Submissions for variant NM_152443.3(RDH12):c.164C>T (p.Thr55Met)

dbSNP: rs766631462

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Center for Human Genetics Tuebingen	RCV001091052	SCV001246889	pathogenic	not provided	2016-10-01	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000993753	SCV001430808	likely pathogenic	Leber congenital amaurosis 13	2020-05-29	criteria provided, single submitter	research	The heterozygous p.Thr55Met variant in RDH12 was identified by our study in 1 individual with leber congenital amaurosis, in a compound heterozygous state with a pathogenic variant (PMID: 32014858). 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.Thr55Met variant has also been reported in an additional individual with leber congenital amaurosis (PMID: 16269441), and it was confirmed to be in trans with a pathogenic variant in that reported individual, which increases the likelihood that the p.Thr55Met variant is pathogenic (PMID: 16269441). This variant has been identified in 0.011% (2/18392) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). 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 Sharon lab, Hadassah-Hebrew University Medical Center and likely pathogenic by Ocular Genomics Institute, Massachusetts Eye and Ear (Variation ID: 805928). In vitro functional studies provide some evidence that the p.Thr55Met variant may slightly impact protein function (PMID: 16269441). However, these types of assays may not accurately represent biological function. 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.Thr55Met 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, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive Leber congenital amaurosis. ACMG/AMP Criteria applied: PP3, PM1_supporting, PM3_strong, PS3_supporting (Richards 2015).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000993753	SCV001586236	pathogenic	Leber congenital amaurosis 13	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 55 of the RDH12 protein (p.Thr55Met). This variant is present in population databases (rs766631462, gnomAD 0.01%). This missense change has been observed in individual(s) with Leber congenital amaurosis or retinitis pigmentosa (PMID: 16269441, 23847139, 31814694). 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: 805928). 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). This variant disrupts the p.Thr55 amino acid residue in RDH12. Other variant(s) that disrupt this residue have been observed in individuals with RDH12-related conditions (PMID: 28471114), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000993753	SCV002807101	pathogenic	Leber congenital amaurosis 13	2021-07-06	criteria provided, single submitter	clinical testing
Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel	RCV001003153	SCV004030281	pathogenic	Leber congenital amaurosis	2023-07-24	criteria provided, single submitter	research	Clinical significance based on ACMG v2.0
Baylor Genetics	RCV000993753	SCV004208579	pathogenic	Leber congenital amaurosis 13	2024-02-17	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001003153	SCV005395158	pathogenic	Leber congenital amaurosis	2024-09-09	criteria provided, single submitter	clinical testing	Variant summary: RDH12 c.164C>T (p.Thr55Met) 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 2.4e-05 in 251482 control chromosomes. c.164C>T has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Leber Congenital Amaurosis or Retinitis Pigmentosa (Wang_2013, Jin_2022, Huang_2016, Peters_2023, Griffith_2022). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (hompson_2005). The most pronounced variant effect results in <10% of normal activity in an in vitro cellular assay. The following publications have been ascertained in the context of this evaluation (PMID: 36011402, 26992781, 21217109, 36909829, 16269441, 23847139, 26848971). ClinVar contains an entry for this variant (Variation ID: 805928). Based on the evidence outlined above, the variant was classified as pathogenic.
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV000993753	SCV001146946	likely pathogenic	Leber congenital amaurosis 13	2019-08-01	no assertion criteria provided	clinical testing
Sharon lab, Hadassah-Hebrew University Medical Center	RCV001003153	SCV001161222	pathogenic	Leber congenital amaurosis	2019-06-23	no assertion criteria provided	research
Natera, Inc.	RCV001003153	SCV002091253	pathogenic	Leber congenital amaurosis	2020-12-20	no assertion criteria provided	clinical testing