chr12-55724427-G-A

Position:

chr12-55724427-G-A

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 (★★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000090 ( 0 hom. )

Consequence

RDH5
NM_002905.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 8.07

Variant links:

Genes affected

RDH5 (HGNC:9940): (retinol dehydrogenase 5) This gene encodes an enzyme belonging to the short-chain dehydrogenases/reductases (SDR) family. This retinol dehydrogenase functions to catalyze the final step in the biosynthesis of 11-cis retinaldehyde, which is the universal chromophore of visual pigments. Mutations in this gene cause autosomal recessive fundus albipunctatus, a rare form of night blindness that is characterized by a delay in the regeneration of cone and rod photopigments. Alternative splicing results in multiple transcript variants. Read-through transcription also exists between this gene and the neighboring upstream BLOC1S1 (biogenesis of lysosomal organelles complex-1, subunit 1) gene. [provided by RefSeq, Dec 2010]

RDH5 links:

ENSG00000258311 (HGNC:):

ENSG00000258311 links:

CD63 (HGNC:1692): (CD63 molecule) The protein encoded by this gene is a member of the transmembrane 4 superfamily, also known as the tetraspanin family. Most of these members are cell-surface proteins that are characterized by the presence of four hydrophobic domains. The proteins mediate signal transduction events that play a role in the regulation of cell development, activation, growth and motility. The encoded protein is a cell surface glycoprotein that is known to complex with integrins. It may function as a blood platelet activation marker. Deficiency of this protein is associated with Hermansky-Pudlak syndrome. Also this gene has been associated with tumor progression. Alternative splicing results in multiple transcript variants encoding different protein isoforms. [provided by RefSeq, Apr 2012]

CD63 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM1

In a topological_domain Lumenal (size 266) in uniprot entity RDH5_HUMAN there are 57 pathogenic changes around while only 2 benign (97%) in NM_002905.5

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 12-55724427-G-A is Pathogenic according to our data. Variant chr12-55724427-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 8005.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-55724427-G-A is described in Lovd as [Likely_pathogenic]. Variant chr12-55724427-G-A is described in Lovd as [Pathogenic]. Variant chr12-55724427-G-A is described in Lovd as [Pathogenic]. Variant chr12-55724427-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RDH5	NM_002905.5 linkuse as main transcript	c.839G>A	p.Arg280His	missense_variant	5/5	ENST00000257895.10	NP_002896.2	Q92781A0A024RB18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RDH5	ENST00000257895.10 linkuse as main transcript	c.839G>A	p.Arg280His	missense_variant	5/5	1	NM_002905.5	ENSP00000257895.6		Q92781
ENSG00000258311	ENST00000550412.5 linkuse as main transcript	c.*2721G>A		3_prime_UTR_variant	4/4	2		ENSP00000447650.1		F8W036

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.0000835

AC:

AN:

251414

Hom.:

AF XY:

0.0000883

AC XY:

AN XY:

135886

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000376

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000896

AC:

131

AN:

1461852

Hom.:

Cov.:

AF XY:

0.0000921

AC XY:

AN XY:

727218

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000313

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000202

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000764

Gnomad4 OTH exome

AF:

0.000381

GnomAD4 genome

AF:

0.000105

AC:

AN:

152156

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.000458

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000192

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.000479

Alfa

AF:

0.000129

Hom.:

Bravo

AF:

0.000185

ExAC

AF:

0.0000576

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 29, 2016	- -

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 (LidÃ©n 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 (LidÃ©n 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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.57

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Pathogenic

0.41

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.095

T;D;D

Eigen

Pathogenic

0.91

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.97

D;.;D

M_CAP

Uncertain

0.25

MetaRNN

Uncertain

0.59

D;D;D

MetaSVM

Pathogenic

0.93

MutationAssessor

Uncertain

2.8

.;M;M

PrimateAI

Uncertain

0.75

PROVEAN

Pathogenic

-4.6

D;D;D

REVEL

Pathogenic

0.91

Sift

Benign

0.080

T;T;T

Sift4G

Uncertain

0.025

D;T;T

Polyphen

1.0

.;D;D

Vest4

0.58

MVP

0.98

MPC

0.55

ClinPred

0.82

GERP RS

4.9

Varity_R

0.44

gMVP

0.83

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over