Submissions for variant NM_152443.3(RDH12):c.701G>A (p.Arg234His)

gnomAD frequency: 0.00010  dbSNP: rs750636662

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000342637	SCV000387967	uncertain significance	Retinitis pigmentosa	2017-04-28	criteria provided, single submitter	clinical testing	The RDH12 c.701G>A (p.Arg234His) missense variant has been identified in at least four studies in which it is found in at least four patients, including at least two individuals with an autosomal recessive form of retinitis pigmentosa (RP) and one individual with macular dystrophy, all three of whom carried the variant in a compound heterozygous state. A fourth individual with RP carried the p.Arg234His variant in a heterozygous state along with a homozygous missense variant in another gene associated with RP, so the contribution of the p.Arg234His variant to disease in this patient is unclear ((Thompson et al. 2005; Ávila-Fernández et al. 2010; Consugar et al. 2014; Méndez-Vidal et al. 2014). Control data are unavailable for the p.Arg234His variant, which is reported at a frequency of 0.00095 in the Latino population of the Exome Aggregation Consortium. Functional analysis in COS-7 cells demonstrated that in the presence of some substrates, protein activity was 44% in cells transfected with the p.Arg234His variant compared to wild type, although notably the p.Arg234His demonstrated a higher activity level than the other variants assessed (Thompson et al. 2005). Further, the variant protein was expressed at levels similar to wild type when assayed by Western blotting and immunohistochemistry, leading the authors to suggest the variant may not be disease-causing. Based on the evidence, the p.Arg234His variant is classified as a variant of unknown significance, but suspicious for pathogenicity for retinitis pigmentosa. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001243727	SCV001416903	pathogenic	Leber congenital amaurosis 13	2024-09-23	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 234 of the RDH12 protein (p.Arg234His). This variant is present in population databases (rs750636662, gnomAD 0.06%). This missense change has been observed in individual(s) with autosomal recessive macular or retinal dystrophy (PMID: 19011012, 30979730; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 313842). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt RDH12 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects RDH12 function (PMID: 16269441). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001753776	SCV001985451	uncertain significance	not provided	2019-12-04	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; In vitro functional studies demonstrated that R234H retained 44% enzyme activity level compared to wild type (Thompson et al., 2005); Observed with a missense variant on the opposite allele (in trans) in individuals with retinal dystrophy in published literature (Thompson et al., 2005; Avila-Fernandez et al., 2010; Consugar et al., 2015); This variant is associated with the following publications: (PMID: 25412400, 16269441, 19011012, 21151602, 25494902, 32790509)
Mendelics	RCV001243727	SCV002517390	likely pathogenic	Leber congenital amaurosis 13	2022-05-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001833459	SCV002819415	pathogenic	Leber congenital amaurosis	2022-12-09	criteria provided, single submitter	clinical testing	Variant summary: RDH12 c.701G>A (p.Arg234His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 9.2e-05 in 248732 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in RDH12 causing Leber Congenital Amaurosis (9.2e-05 vs 0.0016), allowing no conclusion about variant significance. c.701G>A has been reported in the literature as biallelic compound heterozygous genotypes in multiple individuals affected with features of RDH12-related retinal dystrophy (example, Thompson_2005, Valverde_2009, Mendez-Vidal_2014, Glockle_2014, Avila-Fernandez_2010, Martin-Merida_2019, Ba-Abbad_2020, De Zaeytijd_2021). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 44% of normal retinoid reductase activity (Thompson_2005). A threshold effect resulting from co-inheritance with another loss of function (LOF) variant, combined with a reduction in p.R234H activity to less than half of wild-type, resulting in insufficient RDH12 enzyme levels for normal visual cycle function has been proposed (Thompson_2005). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (P/LP, n=3; VUS, n=3). Based on the evidence outlined above, the variant was classified as pathogenic.
Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel	RCV003324525	SCV004030287	uncertain significance	Retinal dystrophy	2023-07-24	criteria provided, single submitter	research	Clinical significance based on ACMG v2.0
Baylor Genetics	RCV001243727	SCV004208563	pathogenic	Leber congenital amaurosis 13	2024-03-14	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV001243727	SCV005629452	pathogenic	Leber congenital amaurosis 13	2024-01-30	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001753776	SCV005892091	pathogenic	not provided	2025-01-01	criteria provided, single submitter	clinical testing	RDH12: PM3:Very Strong, PM2
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV000993746	SCV001146937	likely pathogenic	Macular dystrophy	2019-08-01	no assertion criteria provided	clinical testing
Natera, Inc.	RCV001833459	SCV002091284	uncertain significance	Leber congenital amaurosis	2020-01-30	no assertion criteria provided	clinical testing