ClinVar Genomic variation as it relates to human health
NM_018206.6(VPS35):c.1858G>A (p.Asp620Asn)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_018206.6(VPS35):c.1858G>A (p.Asp620Asn)
Variation ID: 30196 Accession: VCV000030196.6
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16q11.2 16: 46662452 (GRCh38) [ NCBI UCSC ] 16: 46696364 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Sep 19, 2017 Feb 14, 2024 Mar 8, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_018206.6:c.1858G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_060676.2:p.Asp620Asn missense NC_000016.10:g.46662452C>T NC_000016.9:g.46696364C>T NG_029970.1:g.31781G>A Q96QK1:p.Asp620Asn - Protein change
- D620N
- Other names
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- Canonical SPDI
- NC_000016.10:46662451:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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VPS35 | - | - |
GRCh38 GRCh37 |
219 | 256 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
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The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Mar 8, 2023 | RCV000023115.18 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Parkinson disease 17
Affected status: yes
Allele origin:
unknown
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3billion
Accession: SCV004013790.1
First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023 |
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of … (more)
The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (3Cnet: 0.60). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000030196 / PMID: 21763482). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 21763482, 21763483, 22801713, 22991136). The variant has been reported to co-segregate with the disease in at least 7 similarly affected relatives/individuals in at least two unrelated families (PMID: 21763482, 21763483, 22801713, 22991136). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Parkinsonian disorder (present) , Bradykinesia (present) , Tremor (present) , Cogwheel rigidity (present)
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Pathogenic
(Mar 08, 2023)
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criteria provided, single submitter
Method: clinical testing
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Parkinson disease 17
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV004297720.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 620 of the VPS35 protein … (more)
This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 620 of the VPS35 protein (p.Asp620Asn). Experimental studies have shown that this missense change affects VPS35 function (PMID: 23411763, 24740878). For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt VPS35 protein function. ClinVar contains an entry for this variant (Variation ID: 30196). This missense change has been observed in individual(s) with Parkinson disease (PMID: 21763482, 22154191, 22801713). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). (less)
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Pathogenic
(Jul 03, 2021)
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criteria provided, single submitter
Method: clinical testing
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Parkinson disease 17
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002800210.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Oct 01, 2012)
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no assertion criteria provided
Method: literature only
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PARKINSON DISEASE 17
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000044406.4
First in ClinVar: Apr 04, 2013 Last updated: Sep 19, 2017 |
Comment on evidence:
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 … (more)
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. 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. 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. 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. 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. (less)
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not provided
(-)
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no classification provided
Method: literature only
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Parkinson disease 17
Affected status: unknown
Allele origin:
germline
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GeneReviews
Accession: SCV000679666.2
First in ClinVar: Sep 19, 2017 Last updated: Oct 01, 2022
Comment:
Autosomal dominant inheritance. About 85% of affected individuals have an affected parent.
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Number of individuals with the variant: 50
Age: 34-68 years
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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VPS35-Related Parkinson Disease. | Adam MP | - | 2023 | PMID: 28796472 |
VPS35 and DNAJC13 disease-causing variants in essential tremor. | Rajput A | European journal of human genetics : EJHG | 2015 | PMID: 25118025 |
Parkinson's disease-linked mutations in VPS35 induce dopaminergic neurodegeneration. | Tsika E | Human molecular genetics | 2014 | PMID: 24740878 |
Pathogenic mutation in VPS35 impairs its protection against MPP(+) cytotoxicity. | Bi F | International journal of biological sciences | 2013 | PMID: 23411763 |
VPS35 mutation in Japanese patients with typical Parkinson's disease. | Ando M | Movement disorders : official journal of the Movement Disorder Society | 2012 | PMID: 22991136 |
Frequency of the D620N mutation in VPS35 in Parkinson disease. | Kumar KR | Archives of neurology | 2012 | PMID: 22801713 |
Identification of VPS35 mutations replicated in French families with Parkinson disease. | Lesage S | Neurology | 2012 | PMID: 22517097 |
Screening for VPS35 mutations in Parkinson's disease. | Sheerin UM | Neurobiology of aging | 2012 | PMID: 22154191 |
A mutation in VPS35, encoding a subunit of the retromer complex, causes late-onset Parkinson disease. | Zimprich A | American journal of human genetics | 2011 | PMID: 21763483 |
VPS35 mutations in Parkinson disease. | Vilariño-Güell C | American journal of human genetics | 2011 | PMID: 21763482 |
Autosomal dominant dopa-responsive parkinsonism in a multigenerational Swiss family. | Wider C | Parkinsonism & related disorders | 2008 | PMID: 18342564 |
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Text-mined citations for rs188286943 ...
HelpRecord last updated May 01, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.