Variant summary: RLBP1 c.452G>A (p.Arg151Gln) results in a conservative amino acid change located in the CRAL-TRIO lipid binding domain (IPR001251) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251492 control chromosomes. c.452G>A has been reported in the literature as a homozygous genotype in multiple individuals from consanguineous families affected with Retinitis Pigmentosa and Fundus albipunctatus (FA)/retinitis punctata albescens (RPA) (Maw_1997, Katsanis_2001, Abu-Safieh_2013, Zeitz_2015, Patel_2015). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a loss of ability to bind 11-cis-retinaldehyde. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000326.5(RLBP1):c.452G>A (p.Arg151Gln)
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.
(6)
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
6
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000326.5(RLBP1):c.452G>A (p.Arg151Gln)
Variation ID: 13097 Accession: VCV000013097.7
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 15q26.1 15: 89215133 (GRCh38) [ NCBI UCSC ] 15: 89758364 (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 Apr 4, 2013 Feb 14, 2024 Jan 20, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000326.5:c.452G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000317.1:p.Arg151Gln missense NM_000326.4:c.452G>A NC_000015.10:g.89215133C>T NC_000015.9:g.89758364C>T NG_008116.1:g.11559G>A P12271:p.Arg151Gln - Protein change
- R151Q
- Other names
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R150Q
- Canonical SPDI
- NC_000015.10:89215132:C:T
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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
- 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. |
|||
| RLBP1 | - | - |
GRCh38 GRCh37 |
387 | 428 | |
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. |
|---|---|---|---|---|
| Likely pathogenic (2) |
criteria provided, single submitter
|
Feb 23, 2023 | RCV000013973.25 | |
| Pathogenic (1) |
no assertion criteria provided
|
Jun 1, 2001 | RCV000013974.24 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Sep 13, 2021 | RCV001731283.1 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jan 20, 2024 | RCV001857347.4 | |
| Pathogenic (1) |
no assertion criteria provided
|
Dec 20, 2001 | RCV001257814.1 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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. |
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|---|---|---|---|---|---|
|
Pathogenic
(Sep 13, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Retinitis pigmentosa
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001983454.1
First in ClinVar: Oct 30, 2021 Last updated: Oct 30, 2021 |
Comment:
Variant summary: RLBP1 c.452G>A (p.Arg151Gln) results in a conservative amino acid change located in the CRAL-TRIO lipid binding domain (IPR001251) of the encoded protein sequence. … (more)
Variant summary: RLBP1 c.452G>A (p.Arg151Gln) results in a conservative amino acid change located in the CRAL-TRIO lipid binding domain (IPR001251) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251492 control chromosomes. c.452G>A has been reported in the literature as a homozygous genotype in multiple individuals from consanguineous families affected with Retinitis Pigmentosa and Fundus albipunctatus (FA)/retinitis punctata albescens (RPA) (Maw_1997, Katsanis_2001, Abu-Safieh_2013, Zeitz_2015, Patel_2015). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a loss of ability to bind 11-cis-retinaldehyde. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Likely pathogenic
(Feb 23, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Pigmentary retinal dystrophy
Affected status: yes
Allele origin:
unknown
|
3billion
Accession: SCV003841786.1
First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023 |
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). 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: <0.001%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.76; 3Cnet: 0.61). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013097). A different missense change at the same codon (p.Arg151Trp) has been reported to be associated with RLBP1 related disorder (PMID: 14718298). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Rod-cone dystrophy (present)
|
|
|
Pathogenic
(Jan 20, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002242085.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 151 of the RLBP1 protein (p.Arg151Gln). … (more)
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 151 of the RLBP1 protein (p.Arg151Gln). This variant is present in population databases (rs137853290, gnomAD 0.002%). This missense change has been observed in individuals with RLBP1-related conditions (PMID: 9326942, 11453974). It has also been observed to segregate with disease in related individuals. This variant is also known as R150Q. ClinVar contains an entry for this variant (Variation ID: 13097). 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 not expected to disrupt RLBP1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects RLBP1 function (PMID: 9326942). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
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Pathogenic
(Dec 20, 2001)
|
no assertion criteria provided
Method: literature only
|
Autosomal recessive Retinitis Pigmentosa
Affected status: yes
Allele origin:
germline
|
Faculty of Health Sciences, Beirut Arab University
Accession: SCV001434598.1
First in ClinVar: Oct 03, 2020 Last updated: Oct 03, 2020 |
Observation 1:
Number of individuals with the variant: 7
Ethnicity/Population group: Arab
Observation 2:
Number of individuals with the variant: 1
Ethnicity/Population group: Arab
Observation 3:
Number of individuals with the variant: 1
Ethnicity/Population group: Arab
|
|
|
Pathogenic
(Jun 01, 2001)
|
no assertion criteria provided
Method: literature only
|
RETINITIS PUNCTATA ALBESCENS
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000034221.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In a consanguineous sibship with 5 individuals affected with a nonsyndromic retinal dystrophy identified as retinitis pigmentosa, Maw et al. (1997) found homozygosity by descent … (more)
In a consanguineous sibship with 5 individuals affected with a nonsyndromic retinal dystrophy identified as retinitis pigmentosa, Maw et al. (1997) found homozygosity by descent for a 4763G-A nucleotide substitution in the RLBP1 gene. The substitution was predicted to cause an arg150-to-gln (R150Q) amino acid substitution. In this Indian family the parents were first cousins. Three affected sibs living at the same time of the study had onset of night blindness at 3 and 4 years of age, with progression to legal blindness by their late twenties. Fundus examination showed optic disc atrophy, narrowing of the vessels, macular degeneration, and small white dots scattered over the entire fundus; bony spicule pigmentation was not present. Katsanis et al. (2001) studied 4 consanguineous kindreds diagnosed with fundus albipunctatus (136880) from Saudi Arabia. Given the substantial phenotypic variation and overlap between different flecked retinal dystrophies, they evaluated all known genes associated with such conditions by both genetic analysis and direct sequencing. In 1 kindred, they identified a homozygous R150Q alteration in RLBP1. Examination of several patients aged 3 to 20 years over a 9-year period presented no evidence of either retinitis pigmentosa or retinitis punctata albescens (RPA). In contrast, clinical examination of individuals with the same mutation in their fourth and fifth decade revealed signs consistent with RPA. The data suggested that the R150Q mutation in RLBP1 may result in RPA with slow progression. More importantly, younger individuals diagnosed with the milder disorder fundus albipunctatus thought to be stationary may evolve to a more devastating and progressive phenotype. Katsanis et al. (2001) remarked that the phenotype described by Maw et al. (1997) suggested either fundus albipunctatus or RPA, with 'white dots scattered over the whole fundus.' The older patients reported by Katsanis et al. (2001) had a clinical picture consistent with the patients described by Maw et al. (1997). (less)
|
|
|
Pathogenic
(Jun 01, 2001)
|
no assertion criteria provided
Method: literature only
|
FUNDUS ALBIPUNCTATUS
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000034220.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In a consanguineous sibship with 5 individuals affected with a nonsyndromic retinal dystrophy identified as retinitis pigmentosa, Maw et al. (1997) found homozygosity by descent … (more)
In a consanguineous sibship with 5 individuals affected with a nonsyndromic retinal dystrophy identified as retinitis pigmentosa, Maw et al. (1997) found homozygosity by descent for a 4763G-A nucleotide substitution in the RLBP1 gene. The substitution was predicted to cause an arg150-to-gln (R150Q) amino acid substitution. In this Indian family the parents were first cousins. Three affected sibs living at the same time of the study had onset of night blindness at 3 and 4 years of age, with progression to legal blindness by their late twenties. Fundus examination showed optic disc atrophy, narrowing of the vessels, macular degeneration, and small white dots scattered over the entire fundus; bony spicule pigmentation was not present. Katsanis et al. (2001) studied 4 consanguineous kindreds diagnosed with fundus albipunctatus (136880) from Saudi Arabia. Given the substantial phenotypic variation and overlap between different flecked retinal dystrophies, they evaluated all known genes associated with such conditions by both genetic analysis and direct sequencing. In 1 kindred, they identified a homozygous R150Q alteration in RLBP1. Examination of several patients aged 3 to 20 years over a 9-year period presented no evidence of either retinitis pigmentosa or retinitis punctata albescens (RPA). In contrast, clinical examination of individuals with the same mutation in their fourth and fifth decade revealed signs consistent with RPA. The data suggested that the R150Q mutation in RLBP1 may result in RPA with slow progression. More importantly, younger individuals diagnosed with the milder disorder fundus albipunctatus thought to be stationary may evolve to a more devastating and progressive phenotype. Katsanis et al. (2001) remarked that the phenotype described by Maw et al. (1997) suggested either fundus albipunctatus or RPA, with 'white dots scattered over the whole fundus.' The older patients reported by Katsanis et al. (2001) had a clinical picture consistent with the patients described by Maw et al. (1997). (less)
|
Comment:
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.76; 3Cnet: 0.61). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013097). A different missense change at the same codon (p.Arg151Trp) has been reported to be associated with RLBP1 related disorder (PMID: 14718298). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 151 of the RLBP1 protein (p.Arg151Gln). This variant is present in population databases (rs137853290, gnomAD 0.002%). This missense change has been observed in individuals with RLBP1-related conditions (PMID: 9326942, 11453974). It has also been observed to segregate with disease in related individuals. This variant is also known as R150Q. ClinVar contains an entry for this variant (Variation ID: 13097). 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 not expected to disrupt RLBP1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects RLBP1 function (PMID: 9326942). For these reasons, this variant has been classified 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:
Variant summary: RLBP1 c.452G>A (p.Arg151Gln) results in a conservative amino acid change located in the CRAL-TRIO lipid binding domain (IPR001251) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251492 control chromosomes. c.452G>A has been reported in the literature as a homozygous genotype in multiple individuals from consanguineous families affected with Retinitis Pigmentosa and Fundus albipunctatus (FA)/retinitis punctata albescens (RPA) (Maw_1997, Katsanis_2001, Abu-Safieh_2013, Zeitz_2015, Patel_2015). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a loss of ability to bind 11-cis-retinaldehyde. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.76; 3Cnet: 0.61). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013097). A different missense change at the same codon (p.Arg151Trp) has been reported to be associated with RLBP1 related disorder (PMID: 14718298). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 151 of the RLBP1 protein (p.Arg151Gln). This variant is present in population databases (rs137853290, gnomAD 0.002%). This missense change has been observed in individuals with RLBP1-related conditions (PMID: 9326942, 11453974). It has also been observed to segregate with disease in related individuals. This variant is also known as R150Q. ClinVar contains an entry for this variant (Variation ID: 13097). 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 not expected to disrupt RLBP1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects RLBP1 function (PMID: 9326942). For these reasons, this variant has been classified as Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| The genetics of rod-cone dystrophy in Arab countries: a systematic review. | Jaffal L | European journal of human genetics : EJHG | 2021 | PMID: 33188265 |
| Expanding the clinical, allelic, and locus heterogeneity of retinal dystrophies. | Patel N | Genetics in medicine : official journal of the American College of Medical Genetics | 2016 | PMID: 26355662 |
| Congenital stationary night blindness: an analysis and update of genotype-phenotype correlations and pathogenic mechanisms. | Zeitz C | Progress in retinal and eye research | 2015 | PMID: 25307992 |
| Autozygome-guided exome sequencing in retinal dystrophy patients reveals pathogenetic mutations and novel candidate disease genes. | Abu-Safieh L | Genome research | 2013 | PMID: 23105016 |
| Novel mutations in the cellular retinaldehyde-binding protein gene (RLBP1) associated with retinitis punctata albescens: evidence of interfamilial genetic heterogeneity and fundus changes in heterozygotes. | Fishman GA | Archives of ophthalmology (Chicago, Ill. : 1960) | 2004 | PMID: 14718298 |
| Fundus albipunctatus and retinitis punctata albescens in a pedigree with an R150Q mutation in RLBP1. | Katsanis N | Clinical genetics | 2001 | PMID: 11453974 |
| Mutation of the gene encoding cellular retinaldehyde-binding protein in autosomal recessive retinitis pigmentosa. | Maw MA | Nature genetics | 1997 | PMID: 9326942 |
Text-mined citations for rs137853290 ...
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 29, 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.