TPP1

tripeptidyl peptidase 1

Basic information

Region (hg38): 11:6612767-6619448

Previous symbols: [ "CLN2", "SCAR7" ]

Links

ENSG00000166340 ∙ NCBI:1200 ∙ OMIM:607998 ∙ HGNC:2073 ∙ Uniprot:O14773 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• neuronal ceroid lipofuscinosis 2 (Definitive), mode of inheritance: AR
• neuronal ceroid lipofuscinosis 2 (Definitive), mode of inheritance: AR
• neuronal ceroid lipofuscinosis 2 (Strong), mode of inheritance: AR
• neuronal ceroid lipofuscinosis 2 (Strong), mode of inheritance: AR
• neuronal ceroid lipofuscinosis 2 (Supportive), mode of inheritance: AR
• autosomal recessive spinocerebellar ataxia 7 (Supportive), mode of inheritance: AR
• neuronal ceroid lipofuscinosis (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Ceroid lipofuscinosis, neuronal, 2; Spinocerebellar ataxia, autosomal recessive 7	AR	Neurologic	The condition involves neurodevelopmental sequelae, and intraventricular administration of cerliponase alfa has been reported as showing neurological benefit	Musculoskeletal; Neurologic; Ophthalmologic	5634370; 5795346; 4116925; 3146310; 7668319; 9295267; 9788728; 10330339; 12376936; 15965709; 17959406; 18684116; 20820830; 21990111; 22612257; 23266810; 23418007; 26224725; 29688815

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the TPP1 gene.

• not provided (899 variants)
• Neuronal ceroid lipofuscinosis 2 (300 variants)
• Inborn genetic diseases (89 variants)
• not specified (74 variants)
• Neuronal ceroid lipofuscinosis (33 variants)
• Neuronal ceroid lipofuscinosis 2;Autosomal recessive spinocerebellar ataxia 7 (21 variants)
• Autosomal recessive spinocerebellar ataxia 7;Neuronal ceroid lipofuscinosis 2 (16 variants)
• Autosomal recessive spinocerebellar ataxia 7 (13 variants)
• Neuronal Ceroid-Lipofuscinosis, Recessive (12 variants)
• Abnormality of the nervous system (3 variants)
• TPP1-related condition (2 variants)
• Intellectual disability;Seizure (1 variants)
• Seizure;Intellectual disability (1 variants)
• See cases (1 variants)
• Angelman syndrome (1 variants)
• Intellectual disability (1 variants)
• Seizure (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the TPP1 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			3	219	2	224
missense	9	27	312	8	1	357
nonsense	22	12	2			36
start loss		1	1			2
frameshift	34	25				59
inframe indel	3	1	1			5
splice donor/acceptor (+/-2bp)	8	20	1			29
splice region	1	1	19	34	2	57
non coding	3	4	54	122	14	197
Total	79	90	374	349	17

Highest pathogenic variant AF is 0.000486

Variants in TPP1

This is a list of pathogenic ClinVar variants found in the TPP1 region.

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

Position	Type	Phenotype	Significance	ClinVar
11-6612772-C-T		Neuronal ceroid lipofuscinosis 2	Uncertain significance (Jan 12, 2018)
11-6612805-C-A		Neuronal ceroid lipofuscinosis 2	Uncertain significance (Jan 13, 2018)
11-6612831-A-G		Neuronal Ceroid-Lipofuscinosis, Recessive	Uncertain significance (Jun 14, 2016)
11-6612912-A-G		Neuronal ceroid lipofuscinosis 2	Uncertain significance (Jan 13, 2018)
11-6612918-C-T		Neuronal ceroid lipofuscinosis 2	Benign (Jan 13, 2018)
11-6612958-G-A		Neuronal ceroid lipofuscinosis 2	Benign (Jan 13, 2018)
11-6612976-G-A		Neuronal ceroid lipofuscinosis 2	Uncertain significance (Jan 13, 2018)
11-6612986-G-A		Neuronal ceroid lipofuscinosis 2	Uncertain significance (Jan 13, 2018)
11-6613006-A-G		Neuronal ceroid lipofuscinosis 2	Uncertain significance (Jan 13, 2018)
11-6613038-C-T		Neuronal ceroid lipofuscinosis 2	Uncertain significance (Jan 13, 2018)
11-6613068-A-T		Neuronal ceroid lipofuscinosis 2	Uncertain significance (Jan 13, 2018)
11-6613118-A-G		Neuronal ceroid lipofuscinosis 2	Uncertain significance (Jan 12, 2018)
11-6613134-A-C		Neuronal Ceroid-Lipofuscinosis, Recessive	Uncertain significance (Jun 14, 2016)
11-6613235-G-A		Neuronal ceroid lipofuscinosis 2	Uncertain significance (Jan 12, 2018)
11-6613244-T-A		Neuronal ceroid lipofuscinosis 2	Uncertain significance (Jan 12, 2018)
11-6613264-G-T		Neuronal ceroid lipofuscinosis 2	Uncertain significance (Jan 15, 2018)
11-6613296-A-T		Neuronal ceroid lipofuscinosis 2	Uncertain significance (Jan 12, 2018)
11-6613329-C-CA		Neuronal Ceroid-Lipofuscinosis, Recessive	Conflicting classifications of pathogenicity (Jul 01, 2023)
11-6613428-C-G		Neuronal ceroid lipofuscinosis 2	Benign (Jan 12, 2018)
11-6613438-A-G		Neuronal ceroid lipofuscinosis 2	Uncertain significance (Apr 27, 2017)
11-6613546-A-G		Neuronal ceroid lipofuscinosis 2	Uncertain significance (Jan 13, 2018)
11-6613560-G-C		Neuronal ceroid lipofuscinosis 2	Likely benign (Jan 13, 2018)
11-6613562-A-T		Neuronal ceroid lipofuscinosis 2	Uncertain significance (Jan 13, 2018)
11-6613609-G-A		Neuronal ceroid lipofuscinosis 2	Uncertain significance (Jan 13, 2018)
11-6613717-G-A		Neuronal ceroid lipofuscinosis 2	Uncertain significance (Jan 12, 2018)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
TPP1	protein_coding	protein_coding	ENST00000299427	13	6693

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
6.26e-7	0.994	125536	0	212	125748	0.000843

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.221	321	310	1.04	0.0000179	3614
Missense in Polyphen		107	120.1	0.89093		1425
Synonymous	-0.160	127	125	1.02	0.00000674	1190
Loss of Function	2.48	15	29.5	0.508	0.00000148	309

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000759	0.000759
Ashkenazi Jewish	0.000497	0.000496
East Asian	0.000109	0.000109
Finnish	0.000323	0.000323
European (Non-Finnish)	0.00145	0.00145
Middle Eastern	0.000109	0.000109
South Asian	0.000131	0.000131
Other	0.000815	0.000815

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Lysosomal serine protease with tripeptidyl-peptidase I activity. May act as a non-specific lysosomal peptidase which generates tripeptides from the breakdown products produced by lysosomal proteinases. Requires substrates with an unsubstituted N-terminus (By similarity). {ECO:0000250|UniProtKB:Q9EQV6}.
• Disease: DISEASE: Ceroid lipofuscinosis, neuronal, 2 (CLN2) [MIM:204500]: A form of neuronal ceroid lipofuscinosis. Neuronal ceroid lipofuscinoses are progressive neurodegenerative, lysosomal storage diseases characterized by intracellular accumulation of autofluorescent liposomal material, and clinically by seizures, dementia, visual loss, and/or cerebral atrophy. The lipopigment pattern seen most often in CLN2 consists of curvilinear profiles. {ECO:0000269|PubMed:10330339, ECO:0000269|PubMed:10665500, ECO:0000269|PubMed:11241479, ECO:0000269|PubMed:11339651, ECO:0000269|PubMed:11589012, ECO:0000269|PubMed:12376936, ECO:0000269|PubMed:12414822, ECO:0000269|PubMed:12698559, ECO:0000269|PubMed:14736728, ECO:0000269|PubMed:19201763, ECO:0000269|PubMed:20340139, ECO:0000269|PubMed:21990111, ECO:0000269|PubMed:22612257, ECO:0000269|PubMed:9295267}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Spinocerebellar ataxia, autosomal recessive, 7 (SCAR7) [MIM:609270]: Spinocerebellar ataxia defines a clinically and genetically heterogeneous group of cerebellar disorders. Patients show progressive incoordination of gait and often poor coordination of hands, speech and eye movements, due to degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. SCAR7 patients show difficulty walking and writing, dysarthria, limb ataxia, and cerebellar atrophy. {ECO:0000269|PubMed:23418007}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Lysosome - Homo sapiens (human);XBP1(S) activates chaperone genes (Consensus)

Recessive Scores

• pRec: 0.280

Intolerance Scores

• loftool: 0.115
• rvis_EVS: 0.4
• rvis_percentile_EVS: 76.41

Haploinsufficiency Scores

• pHI: 0.143
• hipred: Y
• hipred_score: 0.694
• ghis: 0.454

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.771

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Tpp1
• Phenotype: muscle phenotype; homeostasis/metabolism phenotype; cellular phenotype; 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); 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); 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); behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); respiratory system phenotype

Zebrafish Information Network

• Gene name: tpp1
• Affected structure: mandibular arch skeleton
• Phenotype tag: abnormal
• Phenotype quality: decreased size

Gene ontology

• Biological process: proteolysis;lipid metabolic process;lysosome organization;nervous system development;central nervous system development;protein catabolic process;epithelial cell differentiation;IRE1-mediated unfolded protein response;peptide catabolic process;bone resorption;neuromuscular process controlling balance
• Cellular component: lysosome;melanosome;lysosomal lumen;extracellular exosome
• Molecular function: endopeptidase activity;serine-type endopeptidase activity;protein binding;peptidase activity;serine-type peptidase activity;tripeptidyl-peptidase activity;peptide binding;metal ion binding