ClinVar Genomic variation as it relates to human health
NM_152443.3(RDH12):c.139G>A (p.Ala47Thr)
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.139G>A (p.Ala47Thr)
Variation ID: 852972 Accession: VCV000852972.14
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 14q24.1 14: 67724543 (GRCh38) [ NCBI UCSC ] 14: 68191260 (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 15, 2020 Apr 6, 2024 Feb 11, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_152443.3:c.139G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_689656.2:p.Ala47Thr missense NC_000014.9:g.67724543G>A NC_000014.8:g.68191260G>A NG_008321.1:g.27658G>A - Protein change
- A47T
- Other names
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- Canonical SPDI
- NC_000014.9:67724542: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
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
The Genome Aggregation Database (gnomAD) 0.00003
Trans-Omics for Precision Medicine (TOPMed) 0.00004
- Links
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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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
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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
Help
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 (4) |
criteria provided, multiple submitters, no conflicts
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Feb 11, 2024 | RCV001057696.9 | |
Pathogenic (2) |
criteria provided, single submitter
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Apr 21, 2021 | RCV001420746.3 |
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
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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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Likely pathogenic
(Apr 08, 2021)
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criteria provided, single submitter
Method: research
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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: SCV001573404.1
First in ClinVar: May 10, 2021 Last updated: May 10, 2021 |
Comment:
The RDH12 c.139G>A variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we … (more)
The RDH12 c.139G>A 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, PM3, PS3. Based on this evidence we have classified this variant as Likely Pathogenic. (less)
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Pathogenic
(Apr 21, 2021)
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criteria provided, single submitter
Method: clinical testing
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Leber congenital amaurosis
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001623089.1
First in ClinVar: May 23, 2021 Last updated: May 23, 2021 |
Comment:
Variant summary: RDH12 c.139G>A (p.Ala47Thr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more)
Variant summary: RDH12 c.139G>A (p.Ala47Thr) results in a non-conservative amino acid change in 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 8e-06 in 251486 control chromosomes (gnomAD). c.139G>A has been reported in the literature in multiple individuals affected with Leber Congenital Amaurosis or retinal dystrophy or Retinitis pigmentosa & Rod cone dystrophy (Thompson_2005, Abu-Safieh_2013, Patel_2015). These data indicate that the variant is very likely to be associated with disease. In in vitro functional assays, the variant showed reduced ability to convert all-trans retinal to all-trans retinol exhibiting approximately 10% of wild-type activity (Thompson_2005). One ClinVar submitter (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Jul 25, 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: SCV004208591.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Dec 19, 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: SCV001222200.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 47 of the RDH12 protein (p.Ala47Thr). … (more)
This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 47 of the RDH12 protein (p.Ala47Thr). This variant is present in population databases (rs761231974, gnomAD 0.003%). This missense change has been observed in individual(s) with Leber congenital amaurosis and cone-rod dystrophy (PMID: 16269441, 17197551, 23105016, 26355662, 30134391). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 852972). 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 RDH12 protein function. Experimental studies have shown that this missense change affects RDH12 function (PMID: 16269441). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Feb 11, 2024)
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criteria provided, single submitter
Method: research
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Leber congenital amaurosis 13
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004801131.2
First in ClinVar: Mar 16, 2024 Last updated: Apr 06, 2024 |
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Pathogenic
(May 05, 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: SCV002091251.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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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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PHENOTYPIC VARIABILITY OF RECESSIVE RDH12-ASSOCIATED RETINAL DYSTROPHY. | Zou X | Retina (Philadelphia, Pa.) | 2019 | PMID: 30134391 |
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. | Nykamp K | Genetics in medicine : official journal of the American College of Medical Genetics | 2017 | PMID: 28492532 |
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 |
Autozygome-guided exome sequencing in retinal dystrophy patients reveals pathogenetic mutations and novel candidate disease genes. | Abu-Safieh L | Genome research | 2013 | PMID: 23105016 |
RDH12 and RPE65, visual cycle genes causing leber congenital amaurosis, differ in disease expression. | Jacobson SG | Investigative ophthalmology & visual science | 2007 | PMID: 17197551 |
Retinal degeneration associated with RDH12 mutations results from decreased 11-cis retinal synthesis due to disruption of the visual cycle. | Thompson DA | Human molecular genetics | 2005 | PMID: 16269441 |
Text-mined citations for rs761231974 ...
HelpRecord last updated Apr 06, 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.