RDH12

protein-coding

retinol dehydrogenase 12, the group of Short chain dehydrogenase/reductase superfamily

Gene summary

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]

MANE transcript

NM_152443.3

Inheritance

AR, AD

ClinVar variants

P:178U:208B:177

Top phenotype

Leber congenital amaurosis 13; Retinitis pigmentosa 53

gnomAD constraint

pLI —, LoF o/e 0.92

Max pathogenic AF

—

Genomic locus

chr14:67,701,886-67,734,451

External References & Databases

Ensembl (ENSG00000139988)

Transcript & Mutation Effects

hg38 • Region Span ~32.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

RDH12-related recessive retinopathySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0800099

Submitter: PanelApp Australia

RDH12-related dominant retinopathySTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0800100

Submitter: PanelApp Australia

Leber congenital amaurosis 13DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012990

Submitter: G2P

RDH12-related dominant retinopathyMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0800100

Submitter: ClinGen

*RDH12*, the gene encoding retinol dehydrogenase 12, was first reported in relation to autosomal dominant retinitis pigmentosa in 2008 (Fingert et al., PMID: 18779497). RDH12-related dominant retinopathy is associated with late onset cases typically diagnosed as retinitis pigmentosa with a milder phenotype, characterized by nyctalopia and visual field loss, but relatively preserved central vision. Per criteria outlined by the ClinGen Lumping & Splitting Working Group, the difference in inheritance pattern and phenotypic variability between autosomal dominant and autosomal recessive cases led them to be split into separate disease entities. The split curation for RDH12-related recessive retinopathy has been performed separately. This curation includes three frameshift variants that have been reported in 4 probands in 3 publications (PMIDs: 18779497, 32322264, 34031043). The score for genetic evidence is 6.5 points. The mechanism of pathogenicity is reported to be gain-of-function, most likely due to the creation of an alternate reading frame predicted to escape NMD and lead to a truncated protein with altered C-terminus. This gene-disease association is also supported expression studies and *in vitro* functional assays (PMIDs: 12226107, 15865448). The RDH12 enzyme catalyzes the reduction of all-trans-retinal and its 9-cis-, 11-cis-, and 13-cis-retinal isomers in the presence of NADPH (PMID: 12226107). Human *RDH12* mRNA is most highly expressed in retinal tissues (PMID: 15865448). The experimental evidence score is 1.5 points. In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Retinal Gene Curation Expert Panel on March 3rd, 2022 (SOP Version 8).

Leber congenital amaurosis 13DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0012990

Submitter: Natera

Leber congenital amaurosis 13STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012990

Submitter: Labcorp Genetics (formerly Invitae)

Leber congenital amaurosis 13STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012990

Submitter: Labcorp Genetics (formerly Invitae)

RDH12-related recessive retinopathyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0800099

Submitter: ClinGen

RDH12, Retinol Dehydrogenase 12, was first reported in relation to RDH12-related recessive retinopathy in patient described with Leber congenital amaurosis, LCA, in 2004 (Janeke et al., PMID: 15258582). Variants in RDH12 cause early-onset retinal degeneration leading to vision loss with variable severity. To capture the overlapping spectrum of clinical presentations linked to this gene, it is curated under the disease entity “inherited retinal degeneration”. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found there to be a difference in inheritance pattern phenotypic variability. Therefore, the curation will be split into autosomal recessive inherited retinal degeneration, which includes cases described with autosomal recessive LCA (OMIM: 612712) and autosomal dominant inherited retinal degeneration, which will include autosomal dominant retinitis pigmentosa (OMIM: 268000). The split curation for autosomal dominant condition will be curated separately. Fifteen variants (12 missense, 2 nonsense, 1 frameshift) that have been reported in 11 probands in 2 publications (PMIDs: 15258582, 32014858) are included in this curation. [Additional essential genetic evidence description]. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is reported to be LOF. This gene-disease association is also supported animal models, expression studies and in vitro functional assays (PMIDs: 12226107, 16269441, 17032653). Haesseler et al (12226107) demonstrates that RDH12 enzyme catalyzed the reduction of all-trans-retinal and its 9-cis-, 11-cis-, and 13-cis-retinal isomers in the presence of NADPH. While Thompson et al. (16269441) shows expression of the transcript localizes to the inner segments of rod and cone photoreceptors. Genetic alterations in RDH12 result in significantly decreased enzymatic activity and reduced expression of the protein suggesting LOF. Finally, animal models show photoreceptor degeneration in RDH12 knockouts. In summary, there is definitive evidence to support the relationship between RDH12 and RDH12-related recessive retinopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Retinal GCEP on the meeting date March 3, 2022 (SOP Version 8).

Leber congenital amaurosisSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018998

Submitter: Orphanet

retinitis pigmentosaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019200

Submitter: Orphanet

Leber congenital amaurosis 13DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012990

Submitter: Natera

Clinical Genomic Database (CGD)

Leber congenital amaurosis 13; Retinitis pigmentosa 53AD/AR

Manifestation: Ophthalmologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 15258582; 15322982; 16269441; 17197551; 18779497; 19140180; 19840725; 20736127; 22065924

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to RDH12 variants in ClinVar

20 Conditions Cataloged

Leber congenital amaurosis 13Total: 559

Leber congenital amaurosisTotal: 136

not providedTotal: 123

RDH12-related disorderTotal: 96

not specifiedTotal: 55

Retinal dystrophyTotal: 40

Retinitis pigmentosaTotal: 33

Inborn genetic diseasesTotal: 29

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_152443.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			2 clinvar	174 clinvar		176
missense	11 clinvar	73 clinvar	201 clinvar	2 clinvar		287
nonsense	13 clinvar	11 clinvar		1 clinvar		25
start loss		1 clinvar	1 clinvar			2
frameshift	22 clinvar	22 clinvar	1 clinvar			45
splice donor/acceptor (+/-2bp)	10 clinvar	15 clinvar	3 clinvar			28
Total	56	122	208	177	0	563

Highest pathogenic variant AF is 0.00018009928

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 5 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_152443.3	RefSeq	NP_689656.2	7	MANE Select
ENST00000551171.6	Ensembl	ENSP00000449079.1	7	MANE Select
ENST00000267502.3	Ensembl	ENSP00000267502.3	7	Standard
ENST00000267502.4	Ensembl	ENSP00000267502.3	7	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Retinol metabolism - Homo sapiens (human)
Vitamin A Deficiency
Retinol Metabolism
Vitamin A and Carotenoid Metabolism
Signaling by GPCR

Biological Process

retinoid metabolic process
visual perception
retinol metabolic process
photoreceptor cell maintenance
response to stimulus

Molecular Function

retinol dehydrogenase activity
protein binding
NADP-retinol dehydrogenase activity

Cellular Component

photoreceptor inner segment membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000551171
Coding exons: 7
Length: 32567
Individuals with no LoFs: 125656
Homozygous LoFs: 0
Heterozygous LoFs: 92
Defined: 125748
p: 0.000366

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.142	182	177	1.03	0.0000110	2018
Missense (PolyPhen)		86	78.487	1.0957		924
Synonymous	-1.33	91	76.3	1.19	0.00000463	683
Loss of Function	0.292	14	15.2	0.919	0.00000113	156

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00043	0.00043	rare
Latino/Admixed American	0.00043	0.00043	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00011	0.00011	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00055	0.00055	rare
South Asian	0.000098	0.000098	rare
Other	0.00049	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Exhibits an oxidoreductive catalytic activity towards retinoids. Most efficient as an NADPH-dependent retinal reductase. Displays high activity toward 9-cis and all-trans-retinol. Also involved in the metabolism of short-chain aldehydes. No steroid dehydrogenase activity detected. Might be the key enzyme in the formation of 11-cis-retinal from 11-cis-retinol during regeneration of the cone visual pigments. {ECO:0000269|PubMed:12226107}.;
Disease: DISEASE: Retinitis pigmentosa 53 (RP53) [MIM:612712]: A retinal dystrophy belonging to the group of pigmentary retinopathies. Retinitis pigmentosa is characterized by retinal pigment deposits visible on fundus examination and primary loss of rod photoreceptor cells followed by secondary loss of cone photoreceptors. Patients typically have night vision blindness and loss of midperipheral visual field. As their condition progresses, they lose their far peripheral visual field and eventually central vision as well. {ECO:0000269|PubMed:19140180, ECO:0000269|PubMed:19956407}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.182

Intolerance Scores

LoFtool: 0.289
RVIS EVS: -0.65
RVIS percentile EVS: 16.44

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Indispensability pred.: E
Indispensability score: 0.896

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium