rs62638193
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PP5_Very_Strong
The NM_002905.5(RDH5):c.839G>A(p.Arg280His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000911 in 1,614,008 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R280C) has been classified as Uncertain significance.
Frequency
Consequence
NM_002905.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RDH5 | NM_002905.5 | c.839G>A | p.Arg280His | missense_variant | 5/5 | ENST00000257895.10 | |
BLOC1S1-RDH5 | NR_037658.1 | n.898G>A | non_coding_transcript_exon_variant | 6/6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RDH5 | ENST00000257895.10 | c.839G>A | p.Arg280His | missense_variant | 5/5 | 1 | NM_002905.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000105 AC: 16AN: 152156Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000835 AC: 21AN: 251414Hom.: 0 AF XY: 0.0000883 AC XY: 12AN XY: 135886
GnomAD4 exome AF: 0.0000896 AC: 131AN: 1461852Hom.: 0 Cov.: 31 AF XY: 0.0000921 AC XY: 67AN XY: 727218
GnomAD4 genome ? AF: 0.000105 AC: 16AN: 152156Hom.: 0 Cov.: 32 AF XY: 0.0000942 AC XY: 7AN XY: 74342
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Nov 29, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 27, 2023 | 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). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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. - |
Pigmentary retinal dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Oct 11, 2018 | 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. - |
Fundus albipunctatus, autosomal recessive Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 2000 | - - |
Congenital stationary night blindness Pathogenic:1
Likely pathogenic, criteria provided, single submitter | research | Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel | Jul 24, 2023 | Clinical significance based on ACMG v2.0 - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at