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

gnomAD frequency: 0.00226  dbSNP: rs34424986

Total submissions: 30

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000007466	SCV000461689	pathogenic	Autosomal recessive juvenile 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000514660	SCV000549208	pathogenic	not provided	2024-01-21	criteria provided, single submitter	clinical testing	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.
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, Mass General Brigham Personalized Medicine	RCV000612317	SCV000731591	pathogenic	Young-onset Parkinson disease	2020-06-11	criteria provided, single submitter	clinical testing	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.
Athena Diagnostics	RCV000514660	SCV000843401	pathogenic	not provided	2022-04-05	criteria provided, single submitter	clinical testing	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.
Fulgent Genetics, Fulgent Genetics	RCV000763143	SCV000893705	pathogenic	Leprosy, susceptibility to, 2; Lung carcinoma; Autosomal recessive juvenile Parkinson disease 2; Ovarian neoplasm	2018-10-31	criteria provided, single submitter	clinical testing
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000007466	SCV001149862	pathogenic	Autosomal recessive juvenile Parkinson disease 2	2019-06-07	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000514660	SCV001246502	pathogenic	not provided	2024-06-01	criteria provided, single submitter	clinical testing	PRKN: PM3:Very Strong, PP1:Strong, PS3, PM2:Supporting, PM5:Supporting
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001197176	SCV001367812	pathogenic	See cases	2019-04-24	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM3,PP3.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000514660	SCV001446437	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000007466	SCV001524819	pathogenic	Autosomal recessive juvenile Parkinson disease 2	2020-09-03	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Fulgent Genetics, Fulgent Genetics	RCV000612317	SCV001652805	pathogenic	Young-onset Parkinson disease	2021-05-03	criteria provided, single submitter	clinical testing
GeneDx	RCV000514660	SCV001823764	pathogenic	not provided	2023-07-25	criteria provided, single submitter	clinical testing	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)
Revvity Omics, Revvity	RCV000007466	SCV002019520	pathogenic	Autosomal recessive juvenile Parkinson disease 2	2022-05-25	criteria provided, single submitter	clinical testing
Centogene AG - the Rare Disease Company	RCV000007466	SCV002059556	pathogenic	Autosomal recessive juvenile Parkinson disease 2	2019-11-18	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000514660	SCV002064118	pathogenic	not provided	2019-08-05	criteria provided, single submitter	clinical testing	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).
AiLife Diagnostics, AiLife Diagnostics	RCV000514660	SCV002503260	pathogenic	not provided	2022-03-28	criteria provided, single submitter	clinical testing
Molecular Genetics, Royal Melbourne Hospital	RCV000007466	SCV002503704	pathogenic	Autosomal recessive juvenile Parkinson disease 2	2021-02-26	criteria provided, single submitter	clinical testing	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.
Genetics and Molecular Pathology, SA Pathology	RCV000007466	SCV002556558	pathogenic	Autosomal recessive juvenile Parkinson disease 2	2021-03-24	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000007466	SCV002768549	pathogenic	Autosomal recessive juvenile Parkinson disease 2	2020-05-21	criteria provided, single submitter	clinical testing	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.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000007466	SCV003807128	pathogenic	Autosomal recessive juvenile Parkinson disease 2	2022-07-05	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS3 supporting, PM3 very strong, PP1 strong, PP3 supporting
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000007466	SCV004241079	pathogenic	Autosomal recessive juvenile Parkinson disease 2	2023-12-13	criteria provided, single submitter	clinical testing	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.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000007466	SCV004242496	pathogenic	Autosomal recessive juvenile Parkinson disease 2	2023-12-19	criteria provided, single submitter	clinical testing	Criteria applied: PM3_VSTR,PS3,PM5_STR,PM1
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000007466	SCV004810121	pathogenic	Autosomal recessive juvenile Parkinson disease 2	2024-04-04	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000514660	SCV005196794	likely pathogenic	not provided	2022-05-27	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000514660	SCV005413765	pathogenic	not provided	2023-10-09	criteria provided, single submitter	clinical testing	PS3, PS4
OMIM	RCV000007466	SCV000027666	pathogenic	Autosomal recessive juvenile Parkinson disease 2	2005-09-01	no assertion criteria provided	literature only
GenomeConnect, ClinGen	RCV000007466	SCV002074859	not provided	Autosomal recessive juvenile Parkinson disease 2		no assertion provided	phenotyping only	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.
PreventionGenetics, part of Exact Sciences	RCV003390652	SCV004120437	pathogenic	PRKN-related disorder	2024-05-31	no assertion criteria provided	clinical testing	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.
Solve-RD Consortium	RCV004766985	SCV005091301	likely pathogenic	Ovarian cancer	2022-06-01	no assertion criteria provided	provider interpretation	Variant confirmed as disease-causing by referring clinical team