rs34424986

Positions:

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 10P and 2B. PM1PP5_Very_StrongBP4BS1_Supporting

The NM_004562.3(PRKN):c.823C>T(p.Arg275Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00301 in 1,614,016 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R275Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0022 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0031 ( 9 hom. )

Consequence

PRKN
NM_004562.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:26O:1

Conservation

PhyloP100: 2.05

Variant links:

Genes affected

PRKN (HGNC:8607): (parkin RBR E3 ubiquitin protein ligase) The precise function of this gene is unknown; however, the encoded protein is a component of a multiprotein E3 ubiquitin ligase complex that mediates the targeting of substrate proteins for proteasomal degradation. Mutations in this gene are known to cause Parkinson disease and autosomal recessive juvenile Parkinson disease. Alternative splicing of this gene produces multiple transcript variants encoding distinct isoforms. Additional splice variants of this gene have been described but currently lack transcript support. [provided by RefSeq, Jul 2008]

PRKN links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM1

In a region_of_interest SYT11 binding 2 (size 36) in uniprot entity PRKN_HUMAN there are 5 pathogenic changes around while only 2 benign (71%) in NM_004562.3

PP5

Variant 6-161785820-G-A is Pathogenic according to our data. Variant chr6-161785820-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 7050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-161785820-G-A is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.20339364). . Strength limited to SUPPORTING due to the PP5.

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.0031 (4525/1461730) while in subpopulation NFE AF= 0.00375 (4171/1111924). AF 95% confidence interval is 0.00366. There are 9 homozygotes in gnomad4_exome. There are 2196 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKN	NM_004562.3 linkuse as main transcript	c.823C>T	p.Arg275Trp	missense_variant	7/12	ENST00000366898.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKN	ENST00000366898.6 linkuse as main transcript	c.823C>T	p.Arg275Trp	missense_variant	7/12	1	NM_004562.3	P1	O60260-1

Frequencies

GnomAD3 genomes

AF:

0.00218

AC:

332

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000796

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00294

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00160

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00341

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.00194

AC:

486

AN:

251096

Hom.:

AF XY:

0.00191

AC XY:

259

AN XY:

135720

show subpopulations

Gnomad AFR exome

AF:

0.000370

Gnomad AMR exome

AF:

0.00145

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000523

Gnomad FIN exome

AF:

0.00120

Gnomad NFE exome

AF:

0.00330

Gnomad OTH exome

AF:

0.00196

GnomAD4 exome

AF:

0.00310

AC:

4525

AN:

1461730

Hom.:

Cov.:

AF XY:

0.00302

AC XY:

2196

AN XY:

727150

show subpopulations

Gnomad4 AFR exome

AF:

0.000418

Gnomad4 AMR exome

AF:

0.00148

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000742

Gnomad4 FIN exome

AF:

0.000861

Gnomad4 NFE exome

AF:

0.00375

Gnomad4 OTH exome

AF:

0.00265

GnomAD4 genome

AF:

0.00218

AC:

332

AN:

152286

Hom.:

Cov.:

AF XY:

0.00234

AC XY:

174

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.000794

Gnomad4 AMR

AF:

0.00294

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00160

Gnomad4 NFE

AF:

0.00341

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00269

Hom.:

Bravo

AF:

0.00221

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00519

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00291

AC:

ExAC

AF:

0.00203

AC:

246

EpiCase

AF:

0.00327

EpiControl

AF:

0.00273

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:26Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive juvenile Parkinson disease 2

Pathogenic:13Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 13, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	Nov 18, 2019	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2005	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 03, 2020	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Feb 26, 2021	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Mar 24, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Dec 19, 2023	Criteria applied: PM3_VSTR,PS3,PM5_STR,PM1 -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Jun 07, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 25, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Oct 24, 2017	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Apr 04, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Jul 05, 2022	ACMG classification criteria: PS3 supporting, PM3 very strong, PP1 strong, PP3 supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 21, 2020	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. -

not provided

Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 25, 2023	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 05, 2019	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). -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 05, 2022	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Mar 28, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 21, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	PRKN: PM3:Very Strong, PP1:Strong, PS3, PM2:Supporting, PM5:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 18, 2017	- -

Young-onset Parkinson disease

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 11, 2020	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 03, 2021	- -

PRKN-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 21, 2023

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. -

Lung carcinoma;C0919267:Ovarian neoplasm;C1843632:Leprosy, susceptibility to, 2;C1868675:Autosomal recessive juvenile Parkinson disease 2

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

See cases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Apr 24, 2019

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM3,PP3. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.84

BayesDel_addAF

Uncertain

0.074

BayesDel_noAF

Pathogenic

0.33

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.79

D;.;.;.;.;T

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Benign

0.70

LIST_S2

Pathogenic

0.98

D;D;D;.;D;D

M_CAP

Uncertain

0.099

MetaRNN

Benign

0.20

T;T;T;T;T;T

MetaSVM

Pathogenic

0.84

MutationTaster

Benign

0.96

A;A;A;A;A;A

PrimateAI

Uncertain

0.61

PROVEAN

Pathogenic

-7.2

D;D;D;D;D;D

REVEL

Pathogenic

0.75

Sift

Pathogenic

0.0

D;D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D;D

Polyphen

1.0

D;.;.;.;.;.

Vest4

0.94

MVP

0.97

MPC

0.37

ClinPred

0.058

GERP RS

4.9

Varity_R

0.90

gMVP

0.72

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over