This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
ClinVar Genomic variation as it relates to human health
NM_004562.3(PRKN):c.766C>T (p.Arg256Cys)
Germline
Classification
Help
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.
(6)
Help
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.
Uncertain significance
6
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_004562.3(PRKN):c.766C>T (p.Arg256Cys)
Variation ID: 574874 Accession: VCV000574874.36
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: 6q26 6: 161785877 (GRCh38) [ NCBI UCSC ] 6: 162206909 (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 Oct 10, 2018 Oct 20, 2024 Oct 14, 2022 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_004562.3:c.766C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004553.2:p.Arg256Cys missense NM_013987.3:c.682C>T NP_054642.2:p.Arg228Cys missense NM_013988.3:c.319C>T NP_054643.2:p.Arg107Cys missense NC_000006.12:g.161785877G>A NC_000006.11:g.162206909G>A NG_008289.2:g.946926C>T - Protein change
- R256C, R107C, R228C
- Other names
- -
- Canonical SPDI
- NC_000006.12:161785876:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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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0.00060 (A)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00038
Exome Aggregation Consortium (ExAC) 0.00040
The Genome Aggregation Database (gnomAD), exomes 0.00042
Trans-Omics for Precision Medicine (TOPMed) 0.00045
The Genome Aggregation Database (gnomAD) 0.00046
1000 Genomes Project 30x 0.00047
1000 Genomes Project 0.00060
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
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. |
|||
| PRKN | - | - |
GRCh38 GRCh37 |
560 | 711 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
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
Help
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Uncertain significance (5) |
criteria provided, multiple submitters, no conflicts
|
Oct 14, 2022 | RCV000696926.34 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Apr 27, 2017 | RCV001155245.11 |
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
Help
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
Help
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
Help
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. |
|
|---|---|---|---|---|---|
|
Uncertain significance
(Apr 27, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive juvenile Parkinson disease 2
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV001316664.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
|
|
|
Uncertain significance
(Oct 14, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000825509.4
First in ClinVar: Oct 10, 2018 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 256 of the PARK2 protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 256 of the PARK2 protein (p.Arg256Cys). This variant is present in population databases (rs150562946, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with early- and late-onset Parkinson disease (PMID: 10072423, 12116199, 12730996, 12764050, 16367892, 19405094, 19636047, 32870915). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as 867C>T. ClinVar contains an entry for this variant (Variation ID: 574874). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PARK2 protein function. Experimental studies have shown that this missense change affects PARK2 function (PMID: 14519684, 16049031, 16714300, 25591737, 25939424). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
|
|
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Uncertain significance
(Nov 03, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: not provided
Allele origin:
germline
|
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Accession: SCV002009821.3
First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023 |
|
|
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Uncertain significance
(Sep 01, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001246503.26
First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 1
|
|
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Uncertain significance
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001807760.1 First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 2021 |
|
|
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Uncertain significance
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001968835.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
|
Comment:
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 256 of the PARK2 protein (p.Arg256Cys). This variant is present in population databases (rs150562946, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with early- and late-onset Parkinson disease (PMID: 10072423, 12116199, 12730996, 12764050, 16367892, 19405094, 19636047, 32870915). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as 867C>T. ClinVar contains an entry for this variant (Variation ID: 574874). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PARK2 protein function. Experimental studies have shown that this missense change affects PARK2 function (PMID: 14519684, 16049031, 16714300, 25591737, 25939424). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
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. |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 256 of the PARK2 protein (p.Arg256Cys). This variant is present in population databases (rs150562946, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with early- and late-onset Parkinson disease (PMID: 10072423, 12116199, 12730996, 12764050, 16367892, 19405094, 19636047, 32870915). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as 867C>T. ClinVar contains an entry for this variant (Variation ID: 574874). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PARK2 protein function. Experimental studies have shown that this missense change affects PARK2 function (PMID: 14519684, 16049031, 16714300, 25591737, 25939424). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| A genetic analysis of a Spanish population with early onset Parkinson's disease. | Cristina TP | PloS one | 2020 | PMID: 32870915 |
| Structural and Functional Impact of Parkinson Disease-Associated Mutations in the E3 Ubiquitin Ligase Parkin. | Fiesel FC | Human mutation | 2015 | PMID: 25939424 |
| Parkin maintains mitochondrial levels of the protective Parkinson's disease-related enzyme 17-β hydroxysteroid dehydrogenase type 10. | Bertolin G | Cell death and differentiation | 2015 | PMID: 25591737 |
| Parkin dosage mutations have greater pathogenicity in familial PD than simple sequence mutations. | Pankratz N | Neurology | 2009 | PMID: 19636047 |
| Relative contribution of simple mutations vs. copy number variations in five Parkinson disease genes in the Belgian population. | Nuytemans K | Human mutation | 2009 | PMID: 19405094 |
| Rare heterozygous parkin variants in French early-onset Parkinson disease patients and controls. | Lesage S | Journal of medical genetics | 2008 | PMID: 17766365 |
| Biochemical analysis of Parkinson's disease-causing variants of Parkin, an E3 ubiquitin-protein ligase with monoubiquitylation capacity. | Hampe C | Human molecular genetics | 2006 | PMID: 16714300 |
| Parkin gene variations in late-onset Parkinson's disease: comparison between Norwegian and German cohorts. | Schlitter AM | Acta neurologica Scandinavica | 2006 | PMID: 16367892 |
| Familial-associated mutations differentially disrupt the solubility, localization, binding and ubiquitination properties of parkin. | Sriram SR | Human molecular genetics | 2005 | PMID: 16049031 |
| Early-onset Parkinson's disease in a Chinese population: 99mTc-TRODAT-1 SPECT, Parkin gene analysis and clinical study. | Shyu WC | Parkinsonism & related disorders | 2005 | PMID: 15823482 |
| RING finger 1 mutations in Parkin produce altered localization of the protein. | Cookson MR | Human molecular genetics | 2003 | PMID: 14519684 |
| Parkin mutations are frequent in patients with isolated early-onset parkinsonism. | Periquet M | Brain : a journal of neurology | 2003 | PMID: 12764050 |
| Parkin mutations and susceptibility alleles in late-onset Parkinson's disease. | Oliveira SA | Annals of neurology | 2003 | PMID: 12730996 |
| Complex relationship between Parkin mutations and Parkinson disease. | West A | American journal of medical genetics | 2002 | PMID: 12116199 |
| Evaluation of 50 probands with early-onset Parkinson's disease for Parkin mutations. | Hedrich K | Neurology | 2002 | PMID: 11971093 |
| A wide variety of mutations in the parkin gene are responsible for autosomal recessive parkinsonism in Europe. French Parkinson's Disease Genetics Study Group and the European Consortium on Genetic Susceptibility in Parkinson's Disease. | Abbas N | Human molecular genetics | 1999 | PMID: 10072423 |
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Text-mined citations for rs150562946 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Nov 03, 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.