GRK1

protein-coding

G protein-coupled receptor kinase 1, the group of AGC family kinases

Gene summary

This gene encodes a member of the guanine nucleotide-binding protein (G protein)-coupled receptor kinase subfamily of the Ser/Thr protein kinase family. The protein phosphorylates rhodopsin and initiates its deactivation. Defects in GRK1 are known to cause Oguchi disease 2 (also known as stationary night blindness Oguchi type-2). [provided by RefSeq, Jul 2008]

Previous symbols:

RHOK

MANE transcript

NM_002929.3

Inheritance

ClinVar variants

P:23U:60B:13

Top phenotype

Oguchi disease 2

gnomAD constraint

pLI —, LoF o/e 0.49

Max pathogenic AF

—

Genomic locus

chr13:113,667,219-113,737,736

External References & Databases

Ensembl (ENSG00000185974)

Transcript & Mutation Effects

hg38 • Region Span ~70.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Oguchi diseaseSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019152

Submitter: Orphanet

Oguchi diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019152

Submitter: ClinGen

The relationship between GRK1 and Oguchi disease was evaluated using the ClinGen Clinical Validity Framework as of December 22, 2020. Oguchi disease is an autosomal recessive form of congenital stationary night blindness. It is characterized by the Mizuo–Nakamura phenomenon, a gold coloration of the retina that disappears in the dark-adapted state and reappears shortly after light exposure. Biallelic variants in GRK1 were first reported in patients with Oguchi disease in 1997 (Yamamoto et al, PMID 9020843). Since then, over 20 variants associated with Oguchi disease have been reported in GRK1 (http://dna2.leeds.ac.uk/GRK1_LOVD/variants/GRK1/unique; Poulter et al, 2020, PMID 33252155). The mechanism of disease is loss of function. The GRK1 gene product, rhodopsin kinase, phosphorylates photo-activated rhodopsin, which is then bound by arrestin (encoded by SAG, which is also implicated in Oguchi disease). This is important for quenching and recycling photo-activated rhodopsin. Without this function, photo-activated rhodopsin would continue to activate the phototransduction cascade and the rod photoreceptors would be unable to respond to light. In this curation, data from 12 probands with 11 unique variants (nonsense, frameshift, missense), as well as segregation data from a large, consanguineous family from Pakistan, were collected from 4 publications (Yamamoto et al, 1997, PMID 9020843; Oishi et al, 2007, PMID 17765441; Azam et al, 2009, PMID 19753316; Poulter et al, 2020, PMID 33252155). More data is available in the literature but the maximum score for genetic evidence (12 points) has been reached. This gene-disease relationship is supported by the biochemical function of rhodopsin kinase, described above (Lorenz et al, 1991, PMID 1656454; Palczewski et al, 1993, PMID 8383684; Maeda et al, 2003, PMID 12742390; Métayé et al, 2005, PMID 15894165), expression of GRK1 in photoreceptor cells and low/no expression in other tissues (Lorenz et al, 1991, PMID 1656454; Zhao et al, 1998, PMID 9478965), functional alteration experiments showing the impact of altered GRK1 residues on the ability to phosphorylate rhodopsin (Huang et al, 2009, PMID 19364770), and the phenotype of a Grk1 null mouse (Chen et al, 1999, PMID 10097103). In summary, GRK1 is definitively associated with Oguchi disease. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This clinical validity classification was approved by the ClinGen Retina Gene Curation Expert Panel.

Oguchi disease-2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013259

Submitter: G2P

Oguchi disease-2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013259

Submitter: Labcorp Genetics (formerly Invitae)

Oguchi disease-2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013259

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Oguchi disease 2AR

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: 14281981; 9020843; 17070587; 17765441; 19753316; 22959359

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GRK1 variants in ClinVar

9 Conditions Cataloged

Inborn genetic diseasesTotal: 48

Oguchi disease-2Total: 25

not providedTotal: 13

Retinal dystrophyTotal: 12

GRK1-related disorderTotal: 9

not specifiedTotal: 2

Oguchi diseaseTotal: 1

Congenital stationary night blindnessTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002929.3. 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	9 clinvar		11
missense		9 clinvar	58 clinvar	4 clinvar		71
nonsense	1 clinvar	3 clinvar				4
start loss						0
frameshift	2 clinvar	4 clinvar				6
splice donor/acceptor (+/-2bp)	2 clinvar	2 clinvar				4
Total	5	18	60	13	0	96

Highest pathogenic variant AF is 0.00034757206

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 4 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_002929.3	RefSeq	NP_002920.1	7	MANE Select
ENST00000335678.7	Ensembl	ENSP00000334876.5	7	MANE Select
ENST00001132298.1	Ensembl	ENSP00000807526.1	7	Standard
XM_047430493.1	RefSeq	XP_047286449.1	6	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Endocytosis - Homo sapiens (human)
Chemokine signaling pathway - Homo sapiens (human)
Phototransduction - Homo sapiens (human)
Chemokine signaling pathway
Signaling by GPCR

Biological Process

visual perception
regulation of G protein-coupled receptor signaling pathway
rhodopsin mediated signaling pathway
regulation of rhodopsin mediated signaling pathway
protein autophosphorylation

Molecular Function

protein kinase activity
G protein-coupled receptor kinase activity
ATP binding
rhodopsin kinase activity

Cellular Component

photoreceptor disc membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000335678
Coding exons: 7
Length: 119239
Individuals with no LoFs: 124632
Homozygous LoFs: 1
Heterozygous LoFs: 41
Defined: 124674
p: 0.000168

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.432	314	336	0.934	0.0000210	3702
Missense (PolyPhen)		125	149.79	0.83448		1572
Synonymous	0.275	154	158	0.972	0.0000116	1088
Loss of Function	2.22	11	22.3	0.493	0.00000111	254

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00021	0.00019	rare
Latino/Admixed American	0.00019	0.00017	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00011	0.00011	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000055	0.000053	rare
South Asian	0.00087	0.00082	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Retina-specific kinase involved in the signal turnoff via phosphorylation of rhodopsin (RHO), the G protein- coupled receptor that initiates the phototransduction cascade. This rapid desensitization is essential for scotopic vision and permits rapid adaptation to changes in illumination. {ECO:0000269|PubMed:15946941}.;
Disease: DISEASE: Night blindness, congenital stationary, Oguchi type 2 (CSNBO2) [MIM:613411]: A non-progressive retinal disorder characterized by impaired night vision, often associated with nystagmus and myopia. Congenital stationary night blindness Oguchi type is associated with fundus discoloration and abnormally slow dark adaptation. {ECO:0000269|PubMed:17070587, ECO:0000269|PubMed:9020843}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.180

Essentials

Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.809

Gene Damage Prediction

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