VPS33A

Inheritance Pattern: AR

Disease ID:MONDO:0015012

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0015012

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0015012

Submitter: Genomics England PanelApp

Inheritance Pattern: AR

Disease ID:MONDO:0015012

Submitter: ClinGen

*VPS33A* was first reported in relation to mucopolysaccharidosis-plus syndrome (MPSPS, also known as mucopolysaccharidosis-like syndrome with congenital heart defects and hematopoietic disorders), an autosomal recessive condition, in 2017 (Dursun et al, PMID: 27547915; Kondo et al, PMID: 28013294). Individuals with this condition have been reported to have features typically associated with mucopolysaccharidosis, including coarse facial features, skeletal abnormalities, hepatosplenomegaly, respiratory problems, and intellectual disability, along with features not typically found in individuals with MPS, such as heart defects, and renal and hematopoietic disorders. Most patients die by around 2 years of age. While these patients have variably elevated urinary glycosaminoglycans (GAGs), typically found in the MPS disorders, the activity of lysosomal enzymes associated with MPS are normal. Other features include increased vacuolation observed in cells, increased lysosomal acidity, and normal endocytic and autophagocytic pathway in fibroblasts (Kondo et al, PMID: 28013294; Kondo et al, PMID: 28013294). MPSPS is the only condition known to have been asserted to be caused by variants in *VPS33A*. Only two variants, both of them missense, have been reported in individuals with MPSPS. One of the variants, c.1492C>T (p.Arg498Trp), has been identified in at least 16 probands from the Yakut population of Eastern Siberia, and in siblings from Turkey (Dursun et al, 2017, PMID: 27547915; Kondo et al, 2017, PMID: 28013294; Pavlova et al, 2019, PMID: 31070736; Vasilev et al, 2020, PMID: 31936524; Faraguna et al, 2022, PMID: 35327996; Sofronova et al, 2023, PMID: 37628632). The other variant, c.599G>C (p.Arg200Pro), which was identified in homozygous individuals from Poland and the Mediterranean region, appears to cause an attenuated phenotype (Lipinski et al, 2022, PMID: 36232726; Pavlova et al, 2022, PMID: 36153662). To our knowledge, no additional variants have been reported in the literature. The mechanism of pathogenicity appears to be loss of function based on evidence that the variant results in decreased stability of the gene product. This gene-disease relationship is also supported by experimental evidence. *VPS33A* encodes is a core subunit of the CORVET (class C core vacuole/endosome tethering) and HOPS (homotypic fusion and vacuole protein sorting) complexes. CORVET and HOPS are intracellular, hexameric, membrane‐tethering, protein complexes involved in the endocytic and autophagocytic pathways pathway. The biochemical function of VPS33A is consistent with the clinical features observed in patients and elevation of urine GAGs, as well as observations in their cells, such as vacuolation with disordered endosomal/lysosomal compartments, and abnormal endocytic trafficking (Wartosch et al, 2015,PMID: 25783203). Detailed studies on fibroblasts from a patient homozygous for p.Arg200Pro found that GAG accumulation appears to occur due to decreased levels of the VPS33A protein, leading to impaired endosomal trafficking and ineffective delivery of GAGs to lysosomes where they are degraded (Cyske et al, 2025, PMID: 40758165). Use of inhibitors of protein degradation led to increased VPS33A protein levels and corrected or improved the various cellular defects and lowered levels of heparan sulfate (Cyske et al, 2025, PMID: 41310305). A natural mouse model, the buff mouse, has been reported but the features do not mimic those found in patients, likely due to an alternative disease mechanism. This was not considered to be conflicting evidence for the gene-disease relationship. In summary, there is definitive evidence supporting the relationship between VPS33A and mucopolysaccharidosis-plus syndrome (MPSPS). Previously (October 3, 2023), the ClinGen Lysosomal Diseases Gene Curation Expert Panel classified this gene-disease relationship as moderate. However, with the addition of recent experimental evidence (Cyske et al, 2025, PMID: 40758165, 41310305), the ClinGen General IEM GCEP reclassified this gene disease relationship as definitive. Of note, only two different missense variants in the gene have been reported in patients with symptoms of MPSPS; there is considerable evidence for the role of the c.1492C>T (p.Arg498Trp) variant in this condition in individuals of Turkic/Yakut ancestry. The classification of Definitive was approved by the ClinGen General IEM GCEP on February 27, 2026 (SOP v12).

Inheritance Pattern: AR

Disease ID:MONDO:0015012

Submitter: Ambry Genetics