UCHL1

ubiquitin C-terminal hydrolase L1, the group of Ubiquitin C-terminal hydrolases

Basic information

Region (hg38): 4:41256412-41268455

Previous symbols: [ "PARK5" ]

Links

ENSG00000154277 ∙ NCBI:7345 ∙ OMIM:191342 ∙ HGNC:12513 ∙ Uniprot:P09936 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• early-onset progressive neurodegeneration-blindness-ataxia-spasticity syndrome (Moderate), mode of inheritance: AR
• early-onset progressive neurodegeneration-blindness-ataxia-spasticity syndrome (Supportive), mode of inheritance: AR
• spastic paraplegia 79A, autosomal dominant, with ataxia (Moderate), mode of inheritance: AD
• spastic paraplegia 79A, autosomal dominant, with ataxia (Strong), mode of inheritance: AD
• Parkinson disease 5, autosomal dominant, susceptibility to (Limited), mode of inheritance: AD
• early-onset progressive neurodegeneration-blindness-ataxia-spasticity syndrome (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Parkinson disease 5, autosomal dominant	AD	Neurologic	Levodopa response has been reported	Neurologic; Ophthalmologic	9774100; 16450370; 23359680; 28007905; 35986737
For Parkinson disease 5, autosomal dominant, findings have not been replicated, and gene association has been described as uncertain

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the UCHL1 gene.

• not provided (110 variants)
• Parkinson disease 5, autosomal dominant, susceptibility to (29 variants)
• Inborn genetic diseases (10 variants)
• Early-onset progressive neurodegeneration-blindness-ataxia-spasticity syndrome (6 variants)
• Spastic paraplegia 79A, autosomal dominant, with ataxia (5 variants)
• Early-onset progressive neurodegeneration-blindness-ataxia-spasticity syndrome;Parkinson disease 5, autosomal dominant, susceptibility to (3 variants)
• not specified (3 variants)
• UCHL1-related condition (1 variants)
• Parkinson Disease, Dominant (1 variants)
• Parkinson disease 5, autosomal dominant, susceptibility to;Early-onset progressive neurodegeneration-blindness-ataxia-spasticity syndrome (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the UCHL1 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous				21		21
missense	1		30		1	32
nonsense		1	1			2
start loss						0
frameshift	1	2	1			4
inframe indel	1					1
splice donor/acceptor (+/-2bp)		1	1			2
splice region			6	11	3	20
non coding			9	25	16	50
Total	3	4	42	46	17

Variants in UCHL1

This is a list of pathogenic ClinVar variants found in the UCHL1 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
4-41256670-A-G			Benign (Apr 19, 2021)
4-41256671-A-G			Benign (Mar 24, 2021)
4-41256695-G-C			Benign (May 23, 2021)
4-41256745-G-A			Benign (Mar 24, 2021)
4-41256906-C-G		Parkinson disease 5, autosomal dominant, susceptibility to	Benign (Jan 13, 2018)
4-41256918-C-G		Parkinson disease 5, autosomal dominant, susceptibility to	Uncertain significance (Jan 13, 2018)
4-41256926-C-A		Parkinson disease 5, autosomal dominant, susceptibility to	Uncertain significance (Jan 12, 2018)
4-41256930-C-T		Parkinson disease 5, autosomal dominant, susceptibility to	Uncertain significance (Jan 13, 2018)
4-41256931-T-C		Parkinson disease 5, autosomal dominant, susceptibility to	Uncertain significance (Jan 12, 2018)
4-41256951-C-T		Parkinson disease 5, autosomal dominant, susceptibility to	Uncertain significance (Jan 13, 2018)
4-41256952-T-C		Parkinson disease 5, autosomal dominant, susceptibility to	Uncertain significance (Jan 12, 2018)
4-41256953-A-G		Parkinson disease 5, autosomal dominant, susceptibility to	Benign (Apr 19, 2021)
4-41256960-C-T		Parkinson disease 5, autosomal dominant, susceptibility to	Uncertain significance (Jan 13, 2018)
4-41256961-C-T		Parkinson disease 5, autosomal dominant, susceptibility to	Benign (Apr 19, 2021)
4-41256990-C-T			Uncertain significance (Jan 09, 2024)
4-41256992-A-T		Inborn genetic diseases	Uncertain significance (Aug 11, 2022)
4-41256996-A-C		Early-onset progressive neurodegeneration-blindness-ataxia-spasticity syndrome	Pathogenic (Aug 09, 2022)
4-41256999-T-C			Uncertain significance (Jul 01, 2021)
4-41257002-AC-A			Pathogenic (Jan 24, 2024)
4-41257014-G-C		Parkinson disease 5, autosomal dominant, susceptibility to	Uncertain significance (Jan 13, 2018)
4-41257024-C-T			Likely benign (Dec 09, 2023)
4-41257028-G-A			Likely benign (Oct 04, 2022)
4-41257096-C-T			Benign/Likely benign (Jan 22, 2024)
4-41257107-C-G			Likely benign (Sep 26, 2022)
4-41257108-C-G			Likely benign (Jul 27, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
UCHL1	protein_coding	protein_coding	ENST00000284440	9	12043

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.991	0.00905	125504	0	1	125505	0.00000398

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.699	102	124	0.823	0.00000676	1460
Missense in Polyphen		24	44.714	0.53674		546
Synonymous	-2.27	68	48.0	1.42	0.00000268	421
Loss of Function	3.48	0	14.1	0.00	7.08e-7	164

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.00000880	0.00000880
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Ubiquitin-protein hydrolase involved both in the processing of ubiquitin precursors and of ubiquitinated proteins. This enzyme is a thiol protease that recognizes and hydrolyzes a peptide bond at the C-terminal glycine of ubiquitin. Also binds to free monoubiquitin and may prevent its degradation in lysosomes. The homodimer may have ATP-independent ubiquitin ligase activity. {ECO:0000269|PubMed:12408865, ECO:0000269|PubMed:9790970}.
• Disease: DISEASE: Parkinson disease 5 (PARK5) [MIM:613643]: A complex neurodegenerative disorder with manifestations ranging from typical Parkinson disease to dementia with Lewy bodies. Clinical features include parkinsonian symptoms (resting tremor, rigidity, postural instability and bradykinesia), dementia, diffuse Lewy body pathology, autonomic dysfunction, hallucinations and paranoia. {ECO:0000269|PubMed:12408865, ECO:0000269|PubMed:12705903, ECO:0000269|PubMed:9774100}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Spastic paraplegia 79, autosomal recessive (SPG79) [MIM:615491]: A form of spastic paraplegia, a neurodegenerative disorder characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. Rate of progression and the severity of symptoms are quite variable. Initial symptoms may include difficulty with balance, weakness and stiffness in the legs, muscle spasms, and dragging the toes when walking. In some forms of the disorder, bladder symptoms (such as incontinence) may appear, or the weakness and stiffness may spread to other parts of the body. SPG79 is characterized by childhood onset blindness, cerebellar ataxia, nystagmus, dorsal column dysfunction, and spasticity with upper motor neuron dysfunction. {ECO:0000269|PubMed:23359680, ECO:0000269|PubMed:28007905}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Parkinson,s disease - Homo sapiens (human);Proteasome Degradation;Parkinsons Disease Pathway;Hepatitis C and Hepatocellular Carcinoma;Post-translational protein modification;Metabolism of proteins;UCH proteinases;Deubiquitination;Alpha-synuclein signaling (Consensus)

Recessive Scores

• pRec: 0.107

Intolerance Scores

• loftool: 0.221
• rvis_EVS: -0.14
• rvis_percentile_EVS: 42.88

Haploinsufficiency Scores

• pHI: 0.865
• hipred: Y
• hipred_score: 0.875
• ghis: 0.539

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.908

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Uchl1
• Phenotype: nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); limbs/digits/tail phenotype; digestive/alimentary phenotype; skeleton phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); growth/size/body region phenotype; homeostasis/metabolism phenotype

Gene ontology

• Biological process: response to ischemia;axon target recognition;adult walking behavior;cell population proliferation;regulation of macroautophagy;protein deubiquitination;sensory perception of pain;axonal transport of mitochondrion;eating behavior;proteasome-mediated ubiquitin-dependent protein catabolic process;negative regulation of MAP kinase activity;muscle fiber development;neuromuscular process
• Cellular component: nucleoplasm;cytoplasm;endoplasmic reticulum membrane;cytosol;plasma membrane;neuronal cell body;myelin sheath;neuron projection terminus;axon cytoplasm
• Molecular function: cysteine-type endopeptidase activity;thiol-dependent ubiquitin-specific protease activity;protein binding;omega peptidase activity;ligase activity;ubiquitin protein ligase binding;alpha-2A adrenergic receptor binding;thiol-dependent ubiquitinyl hydrolase activity;ubiquitin binding