VCV000007050.77 - ClinVar

NM_004562.3(PRKN):c.823C>T (p.Arg275Trp)

Germline

Classification

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.

(30)

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.

Pathogenic/Likely pathogenic

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.823C>T (p.Arg275Trp)

Variation ID: 7050 Accession: VCV000007050.77

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 6q26 6: 161785820 (GRCh38) [ NCBI UCSC ] 6: 162206852 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	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	Apr 4, 2013	Dec 22, 2024	Jun 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_004562.3:c.823C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_004553.2:p.Arg275Trp	missense
NM_013987.3:c.739C>T	NP_054642.2:p.Arg247Trp	missense
NM_013988.3:c.376C>T	NP_054643.2:p.Arg126Trp	missense
NC_000006.12:g.161785820G>A
NC_000006.11:g.162206852G>A
NG_008289.2:g.946983C>T
	O60260:p.Arg275Trp

... more HGVS ... less HGVS

Protein change

R275W, R126W, R247W

Other names

Canonical SPDI

NC_000006.12:161785819:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

0.00040 (A)

Allele frequency Help The frequency of the allele represented by this VCV record.

1000 Genomes Project 0.00040

1000 Genomes Project 30x 0.00078

Exome Aggregation Consortium (ExAC) 0.00206

Trans-Omics for Precision Medicine (TOPMed) 0.00213

The Genome Aggregation Database (gnomAD) 0.00226

Links

ClinGen: CA254086 UniProtKB: O60260#VAR_019752 OMIM: 602544.0017 dbSNP: rs34424986 VarSome

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
Gene	OMIM	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	568	724

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.
Autosomal recessive juvenile Parkinson disease 2	Pathogenic (14)	criteria provided, multiple submitters, no conflicts	Apr 4, 2024	RCV000007466.34
not provided	Pathogenic/Likely pathogenic (10)	criteria provided, multiple submitters, no conflicts	Jun 1, 2024	RCV000514660.51
Young-onset Parkinson disease	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	May 3, 2021	RCV000612317.10
Autosomal recessive juvenile Parkinson disease 2 Leprosy, susceptibility to, 2 Lung carcinoma Ovarian neoplasm	Pathogenic (1)	criteria provided, single submitter	Oct 31, 2018	RCV000763143.3
See cases	Pathogenic (1)	criteria provided, single submitter	Apr 24, 2019	RCV001197176.3
PRKN-related disorder	Pathogenic (1)	no assertion criteria provided	May 31, 2024	RCV003390652.6
Ovarian cancer	Likely pathogenic (1)	no assertion criteria provided	Jun 1, 2022	RCV004766985.1

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.
Pathogenic (Apr 18, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics Accession: SCV000610254.1 First in ClinVar: Nov 05, 2017 Last updated: Nov 05, 2017
Pathogenic (Oct 31, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Ovarian cancer Lung cancer Autosomal recessive juvenile Parkinson disease 2 Leprosy, susceptibility to, 2 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000893705.1 First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Pathogenic (Apr 24, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	see cases Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV001367812.2 First in ClinVar: Jul 04, 2020 Last updated: Jul 04, 2020	Comment: This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM3,PP3. Clinical Features: Parkinsonism (present)
Pathogenic (May 03, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Young-onset Parkinson disease Affected status: yes Allele origin: germline	Fulgent Genetics, Fulgent Genetics Accession: SCV001652805.1 First in ClinVar: May 28, 2021 Last updated: May 28, 2021
Pathogenic (Jul 25, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001823764.5 First in ClinVar: Sep 08, 2021 Last updated: Aug 05, 2023	Comment: Published functional studies show the parkin protein with R275W accumulated around the nucleus in aggregations of misfolded protein, while wild type protein localized primarily to … (more) Published functional studies show the parkin protein with R275W accumulated around the nucleus in aggregations of misfolded protein, while wild type protein localized primarily to the cytoplasm and nucleus (Cookson et al., 2003); Published functional studies demonstrated that R275W inhibited differentiation of neural stem cells to astrocyte and neurons (Park et al., 2017).; This variant is associated with the following publications: (PMID: 28808173, 25640678, 26556299, 30609409, 27294386, 28656059, 31409571, 22555654, 12730996, 12891670, 20798600, 16049031, 16714300, 14519684, 20457763, 15390068, 19801972, 22118943, 24082139, 19162522, 25591737, 26764160, 25939424, 26683220, 11889248, 10072423, 31324919, 30537300, 30200940, 29353703, 31147223, 27182553, 26855076, 15970950, 26188007, 25907632, 25815004, 24831986, 26836416, 30994895, 33045815, 33504652, 32970363, 34426522, 34434164, 35747619, 28716427, 33818904, 32864185, 33845304, 32740907, 19636047) (less)
Pathogenic (May 25, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Autosomal recessive juvenile Parkinson disease 2 Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002019520.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Dec 13, 2023)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Autosomal recessive juvenile Parkinson disease 2 Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV004241079.1 First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024	Publications: PubMed (10) PubMed: 30994895‚ 35954270‚ 25939424‚ 12764051‚ 33497488‚ 20558392‚ 12114481‚ 16049031‚ 32970363‚ 35640906 Comment: Variant summary: PRKN c.823C>T (p.Arg275Trp) results in a non-conservative amino acid change located in the RING finger domain (IPR047535) of the encoded protein sequence. Five … (more) Variant summary: PRKN c.823C>T (p.Arg275Trp) results in a non-conservative amino acid change located in the RING finger domain (IPR047535) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.003 in 1,607,042 control chromosomes in the gnomAD database v4.0 dataset, including 10 homozygotes. However, in gnomAD v4.0 many samples are now derived from large biobanks, which can include individuals with disease. The variant, c.823C>T, has been frequently reported in the literature in homozygous- and compound heterozygous state in individuals affected with Autosomal Recessive Juvenile Parkinson Disease, including families with multiple affected siblings (e.g. Nichols_2002, Khan_2003, Marder_2010, Kim_2021). These data indicate that the variant is very likely to be associated with disease. Several publications reported experimental evidence evaluating an impact on protein function, and demonstrated decreased protein stability with intracellular aggregates, impaired ubiquitination activity, and significantly decreased mitophagy, indicating a clear loss-of-function phenotype (e.g. Sriram_2005, Fiesel_2015, Yi_2019, Broadway_2022). Although the variant has also been reported in (apparent) heterozygous state in several affected individuals, recent large-scale studies examining the role of heterozygous PRKN variants (including R275W) found no association for increased Parkinson Disease risk (e.g. Yu_2021, Zhu_2022). The following publications have been ascertained in the context of this evaluation (PMID: 16049031, 25939424, 30994895, 12114481, 12764051, 20558392, 33497488, 32970363, 35640906, 35954270). 22 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Pathogenic (Jan 21, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000549208.10 First in ClinVar: Oct 11, 2015 Last updated: Feb 20, 2024	Publications: PubMed (18) PubMed: 28492532‚ 10072423‚ 11889248‚ 12730996‚ 12891670‚ 15390068‚ 19162522‚ 19636047‚ 22118943‚ 22555654‚ 24082139‚ 24831986‚ 26836416‚ 14519684‚ 16049031‚ 16714300‚ 20457763‚ 25939424 Comment: This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 275 of the PRKN protein … (more) This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 275 of the PRKN protein (p.Arg275Trp). This variant is present in population databases (rs34424986, gnomAD 0.3%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with dementia with Lewy bodies and/or Parkinson's disease (PMID: 10072423, 11889248, 12730996, 12891670, 15390068, 19162522, 19636047, 22118943, 22555654, 24082139, 24831986, 26836416). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 7050). 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 PRKN protein function. Experimental studies have shown that this missense change affects PRKN function (PMID: 14519684, 16049031, 16714300, 20457763, 25939424). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Jun 11, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Young-onset Parkinson disease (Autosomal recessive inheritance) Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000731591.4 First in ClinVar: Apr 09, 2018 Last updated: Apr 20, 2024	Publications: PubMed (18) PubMed: 25939424‚ 14519684‚ 16049031‚ 25815004‚ 25907632‚ 23531835‚ 27182553‚ 27294386‚ 26855076‚ 25591737‚ 26836416‚ 12891670‚ 22555654‚ 15390068‚ 19636047‚ 10072423‚ 19162522‚ 19801972 Comment: The p.Arg275Trp variant in PRKN (also known as PARK2) has been reported in at least 7 compound heterozygous, 2 heterozygous, 1 homozygous and 11 other … (more) The p.Arg275Trp variant in PRKN (also known as PARK2) has been reported in at least 7 compound heterozygous, 2 heterozygous, 1 homozygous and 11 other (unknown zygosity) individuals with early-onset Parkinson disease (Keogh 2016, Zanellati 2015, Mitsuyama 2015, Bognar 2013, Morais 2016, Gorostidi 2016, and Anderson-Mooney 2016), and segregated with disease in 1 affected sibling (Anderson-Mooney 2016). This variant has also been reported in ClinVar (Variation ID 7050) and has been identified in 0.33% (426/128984) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies support that the p.Arg275Trp variant may impact protein function (Bertolin 2015, Fiesel 2015, Cookson 2003, Sriram 2005, and Zanellati 2015). In summary, this variant meets criteria to be classified as pathogenic for early-onset Parkinson disease in an autosomal recessive manner based upon biallelic occurrence in individuals with this disease and supporting functional evidence. ACMG/AMP Criteria applied: PP1, PS3_Moderate, PM3_Very Strong. (less)
Pathogenic (May 21, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Autosomal recessive juvenile Parkinson disease 2 Affected status: yes Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002768549.2 First in ClinVar: Dec 24, 2022 Last updated: Jul 23, 2024	Publications: PubMed (2) PubMed: 14519684‚ 30200940 Comment: A heterozygous missense variant was identified, NM_004562.2(PRKN):c.823C>T in exon 7 of 12 of the PRKN gene. This substitution is predicted to create a major amino … (more) A heterozygous missense variant was identified, NM_004562.2(PRKN):c.823C>T in exon 7 of 12 of the PRKN gene. This substitution is predicted to create a major amino acid change from an arginine to a tryptophan at position 275 of the protein; NP_004553.2(PRKN):p.(Arg275Trp). The arginine at this position has very high conservation (100 vertebrates, UCSC), and is located within the RING finger 1 domain (NCBI, PDB, UniProt). In silico software predicts this variant to be damaging (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD population database at a frequency of 0.2% (557 heterozygotes, 0 homozygotes). This variant has been previously reported as pathogenic and segregated with disease in multiple families with early onset Parkinson’s disease (ClinVar). In addition, functional studies show that this variant causes an aggregation of mutant Parkin protein as large cytoplasmic and nuclear inclusions (Cookson, MR. et al. (2003)) and disrupts glutamatergic synaptic transmission in hippocampal neurons (Zhu, M. et al. (2018)). Based on information available at the time of curation, this variant has been classified as PATHOGENIC. (less)
Likely pathogenic (May 27, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, Skane University Hospital Lund Accession: SCV005196794.1 First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024
Pathogenic (Oct 09, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV005413765.1 First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024	Publications: PubMed (8) PubMed: 10072423‚ 12730996‚ 14519684‚ 16049031‚ 19162522‚ 19636047‚ 32970363‚ 35747619 Comment: PS3, PS4 Number of individuals with the variant: 1
Pathogenic (Jun 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001246502.27 First in ClinVar: May 09, 2020 Last updated: Dec 22, 2024	Comment: PRKN: PM3:Very Strong, PP1:Strong, PS3, PM2:Supporting, PM5:Supporting Number of individuals with the variant: 14
Pathogenic (Oct 24, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019) Method: clinical testing	Autosomal recessive juvenile Parkinson disease 2 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000461689.3 First in ClinVar: Dec 06, 2016 Last updated: May 24, 2019	Publications: PubMed (12) PubMed: 10072423‚ 25907632‚ 24831986‚ 15970950‚ 16049031‚ 15390068‚ 12891670‚ 11558785‚ 14519684‚ 17766365‚ 25815004‚ 26188007 Comment: The PARK2 c.823C>T (p.Arg275Trp) missense variant is well described as one of the most common PARK2 variants (Hedrich et al. 2004; Mitsuyama et al. 2015). … (more) The PARK2 c.823C>T (p.Arg275Trp) missense variant is well described as one of the most common PARK2 variants (Hedrich et al. 2004; Mitsuyama et al. 2015). The p.Arg275Trp variant has been reported in at least nine studies in which it was found in over 102 patients with Parkinson disease (primarily with an early-onset phenotype) including one in a homozygous state, 12 in a compound heterozygous state, and 13 in a heterozygous state. Details of zygosity were not given for the remaining individuals (Abbas et al. 1999; Farrer et al. 2001; Lohmann et al. 2003; Hedrich et al. 2004; Klein et al. 2005; Lesage et al. 2008; Li H et al. 2014; Huttenlocher et al. 2015; Mitsuyama et al. 2015). The variant was also found in a heterozygous state in six unaffected individuals and five of 416 controls, while two additional controls were compound heterozygous for the p.Arg275Trp variant and a CNV in the PARK2 gene. The p.Arg275Trp variant is reported at a frequency of 0.0031 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies showed that the variant protein forms intracellular aggregates, is unable to degrade substrates, and results in mitochondrial impairment, in particular reduction in ATP cellular levels (Cookson et al. 2003; Sriram et al. 2005; Zanellati et al. 2015). Based on the collective evidence, the p.Arg275Trp variant is classified as pathogenic for juvenile-onset Parkinson disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
Pathogenic (Jun 07, 2019)	criteria provided, single submitter (Classification criteria August 2017) Method: clinical testing	Autosomal recessive juvenile Parkinson disease 2 (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München Accession: SCV001149862.1 First in ClinVar: Feb 03, 2020 Last updated: Feb 03, 2020	Zygosity: Compound Heterozygote Sex: male Tissue: blood
Pathogenic (Oct 23, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided (Autosomal unknown) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV001446437.1 First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020	Clinical Features: Dystonic disorder (present) , Action tremor (present) , Abnormal muscle tone (present) , Gait disturbance (present) Sex: male
Pathogenic (Sep 03, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Autosomal recessive juvenile Parkinson disease 2 Affected status: yes Allele origin: unknown	Baylor Genetics Accession: SCV001524819.1 First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021	Comment: This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Pathogenic (Nov 18, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Autosomal recessive juvenile Parkinson disease 2 Affected status: yes Allele origin: germline	Centogene AG - the Rare Disease Company Accession: SCV002059556.1 First in ClinVar: Jan 14, 2022 Last updated: Jan 14, 2022
Pathogenic (Aug 05, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV002064118.1 First in ClinVar: Jan 26, 2022 Last updated: Jan 26, 2022	Comment: DNA sequence analysis of the CLN5 gene demonstrated a sequence change, c.556G>A in exon 3, results in an amino acid change, p.Glu186Lys. This sequence change … (more) DNA sequence analysis of the CLN5 gene demonstrated a sequence change, c.556G>A in exon 3, results in an amino acid change, p.Glu186Lys. This sequence change does not appear to have been previously described in patients with CLN5-related disorders and has also not been described as a known benign sequence change in the CLN5 gene. The p.Glu186Lys change affects a highly conserved amino acid residue located in a domain of the CLN5 protein that is not known to be functional. The p.Glu186Lys substitution appears to be possibly damaging using several in-silico pathogenicity prediction tools (SIFT, CADD, Align GVGD, REVEL). (less)
Pathogenic (Mar 28, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: yes Allele origin: germline	AiLife Diagnostics, AiLife Diagnostics Accession: SCV002503260.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022	Publications: PubMed (25) PubMed: 10072423‚ 25591737‚ 19162522‚ 30609409‚ 14519684‚ 19801972‚ 26764160‚ 25939424‚ 20798600‚ 24082139‚ 16714300‚ 15390068‚ 26683220‚ 26836416‚ 20457763‚ 24831986‚ 12891670‚ 29353703‚ 22118943‚ 12730996‚ 31409571‚ 19636047‚ 11889248‚ 22555654‚ 30200940 Number of individuals with the variant: 13 Secondary finding: no
Pathogenic (Mar 24, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Autosomal recessive juvenile Parkinson disease 2 (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Genetics and Molecular Pathology, SA Pathology Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002556558.2 First in ClinVar: Aug 08, 2022 Last updated: Dec 17, 2022
Pathogenic (Jul 05, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Autosomal recessive juvenile Parkinson disease 2 Affected status: yes Allele origin: germline	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein Accession: SCV003807128.1 First in ClinVar: Mar 04, 2023 Last updated: Mar 04, 2023	Comment: ACMG classification criteria: PS3 supporting, PM3 very strong, PP1 strong, PP3 supporting Number of individuals with the variant: 1 Clinical Features: Maternal fever in pregnancy (present) , Delayed ability to walk (present) , Neurodevelopmental delay (present) , Neonatal respiratory distress (present) , Moderate global developmental delay … (more) Maternal fever in pregnancy (present) , Delayed ability to walk (present) , Neurodevelopmental delay (present) , Neonatal respiratory distress (present) , Moderate global developmental delay (present) , Premature birth (present) , Maternal first trimester fever (present) , Abnormality of the lung (present) , Neonatal sepsis (present) , Delayed fine motor development (present) , Intellectual disability, moderate (present) , Expressive language delay (present) , Global developmental delay (present) , Poor suck (present) , Delayed gross motor development (present) , Neonatal inspiratory stridor (present) , Delayed speech and language development (present) , Mild receptive language delay (present) , Receptive language delay (present) , Seizure (present) , Mild expressive language delay (present) , Premature birth following premature rupture of fetal membranes (present) , Oxygen desaturation on exertion (present) (less) Geographic origin: Brazil Method: Paired-end whole-genome sequencing
Pathogenic (Apr 05, 2022)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Athena Diagnostics Accession: SCV000843401.4 First in ClinVar: Nov 05, 2017 Last updated: Jan 26, 2024	Publications: PubMed (20) PubMed: 24831986‚ 12730996‚ 11889248‚ 22555654‚ 16049031‚ 10072423‚ 14519684‚ 15390068‚ 16714300‚ 30200940‚ 30537300‚ 30994895‚ 32970363‚ 33045815‚ 33845304‚ 27294386‚ 27182553‚ 17766365‚ 15970950‚ 11558785 Comment: The frequency of this variant in the general population is consistent with pathogenicity (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). Multiple individuals with early-onset … (more) The frequency of this variant in the general population is consistent with pathogenicity (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). Multiple individuals with early-onset Parkinson disease (EOPD) have been identified with this variant in both the compound heterozygous and heterozygous state. However, the association of heterozygous pathogenic PRKN variants with Parkinson disease remains inconclusive (PMID: 32970363). Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant leads to altered protein localization in the formation of visible aggregates (PMID: 14519684, 16049031, 16714300). In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. (less)
Pathogenic (Dec 19, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Autosomal recessive juvenile Parkinson disease 2 (Autosomal recessive inheritance) Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV004242496.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024	Comment: Criteria applied: PM3_VSTR,PS3,PM5_STR,PM1 Clinical Features: Parkinsonism with favorable response to dopaminergic medication (present) Sex: female
Pathogenic (Apr 04, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Autosomal recessive juvenile Parkinson disease 2 Affected status: unknown Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV004810121.1 First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024
Pathogenic (Feb 26, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Autosomal recessive juvenile Parkinson disease 2 Affected status: yes Allele origin: germline	Molecular Genetics, Royal Melbourne Hospital Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002503704.2 First in ClinVar: Apr 28, 2022 Last updated: Apr 15, 2024	Publications: PubMed (6) PubMed: 12891670‚ 14519684‚ 22555654‚ 24647965‚ 24831986‚ 25939424 Comment: This sequence change is predicted to replace arginine with tryptophan at codon 275 of the PRKN protein (p.Arg275Trp). The arginine residue is highly conserved (100 … (more) This sequence change is predicted to replace arginine with tryptophan at codon 275 of the PRKN protein (p.Arg275Trp). The arginine residue is highly conserved (100 vertebrates, UCSC), and located in the RING/Ubox-like zinc-binding domain (Uniprot). There is a large physicochemical difference between arginine and tryptophan. The variant is present in a large population cohort at a frequency of 0.2% (rs34424986, 557/282,496 alleles, 0 homozygotes in gnomAD v2.1). The variant has been identified with a second pathogenic allele in multiple individuals with early-onset Parkinson disease, and segregates with this condition in multiple families (PM3_VeryStrong, PP1_Strong; PMID: 12891670, 22555654, 24831986). The variant causes impaired localisation, mitochondrial ubiquitination, and protein formation in in vitro assays (PS3_Supporting; PMID: 14519684, 24647965, 25939424). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (PP3; 7/7 algorithms). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PP1_Strong, PS3_Supporting, PP3. (less)
Pathogenic (Sep 01, 2005)	no assertion criteria provided Method: literature only	PARKINSON DISEASE 2, AUTOSOMAL RECESSIVE JUVENILE Affected status: not provided Allele origin: germline	OMIM Accession: SCV000027666.2 First in ClinVar: Apr 04, 2013 Last updated: Dec 31, 2022	Publications: PubMed (3) PubMed: 15970950‚ 14519684‚ 16049031 Comment on evidence: In 2 of 65 unrelated Italian patients with autosomal recessive early-onset parkinsonism (600116), Klein et al. (2005) identified a 924C-T transition in exon 7 of … (more) In 2 of 65 unrelated Italian patients with autosomal recessive early-onset parkinsonism (600116), Klein et al. (2005) identified a 924C-T transition in exon 7 of the PARK2 gene, resulting in an arg275-to-trp (R275W) substitution. One patient was heterozygous for the R275W mutation, and the other patient was compound heterozygous for R275W and a 734A-T transversion in exon 6 of the PARK2 gene, resulting in a lys211-to-asn (K211N; 602544.0018) substitution. Cookson et al. (2003) found that R275W parkin was distributed in large cytoplasmic and nuclear inclusions in transfected human embryonic kidney cells and in primary cultured neurons. Accumulation/colocalization with vimentin (VIM; 193060) indicated that the inclusion bodies were aggresomes, a cellular response to misfolded protein. Sriram et al. (2005) showed that the R275W mutation results in reduced binding of substrate JTV1 (600859) but retained ubiquitination activity for self and substrates. They suggested that the R275W mutation could impair the ubiquitin-proteasome system through sequestration into aggresome-like structures in the cell and away from their site of normal function. (less)
Likely pathogenic (Jun 01, 2022)	no assertion criteria provided Method: provider interpretation	Ovarian cancer Affected status: yes Allele origin: inherited	Solve-RD Consortium Accession: SCV005091301.1 First in ClinVar: Oct 26, 2024 Last updated: Oct 26, 2024 Comment: Variant identified during reanalysis of unsolved cases by the Solve-RD project. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and … (more) Variant identified during reanalysis of unsolved cases by the Solve-RD project. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 779257. (less)	Comment: Variant confirmed as disease-causing by referring clinical team
Pathogenic (May 31, 2024)	no assertion criteria provided Method: clinical testing	PRKN-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004120437.3 First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024	Comment: The PRKN c.823C>T variant is predicted to result in the amino acid substitution p.Arg275Trp. This variant (previously denoted as c.924C>T using legacy nomenclature) has been … (more) The PRKN c.823C>T variant is predicted to result in the amino acid substitution p.Arg275Trp. This variant (previously denoted as c.924C>T using legacy nomenclature) has been reported in both the homozygous and compound heterozygous states in individuals with early-onset Parkinson disease (see for example Abbas et al. 1999. PubMed ID: 10072423; Oliveira et al. 2003. PubMed ID: 12730996). This variant is considered a founder variant in the European (Non-Finnish) population with an allele frequency of 0.33% (Hedrich et al. 2004. PubMed ID: 15390068). Missense prediction programs classify this amino acid substitution as damaging, and an in vitro functional study found that this substitution decreased the solubility of the PRKN protein (Hampe et al. 2006. PubMed ID: 16714300). This variant has been classified as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/7050/). Given the evidence, we interpret c.823C>T (p.Arg275Trp) as pathogenic. (less)
not provided (-)	no classification provided Method: phenotyping only	Autosomal recessive juvenile Parkinson disease 2 Affected status: unknown Allele origin: unknown	GenomeConnect, ClinGen Accession: SCV002074859.1 First in ClinVar: Feb 11, 2022 Last updated: Feb 11, 2022	Comment: Variant interpreted as Pathogenic and reported on 10-14-2019 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided … (more) Variant interpreted as Pathogenic and reported on 10-14-2019 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less) Clinical Features: Movement disorder (present) , Depression (present) , Abnormal pattern of respiration (present) , Abnormality of the male genitalia (present) Indication for testing: Diagnostic Age: 50-59 years Sex: male Method: Sanger Sequencing Testing laboratory: GeneDx Date variant was reported to submitter: 2019-10-14 Testing laboratory interpretation: Pathogenic
click to load more click to collapse

Comment:

Published functional studies show the parkin protein with R275W accumulated around the nucleus in aggregations of misfolded protein, while wild type protein localized primarily to the cytoplasm and nucleus (Cookson et al., 2003); Published functional studies demonstrated that R275W inhibited differentiation of neural stem cells to astrocyte and neurons (Park et al., 2017).; This variant is associated with the following publications: (PMID: 28808173, 25640678, 26556299, 30609409, 27294386, 28656059, 31409571, 22555654, 12730996, 12891670, 20798600, 16049031, 16714300, 14519684, 20457763, 15390068, 19801972, 22118943, 24082139, 19162522, 25591737, 26764160, 25939424, 26683220, 11889248, 10072423, 31324919, 30537300, 30200940, 29353703, 31147223, 27182553, 26855076, 15970950, 26188007, 25907632, 25815004, 24831986, 26836416, 30994895, 33045815, 33504652, 32970363, 34426522, 34434164, 35747619, 28716427, 33818904, 32864185, 33845304, 32740907, 19636047)

Comment:

Variant summary: PRKN c.823C>T (p.Arg275Trp) results in a non-conservative amino acid change located in the RING finger domain (IPR047535) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.003 in 1,607,042 control chromosomes in the gnomAD database v4.0 dataset, including 10 homozygotes. However, in gnomAD v4.0 many samples are now derived from large biobanks, which can include individuals with disease. The variant, c.823C>T, has been frequently reported in the literature in homozygous- and compound heterozygous state in individuals affected with Autosomal Recessive Juvenile Parkinson Disease, including families with multiple affected siblings (e.g. Nichols_2002, Khan_2003, Marder_2010, Kim_2021). These data indicate that the variant is very likely to be associated with disease. Several publications reported experimental evidence evaluating an impact on protein function, and demonstrated decreased protein stability with intracellular aggregates, impaired ubiquitination activity, and significantly decreased mitophagy, indicating a clear loss-of-function phenotype (e.g. Sriram_2005, Fiesel_2015, Yi_2019, Broadway_2022). Although the variant has also been reported in (apparent) heterozygous state in several affected individuals, recent large-scale studies examining the role of heterozygous PRKN variants (including R275W) found no association for increased Parkinson Disease risk (e.g. Yu_2021, Zhu_2022). The following publications have been ascertained in the context of this evaluation (PMID: 16049031, 25939424, 30994895, 12114481, 12764051, 20558392, 33497488, 32970363, 35640906, 35954270). 22 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 275 of the PRKN protein (p.Arg275Trp). This variant is present in population databases (rs34424986, gnomAD 0.3%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with dementia with Lewy bodies and/or Parkinson's disease (PMID: 10072423, 11889248, 12730996, 12891670, 15390068, 19162522, 19636047, 22118943, 22555654, 24082139, 24831986, 26836416). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 7050). 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 PRKN protein function. Experimental studies have shown that this missense change affects PRKN function (PMID: 14519684, 16049031, 16714300, 20457763, 25939424). For these reasons, this variant has been classified as Pathogenic.

Comment:

The p.Arg275Trp variant in PRKN (also known as PARK2) has been reported in at least 7 compound heterozygous, 2 heterozygous, 1 homozygous and 11 other (unknown zygosity) individuals with early-onset Parkinson disease (Keogh 2016, Zanellati 2015, Mitsuyama 2015, Bognar 2013, Morais 2016, Gorostidi 2016, and Anderson-Mooney 2016), and segregated with disease in 1 affected sibling (Anderson-Mooney 2016). This variant has also been reported in ClinVar (Variation ID 7050) and has been identified in 0.33% (426/128984) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies support that the p.Arg275Trp variant may impact protein function (Bertolin 2015, Fiesel 2015, Cookson 2003, Sriram 2005, and Zanellati 2015). In summary, this variant meets criteria to be classified as pathogenic for early-onset Parkinson disease in an autosomal recessive manner based upon biallelic occurrence in individuals with this disease and supporting functional evidence. ACMG/AMP Criteria applied: PP1, PS3_Moderate, PM3_Very Strong.

Comment:

A heterozygous missense variant was identified, NM_004562.2(PRKN):c.823C>T in exon 7 of 12 of the PRKN gene. This substitution is predicted to create a major amino acid change from an arginine to a tryptophan at position 275 of the protein; NP_004553.2(PRKN):p.(Arg275Trp). The arginine at this position has very high conservation (100 vertebrates, UCSC), and is located within the RING finger 1 domain (NCBI, PDB, UniProt). In silico software predicts this variant to be damaging (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD population database at a frequency of 0.2% (557 heterozygotes, 0 homozygotes). This variant has been previously reported as pathogenic and segregated with disease in multiple families with early onset Parkinson’s disease (ClinVar). In addition, functional studies show that this variant causes an aggregation of mutant Parkin protein as large cytoplasmic and nuclear inclusions (Cookson, MR. et al. (2003)) and disrupts glutamatergic synaptic transmission in hippocampal neurons (Zhu, M. et al. (2018)). Based on information available at the time of curation, this variant has been classified as PATHOGENIC.

Comment:

The PARK2 c.823C>T (p.Arg275Trp) missense variant is well described as one of the most common PARK2 variants (Hedrich et al. 2004; Mitsuyama et al. 2015). The p.Arg275Trp variant has been reported in at least nine studies in which it was found in over 102 patients with Parkinson disease (primarily with an early-onset phenotype) including one in a homozygous state, 12 in a compound heterozygous state, and 13 in a heterozygous state. Details of zygosity were not given for the remaining individuals (Abbas et al. 1999; Farrer et al. 2001; Lohmann et al. 2003; Hedrich et al. 2004; Klein et al. 2005; Lesage et al. 2008; Li H et al. 2014; Huttenlocher et al. 2015; Mitsuyama et al. 2015). The variant was also found in a heterozygous state in six unaffected individuals and five of 416 controls, while two additional controls were compound heterozygous for the p.Arg275Trp variant and a CNV in the PARK2 gene. The p.Arg275Trp variant is reported at a frequency of 0.0031 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies showed that the variant protein forms intracellular aggregates, is unable to degrade substrates, and results in mitochondrial impairment, in particular reduction in ATP cellular levels (Cookson et al. 2003; Sriram et al. 2005; Zanellati et al. 2015). Based on the collective evidence, the p.Arg275Trp variant is classified as pathogenic for juvenile-onset Parkinson disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

Comment:

DNA sequence analysis of the CLN5 gene demonstrated a sequence change, c.556G>A in exon 3, results in an amino acid change, p.Glu186Lys. This sequence change does not appear to have been previously described in patients with CLN5-related disorders and has also not been described as a known benign sequence change in the CLN5 gene. The p.Glu186Lys change affects a highly conserved amino acid residue located in a domain of the CLN5 protein that is not known to be functional. The p.Glu186Lys substitution appears to be possibly damaging using several in-silico pathogenicity prediction tools (SIFT, CADD, Align GVGD, REVEL).

Comment:

The frequency of this variant in the general population is consistent with pathogenicity (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). Multiple individuals with early-onset Parkinson disease (EOPD) have been identified with this variant in both the compound heterozygous and heterozygous state. However, the association of heterozygous pathogenic PRKN variants with Parkinson disease remains inconclusive (PMID: 32970363). Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant leads to altered protein localization in the formation of visible aggregates (PMID: 14519684, 16049031, 16714300). In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic.

Comment:

This sequence change is predicted to replace arginine with tryptophan at codon 275 of the PRKN protein (p.Arg275Trp). The arginine residue is highly conserved (100 vertebrates, UCSC), and located in the RING/Ubox-like zinc-binding domain (Uniprot). There is a large physicochemical difference between arginine and tryptophan. The variant is present in a large population cohort at a frequency of 0.2% (rs34424986, 557/282,496 alleles, 0 homozygotes in gnomAD v2.1). The variant has been identified with a second pathogenic allele in multiple individuals with early-onset Parkinson disease, and segregates with this condition in multiple families (PM3_VeryStrong, PP1_Strong; PMID: 12891670, 22555654, 24831986). The variant causes impaired localisation, mitochondrial ubiquitination, and protein formation in in vitro assays (PS3_Supporting; PMID: 14519684, 24647965, 25939424). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (PP3; 7/7 algorithms). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PP1_Strong, PS3_Supporting, PP3.

Comment:

The PRKN c.823C>T variant is predicted to result in the amino acid substitution p.Arg275Trp. This variant (previously denoted as c.924C>T using legacy nomenclature) has been reported in both the homozygous and compound heterozygous states in individuals with early-onset Parkinson disease (see for example Abbas et al. 1999. PubMed ID: 10072423; Oliveira et al. 2003. PubMed ID: 12730996). This variant is considered a founder variant in the European (Non-Finnish) population with an allele frequency of 0.33% (Hedrich et al. 2004. PubMed ID: 15390068). Missense prediction programs classify this amino acid substitution as damaging, and an in vitro functional study found that this substitution decreased the solubility of the PRKN protein (Hampe et al. 2006. PubMed ID: 16714300). This variant has been classified as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/7050/). Given the evidence, we interpret c.823C>T (p.Arg275Trp) as pathogenic.

Comment:

Variant interpreted as Pathogenic and reported on 10-14-2019 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Systematic Functional Analysis of PINK1 and PRKN Coding Variants.	Broadway BJ	Cells	2022	PMID: 35954270
Genome Sequencing in the Parkinson Disease Clinic.	Hill EJ	Neurology. Genetics	2022	PMID: 35747619
Heterozygous PRKN mutations are common but do not increase the risk of Parkinson's disease.	Zhu W	Brain : a journal of neurology	2022	PMID: 35640906
Frequency of mutations in PRKN, PINK1, and DJ1 in Patients With Early-Onset Parkinson Disease from neighboring countries in Central Europe.	Milanowski ŁM	Parkinsonism & related disorders	2021	PMID: 33845304
The Parkinson's Disease DNA Variant Browser.	Kim JJ	Movement disorders : official journal of the Movement Disorder Society	2021	PMID: 33497488
Analysis of Heterozygous PRKN Variants and Copy-Number Variations in Parkinson's Disease.	Yu E	Movement disorders : official journal of the Movement Disorder Society	2021	PMID: 32970363
Characterization of Recessive Parkinson Disease in a Large Multicenter Study.	Lesage S	Annals of neurology	2020	PMID: 33045815
Expanding the canvas of PRKN mutations in familial and early-onset Parkinson disease.	Pandey S	Parkinsonism & related disorders	2019	PMID: 31409571
The landscape of Parkin variants reveals pathogenic mechanisms and therapeutic targets in Parkinson's disease.	Yi W	Human molecular genetics	2019	PMID: 30994895
Interpretation of Genomic Sequencing Results in Healthy and Ill Newborns: Results from the BabySeq Project.	Ceyhan-Birsoy O	American journal of human genetics	2019	PMID: 30609409
Utility and implications of exome sequencing in early-onset Parkinson's disease.	Trinh J	Movement disorders : official journal of the Movement Disorder Society	2019	PMID: 30537300
Parkinson's disease-linked Parkin mutations impair glutamatergic signaling in hippocampal neurons.	Zhu M	BMC biology	2018	PMID: 30200940
Generation of an induced pluripotent stem cell line (CSC-44) from a Parkinson's disease patient carrying a compound heterozygous mutation (c.823C>T and EX6 del) in the PARK2 gene.	Marote A	Stem cell research	2018	PMID: 29353703
Genetic Mutation Analysis of Parkinson's Disease Patients Using Multigene Next-Generation Sequencing Panels.	Gorostidi A	Molecular diagnosis & therapy	2016	PMID: 27294386
Genomic mechanisms underlying PARK2 large deletions identified in a cohort of patients with PD.	Morais S	Neurology. Genetics	2016	PMID: 27182553
Neurocognitive & neuropsychiatric phenotypes of PARK2-associated early-onset Parkinson's disease in two siblings.	Anderson-Mooney AJ	Clinical neurology and neurosurgery	2016	PMID: 26855076
Exome sequencing in dementia with Lewy bodies.	Keogh MJ	Translational psychiatry	2016	PMID: 26836416
267 Spanish Exomes Reveal Population-Specific Differences in Disease-Related Genetic Variation.	Dopazo J	Molecular biology and evolution	2016	PMID: 26764160
PARKIN Inactivation Links Parkinson's Disease to Melanoma.	Hu HH	Journal of the National Cancer Institute	2015	PMID: 26683220
Heterozygote carriers for CNVs in PARK2 are at increased risk of Parkinson's disease.	Huttenlocher J	Human molecular genetics	2015	PMID: 26188007
Structural and Functional Impact of Parkinson Disease-Associated Mutations in the E3 Ubiquitin Ligase Parkin.	Fiesel FC	Human mutation	2015	PMID: 25939424
The KM-parkin-DB: A Sub-set MutationView Database Specialized for PARK2 (PARKIN) Variants.	Mitsuyama S	Human mutation	2015	PMID: 25907632
Mitochondrial dysfunction in Parkinson disease: evidence in mutant PARK2 fibroblasts.	Zanellati MC	Frontiers in genetics	2015	PMID: 25815004
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
Mutation analysis of PARK2 in a Uyghur family with early-onset Parkinson's disease in Xinjiang, China.	Li H	Journal of the neurological sciences	2014	PMID: 24831986
Phosphorylation of Parkin at Serine65 is essential for activation: elaboration of a Miro1 substrate-based assay of Parkin E3 ligase activity.	Kazlauskaite A	Open biology	2014	PMID: 24647965
Personalized genomic disease risk of volunteers.	Gonzalez-Garay ML	Proceedings of the National Academy of Sciences of the United States of America	2013	PMID: 24082139
Analysis of Leucine-rich repeat kinase 2 (LRRK2) and Parkinson protein 2 (parkin, PARK2) genes mutations in Slovak Parkinson disease patients.	Bognar C	General physiology and biophysics	2013	PMID: 23531835
Lewy body pathology and typical Parkinson disease in a patient with a heterozygous (R275W) mutation in the Parkin gene (PARK2).	Ruffmann C	Acta neuropathologica	2012	PMID: 22555654
DLB and PDD: a role for mutations in dementia and Parkinson disease genes?	Meeus B	Neurobiology of aging	2012	PMID: 22118943
The PINK1/Parkin-mediated mitophagy is compromised by PD-associated mutations.	Geisler S	Autophagy	2010	PMID: 20798600
Predictors of parkin mutations in early-onset Parkinson disease: the consortium on risk for early-onset Parkinson disease study.	Marder KS	Archives of neurology	2010	PMID: 20558392
Disease-causing mutations in parkin impair mitochondrial ubiquitination, aggregation, and HDAC6-dependent mitophagy.	Lee JY	The Journal of cell biology	2010	PMID: 20457763
Transcriptional repression of p53 by parkin and impairment by mutations associated with autosomal recessive juvenile Parkinson's disease.	da Costa CA	Nature cell biology	2009	PMID: 19801972
Parkin dosage mutations have greater pathogenicity in familial PD than simple sequence mutations.	Pankratz N	Neurology	2009	PMID: 19636047
Frequency of heterozygous Parkin mutations in healthy subjects: need for careful prospective follow-up examination of mutation carriers.	Brüggemann N	Parkinsonism & related disorders	2009	PMID: 19162522
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
Familial-associated mutations differentially disrupt the solubility, localization, binding and ubiquitination properties of parkin.	Sriram SR	Human molecular genetics	2005	PMID: 16049031
PINK1, Parkin, and DJ-1 mutations in Italian patients with early-onset parkinsonism.	Klein C	European journal of human genetics : EJHG	2005	PMID: 15970950
Distribution, type, and origin of Parkin mutations: review and case studies.	Hedrich K	Movement disorders : official journal of the Movement Disorder Society	2004	PMID: 15390068
RING finger 1 mutations in Parkin produce altered localization of the protein.	Cookson MR	Human molecular genetics	2003	PMID: 14519684
How much phenotypic variation can be attributed to parkin genotype?	Lohmann E	Annals of neurology	2003	PMID: 12891670
Parkin disease: a phenotypic study of a large case series.	Khan NL	Brain : a journal of neurology	2003	PMID: 12764051
Parkin mutations and susceptibility alleles in late-onset Parkinson's disease.	Oliveira SA	Annals of neurology	2003	PMID: 12730996
Linkage stratification and mutation analysis at the Parkin locus identifies mutation positive Parkinson's disease families.	Nichols WC	Journal of medical genetics	2002	PMID: 12114481
Parkin mutations in a patient with hemiparkinsonism-hemiatrophy: a clinical-genetic and PET study.	Pramstaller PP	Neurology	2002	PMID: 11889248
Lewy bodies and parkinsonism in families with parkin mutations.	Farrer M	Annals of neurology	2001	PMID: 11558785
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
click to load more click to collapse

Text-mined citations for rs34424986 ...

These 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 Jan 13, 2025

ClinVar Genomic variation as it relates to human health

NM_004562.3(PRKN):c.823C>T (p.Arg275Trp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs34424986 ...