ClinVar Miner

Submissions for variant NM_152443.3(RDH12):c.184C>T (p.Arg62Ter) (rs104894471)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000002131 SCV000938000 pathogenic Leber congenital amaurosis 13 2019-12-20 criteria provided, single submitter clinical testing 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. This variant is present in population databases (rs104894471, ExAC 0.02%). This variant has been observed in several families affected with Leber congenital amaurosis or retinitis pigmentosa (PMID: 15258582, 15322982, 29186038, 26497376). ClinVar contains an entry for this variant (Variation ID: 2050). Loss-of-function variants in RDH12 are known to be pathogenic (PMID: 17964524, 22065924). For these reasons, this variant has been classified as Pathogenic.
Mendelics RCV000002131 SCV001139476 pathogenic Leber congenital amaurosis 13 2019-05-28 criteria provided, single submitter clinical testing
Blueprint Genetics RCV001075533 SCV001241159 pathogenic Retinal dystrophy 2018-12-04 criteria provided, single submitter clinical testing
Broad Institute Rare Disease Group,Broad Institute RCV001254729 SCV001430807 pathogenic Leber congenital amaurosis 2020-05-29 criteria provided, single submitter research 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).
OMIM RCV000002131 SCV000022289 pathogenic Leber congenital amaurosis 13 2004-10-01 no assertion criteria provided literature only
Ocular Genomics Institute,Massachusetts Eye and Ear RCV000002131 SCV001146947 pathogenic Leber congenital amaurosis 13 2019-08-01 no assertion criteria provided clinical testing
Laboratory of Genetics in Ophthalmology,Institut Imagine RCV000002131 SCV001432269 pathogenic Leber congenital amaurosis 13 no assertion criteria provided research
Natera, Inc. RCV001254729 SCV001464100 pathogenic Leber congenital amaurosis 2020-09-16 no assertion criteria provided clinical testing

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