Submissions for variant NM_152443.3(RDH12):c.185G>T (p.Arg62Leu)

dbSNP: rs778481181

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001246206	SCV001419547	uncertain significance	Leber congenital amaurosis 13	2024-11-18	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 62 of the RDH12 protein (p.Arg62Leu). This variant is present in population databases (rs778481181, gnomAD 0.1%). This missense change has been observed in individual(s) with RDH12-related conditions (PMID: 30979730, 32014858). ClinVar contains an entry for this variant (Variation ID: 805923). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Fulgent Genetics, Fulgent Genetics	RCV001246206	SCV002778523	uncertain significance	Leber congenital amaurosis 13	2021-10-30	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001246206	SCV004208556	uncertain significance	Leber congenital amaurosis 13	2024-11-30	criteria provided, single submitter	clinical testing	This variant has been reported in conjunction with another variant in individual(s) with scotomas (PMID: 30979730, 32014858), but it has also been reported in a homozygous state in unaffected individual(s) in gnomAD v4.1.0.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004768764	SCV005380874	uncertain significance	not specified	2024-08-08	criteria provided, single submitter	clinical testing	Variant summary: RDH12 c.185G>T (p.Arg62Leu) 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 0.00017 in 251402 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in RDH12 causing Leber Congenital Amaurosis (0.00017 vs 0.0016), allowing no conclusion about variant significance. c.185G>T has been reported in the literature as a biallelic compound heterozygous genotype in at-least three individuals affected with features of RDH12-associated early-onset severe retinal dystrophy (EOSRD)/retinal degeneration/macular dystrophy in an unselected cohort of individuals with hereditary retinal disorders (example, Fahim_2019, Scott_2020, Ganapathi_2022 and a non-primary citation in De Zaeytijd_2021 and Wang_2022). To our knowledge no affected heterozygous individuals supporting a dominant inheritance pattern have been reported. These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34001834, 30979730, 35672425, 32014858, 35994252). ClinVar contains an entry for this variant (Variation ID: 805923). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV000993748	SCV001146939	likely pathogenic	Macular dystrophy	2019-08-01	no assertion criteria provided	clinical testing
Natera, Inc.	RCV001827142	SCV002091254	uncertain significance	Leber congenital amaurosis	2020-02-15	no assertion criteria provided	clinical testing