Submissions for variant NM_152443.3(RDH12):c.164C>T (p.Thr55Met) (rs766631462)

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Praxis fuer Humangenetik Tuebingen	RCV001091052	SCV001246889	pathogenic	not provided	2016-10-01	criteria provided, single submitter	clinical testing
Broad Institute Rare Disease Group, Broad Institute	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).
Invitae	RCV000993753	SCV001586236	pathogenic	Leber congenital amaurosis 13	2020-08-27	criteria provided, single submitter	clinical testing	This sequence change replaces threonine with methionine at codon 55 of the RDH12 protein (p.Thr55Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs766631462, ExAC 0.01%). This variant has been observed in combination with another RDH12 variant in individual(s) with Leber congenital amaurosis or retinitis pigmentosa (PMID: 16269441, 23847139, 31814694). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 805928). This variant has been reported to affect RDH12 protein 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.
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