rs191486604

Positions:

chr6-161350208-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_004562.3(PRKN):c.1289G>A(p.Gly430Asp) variant causes a missense change. The variant allele was found at a frequency of 0.000224 in 1,611,754 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00023 ( 0 hom. )

Consequence

PRKN
NM_004562.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 5.91

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:

PRKN (HGNC:):

PRKN links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a mutagenesis_site Loss of self-ubiquitination. (size 0) in uniprot entity PRKN_HUMAN

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.949

PP5

Variant 6-161350208-C-T is Pathogenic according to our data. Variant chr6-161350208-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 356016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRKN	NM_004562.3 linkuse as main transcript	c.1289G>A	p.Gly430Asp	missense_variant	12/12	ENST00000366898.6	NP_004553.2	O60260-1X5DR79

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRKN	ENST00000366898.6 linkuse as main transcript	c.1289G>A	p.Gly430Asp	missense_variant	12/12	1	NM_004562.3	ENSP00000355865.1		O60260-1

Frequencies

GnomAD3 genomes

AF:

0.000131

AC:

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000235

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000603

AC:

AN:

248694

Hom.:

AF XY:

0.0000593

AC XY:

AN XY:

134804

show subpopulations

Gnomad AFR exome

AF:

0.0000628

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000125

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000234

AC:

341

AN:

1459608

Hom.:

Cov.:

AF XY:

0.000234

AC XY:

170

AN XY:

726086

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000281

Gnomad4 OTH exome

AF:

0.000464

GnomAD4 genome

AF:

0.000131

AC:

AN:

152146

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74312

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000235

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000167

Hom.:

Bravo

AF:

0.000132

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.0000989

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 22, 2023	PP3, PM1, PM2, PS3, PS4_moderate -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	PRKN: PM3:Very Strong, PS3, PM2 -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 20, 2023	This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 430 of the PRKN protein (p.Gly430Asp). This variant is present in population databases (rs191486604, gnomAD 0.01%). This missense change has been observed in individuals with early-onset Parkinson's disease (PMID: 11179010, 12764051, 15090472, 18486522). It has also been observed to segregate with disease in related individuals. This variant is also known as 1390G>A. ClinVar contains an entry for this variant (Variation ID: 356016). 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: 16049031, 16339143, 20404107, 20604804, 20798600, 23751051). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 26, 2018	The best available variant frequency is uninformative because it is below the disease allele frequency. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Located in potentially critical domain of the protein. Occurs in three or more cases with a recessive pathogenic variant in the same gene. Damaging to protein function(s) relevant to disease mechanism. -
Pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Mar 29, 2022	- -

PRKN-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 26, 2024

The PRKN c.1289G>A variant is predicted to result in the amino acid substitution p.Gly430Asp. This variant was reported in individuals with autosomal recessive early-onset Parkinson disease (Lücking et al. 2000. PubMed ID: 10824074; Mellick et al. 2009. PubMed ID: 18486522; Figure 1A, Lesage et al. 2020. PubMed ID: 33045815). Functional studies showed that this variant could impact protein function (Sriram et al. 2005. PubMed ID: 16049031; Fiesel et al. 2015. PubMed ID: 25939424; Yi et al. 2019. PubMed ID: 30994895). This variant is reported in 0.013% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as likely pathogenic. -

Lung cancer;C0919267:Ovarian neoplasm;C1868675:Autosomal recessive juvenile Parkinson disease 2

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 04, 2022

- -

Ovarian cancer

Pathogenic:1

Likely pathogenic, no assertion criteria provided

provider interpretation

Solve-RD Consortium

Jun 01, 2022

Variant confirmed as disease-causing by referring clinical team -

Autosomal recessive juvenile Parkinson disease 2

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

The PARK2 c.1289G>A (p.Gly430Asp) missense variant has been reported in at least four studies in which it was found in a total of five individuals with Parkinson disease with onset of disease under the age of 40 years, including one who was homozygous for the variant and four who were compound heterozygous (Scherfler et al. 2004; Mellick et al. 2009; Haylett et al. 2012; Angeli et al. 2013). The p.Gly430Asp variant was absent from 212 ethnically-matched control chromosomes but is reported at a frequency of 0.00035 in the European American population of the Exome Sequencing Project. Fiesel et al. (2015) demonstrated through molecular dynamic simulations that the p.Gly430Asp variant alters the active site of the enzyme through the introduction of a negative charge. In addition, the in vitro E3 ligase activity of the variant protein on a model substrate was reduced and mitochondrial relocalization was hampered in cells transfected with variant PARK2, as compared to wild type (Sriram et al. 2005; Okatsu et al. 2010; Fiesel et al. 2015). Based on the collective evidence, the p.Gly430Asp variant is classified as pathogenic for the juvenile form of Parkinson disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Young-onset Parkinson disease

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 10, 2015

The p.Gly430Asp variant in PARK2 has been reported in at least 4 compound heterozygous (Khan 2003, Oliveira 2003) and 1 homozygous (Mellick 2009) individuals with Parkinson disease out of a combined total of 794 cases. This variant has also been identified in 0.02% (10/56,440) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs191486604). This difference in frequency is considered statistically significant (7/794 vs 10/56440; p <0.0001). Computational prediction tools and conservation analysis suggest that the p.Gly430Asp variant may impact the protein and in vitro functional studies provide some evidence that the p.Gly430Asp variant may impact protein function (Sriram 2005). However, these types of assays and analyses may not accurately represent biological function. Homozygous or compound heterozygous mutations in PARK2 have been associated with Parkinson disease. In summary, although additional studies are required to fully establish its clinical significance, the p.Gly430Arg variant is likely pathogenic for autosomal recessive Parkinson disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.55

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.88

D;.;.;.;.;.

Eigen

Pathogenic

0.91

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Uncertain

0.89

LIST_S2

Pathogenic

1.0

D;D;D;D;.;D

M_CAP

Uncertain

0.18

MetaRNN

Pathogenic

0.95

D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

PrimateAI

Uncertain

0.57

PROVEAN

Pathogenic

-5.3

D;D;D;.;D;D

REVEL

Pathogenic

0.96

Sift

Pathogenic

0.0

D;D;D;.;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D;D

Polyphen

1.0

D;.;.;.;.;.

Vest4

0.95

MVP

0.98

MPC

0.40

ClinPred

0.99

GERP RS

5.3

Varity_R

0.98

gMVP

0.84

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