rs137853054

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP5BP4

The NM_004562.3(PRKN):c.719C>T(p.Thr240Met) variant causes a missense change. The variant allele was found at a frequency of 0.000274 in 1,610,406 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00028 ( 1 hom. )

Consequence

PRKN
NM_004562.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:14U:1

Conservation

PhyloP100: 7.04

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 Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 6-161973317-G-A is Pathogenic according to our data. Variant chr6-161973317-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 7054.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=4, Uncertain_significance=1, Pathogenic=9}. Variant chr6-161973317-G-A is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.22862995). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRKN	NM_004562.3 linkuse as main transcript	c.719C>T	p.Thr240Met	missense_variant	6/12	ENST00000366898.6	NP_004553.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRKN	ENST00000366898.6 linkuse as main transcript	c.719C>T	p.Thr240Met	missense_variant	6/12	1	NM_004562.3	ENSP00000355865	P1	O60260-1

Frequencies

GnomAD3 genomes

AF:

0.000237

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000720

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00228

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.000374

AC:

AN:

251448

Hom.:

AF XY:

0.000508

AC XY:

AN XY:

135896

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000376

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00170

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000237

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000278

AC:

405

AN:

1458124

Hom.:

Cov.:

AF XY:

0.000339

AC XY:

246

AN XY:

725658

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00168

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000184

Gnomad4 OTH exome

AF:

0.000382

GnomAD4 genome

AF:

0.000243

AC:

AN:

152282

Hom.:

Cov.:

AF XY:

0.000269

AC XY:

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.000719

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00228

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000256

Hom.:

Bravo

AF:

0.000366

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000288

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:14Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Autosomal recessive juvenile Parkinson disease 2

Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	Aug 18, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2006	- -
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	Illumina Laboratory Services, Illumina	Oct 20, 2017	Across a selection of the available literature, the PARK2 c.719C>T (p.Thr240Met) missense variant has been reported in a biallelic state in at least six individuals with Parkinson disease (PD) from three families, with age of onset ranging from 22 to 40 years (Madegowda et al. 2005; Deng et al. 2006; Camargos et al. 2009). Two additional siblings with PD onset at age 45 and 55 were heterozygous for the p.Thr240Met variant, a second missense variant, and a deletion of exon three and parts of introns two and three, zygosity unspecified (Al-Mubarak et al. 2015). Notably, one unaffected 56-year-old individual was found to have the same genotype as her four affected compound heterozygous siblings who all displayed symptoms by age 38, suggesting reduced penetrance (Deng et al. 2006). In addition, the p.Thr240Met variant has been reported in a heterozygous state in at least four unrelated affected individuals (onset at age 33, <51, 55, and unspecified) as well as in five unaffected individuals from the same family as the five compound heterozygous individuals described above (Foroud et al. 2003; Deng et al. 2006; Bras et al. 2008; Camargos et al. 2009; Moura et al. 2013). Based on this information, this variant is expected to confer recessive disease although dominant disease implications cannot be completely ruled out. The p.Thr240Met variant was absent from 660 control chromosomes and is reported at a frequency of 0.00172 in the South Asian population of the Genome Aggregation Database. Compared to the wildtype, the parkin protein containing the p.Thr240Met variant, which occurs at a moderately conserved residue in the RING1 protein domain, showed decreased Î²-catenin ubiquitinating activity when expressed in HEK293T cells (Lin et al. 2015). Two other missense variants at the same position have also been reported in association with PD. Based on the collective evidence, the p.Thr240Met variant is classified as pathogenic for juvenile 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	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 30, 2023	Variant summary: PARK2 c.719C>T (p.Thr240Met) results in a non-conservative amino acid change located in the RING/Ubox-like zinc-binding domain (IPR041170) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00037 in 251448 control chromosomes (gnomAD). c.719C>T has been reported in the literature in multiple bi-allelic individuals affected with Autosomal Recessive Juvenile Parkinson Disease (examples: Foroud_2003, Periquet_2003, Madegowda_2005, Camargos_2009) and in at-least one of these families the variant segregated with the disease (Deng_2006). 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: 19205068 , 12764050, 12629236, 16227559, 16476817). Eleven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic/likely pathogenic (n=10) and VUS (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Intergen, Intergen Genetics and Rare Diseases Diagnosis Center	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 26, 2024	- -

not provided

Pathogenic:5Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Mar 29, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 27, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32807662, 16367892, 24167364, 12629236, 26274610, 26556299, 12764050, 18973255, 23275044, 18519021, 16476817, 19205068, 30200940, 31409571, 33019779, 32802956, 32849182, 33640967, 18211709, 25877876, 34426522, 32870915, 33045815, 34434164, 16227559, 30994895) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	PRKN: PM3:Very Strong, PM2, PP1, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 09, 2024	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 240 of the PRKN protein (p.Thr240Met). This variant is present in population databases (rs137853054, gnomAD 0.2%). This missense change has been observed in individual(s) with early onset Parkinson's disease (PMID: 12764050, 16476817, 18519021, 18973255, 19205068, 23275044, 26274610). 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: 7054). 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. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 03, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jul 06, 2016	- -

Young-onset Parkinson disease

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 03, 2021

- -

Ovarian neoplasm

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

May 03, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Uncertain

0.085

BayesDel_noAF

Pathogenic

0.33

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.28

T;.;.;.;.;T

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.95

D;D;D;.;D;D

M_CAP

Benign

0.033

MetaRNN

Benign

0.23

T;T;T;T;T;T

MetaSVM

Uncertain

0.25

MutationTaster

Benign

1.0

N;N;N;N;N;N

PrimateAI

Benign

0.40

PROVEAN

Benign

-2.0

N;N;N;N;N;N

REVEL

Uncertain

0.64

Sift

Uncertain

0.0020

D;D;D;D;D;D

Sift4G

Uncertain

0.0030

D;D;D;T;T;D

Polyphen

0.88

P;.;.;.;.;.

Vest4

0.71

MVP

0.97

MPC

0.14

ClinPred

0.15

GERP RS

5.1

Varity_R

0.36

gMVP

0.46

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