Submissions for variant NM_002905.5(RDH5):c.839G>A (p.Arg280His)

gnomAD frequency: 0.00011  dbSNP: rs62638193

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000592822	SCV000703237	pathogenic	not provided	2016-11-29	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000779108	SCV000915601	pathogenic	Pigmentary retinal dystrophy	2018-10-11	criteria provided, single submitter	clinical testing	The RDH5 c.839G>A (p.Arg280His) missense variant has been reported in at least five studies in which is found in a compound heterozygous state in a total of eight individuals with fundus albipunctatus (FA) (including one set of monozygotic twins and a pair of siblings) and in a heterozygous state in three unaffected family members (Gonzalez-Fernandez et al. 1999; Nakamura et al. 2000; Kuroiwa et al. 2000; Sato et al. 2004; Nakamura et al. 2004). The p.Arg280His variant was absent from 310 control alleles but is reported at a frequency of 0.000349 in the Latino population of the Genome Aggregation Database. The p.Arg280His variant is located in the catalytic domain of the protein. Functional studies in COS-1 cells showed that the variant resulted in 2% protein expression and less than 1% enzyme activity compared to wild type (Lidén et al. 2001). Co-expression studies showed the reduction of enzyme activity was dose-dependent. The variant is suggested to have a dominant-negative effect (Lidén et al. 2001). Based on the collective evidence, the p.Arg280His variant is classified as pathogenic for fundus albipunctatus. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000592822	SCV001378792	pathogenic	not provided	2024-09-10	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 280 of the RDH5 protein (p.Arg280His). This variant is present in population databases (rs62638193, gnomAD 0.03%). This missense change has been observed in individual(s) with fundus albipunctatus (PMID: 10617778, 11053295, 15007239). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8005). 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 expected to disrupt RDH5 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects RDH5 function (PMID: 11675386). For these reasons, this variant has been classified as Pathogenic.
Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel	RCV003324487	SCV004030289	likely pathogenic	Congenital stationary night blindness	2023-07-24	criteria provided, single submitter	research	Clinical significance based on ACMG v2.0
OMIM	RCV000008469	SCV000028677	pathogenic	Fundus albipunctatus, autosomal recessive	2000-11-01	no assertion criteria provided	literature only