ClinVar Miner

Submissions for variant NM_004562.3(PRKN):c.823C>T (p.Arg275Trp) (rs34424986)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000007466 SCV000461689 pathogenic Parkinson disease 2 2017-10-24 criteria provided, single submitter clinical testing 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.
Invitae RCV000514660 SCV000549208 pathogenic not provided 2019-12-30 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 275 of the PRKN protein (p.Arg275Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs34424986, ExAC 0.3%). This variant has been reported in individuals and families affected with Parkinson's disease (PD) (PMID: 10072423, 19636047, 12891670, 22555654, 15390068, 12730996, 24831986, 11889248), dementia with Lewy bodies (PMID: 26836416) and Parkinson's disease with dementia (PMID: 22118943). This variant has been observed on the opposite chromosome (in trans) from other pathogenic variants in multiple individuals affected with early-onset PD (PMID: 12891670, 24831986, 22555654). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. This variant has also been reported in the heterozygous state in affected and unaffected individuals (PMID: 19636047, 12891670, 19162522, 24082139, 22555654, 15390068, 12730996). ClinVar contains an entry for this variant (Variation ID: 7050). Experimental studies have shown that this variant impairs the function of the PRKN protein by causing a change in conformation, reducing solubility, and increasing cytoplasmic and nuclear aggregates (PMID: 16049031, 14519684, 16714300, 25939424, 20457763). For these reasons, this variant has been classified as Pathogenic.
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000514660 SCV000610254 pathogenic not provided 2017-04-18 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000612317 SCV000731591 pathogenic Young-onset Parkinson disease 2020-03-30 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
Athena Diagnostics Inc RCV000514660 SCV000843401 pathogenic not provided 2017-11-30 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763143 SCV000893705 pathogenic Leprosy 2; Lung cancer; Parkinson disease 2; Neoplasm of ovary 2018-10-31 criteria provided, single submitter clinical testing
Institute of Human Genetics,Klinikum rechts der Isar RCV000007466 SCV001149862 pathogenic Parkinson disease 2 2019-06-07 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000514660 SCV001246502 pathogenic not provided 2020-03-01 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001197176 SCV001367812 pathogenic Parkinsonism 2019-04-24 criteria provided, single submitter clinical testing This variant was classified as: Benign. The following ACMG criteria were applied in classifying this variant: BS1,BS2. This variant was detected in heterozygous state.
OMIM RCV000007466 SCV000027666 pathogenic Parkinson disease 2 2005-09-01 no assertion criteria provided literature only

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