NM_004562.3(PRKN):c.823C>T (p.Arg275Trp) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (10 submissions)
Last evaluated:: Jun 1, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000514660.51

Allele description [Variation Report for NM_004562.3(PRKN):c.823C>T (p.Arg275Trp)]

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

Gene:

PRKN:parkin RBR E3 ubiquitin protein ligase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

6q26

Genomic location:

Preferred name:

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

HGVS:

NC_000006.12:g.161785820G>A
NG_008289.2:g.946983C>T
NM_004562.3:c.823C>TMANE SELECT
NM_013987.3:c.739C>T
NM_013988.3:c.376C>T
NP_004553.2:p.Arg275Trp
NP_054642.2:p.Arg247Trp
NP_054643.2:p.Arg126Trp
NC_000006.11:g.162206852G>A
NM_004562.2:c.823C>T
O60260:p.Arg275Trp

Protein change:

R126W; ARG275TRP

Links:

UniProtKB: O60260#VAR_019752; OMIM: 602544.0017; dbSNP: rs34424986

NCBI 1000 Genomes Browser:

rs34424986

Molecular consequence:

NM_004562.3:c.823C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_013987.3:c.739C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_013988.3:c.376C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided; RECLASSIFIED - ADRA2C POLYMORPHISM; RECLASSIFIED - ADRB1 POLYMORPHISM
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000549208	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 21, 2024)	germline	clinical testing	PubMed (18) [See all records that cite these PMIDs] 10072423, 11889248, 12730996, 12891670, 15390068, 19162522, 19636047, 22118943, 22555654, 24082139, 24831986, 26836416, 14519684, 16049031, 16714300, 20457763, 25939424, 28492532
SCV000610254	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 18, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000843401	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	Pathogenic (Apr 5, 2022)	unknown	clinical testing	PubMed (21) [See all records that cite these PMIDs] 24831986, 12730996, 11889248, 22555654, 16049031, 10072423, 14519684, 15390068, 16714300, 30200940, 30537300, 30994895, 32970363, 33045815, 33845304, 27294386, 27182553, 17766365, 15970950, 11558785, 26467025
SCV001246502	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Jun 1, 2024)	germline	clinical testing	Citation Link,
SCV001446437	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 23, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001823764	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Jul 25, 2023)	germline	clinical testing	Citation Link,
SCV002064118	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 5, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002503260	AiLife Diagnostics, AiLife Diagnostics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 28, 2022)	germline	clinical testing	PubMed (26) [See all records that cite these PMIDs] 10072423, 25591737, 19162522, 30609409, 14519684, 19801972, 26764160, 25939424, 20798600, 24082139, 16714300, 15390068, 26683220, 26836416, 20457763, 24831986, 12891670, 29353703, 22118943, 12730996, 31409571, 19636047, 11889248, 22555654, 30200940, 25741868
SCV005196794	Clinical Genetics Laboratory, Skane University Hospital Lund	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (May 27, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005413765	Mayo Clinic Laboratories, Mayo Clinic	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 9, 2023)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 10072423, 12730996, 14519684, 16049031, 19162522, 19636047, 32970363, 35747619, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	27	not provided	not provided	1	not provided	clinical testing
not provided	germline	unknown	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group, Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Utility and implications of exome sequencing in early-onset Parkinson's disease.

Trinh J, Lohmann K, Baumann H, Balck A, Borsche M, Brüggemann N, Dure L, Dean M, Volkmann J, Tunc S, Prasuhn J, Pawlack H, Imhoff S, Lill CM, Kasten M, Bauer P, Rolfs A; International Parkinson's Disease Genomics Consortium (IPDGC), Klein C.

Mov Disord. 2019 Jan;34(1):133-137. doi: 10.1002/mds.27559. Epub 2018 Dec 10.

PubMed [citation]

PMID:: 30537300
PMCID:: PMC8950081

See all PubMed Citations (40)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000549208.10

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (18)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics, SCV000610254.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	0.002402	not provided	not provided

From Athena Diagnostics, SCV000843401.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (21)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From CeGaT Center for Human Genetics Tuebingen, SCV001246502.27

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	14	not provided	not provided	clinical testing	not provided

Description

PRKN: PM3:Very Strong, PP1:Strong, PS3, PM2:Supporting, PM5:Supporting

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		14	not provided	not provided	not provided

From Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen, SCV001446437.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	not provided		not provided	not provided	not provided	not provided

From GeneDx, SCV001823764.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

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)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genetic Services Laboratory, University of Chicago, SCV002064118.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

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).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From AiLife Diagnostics, AiLife Diagnostics, SCV002503260.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	13	not provided	not provided	clinical testing	PubMed (26)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		13	not provided	not provided	not provided

From Clinical Genetics Laboratory, Skane University Hospital Lund, SCV005196794.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Mayo Clinic Laboratories, Mayo Clinic, SCV005413765.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (9)

Description

PS3, PS4

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Jan 13, 2025

Relating variation to medicine