_000015.10:g.89210794G>A NC_000015.9:g.89754025G>A NG_008116.1:g.15898C>T P12271:p.Arg234Trp - Protein change
- R234W
- Other names
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- Canonical SPDI
- NC_000015.10:89210793: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.
Exome Aggregation Consortium (ExAC) 0.00024
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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RLBP1 | - | - |
GRCh38 GRCh37 |
383 | 423 |
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
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
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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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Pathogenic (1) |
no assertion criteria provided
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Jun 1, 2001 | RCV000013978.32 | |
Pathogenic (1) |
no assertion criteria provided
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Jun 1, 2001 | RCV000013979.32 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 28, 2017 | RCV000345884.13 | |
Pathogenic (2) |
criteria provided, single submitter
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Aug 2, 2023 | RCV001003174.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 1, 2023 | RCV003887865.1 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Sep 21, 2023 | RCV001387783.17 |
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
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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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Pathogenic
(Aug 02, 2023)
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criteria provided, single submitter
Method: clinical testing
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Retinitis pigmentosa
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004039157.1
First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023 |
Comment:
Variant summary: RLBP1 c.700C>T (p.Arg234Trp) results in a non-conservative amino acid change to a highly conserved residue (HGMD) located in the CRAL-TRIO lipid binding domain … (more)
Variant summary: RLBP1 c.700C>T (p.Arg234Trp) results in a non-conservative amino acid change to a highly conserved residue (HGMD) located in the CRAL-TRIO lipid binding domain (IPR001251) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.6e-05 in 209368 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in RLBP1 causing Retinitis Pigmentosa (8.6e-05 vs 0.00063), allowing no conclusion about variant significance. c.700C>T has been reported in the literature in multiple individuals affected with Retinitis Pigmentosa or Bothnia dystrophy with strong evidence of cosegregation with disease (Sharon_2019, Burstedt_1999, Kohn_2008), and some were reported as compound heterozygous with another pathogenic variant. These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 31456290, 10102298, 18344446). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Sep 21, 2023)
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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: SCV001588499.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects RLBP1 function (PMID: 19846785). Advanced modeling … (more)
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects RLBP1 function (PMID: 19846785). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RLBP1 protein function. ClinVar contains an entry for this variant (Variation ID: 13100). This missense change has been observed in individuals with Bothnia retinal dystrophy (PMID: 10102298, 22171637). It is commonly reported in individuals of Swedish ancestry (PMID: 10102298). This variant is present in population databases (rs28933990, gnomAD 0.02%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 234 of the RLBP1 protein (p.Arg234Trp). (less)
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Pathogenic
(Apr 28, 2017)
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criteria provided, single submitter
Method: clinical testing
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RLBP1-Related Disorders
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000394105.3
First in ClinVar: Dec 06, 2016 Last updated: May 24, 2019 |
Comment:
Across a selection of the available literature, the RLBP1 c.700C>T (p.Arg234Trp) missense variant has been identified in a homozygous state in 89 patients and in … (more)
Across a selection of the available literature, the RLBP1 c.700C>T (p.Arg234Trp) missense variant has been identified in a homozygous state in 89 patients and in a compound heterozygous state in 11 patients with RLBP1-related disorders (Burstedt et al. 1999; Morimura et al. 1999; Nakamura et al. 2005; Golovleva et al. 2010; Hipp et al. 2015). The p.Arg234Trp variant was reported in six out of 588 control chromosomes and is reported at a frequency of 0.00047 in the European (non-Finnish) population of the Exome Aggregation Consortium. The crystal structure of the variant protein bound to its endogenous ligand, 11-cis-retinal, was compared with the crystal structure of the wild type protein similarly bound to 11-cis-retinal (He et al. 2009; He et al. 2012). The structural analysis revealed an altered retinoid binding pocket in the p.Arg234Trp variant protein, which resulted in a 5-fold tighter binding of the variant protein to 11-cis-retinal, and hence impaired release, compared to wild type (Golovleva et al. 2003). Based on the collective evidence, the p.Arg234Trp variant is classified as pathogenic for RLBP1-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Likely pathogenic
(Sep 04, 2019)
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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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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001473243.1
First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021 |
Comment:
The RLBP1 c.700C>T; p.Arg234Trp (rs28933990) variant is reported in several individuals and families with retinal dystrophy (Burstedt 1999, Granse 2001, Hipp 2015, Morimura 1999, Nakamura … (more)
The RLBP1 c.700C>T; p.Arg234Trp (rs28933990) variant is reported in several individuals and families with retinal dystrophy (Burstedt 1999, Granse 2001, Hipp 2015, Morimura 1999, Nakamura 2005). The variant is reported as pathogenic in ClinVar (Variation ID: 13100) and is reported in the general population with an overall allele frequency of 0.009% (18/209,368 alleles) in the Genome Aggregation Database. The arginine at codon 234 is highly conserved and computational algorithms (PolyPhen-2, SIFT) predict this variant is deleterious. Considering available information, this variant is classified as likely pathogenic. References: Burstedt MS et al. Bothnia dystrophy caused by mutations in the cellular retinaldehyde-binding protein gene (RLBP1) on chromosome 15q26. Invest Ophthalmol Vis Sci. 1999 Apr;40(5):995-1000. Granse L et al. Electrophysiological findings in two young patients with Bothnia dystrophy and a mutation in the RLBP1 gene. Ophthalmic Genet. 2001 Jun;22(2):97-105. Hipp S et al. Phenotype variations of retinal dystrophies caused by mutations in the RLBP1 gene. Acta Ophthalmol. 2015 Jun;93(4):e281-6. Morimura H et al. Recessive mutations in the RLBP1 gene encoding cellular retinaldehyde-binding protein in a form of retinitis punctata albescens. Invest Ophthalmol Vis Sci. 1999 Apr;40(5):1000-4. Nakamura M et al. Novel mutation in RLBP1 gene in a Japanese patient with retinitis punctata albescens. Am J Ophthalmol. 2005 Jun;139(6):1133-5. (less)
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Pathogenic
(Oct 01, 2023)
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criteria provided, single submitter
Method: research
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Retinal dystrophy
Affected status: yes
Allele origin:
germline
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Dept Of Ophthalmology, Nagoya University
Accession: SCV004704923.1
First in ClinVar: Mar 10, 2024 Last updated: Mar 10, 2024 |
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Pathogenic
(Jun 01, 2001)
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no assertion criteria provided
Method: literature only
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BOTHNIA RETINAL DYSTROPHY
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000034225.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
A homozygous missense mutation in exon 7 of the RLBP1 gene, 9096C-T, which causes an arg234-to-trp (R234W) amino acid substitution, was associated with both Bothnia … (more)
A homozygous missense mutation in exon 7 of the RLBP1 gene, 9096C-T, which causes an arg234-to-trp (R234W) amino acid substitution, was associated with both Bothnia retinal dystrophy (607475) (Burstedt et al., 1999, 2001; Granse et al., 2001) and retinitis punctata albescens (136880) (Morimura et al., 1999). (less)
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Pathogenic
(Jun 01, 2001)
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no assertion criteria provided
Method: literature only
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RETINITIS PUNCTATA ALBESCENS
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000034226.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
A homozygous missense mutation in exon 7 of the RLBP1 gene, 9096C-T, which causes an arg234-to-trp (R234W) amino acid substitution, was associated with both Bothnia … (more)
A homozygous missense mutation in exon 7 of the RLBP1 gene, 9096C-T, which causes an arg234-to-trp (R234W) amino acid substitution, was associated with both Bothnia retinal dystrophy (607475) (Burstedt et al., 1999, 2001; Granse et al., 2001) and retinitis punctata albescens (136880) (Morimura et al., 1999). (less)
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Pathogenic
(Jun 23, 2019)
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no assertion criteria provided
Method: research
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Retinitis pigmentosa
Affected status: yes
Allele origin:
inherited
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Sharon lab, Hadassah-Hebrew University Medical Center
Accession: SCV001161250.1
First in ClinVar: Feb 16, 2020 Last updated: Feb 16, 2020 |
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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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A nationwide genetic analysis of inherited retinal diseases in Israel as assessed by the Israeli inherited retinal disease consortium (IIRDC). | Sharon D | Human mutation | 2020 | PMID: 31456290 |
Phenotype variations of retinal dystrophies caused by mutations in the RLBP1 gene. | Hipp S | Acta ophthalmologica | 2015 | PMID: 25429852 |
Molecular clues to Bothnia-type retinal dystrophy. | He X | Advances in experimental medicine and biology | 2012 | PMID: 22183382 |
Clinical features of a Japanese case with Bothnia dystrophy. | Nojima K | Ophthalmic genetics | 2012 | PMID: 22171637 |
Mutation spectra in autosomal dominant and recessive retinitis pigmentosa in northern Sweden. | Golovleva I | Advances in experimental medicine and biology | 2010 | PMID: 20238024 |
Bothnia dystrophy is caused by domino-like rearrangements in cellular retinaldehyde-binding protein mutant R234W. | He X | Proceedings of the National Academy of Sciences of the United States of America | 2009 | PMID: 19846785 |
Carrier of R14W in carbonic anhydrase IV presents Bothnia dystrophy phenotype caused by two allelic mutations in RLBP1. | Köhn L | Investigative ophthalmology & visual science | 2008 | PMID: 18344446 |
Novel mutation in RLBP1 gene in a Japanese patient with retinitis punctata albescens. | Nakamura M | American journal of ophthalmology | 2005 | PMID: 15953459 |
Disease-causing mutations in the cellular retinaldehyde binding protein tighten and abolish ligand interactions. | Golovleva I | The Journal of biological chemistry | 2003 | PMID: 12536144 |
Electrophysiological findings in two young patients with Bothnia dystrophy and a mutation in the RLBP1 gene. | Gränse L | Ophthalmic genetics | 2001 | PMID: 11449319 |
Recessive mutations in the RLBP1 gene encoding cellular retinaldehyde-binding protein in a form of retinitis punctata albescens. | Morimura H | Investigative ophthalmology & visual science | 1999 | PMID: 10102299 |
Bothnia dystrophy caused by mutations in the cellular retinaldehyde-binding protein gene (RLBP1) on chromosome 15q26. | Burstedt MS | Investigative ophthalmology & visual science | 1999 | PMID: 10102298 |
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Text-mined citations for rs28933990 ...
HelpRecord last updated May 19, 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.