Submissions for variant NM_152443.3(RDH12):c.883C>T (p.Arg295Ter)

dbSNP: rs200387832

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000811812	SCV000952099	pathogenic	Leber congenital amaurosis 13	2024-08-04	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg295*) in the RDH12 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 22 amino acid(s) of the RDH12 protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individuals with autosomal recessive RDH12-related conditions (PMID: 16269441, 22065924, 26047050, 28559085). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 655601). For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics	RCV001074674	SCV001240267	pathogenic	Retinal dystrophy	2019-03-06	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001171676	SCV001334490	pathogenic	not provided	2020-03-01	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000811812	SCV001367155	pathogenic	Leber congenital amaurosis 13	2018-10-11	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000811812	SCV001430785	likely pathogenic	Leber congenital amaurosis 13	2020-05-29	criteria provided, single submitter	research	The heterozygous p.Arg295Ter variant in RDH12 was identified by our study in 1 individual with Leber congenital amaurosis, along with a variant of uncertain significance. The p.Arg295Ter variant in RDH12 has been reported in at least 3 individuals with Leber congenital amaurosis, including the individual from this study (PMID: 22065924, 32014858, 28559085). The presence of this variant in combination with a reported likely pathogenic variant, and in 3 individuals with Leber congenital amaurosis increases the likelihood that the p.Arg295Ter variant is pathogenic (PMID: 28559085, 22065924). This variant has been identified in (2/129144) 0.0015% of European (Non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). 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 Blueprint Genetics and Invitae and as likely pathogenic by Ocular Genomics Institute, Massachusetts Eye and Ear (Variation ID:655601). This nonsense variant leads to a premature termination codon at position 295. This alteration occurs within the last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. While there is some evidence to suggest that loss of function of the RDH12 gene is a disease mechanism in autosomal recessive Leber congenital amaurosis, this association is not yet strongly established based on the criteria laid out in Tayoun, 2018 (PMID: 30192042). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PVS1_supporting, PM2, PM3_strong (Richards 2015).
Baylor Genetics	RCV000811812	SCV004208554	pathogenic	Leber congenital amaurosis 13	2024-03-14	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000811812	SCV005629456	pathogenic	Leber congenital amaurosis 13	2024-05-03	criteria provided, single submitter	clinical testing
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV000993757	SCV001146951	likely pathogenic	Retinitis pigmentosa	2019-08-01	no assertion criteria provided	clinical testing
Laboratory of Genetics in Ophthalmology, Institut Imagine	RCV000811812	SCV001432289	pathogenic	Leber congenital amaurosis 13		no assertion criteria provided	research