ClinVar Miner

Submissions for variant NM_152443.3(RDH12):c.806_810del (p.Ala269fs) (rs386834261)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000726539 SCV000345340 pathogenic not provided 2016-09-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000779141 SCV000915647 pathogenic RDH12-Related Disorders 2018-08-15 criteria provided, single submitter clinical testing The RDH12 c.806_810delCCCTG (p.Ala269GlyfsTer2) variant results in a frameshift and is predicted to result in premature truncation of the protein. Across a selection of the available literature, the p.Ala269GlyfsTer2 variant has been found in at least 18 individuals affected with retinal disorders, including in 12 in a compound heterozygous state, in five in a homozygous state and in one in a heterozygous state (Perrault et al. 2004; Thompson et al. 2005; Coppieters et al. 2010; Wang et al. 2013; Boulanger-Scemama et al. 2015; Ge et al. 2015). The p.Ala269GlyfsTer2 variant was absent from at least 699 controls (Perrault et al. 2004; Coppieters et al. 2010; Sun et al. 2007) and is reported at a frequency of 0.0003 in the European (non-Finnish) population of the Genome Aggregation Database. The functional effect of the variant was assayed by transfection in COS-7 cells, which led to undetectable levels of RDH12 expression, and a dramatic reduction in ability to produce all-trans-retinol from all-trans-retinal, as compared to wild type (Sun et al. 2007). Based on the collective evidence, the p.Ala269GlyfsTer2 variant is classified as pathogenic for RDH12-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000002128 SCV000932585 pathogenic Leber congenital amaurosis 13 2019-01-06 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the RDH12 gene (p.Ala269Glyfs*2). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 48 amino acids of the RDH12 protein. This variant is present in population databases (rs758435713, ExAC 0.02%). This variant has been observed to be homozygous or in combination with another RDH12 variant in several individuals affected with Leber congenital amaurosis (PMID: 23847139, 22065924, 17389517). ClinVar contains an entry for this variant (Variation ID: 2047). This variant disrupts the C-terminus of the RDH12 protein. Other variant(s) that disrupt this region (p.Arg295*) have been determined to be pathogenic (PMID: 16269441, 26047050, 22065924). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000002128 SCV000022286 pathogenic Leber congenital amaurosis 13 2004-10-01 no assertion criteria provided literature only
GeneReviews RCV000002128 SCV000087050 pathologic Leber congenital amaurosis 13 2013-05-02 no assertion criteria provided curation Converted during submission to Pathogenic.
NIHR Bioresource Rare Diseases, University of Cambridge RCV000504734 SCV000599187 pathogenic Abnormality of the eye 2015-01-01 no assertion criteria provided research Rare ocular disorder associated to additional undetermined phenotypes
NIHR Bioresource Rare Diseases, University of Cambridge RCV000504920 SCV000599188 pathogenic Retinal dystrophy 2015-01-01 no assertion criteria provided research
Human Genetics - Radboudumc,Radboudumc RCV000678608 SCV000804693 pathogenic Retinitis pigmentosa 2016-09-01 no assertion criteria provided clinical testing

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