ClinVar Genomic variation as it relates to human health
NM_152443.3(RDH12):c.184C>T (p.Arg62Ter)
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_152443.3(RDH12):c.184C>T (p.Arg62Ter)
Variation ID: 2050 Accession: VCV000002050.24
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 14q24.1 14: 67724588 (GRCh38) [ NCBI UCSC ] 14: 68191305 (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 Jul 5, 2015 Feb 14, 2024 Dec 18, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_152443.3(RDH12):c.184C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_152443.3:c.184C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_689656.2:p.Arg62Ter nonsense NC_000014.9:g.67724588C>T NC_000014.8:g.68191305C>T NG_008321.1:g.27703C>T - Protein change
- R62*
- Other names
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- Canonical SPDI
- NC_000014.9:67724587:C:T
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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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0.00020 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00003
The Genome Aggregation Database (gnomAD), exomes 0.00006
The Genome Aggregation Database (gnomAD) 0.00007
Trans-Omics for Precision Medicine (TOPMed) 0.00012
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
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 | ||
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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
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. |
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GPHN | Some evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
742 | 1857 | |
RDH12 | - | - |
GRCh38 GRCh37 |
3 | 611 |
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. |
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Pathogenic (8) |
criteria provided, multiple submitters, no conflicts
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Dec 18, 2023 | RCV000002131.17 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 4, 2018 | RCV001075533.2 | |
Pathogenic (2) |
criteria provided, single submitter
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May 29, 2020 | RCV001254729.3 | |
Pathogenic (3) |
criteria provided, single submitter
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Apr 15, 2019 | RCV001567801.6 |
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
(Dec 04, 2018)
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criteria provided, single submitter
Method: clinical testing
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Retinal dystrophy
Affected status: yes
Allele origin:
germline
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Blueprint Genetics
Accession: SCV001241159.1
First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020
Comment:
My Retina Tracker patient
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Pathogenic
(May 29, 2020)
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criteria provided, single submitter
Method: research
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Leber congenital amaurosis
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV001430807.1
First in ClinVar: Aug 23, 2020 Last updated: Aug 23, 2020 |
Comment:
The heterozygous p.Arg62Ter variant in RDH12 was identified by our study in 1 individual with Leber congenital amaurosis, in a compound heterozygous state with a … (more)
The heterozygous p.Arg62Ter variant in RDH12 was identified by our study in 1 individual with Leber congenital amaurosis, in a compound heterozygous state with a likely pathogenic variant. Please note that this variant has been identified by a collaborative research study and was also be submitted by Massachusetts Eye and Ear. The p.Arg62Ter variant has been reported in at least 10 individuals with Leber congenital amaurosis (PMID: 15322982,15258582, 29186038, 32014858, 26497376, 30134391). The presence of this variant in at least 2 homozygotes, and in combination with a reported pathogenic variant, and in at least 1 individual with Leber congenital amaurosis increases the likelihood that the p.Arg62Ter variant is pathogenic (PMID: 15258582, 26497376, 30134391) and has been identified in 0.016% (4/24952) of African, 0.009% (11/129094) of European (Non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs104894471). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar as pathogenic by Mendellics, Invitae, OMIM, Ocular Genomics Institute, Massachusetts Eye and Ear, Blueprint Genetics (VariationID: 2050). This nonsense variant leads to a premature termination codon at position 62, which is predicted to lead to a truncated or absent protein. Loss of function of the RDH12 gene is a moderately established disease mechanism in autosomal recessive Leber congenital amaurosis. The p.Arg62Ter variant is located in a region of RDH12 that is essential to protein folding and stability, suggesting that this variant is in a functional domain and slightly supports pathogenicity (PMID: 32014858). In summary, this variant meets criteria to be classified as pathogenic for Leber congenital amaurosis in an autosomal recessive manner based on the predicted loss of function effect of this variant and the presence of this variant in the homozygous state and in combination with other pathogenic variants in affected individuals. ACMG/AMP Criteria applied: PVS1_strong, PM1_supporting, PM3_strong (Richards 2015). (less)
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Pathogenic
(Jul 22, 2021)
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criteria provided, single submitter
Method: clinical testing
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Leber congenital amaurosis 13
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV001810588.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Sex: mixed
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Pathogenic
(Jul 22, 2022)
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criteria provided, single submitter
Method: clinical testing
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Leber congenital amaurosis 13
Affected status: yes
Allele origin:
germline
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MGZ Medical Genetics Center
Accession: SCV002581147.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PVS1, PM3_STR, PS4_MOD, PM2_SUP, PP1
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Number of individuals with the variant: 2
Sex: male
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Pathogenic
(Oct 10, 2023)
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criteria provided, single submitter
Method: clinical testing
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Leber congenital amaurosis 13
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004208566.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Dec 18, 2023)
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criteria provided, single submitter
Method: clinical testing
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Leber congenital amaurosis 13
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000938000.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg62*) in the RDH12 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Arg62*) in the RDH12 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RDH12 are known to be pathogenic (PMID: 17964524, 22065924, 32014858, 34001834). This variant is present in population databases (rs104894471, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with autosomal recessive Leber congenital amaurosis or retinitis pigmentosa (PMID: 15258582, 15322982, 26497376, 29186038). ClinVar contains an entry for this variant (Variation ID: 2050). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(May 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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Leber congenital amaurosis 13
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV001139476.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Pathogenic
(Apr 15, 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: SCV001791551.1
First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021 |
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Observed … (more)
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Observed in 4/24,014 (0.017%) alleles from individuals of African background and in 13/277,094 (0.005%) global alleles, in large population cohorts and no individuals were reported to be homozygous (Lek et al., 2016); This variant is associated with the following publications: (PMID: 32865313, 31054281, 30134391, 29186038, 15258582, 29068479, 15322982, 26497376) (less)
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Pathogenic
(Oct 01, 2004)
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no assertion criteria provided
Method: literature only
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LEBER CONGENITAL AMAUROSIS 13
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000022289.2
First in ClinVar: Apr 04, 2013 Last updated: Jul 05, 2015 |
Comment on evidence:
For discussion of the arg62-to-ter (R62X) mutation in the RDH12 gene that was found in compound heterozygous state in a patient with Leber congenital amaurosis-13 … (more)
For discussion of the arg62-to-ter (R62X) mutation in the RDH12 gene that was found in compound heterozygous state in a patient with Leber congenital amaurosis-13 (LCA13; 612712) by Janecke et al. (2004), see 608830.0004. In affected members of a French family with LCA13, Perrault et al. (2004) identified compound heterozygosity for mutations in the RDH12 gene: the arg62-to-ter (R62X) substitution and a 152T-A transversion in exon 2, resulting in an ile51-to-asn (I51N; 608830.0012) substitution. (less)
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Pathogenic
(Aug 01, 2019)
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no assertion criteria provided
Method: clinical testing
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Leber congenital amaurosis 13
Affected status: yes
Allele origin:
germline
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Ocular Genomics Institute, Massachusetts Eye and Ear
Accession: SCV001146947.1
First in ClinVar: Jan 27, 2020 Last updated: Jan 27, 2020 |
Number of individuals with the variant: 1
Secondary finding: no
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001959758.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001973483.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: research
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Leber congenital amaurosis 13
Affected status: yes
Allele origin:
inherited
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Laboratory of Genetics in Ophthalmology, Institut Imagine
Accession: SCV001432269.1
First in ClinVar: Sep 18, 2020 Last updated: Sep 18, 2020 |
Number of individuals with the variant: 2
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Pathogenic
(Sep 16, 2020)
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no assertion criteria provided
Method: clinical testing
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Leber congenital amaurosis
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV001464100.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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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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ISOLATED MACULOPATHY AND MODERATE ROD-CONE DYSTROPHY REPRESENT THE MILDER END OF THE RDH12-RELATED RETINAL DYSTROPHY SPECTRUM. | De Zaeytijd J | Retina (Philadelphia, Pa.) | 2021 | PMID: 34001834 |
Expanding the phenotypic spectrum in RDH12-associated retinal disease. | Scott HA | Cold Spring Harbor molecular case studies | 2020 | PMID: 32014858 |
PHENOTYPIC VARIABILITY OF RECESSIVE RDH12-ASSOCIATED RETINAL DYSTROPHY. | Zou X | Retina (Philadelphia, Pa.) | 2019 | PMID: 30134391 |
Molecular Screening of 43 Brazilian Families Diagnosed with Leber Congenital Amaurosis or Early-Onset Severe Retinal Dystrophy. | Porto FBO | Genes | 2017 | PMID: 29186038 |
Impact of whole exome sequencing among Iranian patients with autosomal recessive retinitis pigmentosa. | Beheshtian M | Archives of Iranian medicine | 2015 | PMID: 26497376 |
RDH12 retinopathy: novel mutations and phenotypic description. | Mackay DS | Molecular vision | 2011 | PMID: 22065924 |
Leber congenital amaurosis - a model for efficient genetic testing of heterogeneous disorders: LXIV Edward Jackson Memorial Lecture. | Stone EM | American journal of ophthalmology | 2007 | PMID: 17964524 |
Retinal dehydrogenase 12 (RDH12) mutations in leber congenital amaurosis. | Perrault I | American journal of human genetics | 2004 | PMID: 15322982 |
Mutations in RDH12 encoding a photoreceptor cell retinol dehydrogenase cause childhood-onset severe retinal dystrophy. | Janecke AR | Nature genetics | 2004 | PMID: 15258582 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/c9008217-20d8-48bf-996e-41797530922c | - | - | - | - |
Text-mined citations for rs104894471 ...
HelpRecord last updated May 08, 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.