PDE6B

protein-coding

phosphodiesterase 6B, the group of Phosphodiesterases

Gene summary

Photon absorption triggers a signaling cascade in rod photoreceptors that activates cGMP phosphodiesterase (PDE), resulting in the rapid hydrolysis of cGMP, closure of cGMP-gated cation channels, and hyperpolarization of the cell. PDE is a peripheral membrane heterotrimeric enzyme made up of alpha, beta, and gamma subunits. This gene encodes the beta subunit. Mutations in this gene result in retinitis pigmentosa and autosomal dominant congenital stationary night blindness. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2009]

Previous symbols:

PDEB

MANE transcript

NM_000283.4

Inheritance

AR, AD

ClinVar variants

P:210U:575B:290

Top phenotype

Night blindness, congenital stationary, autosomal dominant 2; Joubert syndrome 22; Retinitis pigmentosa 40

gnomAD constraint

pLI —, LoF o/e 0.92

Max pathogenic AF

—

Genomic locus

chr4:625,573-670,782

External References & Databases

Ensembl (ENSG00000133256)

Transcript & Mutation Effects

hg38 • Region Span ~45.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

retinitis pigmentosa 40STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013429

Submitter: PanelApp Australia

retinitis pigmentosa 40DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013429

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

congenital stationary night blindness autosomal dominant 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008099

Submitter: PanelApp Australia

inherited retinal dystrophyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019118

Submitter: ClinGen

*PDE6B* was first reported in relation to autosomal recessive retinitis pigmentosa (RP) in 1993 (McLaughlin et al., PMID: 8394174). In 1994, the *PDE6B* gene was also reported to be associated with autosomal dominant congenital stationary night blindness (CSNB) in a large Danish family referred to as the “Rambusch pedigree” (Gal et al., PMID: 8075643). Since the initial reports of PDE6B-related retinopathy, over 100 homozygous or compound heterozygous PDE6B variants have been identified in individuals and families with autosomal recessive RP (ClinVar). In some cases, carrier parents have been available for clinical evaluation and have been reported to be unaffected (PMIDs: 8394174, 7599633). In one autosomal recessive *PDE6B* family, the carrier parents were reported to be asymptomatic with normal fundus exam (both over age 70), however they were noted to have reduced rod electroretinograms (PMID: 25827439). To date, there is only one well-established *PDE6B* variant associated with autosomal dominant CSNB: c.772C>A (p.His258Asn) (PMIDs: 8075643, 17044014), which does not appear to be reported in patients with autosomal recessive RP. At least one other variant, a frameshift variant, has been reported to be associated with autosomal dominant CSNB (PMID: 24760071). Per criteria outlined by the ClinGen Lumping & Splitting Working Group, we found notable differences in the inheritance pattern, phenotype, and disease variants, so autosomal recessive and autosomal dominant cases of retinopathy have been split into separate curations. This curation is for PDE6B-related recessive retinopathy, while the split curation for PDE6B-related dominant retinopathy will be performed separately. Affected individuals with PDE6B-related autosomal recessive retinopathy typically have classic RP signs and symptoms including nyctalopia, peripheral field constriction, abnormal fundus exam (attenuated retinal vessels and bone spicules), and abnormal full-field electroretinogram. Disease onset and progression is variable, however symptom onset, particularly nyctalopia, in the first decade is often reported. Ten variants (including missense, nonsense, frameshift, and duplication variants) that have been reported in eight probands in six publications (PMIDs: 8394174, 7599633, 18854872, 33177553, 33673512, 25827439) are included in this curation. 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 loss of function. This gene-disease relationship is also supported by experimental evidence (e.g. animal models, expression studies, *in vitro* functional assays, etc.) (PMIDs: 227876, 11853768, 20940301, 26877830, 31009522, 39359097). Pde6b is expressed in the mouse retina (PMID: 26877830), and *in vitro* assays indicate that PDE6B forms a complex with PDE6A and PDE6G, which are both associated with retinitis pigmentosa as well (PMID: 227876). There is a naturally occurring mouse model for PDE6B-related retinitis pigmentosa. The rd1 mouse aka "rodless" has a murine viral insert in intron 1 and a second nonsense mutation in exon 7 of the *Pde6b* gene. Homozygous rd1 mice have retinal degeneration with rapid degeneration of rod photoreceptors and cone photoreceptor loss later (PMID: 11853768). Additional animal knockout models, such as rat, have also been created and exhibit similar retinal degeneration (PMID: 31009522). AAV2-PDE6B has been shown to restore retinal structure and function in Pde6b deficient mice (PMID: 39359097). In summary, there is definitive evidence supporting the relationship between *PDE6B* and PDE6B-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 Retina GCEP on January 2nd, 2025 (SOP Version 11).

retinitis pigmentosa 40STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013429

Submitter: Labcorp Genetics (formerly Invitae)

congenital stationary night blindness autosomal dominant 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008099

Submitter: G2P

retinitis pigmentosa 40DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013429

Submitter: G2P

congenital stationary night blindness autosomal dominant 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008099

Submitter: Labcorp Genetics (formerly Invitae)

congenital stationary night blindness autosomal dominant 2LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0008099

Submitter: Ambry Genetics

retinitis pigmentosaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019200

Submitter: Orphanet

Clinical Genomic Database (CGD)

Night blindness, congenital stationary, autosomal dominant 2; Joubert syndrome 22; Retinitis pigmentosa 40AD/AR

Manifestation: Musculoskeletal; Neurologic; 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: 8394174; 8075643; 7599633; 17044014; 18854872; 20655036; 24166846; 30423442

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PDE6B variants in ClinVar

21 Conditions Cataloged

not providedTotal: 1133

PDE6B-related disorderTotal: 231

not specifiedTotal: 192

Retinitis pigmentosaTotal: 140

Inborn genetic diseasesTotal: 130

Retinal dystrophyTotal: 121

Congenital stationary night blindness autosomal dominant 2Total: 114

Retinitis pigmentosa 40Total: 111

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000283.4. 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			19 clinvar	242 clinvar	2 clinvar	263
missense	5 clinvar	51 clinvar	545 clinvar	43 clinvar	3 clinvar	647
nonsense	29 clinvar	14 clinvar	1 clinvar			44
start loss		1 clinvar	1 clinvar			2
frameshift	33 clinvar	26 clinvar	1 clinvar			60
splice donor/acceptor (+/-2bp)	19 clinvar	32 clinvar	8 clinvar			59
Total	86	124	575	285	5	1075

Highest pathogenic variant AF is 0.00018555962

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 25 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000283.4	RefSeq	NP_000274.3	22	MANE Select
ENST00000496514.6	Ensembl	ENSP00000420295.1	22	MANE Select
NM_001145291.2	RefSeq	NP_001138763.2	22	Standard
NM_001145292.2	RefSeq	NP_001138764.2	19	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Purine metabolism - Homo sapiens (human)
Phototransduction - Homo sapiens (human)
Phosphodiesterases in neuronal function
Signaling by GPCR
Signaling by WNT

Biological Process

G protein-coupled receptor signaling pathway
visual perception
phototransduction, visible light
rhodopsin mediated signaling pathway
regulation of rhodopsin mediated signaling pathway

Molecular Function

metal ion binding
3',5'-cyclic-GMP phosphodiesterase activity

Cellular Component

plasma membrane
photoreceptor disc membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000496514
Coding exons: 22
Length: 45199
Individuals with no LoFs: 117011
Homozygous LoFs: 197
Heterozygous LoFs: 8540
Defined: 125748
p: 0.0354

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.798	572	521	1.10	0.0000357	5664
Missense (PolyPhen)		222	204.81	1.0839		2289
Synonymous	-1.42	257	230	1.12	0.0000186	1562
Loss of Function	0.506	43	46.7	0.920	0.00000235	524

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0097	0.0096	notable
Latino/Admixed American	0.022	0.022	notable
Ashkenazi Jewish	0.010	0.010	notable
East Asian	0.00082	0.00076	rare
Finnish	0.043	0.043	notable
European (Non-Finnish)	0.058	0.057	notable
South Asian	0.0093	0.0092	notable
Other	0.040	0.040	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: This protein participates in processes of transmission and amplification of the visual signal. Necessary for the formation of a functional phosphodiesterase holoenzyme.;
Disease: DISEASE: Retinitis pigmentosa 40 (RP40) [MIM:613801]: 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:22334370, ECO:0000269|PubMed:8394174, ECO:0000269|PubMed:8557257, ECO:0000269|PubMed:8595886, ECO:0000269|PubMed:8698075, ECO:0000269|PubMed:8956055, ECO:0000269|PubMed:9543643}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Night blindness, congenital stationary, autosomal dominant 2 (CSNBAD2) [MIM:163500]: A non-progressive retinal disorder characterized by impaired night vision, often associated with nystagmus and myopia. {ECO:0000269|PubMed:8075643}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.556

Intolerance Scores

LoFtool: 0.868
RVIS EVS: -0.54
RVIS percentile EVS: 20.05

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.157

Gene Damage Prediction

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