VPS33B

Chr 15

VPS33B late endosome and lysosome associated

Also known as: KDIDAR, PFIC12

NCBI Gene: 26276 ENSG00000184056 UniProt: Q9H267

VPS33B encodes a protein that mediates vesicle trafficking to lysosomes and is required for proper collagen processing and maintenance of cellular polarity in epithelial cells. Mutations cause autosomal recessive disorders including arthrogryposis-renal dysfunction-cholestasis syndrome, progressive familial intrahepatic cholestasis type 12, and keratoderma-ichthyosis-deafness syndrome, affecting multiple organ systems including liver, kidney, skin, and musculoskeletal system. The gene shows extreme intolerance to loss-of-function variants (pLI near 1), indicating that complete protein loss is likely incompatible with normal development.

ResearchSummary from RefSeq, OMIM, UniProt

Vesicle mediated protein sorting plays an important role in segregation of intracellular molecules into distinct organelles. Genetic studies in yeast have identified more than 40 vacuolar protein sorting (VPS) genes involved in vesicle transport to vacuoles. This gene is a member of the Sec-1 domain family, and encodes the human ortholog of rat Vps33b which is homologous to the yeast class C Vps33 protein. The mammalian class C vacuolar protein sorting proteins are predominantly associated with late endosomes/lysosomes, and like their yeast counterparts, may mediate vesicle trafficking steps in the endosome/lysosome pathway. Mutations in this gene are associated with arthrogryposis-renal dysfunction-cholestasis syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]

ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtArthrogryposis, renal dysfunction, and cholestasis 1

UniProtKeratoderma-ichthyosis-deafness syndrome, autosomal recessive

UniProtCholestasis, progressive familial intrahepatic, 12

Clinical highlights

Gene-disease validity (ClinGen)

arthrogryposis, renal dysfunction, and cholestasis 1 · ARDefinitivesufficient evidence for diagnostic panels

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.96

LOEUF

LOF

Mechanism· G2P

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429