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

gnomAD frequency: 0.00004  dbSNP: rs116733939

Total submissions: 12

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
Labcorp Genetics (formerly Invitae), Labcorp	RCV000993755	SCV001234450	pathogenic	Leber congenital amaurosis 13	2025-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 175 of the RDH12 protein (p.Ser175Leu). This variant is present in population databases (rs116733939, gnomAD 0.005%). This missense change has been observed in individuals with autosomal recessive Leber congenital amaurosis (PMID: 20683928, 22065924, 30134391). ClinVar contains an entry for this variant (Variation ID: 559527). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt RDH12 protein function with a positive predictive value of 80%. 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 Center for Mendelian Genomics, Broad Institute of MIT and Harvard	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).
GeneDx	RCV001584547	SCV001820251	likely pathogenic	not provided	2022-03-18	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30870047, 20683928, 22065924, 24123792, 27208204, 30134391, 32014858, 34001834, 35006499)
Fulgent Genetics, Fulgent Genetics	RCV000993755	SCV002807201	pathogenic	Leber congenital amaurosis 13	2024-03-29	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000993755	SCV004208587	pathogenic	Leber congenital amaurosis 13	2024-03-30	criteria provided, single submitter	clinical testing
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV004817913	SCV005069671	likely pathogenic	Retinal dystrophy	2022-01-01	criteria provided, single submitter	clinical testing
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
Clinical Genetics, Academic Medical Center	RCV001584547	SCV001920136	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001584547	SCV001958023	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001584547	SCV001969735	pathogenic	not provided		no assertion criteria provided	clinical testing