rs104894471

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_152443.3(RDH12):c.184C>T(p.Arg62Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000776 in 1,611,290 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R62R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000078 ( 0 hom. )

Consequence

RDH12
NM_152443.3 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:14

Conservation

PhyloP100: 2.27

Variant links:

Genes affected

RDH12 (HGNC:19977): (retinol dehydrogenase 12) The protein encoded by this gene is an NADPH-dependent retinal reductase whose highest activity is toward 9-cis and all-trans-retinol. The encoded enzyme also plays a role in the metabolism of short-chain aldehydes but does not exhibit steroid dehydrogenase activity. Defects in this gene are a cause of Leber congenital amaurosis type 13 and Retinitis Pigmentosa 53. [provided by RefSeq, Sep 2015]

RDH12 links:

GPHN (HGNC:):

GPHN links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 14-67724588-C-T is Pathogenic according to our data. Variant chr14-67724588-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 2050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-67724588-C-T is described in Lovd as [Pathogenic]. Variant chr14-67724588-C-T is described in Lovd as [Likely_pathogenic]. Variant chr14-67724588-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
RDH12	NM_152443.3 linkuse as main transcript	c.184C>T	p.Arg62Ter	stop_gained	4/9	ENST00000551171.6
RDH12	XM_047430965.1 linkuse as main transcript	c.184C>T	p.Arg62Ter	stop_gained	4/9
GPHN	XM_047430879.1 linkuse as main transcript	c.1313-10607C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RDH12	ENST00000551171.6 linkuse as main transcript	c.184C>T	p.Arg62Ter	stop_gained	4/9	1	NM_152443.3	P1
RDH12	ENST00000267502.3 linkuse as main transcript	c.184C>T	p.Arg62Ter	stop_gained	3/8	5		P1

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152068

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000557

AC:

AN:

251424

Hom.:

AF XY:

0.0000589

AC XY:

AN XY:

135904

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000879

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000781

AC:

114

AN:

1459104

Hom.:

Cov.:

AF XY:

0.0000661

AC XY:

AN XY:

726006

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000910

Gnomad4 OTH exome

AF:

0.000149

GnomAD4 genome

AF:

0.0000723

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74398

show subpopulations

Gnomad4 AFR

AF:

0.000144

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000111

Hom.:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Leber congenital amaurosis 13

Pathogenic:8

Pathogenic, no assertion criteria provided	clinical testing	Ocular Genomics Institute, Massachusetts Eye and Ear	Aug 01, 2019	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2004	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 10, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 18, 2023	This sequence change creates a premature translational stop signal (p.Arg62*) in the RDH12 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RDH12 are known to be pathogenic (PMID: 17964524, 22065924, 32014858, 34001834). This variant is present in population databases (rs104894471, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with autosomal recessive Leber congenital amaurosis or retinitis pigmentosa (PMID: 15258582, 15322982, 26497376, 29186038). ClinVar contains an entry for this variant (Variation ID: 2050). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jul 22, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, no assertion criteria provided	research	Laboratory of Genetics in Ophthalmology, Institut Imagine	-	- -

not provided

Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 15, 2019	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Observed in 4/24,014 (0.017%) alleles from individuals of African background and in 13/277,094 (0.005%) global alleles, in large population cohorts and no individuals were reported to be homozygous (Lek et al., 2016); This variant is associated with the following publications: (PMID: 32865313, 31054281, 30134391, 29186038, 15258582, 29068479, 15322982, 26497376) -

Leber congenital amaurosis

Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	May 29, 2020	The heterozygous p.Arg62Ter variant in RDH12 was identified by our study in 1 individual with Leber congenital amaurosis, in a compound heterozygous state with a likely pathogenic variant. Please note that this variant has been identified by a collaborative research study and was also be submitted by Massachusetts Eye and Ear. The p.Arg62Ter variant has been reported in at least 10 individuals with Leber congenital amaurosis (PMID: 15322982,15258582, 29186038, 32014858, 26497376, 30134391). The presence of this variant in at least 2 homozygotes, and in combination with a reported pathogenic variant, and in at least 1 individual with Leber congenital amaurosis increases the likelihood that the p.Arg62Ter variant is pathogenic (PMID: 15258582, 26497376, 30134391) and has been identified in 0.016% (4/24952) of African, 0.009% (11/129094) of European (Non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs104894471). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar as pathogenic by Mendellics, Invitae, OMIM, Ocular Genomics Institute, Massachusetts Eye and Ear, Blueprint Genetics (VariationID: 2050). This nonsense variant leads to a premature termination codon at position 62, which is predicted to lead to a truncated or absent protein. Loss of function of the RDH12 gene is a moderately established disease mechanism in autosomal recessive Leber congenital amaurosis. The p.Arg62Ter variant is located in a region of RDH12 that is essential to protein folding and stability, suggesting that this variant is in a functional domain and slightly supports pathogenicity (PMID: 32014858). In summary, this variant meets criteria to be classified as pathogenic for Leber congenital amaurosis in an autosomal recessive manner based on the predicted loss of function effect of this variant and the presence of this variant in the homozygous state and in combination with other pathogenic variants in affected individuals. ACMG/AMP Criteria applied: PVS1_strong, PM1_supporting, PM3_strong (Richards 2015). -

Retinal dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Dec 04, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.59

Cadd

Pathogenic

Dann

Uncertain

1.0

Eigen

Uncertain

0.36

Eigen_PC

Benign

0.19

FATHMM_MKL

Uncertain

0.82

MutationTaster

Benign

1.0

A;A;A

Vest4

0.88

GERP RS

2.9

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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