Submissions for variant NM_152443.3(RDH12):c.806_810del (p.Ala269fs)

dbSNP: rs386834261

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000726539	SCV000345340	pathogenic	not provided	2016-09-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000779141	SCV000915647	pathogenic	RDH12-related disorder	2018-08-15	criteria provided, single submitter	clinical testing	The RDH12 c.806_810delCCCTG (p.Ala269GlyfsTer2) variant results in a frameshift and is predicted to result in premature truncation of the protein. Across a selection of the available literature, the p.Ala269GlyfsTer2 variant has been found in at least 18 individuals affected with retinal disorders, including in 12 in a compound heterozygous state, in five in a homozygous state and in one in a heterozygous state (Perrault et al. 2004; Thompson et al. 2005; Coppieters et al. 2010; Wang et al. 2013; Boulanger-Scemama et al. 2015; Ge et al. 2015). The p.Ala269GlyfsTer2 variant was absent from at least 699 controls (Perrault et al. 2004; Coppieters et al. 2010; Sun et al. 2007) and is reported at a frequency of 0.0003 in the European (non-Finnish) population of the Genome Aggregation Database. The functional effect of the variant was assayed by transfection in COS-7 cells, which led to undetectable levels of RDH12 expression, and a dramatic reduction in ability to produce all-trans-retinol from all-trans-retinal, as compared to wild type (Sun et al. 2007). Based on the collective evidence, the p.Ala269GlyfsTer2 variant is classified as pathogenic for RDH12-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000002128	SCV000932585	pathogenic	Leber congenital amaurosis 13	2024-01-08	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ala269Glyfs*2) in the RDH12 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 48 amino acid(s) of the RDH12 protein. This variant is present in population databases (rs758435713, gnomAD 0.03%). This premature translational stop signal has been observed in individuals with autosomal recessive Leber congenital amaurosis (PMID: 17389517, 22065924, 23847139). ClinVar contains an entry for this variant (Variation ID: 2047). This variant disrupts a region of the RDH12 protein in which other variant(s) (p.Arg295*) have been determined to be pathogenic (PMID: 16269441, 22065924, 26047050). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000726539	SCV001167823	pathogenic	not provided	2022-11-17	criteria provided, single submitter	clinical testing	Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 48 amino acids are lost and replaced with 1 incorrect amino acid; This variant is associated with the following publications: (PMID: 17512964, 32531858, 15258582, 20683928, 20301475, 17964524, 23847139, 15322982, 19011012, 16269441, 26667666, 30372751, 22065924, 31424981, 30979730, 30653986, 32036094, 32581362, 31589614, 32865313)
Blueprint Genetics	RCV000504920	SCV001239088	pathogenic	Retinal dystrophy	2019-05-22	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000726539	SCV001248740	pathogenic	not provided	2016-10-01	criteria provided, single submitter	clinical testing
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV000002128	SCV001573673	pathogenic	Leber congenital amaurosis 13	2021-04-08	criteria provided, single submitter	research	The RDH12 c.806_810del variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PVS1, PS3, PP1-S, PM2. Based on this evidence we have classified this variant as Pathogenic.
Revvity Omics, Revvity	RCV000002128	SCV002019652	pathogenic	Leber congenital amaurosis 13	2021-06-24	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000002128	SCV002812648	pathogenic	Leber congenital amaurosis 13	2021-12-07	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000002128	SCV004025922	pathogenic	Leber congenital amaurosis 13	2023-08-18	criteria provided, single submitter	clinical testing	hom
Baylor Genetics	RCV000002128	SCV004208558	pathogenic	Leber congenital amaurosis 13	2024-03-20	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001277207	SCV005077079	pathogenic	Leber congenital amaurosis	2024-04-22	criteria provided, single submitter	clinical testing	Variant summary: RDH12 c.806_810delCCCTG (p.Ala269GlyfsX2) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00018 in 239486 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in RDH12 causing Leber Congenital Amaurosis (0.00018 vs 0.0016), allowing no conclusion about variant significance. c.806_810delCCCTG has been reported in the literature in multiple individuals affected with Leber Congenital Amaurosis and the variant segregated with the disease in four families (e.g. Aleman_2018, Wang_2013). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence that this variant causes absent protein expression and a dramatic reduction in activity (Sun_2007). The following publications have been ascertained in the context of this evaluation (PMID: 30372751, 17512964, 23847139). ClinVar contains an entry for this variant (Variation ID: 2047). Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000002128	SCV000022286	pathogenic	Leber congenital amaurosis 13	2004-10-01	no assertion criteria provided	literature only
GeneReviews	RCV000002128	SCV000087050	not provided	Leber congenital amaurosis 13		no assertion provided	literature only
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000504734	SCV000599187	pathogenic	Abnormality of the eye	2015-01-01	no assertion criteria provided	research	Rare ocular disorder associated to additional undetermined phenotypes
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000504920	SCV000599188	pathogenic	Retinal dystrophy	2015-01-01	no assertion criteria provided	research
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000678608	SCV000804693	pathogenic	Retinitis pigmentosa	2016-09-01	no assertion criteria provided	clinical testing
Laboratory of Genetics in Ophthalmology, Institut Imagine	RCV000002128	SCV001432283	pathogenic	Leber congenital amaurosis 13		no assertion criteria provided	research
Natera, Inc.	RCV001277207	SCV001464106	pathogenic	Leber congenital amaurosis	2020-09-16	no assertion criteria provided	clinical testing