ClinVar Miner

Submissions for variant NM_152443.3(RDH12):c.524C>T (p.Ser175Leu) (rs116733939)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Cytogenetics and Genomics Laboratory,Medical University of South Carolina RCV000754982 SCV000803392 likely pathogenic Leber congenital amaurosis 2018-06-01 criteria provided, single submitter research
Invitae RCV000993755 SCV001234450 pathogenic Leber congenital amaurosis 13 2019-11-30 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 175 of the RDH12 protein (p.Ser175Leu). The serine residue is highly conserved and there is a large physicochemical difference between serine and leucine. This variant is present in population databases (rs116733939, ExAC 0.004%). This variant has been observed in individuals affected with Leber congenital amaurosis (PMID: 20683928, 22065924, 30134391). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Ser175 amino acid residue in RDH12. Other variant(s) that disrupt this residue have been observed in individuals with RDH12-related conditions (PMID: 15322982), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Broad Institute Rare Disease Group,Broad Institute RCV000993755 SCV001430786 likely pathogenic Leber congenital amaurosis 13 2020-05-29 criteria provided, single submitter research The heterozygous p.Ser175Leu variant in RDH12 was identified by our study in 1 individual with Leber congenital amaurosis, along with a variant of uncertain significance. Please note that this variant has been identified by a collaborative research study and was also be submitted by Massachusetts Eye and Ear (PMID: 32014858). The p.Ser175Leu variant has been reported, in trans with another likely pathogenic variant, in 1 additional individual with Leber congenital amaurosis (PMID: 20683928). This variant has been identified in 0.004% (1/24970) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs116733939). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar as pathogenic by Invitae and likely pathogenic by Cytogenetics and Genomics Laboratory, Medical University of South Carolina and Ocular Genomics Institute, Massachusetts Eye and Ear (Variation ID: 559527). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The p.Ser175Leu 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: 20683928). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PM3, PP3, PM1_supporting (Richards 2015).
Ocular Genomics Institute,Massachusetts Eye and Ear RCV000993755 SCV001146949 likely pathogenic Leber congenital amaurosis 13 2019-08-01 no assertion criteria provided clinical testing
Laboratory of Genetics in Ophthalmology,Institut Imagine RCV000993755 SCV001432278 pathogenic Leber congenital amaurosis 13 no assertion criteria provided research

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