rs191486604

Variant names:

• chr6-161350208-C-T
• rs191486604
• NM_004562.3:c.1289G>A

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM5 PP3_Strong PP5_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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G430S) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00023 (0 hom.)
• Consequence: PRKN NM_004562.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 5.91
• Publications: 74 publications found

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 Gene-Disease associations (from GenCC):

• autosomal recessive juvenile Parkinson disease 2

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Genomics England PanelApp
• Parkinson disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• young-onset Parkinson disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_004562.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-161350209-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1120007.
• 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 356016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKN	NM_004562.3	c.1289G>A	p.Gly430Asp	missense_variant	Exon 12 of 12	ENST00000366898.6	NP_004553.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKN	ENST00000366898.6	c.1289G>A	p.Gly430Asp	missense_variant	Exon 12 of 12	1	NM_004562.3	ENSP00000355865.1

Frequencies

GnomAD3 genomes AF: 0.000131 AC: 20 AN: 152146 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.0000603 AC: 15 AN: 248694 AF XY: 0.0000593

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 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.: 0 Cov.: 30 AF XY: 0.000234 AC XY: 170 AN XY: 726086

African (AFR) AF: 0.0000299 AC: 1 AN: 33438

American (AMR) AF: 0.00 AC: 0 AN: 44664

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39656

South Asian (SAS) AF: 0.00 AC: 0 AN: 86126

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52996

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.000281 AC: 312 AN: 1110550

Other (OTH) AF: 0.000464 AC: 28 AN: 60286

GnomAD4 genome AF: 0.000131 AC: 20 AN: 152146 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74312

African (AFR) AF: 0.0000724 AC: 3 AN: 41438

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 68036

Other (OTH) AF: 0.000478 AC: 1 AN: 2094

Alfa AF: 0.000176 Hom.: 1

Bravo AF: 0.000132

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.0000989 AC: 12

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:5

Oct 26, 2018

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Mar 29, 2022

AiLife Diagnostics, AiLife Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 22, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP3, PM1, PM2, PS3, PS4_moderate -

Mar 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Apr 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PRKN: PM3:Very Strong, PS3, PM2 -

Autosomal recessive juvenile Parkinson disease 2 Pathogenic:3

May 05, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PRKN c.1289G>A (p.Gly430Asp) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. The variant allele was found at a frequency of 6.8e-05 in 280080 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in PRKN causing Autosomal Recessive Juvenile Parkinson Disease 2, allowing no conclusion about variant significance. c.1289G>A has been observed in multiple individuals affected with Autosomal Recessive Juvenile Parkinson Disease 2 (example: Keogh_2016, Periquet_2001, Khan_2003). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 11179010, 26836416, 12764051). ClinVar contains an entry for this variant (Variation ID: 356016). Based on the evidence outlined above, the variant was classified as pathogenic. -

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Sep 08, 2024

Molecular Genetics, Royal Melbourne Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change in PRKN is predicted to replace glycine with aspartic acid at codon 430, p.(Gly430Asp). The Gly430 residue is highly conserved (100 vertebrates, Multiz Alignments), and is located in the RING2 annotated domain. There is a moderate physicochemical difference between glycine and aspartic acid. The highest population minor allele frequency in the population database gnomAD v4.1 is 0.03% (328/1,178,586 alleles) in the European (non-Finnish) population, consistent with recessive disease. This variant has been detected as homozygous and compound heterozygous in multiple individuals with early-onset Parkinson disease and segregates with disease in multiple families (PMID: 18486522, 20558392, 31324919). Functional studies with limited validation assaying cellular mitophagy are supportive of a damaging effect on protein function (PMID: 20098416). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.96) and predicts no impact on splicing (SpliceAI) for the nucleotide change. Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.7.0, this variant is classified as PATHOGENIC. Following criteria are met: PM3_Strong, PP1_Moderate, PP3_Moderate, PM2_Supporting, PS3_Supporting. -

PRKN-related disorder Pathogenic:1

Feb 26, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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;C1140680:Ovarian cancer;C1868675:Autosomal recessive juvenile Parkinson disease 2 Pathogenic:1

May 08, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ovarian cancer Pathogenic:1

Jun 01, 2022

Solve-RD Consortium

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: provider interpretation

Variant confirmed as disease-causing by referring clinical team -

Young-onset Parkinson disease Pathogenic:1

Feb 10, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D;.;.;.;.;.
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Pathogenic	1.0	D;D;D;D;.;D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
PhyloP100		5.9
PrimateAI	Uncertain	0.57	T
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	D
GERP RS		5.3
Varity_R		0.98
gMVP		0.84
Mutation Taster		=2/98	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs191486604; hg19: chr6-161771240;