ClinVar Genomic variation as it relates to human health
NM_000326.5(RLBP1):c.141+2T>C
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.141+2T>C
Variation ID: 503712 Accession: VCV000503712.18
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 15q26.1 15: 89218563 (GRCh38) [ NCBI UCSC ] 15: 89761794 (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 Feb 14, 2024 Nov 27, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000326.5:c.141+2T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice donor NC_000015.10:g.89218563A>G NC_000015.9:g.89761794A>G NG_008116.1:g.8129T>C - Protein change
- Other names
- IVS3, T-C, +2
- Canonical SPDI
- NC_000015.10:89218562:A:G
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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) 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
- Comment on variant
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/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Nov 27, 2023 | RCV000598659.17 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 23, 2018 | RCV000779175.12 | |
Pathogenic (1) |
no assertion criteria provided
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Apr 1, 2002 | RCV001800829.9 |
Submissions - Germline
Classification
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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
(Oct 23, 2018)
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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: SCV000915696.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
The RLBP1 c.141+2T>C variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. The c.141+2T>C … (more)
The RLBP1 c.141+2T>C variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. The c.141+2T>C variant, also known as IVS+2T>C, has been reported in two studies and is found in a total of nine probands from four families, including one in a homozygous state and eight in a compound heterozygous state (Morimura et al. 1999; Eichers et al. 2002). Eight of these probands had Newfoundland rod-cone dystrophy, and one compound heterozygote had retinitis punctata albescens. The variant is also found in a heterozygous state in eight unaffected family members of these probands (Morimura et al. 1999; Eichers et al. 2002). There is segregation data in a three-generation family with Newfoundland rod-cone dystrophy showing that the affected family members are either homozygous or compound heterozygous for the variant (Eichers et al. 2002). The c.141+2T>C variant was absent from 106 control chromosomes (Morimura et al. 1999; Eichers et al. 2002) and is reported at a frequency of 0.000018 in the European (non-Finnish) population of the Genome Aggregation Database but this is based on two alleles in a region of good sequence coverage so the variant is presumed to be rare. Due to the potential impact of splice donor variants and the evidence in the literature, the c.141+2T>C 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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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: SCV001473246.1
First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021 |
Comment:
The RLBP1 c.141+2T>C variant (rs760650165), also published as IVS3+2T>C, is reported in the medical literature in both the homozygous and compound heterozygous state in individuals … (more)
The RLBP1 c.141+2T>C variant (rs760650165), also published as IVS3+2T>C, is reported in the medical literature in both the homozygous and compound heterozygous state in individuals with retinal dystrophy (Eichers 2002, Morimura 1999). The variant is reported in the ClinVar database (Variation ID: 503712) and is only found in 2 out of 251,384 alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant disrupts the canonical splice donor site, which is likely to negatively impact gene function. Considering available information, this variant is classified as pathogenic. References: Eichers ER et al. Newfoundland rod-cone dystrophy, an early-onset retinal dystrophy, is caused by splice-junction mutations in RLBP1. Am J Hum Genet. 2002 Apr;70(4):955-64. 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. (less)
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Likely pathogenic
(Sep 17, 2019)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000709978.2
First in ClinVar: Apr 02, 2018 Last updated: Apr 02, 2018 |
Comment:
Canonical splice site variant predicted to result in an in-frame deletion of a critical region; Not observed at a significant frequency in large population cohorts … (more)
Canonical splice site variant predicted to result in an in-frame deletion of a critical region; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 11868161, 10102299, 25525159) (less)
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Pathogenic
(Nov 27, 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: SCV003441695.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This sequence change affects a donor splice site in intron 4 of the RLBP1 gene. It is expected to disrupt RNA splicing. Variants that disrupt … (more)
This sequence change affects a donor splice site in intron 4 of the RLBP1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in RLBP1 are known to be pathogenic (PMID: 2392416, 11301032, 21447491, 25429852). This variant is present in population databases (rs760650165, gnomAD 0.002%). Disruption of this splice site has been observed in individual(s) with retinitis punctata albescens (PMID: 10102299, 11868161). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as IVS3+2 (GT to GC). ClinVar contains an entry for this variant (Variation ID: 503712). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Apr 01, 2002)
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no assertion criteria provided
Method: literature only
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NEWFOUNDLAND ROD-CONE DYSTROPHY
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000034222.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In cases of Newfoundland rod-cone dystrophy (607476), Eichers et al. (2002) found homozygosity for an IVS3+2T-C splice mutation in the RLBP1 gene, or compound heterozygosity … (more)
In cases of Newfoundland rod-cone dystrophy (607476), Eichers et al. (2002) found homozygosity for an IVS3+2T-C splice mutation in the RLBP1 gene, or compound heterozygosity of this splice site mutation with 324G-A (180090.0003). (less)
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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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Phenotype variations of retinal dystrophies caused by mutations in the RLBP1 gene. | Hipp S | Acta ophthalmologica | 2015 | PMID: 25429852 |
Mutations in RLBP1 associated with fundus albipunctatus in consanguineous Pakistani families. | Naz S | The British journal of ophthalmology | 2011 | PMID: 21447491 |
Splicing in action: assessing disease causing sequence changes. | Baralle D | Journal of medical genetics | 2005 | PMID: 16199547 |
Newfoundland rod-cone dystrophy, an early-onset retinal dystrophy, is caused by splice-junction mutations in RLBP1. | Eichers ER | American journal of human genetics | 2002 | PMID: 11868161 |
Visual cycle impairment in cellular retinaldehyde binding protein (CRALBP) knockout mice results in delayed dark adaptation. | Saari JC | Neuron | 2001 | PMID: 11301032 |
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 |
Non-steroidal anti-inflammatories. | Hynes D | The Practitioner | 1990 | PMID: 2392416 |
Text-mined citations for rs760650165 ...
HelpRecord last updated May 27, 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.
NCBI staff provided an HGVS expression for this allele based on the sequence and exon numbering system in Figure 4 of the paper by Eichers et al., 2002 (PubMed 11868161).