UniProtKB/Swiss-Prot Q96QK1: Variant p.Asp620Asn

Vacuolar protein sorting-associated protein 35
Gene: VPS35
Chromosomal location: 16q13-q21
Variant information

Variant position:  620
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Type of variant:  Disease [Disclaimer]
The variants are classified into three categories: Disease, Polymorphism and Unclassified.
  • Disease: Variants implicated in disease according to literature reports.
  • Polymorphism: Variants not reported to be implicated in disease.
  • Unclassified: Variants with uncertain implication in disease according to literature reports. Evidence against or in favor of a pathogenic role is limited and/or conflicting.

Residue change:  From Aspartate (D) to Asparagine (N) at position 620 (D620N, p.Asp620Asn).
Indicates the amino acid change of the variant. The one-letter and three-letter codes for amino acids used in UniProtKB/Swiss-Prot are those adopted by the commission on Biochemical Nomenclature of the IUPAC-IUB.

Physico-chemical properties:  Change from medium size and acidic (D) to medium size and polar (N)
The physico-chemical property of the reference and variant residues and the change implicated.

BLOSUM score:  1
The score within a Blosum matrix for the corresponding wild-type to variant amino acid change. The log-odds score measures the logarithm for the ratio of the likelihood of two amino acids appearing by chance. The Blosum62 substitution matrix is used. This substitution matrix contains scores for all possible exchanges of one amino acid with another:
  • Lowest score: -4 (low probability of substitution).
  • Highest score: 11 (high probability of substitution).
More information can be found on the following page

Involvement in disease:  Parkinson disease 17 (PARK17) [MIM:614203]: An autosomal dominant, adult-onset form of Parkinson disease. Parkinson disease is a complex neurodegenerative disorder characterized by bradykinesia, resting tremor, muscular rigidity and postural instability, as well as by a clinically significant response to treatment with levodopa. The pathology involves the loss of dopaminergic neurons in the substantia nigra and the presence of Lewy bodies (intraneuronal accumulations of aggregated proteins), in surviving neurons in various areas of the brain. {ECO:0000269|PubMed:21763482, ECO:0000269|PubMed:21763483, ECO:0000269|PubMed:22517097, ECO:0000269|PubMed:23395371, ECO:0000269|PubMed:24819384, ECO:0000269|PubMed:24980502}. Note=The disease is caused by mutations affecting the gene represented in this entry.
The name and a short description of the disease associated with the variant. For more information about the disease, the user can refer to OMIM, following the link provided after the disease acronym.

Variant description:  In PARK17; decreases interaction with WASHC2C, FKBP15 and the WASH complex; impairs recruitment of the WASH complex to endosomes; shows reduced retrograde transport of selective cargo between lysosomes and the Golgi apparatus; shows a progressive reduction in neurite length and branching.
Any additional useful information about the variant.

Other resources:  
Links to websites of interest for the variant.

Sequence information

Variant position:  620
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  796
The length of the canonical sequence.

The residue change on the sequence. Unless the variant is located at the beginning or at the end of the protein sequence, both residues upstream (20) and downstream (20) of the variant will be shown.

Residue conservation: 
The multiple alignment of the region surrounding the variant against various orthologous sequences.







Sequence annotation in neighborhood:  
The regions or sites of interest surrounding the variant. In general the features listed are posttranslational modifications, binding sites, enzyme active sites, local secondary structure or other characteristics reported in the cited references. The "Sequence annotation in neighborhood" lines have a fixed format:
  • Type: the type of sequence feature.
  • Positions: endpoints of the sequence feature.
  • Description: contains additional information about the feature.

Chain 1 – 796 Vacuolar protein sorting-associated protein 35
Region 438 – 796 Interaction with SLC11A2
Region 500 – 693 Interaction with IGF2R cytoplasmic domain

Literature citations

RAB7L1 interacts with LRRK2 to modify intraneuronal protein sorting and Parkinson's disease risk.
MacLeod D.A.; Rhinn H.; Kuwahara T.; Zolin A.; Di Paolo G.; McCabe B.D.; MacCabe B.D.; Marder K.S.; Honig L.S.; Clark L.N.; Small S.A.; Abeliovich A.;
Neuron 77:425-439(2013)

Retromer binding to FAM21 and the WASH complex is perturbed by the Parkinson disease-linked VPS35(D620N) mutation.
McGough I.J.; Steinberg F.; Jia D.; Barbuti P.A.; McMillan K.J.; Heesom K.J.; Whone A.L.; Caldwell M.A.; Billadeau D.D.; Rosen M.K.; Cullen P.J.;
Curr. Biol. 24:1670-1676(2014)

Mutation in VPS35 associated with Parkinson's disease impairs WASH complex association and inhibits autophagy.
Zavodszky E.; Seaman M.N.; Moreau K.; Jimenez-Sanchez M.; Breusegem S.Y.; Harbour M.E.; Rubinsztein D.C.;
Nat. Commun. 5:3828-3828(2014)

VPS35 mutations in Parkinson disease.
Vilarino-Guell C.; Wider C.; Ross O.A.; Dachsel J.C.; Kachergus J.M.; Lincoln S.J.; Soto-Ortolaza A.I.; Cobb S.A.; Wilhoite G.J.; Bacon J.A.; Behrouz B.; Melrose H.L.; Hentati E.; Puschmann A.; Evans D.M.; Conibear E.; Wasserman W.W.; Aasly J.O.; Burkhard P.R.; Djaldetti R.; Ghika J.; Hentati F.; Krygowska-Wajs A.; Lynch T.; Melamed E.; Rajput A.; Rajput A.H.; Solida A.; Wu R.M.; Uitti R.J.; Wszolek Z.K.; Vingerhoets F.; Farrer M.J.;
Am. J. Hum. Genet. 89:162-167(2011)
Cited for: VARIANT PARK17 ASN-620; VARIANTS SER-316 AND VAL-737;

A mutation in VPS35, encoding a subunit of the retromer complex, causes late-onset Parkinson disease.
Zimprich A.; Benet-Pages A.; Struhal W.; Graf E.; Eck S.H.; Offman M.N.; Haubenberger D.; Spielberger S.; Schulte E.C.; Lichtner P.; Rossle S.C.; Klopp N.; Wolf E.; Seppi K.; Pirker W.; Reinthaler E.; Harutyunyan A.; Kralovics R.; Peters A.; Zimprich F.; Brucke T.; Poewe W.; Auff E.; Trenkwalder C.; Rost B.; Ransmayr G.; Winkelmann J.; Meitinger T.; Strom T.M.;
Am. J. Hum. Genet. 89:168-175(2011)
Cited for: VARIANT PARK17 ASN-620; VARIANTS SER-51; ILE-57; ARG-82; MET-241; TRP-524 AND MET-774;

Identification of VPS35 mutations replicated in French families with Parkinson disease.
Lesage S.; Condroyer C.; Klebe S.; Honore A.; Tison F.; Brefel-Courbon C.; Durr A.; Brice A.;
Neurology 78:1449-1450(2012)
Cited for: VARIANT PARK17 ASN-620;

Disclaimer: Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. They are not in any way intended to be used as a substitute for professional medical advice, diagnostic, treatment or care.