NM_018206.4(VPS35):c.1858G>A (p.Asp620Asn)

NM_018206.4(VPS35):c.1858G>A (p.Asp620Asn)

Variant type:
single nucleotide variant
Cytogenetic location:
16q11.2
Genomic location:
  • Chr16:46696364 (on Assembly GRCh37)
  • Chr16:46662452 (on Assembly GRCh38)
Protein change:
D620N
HGVS:
  • NG_029970.1:g.31781G>A
  • NM_018206.4:c.1858G>A
  • NC_000016.10:g.46662452C>T (GRCh38)
  • NP_060676.2:p.Asp620Asn
  • NC_000016.9:g.46696364C>T (GRCh37)
Links:
NCBI 1000 Genomes Browser:
rs188286943
Molecular consequence:
NM_018206.4:c.1858G>A: missense variant [Sequence Ontology SO:0001583]

Clinical significance

NM_018206.4(VPS35):c.1858G>A (p.Asp620Asn)

Clinical significance:
Pathogenic
Review status:
1 star out of maximum of 4 stars
classified by single submitter
Number of submission(s):
1
Condition(s)
See supporting ClinVar records

1 Affected gene

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Recent activity

Assertion and evidence details

Germline

Clinical significance
(Last evaluated)
Review status
(Assertion method)
Collection methodCondition(s)
(Mode of inheritance)
OriginCitationsSubmitter - Study name
(Last submitted)
Submission accession
Pathogenic
(Jan 9, 2015)
classified by single submitter
(literature only)
literature onlygermlinePubMed (6)
[See all records that cite these PMIDs]
OMIM

(Sep 2, 2011)

SCV000044406

Summary

FamiliesIndividualsSegregationAllele originEthnicityGeographic origin
not providednot providednot providedgermlinenot providednot provided

OMIM

Data published from literature

FamiliesIndividualsSegregationsAllele originCitations
not providednot providednot providedgermline

Description

By exome sequencing of affected members of a Swiss family with autosomal dominant Parkinson disease-17 (PARK17; 614203) reported by Wider et al. (2008), Vilarino-Guell et al. (2011) identified a heterozygous 1858G-A transition in the VPS35 gene, resulting in an asp620-to-asn (D620N) substitution in a highly conserved residue. Subsequent sequencing of this gene in 4,326 PD patients identified 4 more with the same mutation: 3 familial cases and 1 with sporadic disease. Haplotype analysis indicated independent mutational events, suggesting a mutational hotspot. The mutation was not found in 3,309 controls. The average age at onset was 50.6 years, and patients had tremor-predominant, levodopa-responsive parkinsonism.
By specific screening for the D620N mutation among Japanese patients with Parkinson disease, Ando et al. (2012) identified the heterozygous mutation in 3 (1.0%) of 330 patients with autosomal dominant PD and in 1 (0.23%) of 433 patients with sporadic PD. Haplotype analysis suggested at least 3 independent founders in this population, indicating that it may be a mutational hotspot. Patients with this mutation showed typical adult-onset, tremor-predominant PD with good response to levodopa treatment. The mutation was not found in 1,158 control chromosomes.
By targeted sequencing, Kumar et al. (2012) identified a heterozygous VPS35 D620N mutation in 1 of 1,774 patients with Parkinson disease. The patients were ascertained from several tertiary referral centers in Germany, Serbia, Chile, and the United States. The patient with the mutation was a German man who developed typical PD at age 45 years. Family history revealed an affected paternal aunt who carried the mutation, as well as 3 reportedly unaffected sibs in their fifties and sixties who also carried the mutation, indicating incomplete penetrance. Kumar et al. (2012) concluded that VPS35 mutations are a rare cause of PD, and they estimated a carrier frequency for the D620N mutation of 0.1% among patients with PD.
Lesage et al. (2012) identified a heterozygous D620N mutation in 3 (1.2%) of 246 mostly French probands with autosomal dominant typical PD. All 3 index patients were of French origin, and the mutation was shown to segregate with the disorder in 1 family; segregation analyses were not available for the 2 remaining families. Two of the French families shared a common haplotype. The mutation was not found in 245 European controls, and no additional pathogenic VPS35 variants were identified.
Simultaneously and independently, Zimprich et al. (2011) used exome sequencing to identify the D620N mutation in affected members of a large Austrian family with autosomal dominant parkinsonism. The mutation occurred in exon 15 of the gene. Two additional carriers of this mutation were found among 486 PD patients in Austria. Age-dependent incomplete penetrance was observed.

Last Updated: Mar 24, 2015