LRRK1

protein-coding

leucine rich repeat kinase 1, the group of ROCO family

Gene summary

This gene encodes a multi-domain protein that is a leucine-rich repeat kinase and a GDP/GTP binding protein. The encoded protein is thought to play a role in the regulation of bone mass. Mice lacking a similar gene showed severe osteopetrosis, increased bone mineralization and decreased bone resorption. [provided by RefSeq, Jan 2017]

MANE transcript

NM_024652.6

Inheritance

ClinVar variants

P:26U:475B:397

Top phenotype

Osteosclerotic metaphyseal dysplasia

gnomAD constraint

pLI —, LoF o/e 0.37

Max pathogenic AF

—

Genomic locus

chr15:100,919,327-101,078,257

External References & Databases

Ensembl (ENSG00000154237)

Transcript & Mutation Effects

hg38 • Region Span ~158.9 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

osteosclerotic metaphyseal dysplasiaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014080

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Osteosclerotic metaphyseal dysplasiaAR

Manifestation: Musculoskeletal

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: 23610867; 27055475; 27829680; 31571209; 32119750

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to LRRK1 variants in ClinVar

5 Conditions Cataloged

not providedTotal: 824

Inborn genetic diseasesTotal: 317

LRRK1-related disorderTotal: 78

not specifiedTotal: 32

Osteosclerotic metaphyseal dysplasiaTotal: 15

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_024652.6. 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	1 clinvar		7 clinvar	320 clinvar	21 clinvar	349
missense			455 clinvar	43 clinvar	12 clinvar	510
nonsense	9 clinvar	1 clinvar	4 clinvar			14
start loss						0
frameshift	7 clinvar	1 clinvar	1 clinvar			9
splice donor/acceptor (+/-2bp)	1 clinvar	6 clinvar	8 clinvar		1 clinvar	16
Total	18	8	475	363	34	898

Highest pathogenic variant AF is 0.000006563144

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 12 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_024652.6	RefSeq	NP_078928.3	33	MANE Select
ENST00000388948.8	Ensembl	ENSP00000373600.3	33	MANE Select
ENST00000525284.5	Ensembl	ENSP00000433069.1	15	Standard
ENST00000526457.3	Ensembl	ENSP00000436672.2	9	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

protein phosphorylation
osteoclast development
bone resorption
positive regulation of peptidyl-tyrosine phosphorylation
negative regulation of peptidyl-tyrosine phosphorylation

Molecular Function

protein serine/threonine kinase activity
protein binding
ATP binding
GTP binding
identical protein binding

Cellular Component

mitochondrion
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000388948
Coding exons: 33
Length: 150898
Individuals with no LoFs: 125548
Homozygous LoFs: 0
Heterozygous LoFs: 70
Defined: 125618
p: 0.000279

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.72	931	1.20e+3	0.779	0.0000748	13108
Missense (PolyPhen)		271	470.79	0.57562		5210
Synonymous	-1.04	554	524	1.06	0.0000371	4032
Loss of Function	5.54	33	89.5	0.369	0.00000435	1043

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00013	0.00012	rare
Latino/Admixed American	0.00026	0.00026	rare
Ashkenazi Jewish	0.00030	0.00030	rare
East Asian	0.00028	0.00027	rare
Finnish	0.00016	0.00014	rare
European (Non-Finnish)	0.00028	0.00027	rare
South Asian	0.00043	0.00042	rare
Other	0.00066	0.00065	rare

dbNSFP Gene Annotations

Source: dbNSFP

Recessive Scores

pRec: 0.109

Intolerance Scores

LoFtool: 0.478
RVIS EVS: -1.61
RVIS percentile EVS: 2.97

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.723

Gene Damage Prediction

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