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

Total submissions: 8

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