VPS35

VPS35 retromer complex component, the group of Armadillo like helical domain containing

Basic information

Region (hg38): 16:46656131-46689518

Links

ENSG00000069329 ∙ NCBI:55737 ∙ OMIM:601501 ∙ HGNC:13487 ∙ Uniprot:Q96QK1 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Parkinson disease 17 (Strong), mode of inheritance: AD
• hereditary late onset Parkinson disease (Supportive), mode of inheritance: AD
• Parkinson disease 17 (Moderate), mode of inheritance: AD
• intellectual disability (Limited), mode of inheritance: AR
• Parkinson disease 17 (Strong), mode of inheritance: AD
• Parkinson disease (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Parkinson disease 17	AD	Neurologic	Individuals have been described with levodopa response	Neurologic	18342564; 21763482; 21763483; 22517097; 23408866; 23623008

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the VPS35 gene.

• Parkinson disease 17 (128 variants)
• not provided (52 variants)
• Parkinson Disease, Dominant (17 variants)
• Inborn genetic diseases (7 variants)
• not specified (1 variants)
• VPS35-related condition (1 variants)
• Meier-Gorlin syndrome (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the VPS35 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			2	28	2	32
missense	1	1	46	3	2	53
nonsense			2			2
start loss						0
frameshift						0
inframe indel						0
splice donor/acceptor (+/-2bp)						0
splice region			3	4	2	9
non coding			26	34	20	80
Total	1	1	76	65	24

Variants in VPS35

This is a list of pathogenic ClinVar variants found in the VPS35 region.

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

Position	Type	Phenotype	Significance	ClinVar
16-46659709-C-CA		Parkinson Disease, Dominant	Likely benign (Jun 14, 2016)
16-46659709-C-CAA		Parkinson Disease, Dominant	Uncertain significance (Jun 14, 2016)
16-46659855-T-C		Parkinson disease 17	Uncertain significance (Jan 13, 2018)
16-46659897-T-A		Parkinson disease 17	Uncertain significance (Jan 12, 2018)
16-46660050-G-T		Parkinson disease 17	Benign (Jan 13, 2018)
16-46660071-C-T		Parkinson disease 17	Uncertain significance (Jan 12, 2018)
16-46660092-C-T		Parkinson disease 17	Uncertain significance (Jan 13, 2018)
16-46660118-C-G		Parkinson disease 17	Benign (Jan 13, 2018)
16-46660126-C-T		Parkinson disease 17	Benign (Jan 13, 2018)
16-46660127-A-C		Parkinson disease 17	Uncertain significance (Jan 13, 2018)
16-46660183-G-A		Parkinson disease 17	Likely benign (Jan 12, 2018)
16-46660184-G-GT		Parkinson Disease, Dominant	Uncertain significance (Jun 14, 2016)
16-46660184-G-GGTT		Parkinson Disease, Dominant	Uncertain significance (Jun 14, 2016)
16-46660184-G-GTTT		Parkinson Disease, Dominant	Uncertain significance (Jun 14, 2016)
16-46660184-G-GGTTT		Parkinson Disease, Dominant	Uncertain significance (Jun 14, 2016)
16-46660187-TTG-T		Parkinson Disease, Dominant	Uncertain significance (Jun 14, 2016)
16-46660188-TG-T		Parkinson Disease, Dominant	Conflicting classifications of pathogenicity (Sep 02, 2019)
16-46660189-G-T		Parkinson disease 17	Uncertain significance (Jan 13, 2018)
16-46660189-G-GTTTTTT			Likely benign (Mar 01, 2023)
16-46660189-G-GTTTTTTT			Benign (Aug 01, 2022)
16-46660191-G-TTTT		Parkinson Disease, Dominant	Uncertain significance (Jun 14, 2016)
16-46660191-G-TTTTT		Parkinson Disease, Dominant	Uncertain significance (Jun 14, 2016)
16-46660192-T-TTTTG		Parkinson Disease, Dominant	Uncertain significance (Jun 14, 2016)
16-46660193-T-TTTG		Parkinson Disease, Dominant	Uncertain significance (Jun 14, 2016)
16-46660194-T-TTG		Parkinson Disease, Dominant	Uncertain significance (Jun 14, 2016)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
VPS35	protein_coding	protein_coding	ENST00000299138	17	33377

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.969	0.0308	125717	0	30	125747	0.000119

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	3.53	220	425	0.518	0.0000220	5274
Missense in Polyphen		41	140.16	0.29253		1834
Synonymous	0.261	141	145	0.972	0.00000720	1464
Loss of Function	5.20	8	46.0	0.174	0.00000261	522

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000347	0.000347
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.0000924	0.0000924
European (Non-Finnish)	0.000132	0.000132
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.000163	0.000163

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Acts as component of the retromer cargo-selective complex (CSC). The CSC is believed to be the core functional component of retromer or respective retromer complex variants acting to prevent missorting of selected transmembrane cargo proteins into the lysosomal degradation pathway. The recruitment of the CSC to the endosomal membrane involves RAB7A and SNX3. The CSC seems to associate with the cytoplasmic domain of cargo proteins predominantly via VPS35; however, these interactions seem to be of low affinity and retromer SNX proteins may also contribute to cargo selectivity thus questioning the classical function of the CSC. The SNX-BAR retromer mediates retrograde transport of cargo proteins from endosomes to the trans-Golgi network (TGN) and is involved in endosome-to-plasma membrane transport for cargo protein recycling. The SNX3-retromer mediates the retrograde endosome-to-TGN transport of WLS distinct from the SNX-BAR retromer pathway. The SNX27-retromer is believed to be involved in endosome-to-plasma membrane trafficking and recycling of a broad spectrum of cargo proteins. The CSC seems to act as recruitment hub for other proteins, such as the WASH complex and TBC1D5 (Probable). Required for retrograde transport of lysosomal enzyme receptor IGF2R and SLC11A2. Required to regulate transcytosis of the polymeric immunoglobulin receptor (pIgR-pIgA) (PubMed:15078903, PubMed:15247922, PubMed:20164305). Required for endosomal localization of WASHC2C (PubMed:22070227). Mediates the association of the CSC with the WASH complex via WASHC2 (PubMed:22070227, PubMed:24980502, PubMed:24819384). Required for the endosomal localization of TBC1D5 (PubMed:20923837). {ECO:0000269|PubMed:15078903, ECO:0000269|PubMed:15247922, ECO:0000269|PubMed:20164305, ECO:0000269|PubMed:20923837, ECO:0000269|PubMed:22070227, ECO:0000269|PubMed:23395371, ECO:0000269|PubMed:24819384, ECO:0000269|PubMed:24980502, ECO:0000303|PubMed:21725319, ECO:0000303|PubMed:22070227, ECO:0000303|PubMed:22513087, ECO:0000303|PubMed:23563491}.
• Pathway: Endocytosis - Homo sapiens (human);Signaling by WNT;Signal Transduction;WNT ligand biogenesis and trafficking (Consensus)

Recessive Scores

• pRec: 0.203

Intolerance Scores

• loftool: 0.406
• rvis_EVS: -0.69
• rvis_percentile_EVS: 15.12

Haploinsufficiency Scores

• pHI: 0.519
• hipred: Y
• hipred_score: 0.749
• ghis: 0.616

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: E
• gene_indispensability_pred: E
• gene_indispensability_score: 0.945

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Vps35
• Phenotype: normal phenotype; 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); behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); 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); digestive/alimentary phenotype; cellular phenotype; homeostasis/metabolism phenotype

Gene ontology

• Biological process: intracellular protein transport;lysosome organization;synapse assembly;positive regulation of gene expression;negative regulation of gene expression;regulation of mitochondrion organization;viral process;Wnt signaling pathway;regulation of macroautophagy;regulation of protein stability;protein destabilization;regulation of cellular protein metabolic process;negative regulation of protein homooligomerization;protein localization to organelle;retrograde transport, endosome to Golgi;mitochondrial fragmentation involved in apoptotic process;transcytosis;negative regulation of inflammatory response;voluntary musculoskeletal movement;positive regulation of dopamine receptor signaling pathway;negative regulation of cell death;positive regulation of Wnt protein secretion;positive regulation of mitochondrial fission;positive regulation of canonical Wnt signaling pathway;positive regulation of locomotion involved in locomotory behavior;neurotransmitter receptor transport, endosome to postsynaptic membrane;vesicle-mediated transport in synapse;mitochondrion to lysosome transport;neurotransmitter receptor transport, endosome to plasma membrane;negative regulation of neuron death;negative regulation of late endosome to lysosome transport;regulation of dendritic spine maintenance;positive regulation of dopamine biosynthetic process;positive regulation of cellular protein catabolic process;negative regulation of cellular protein localization;negative regulation of lysosomal protein catabolic process;regulation of presynapse assembly;retrograde transport, endosome to plasma membrane;regulation of terminal button organization
• Cellular component: mitochondrion;lysosome;lysosomal membrane;endosome;early endosome;late endosome;cytosol;plasma membrane;endosome membrane;postsynaptic density;retromer complex;retromer, cargo-selective complex;neuron projection;neuronal cell body;perinuclear region of cytoplasm;extracellular exosome;tubular endosome;presynapse;glutamatergic synapse;mitochondrion-derived vesicle
• Molecular function: protein binding;protein transporter activity;D1 dopamine receptor binding