VCV000468584.26 - ClinVar

NM_004562.3(PRKN):c.101A>G (p.Gln34Arg)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(6)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Benign/Likely benign

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_004562.3(PRKN):c.101A>G (p.Gln34Arg)

Variation ID: 468584 Accession: VCV000468584.26

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 6q26 6: 162443380 (GRCh38) [ NCBI UCSC ] 6: 162864412 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Dec 26, 2017	Oct 20, 2024	Jul 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_004562.3:c.101A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_004553.2:p.Gln34Arg	missense
NM_013987.3:c.101A>G	NP_054642.2:p.Gln34Arg	missense
NM_013988.3:c.101A>G	NP_054643.2:p.Gln34Arg	missense
NC_000006.12:g.162443380T>C
NC_000006.11:g.162864412T>C
NG_008289.2:g.289423A>G

... more HGVS ... less HGVS

Protein change

Q34R

Other names

Canonical SPDI

NC_000006.12:162443379:T:C

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00819 (C)

Allele frequency Help The frequency of the allele represented by this VCV record.

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00246

The Genome Aggregation Database (gnomAD), exomes 0.00292

The Genome Aggregation Database (gnomAD) 0.00303

Trans-Omics for Precision Medicine (TOPMed) 0.00323

Exome Aggregation Consortium (ExAC) 0.00343

1000 Genomes Project 0.00819

Links

ClinGen: CA4090514 dbSNP: rs148851677 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
PRKN		-	-	GRCh38 GRCh37	560	711

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Autosomal recessive juvenile Parkinson disease 2	Likely benign (2)	criteria provided, multiple submitters, no conflicts	Apr 28, 2017	RCV000537921.10
not provided	Benign/Likely benign (3)	criteria provided, multiple submitters, no conflicts	Jul 1, 2024	RCV001507187.17
not specified	Benign (1)	criteria provided, single submitter	Nov 12, 2020	RCV001662570.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely benign (Apr 28, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Autosomal recessive juvenile Parkinson disease 2 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001315878.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Publications: PubMed (10) PubMed: 22995991‚ 18514563‚ 16793319‚ 22766139‚ 21348451‚ 16500134‚ 25558820‚ 25174650‚ 21996382‚ 26274610 Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
Likely benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Autosomal recessive juvenile Parkinson disease 2 (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard Accession: SCV001435218.1 First in ClinVar: Oct 03, 2020 Last updated: Oct 03, 2020	Publications: PubMed (4) PubMed: 16793319‚ 22995991‚ 22766139‚ 21348451 Comment: The heterozygous p.Gln34Arg variant in PARK2 has been identified in at least 5 individuals with Parkinson disease (PMID: 16793319, 22766139), but also has been identified … (more) The heterozygous p.Gln34Arg variant in PARK2 has been identified in at least 5 individuals with Parkinson disease (PMID: 16793319, 22766139), but also has been identified in >1% of South Asian chromosomes and 7 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In vitro functional studies provide some evidence that the p.Gln34Arg variant may not impact protein structure (PMID: 21348451). However, these types of assays may not accurately represent biological function. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely benign for Parkinson disease. (less)
Benign (Nov 12, 2020)	criteria provided, single submitter (Athena Diagnostics criteria) Method: clinical testing	not specified Affected status: unknown Allele origin: unknown	Athena Diagnostics Accession: SCV001879939.1 First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021	Publications: PubMed (9) PubMed: 16500134‚ 16793319‚ 18514563‚ 19087301‚ 21348451‚ 26274610‚ 31429726‚ 21996382‚ 22766139
Benign (Jan 15, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000645378.7 First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024
Likely benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005226274.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
Benign (Jul 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV004158600.10 First in ClinVar: Nov 20, 2023 Last updated: Oct 20, 2024	Comment: PRKN: BS1, BS2 Number of individuals with the variant: 2

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Comment:

The heterozygous p.Gln34Arg variant in PARK2 has been identified in at least 5 individuals with Parkinson disease (PMID: 16793319, 22766139), but also has been identified in >1% of South Asian chromosomes and 7 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In vitro functional studies provide some evidence that the p.Gln34Arg variant may not impact protein structure (PMID: 21348451). However, these types of assays may not accurately represent biological function. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely benign for Parkinson disease.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Parkin gene mutations are not common, but its epigenetic inactivation is a frequent event and predicts poor survival in advanced breast cancer patients.	Wahabi K	BMC cancer	2019	PMID: 31429726
Parkinson's Disease in Saudi Patients: A Genetic Study.	Al-Mubarak BR	PloS one	2015	PMID: 26274610
Defining neurodegeneration on Guam by targeted genomic sequencing.	Steele JC	Annals of neurology	2015	PMID: 25558820
Mutation analysis of patients with neurodegenerative disorders using NeuroX array.	Ghani M	Neurobiology of aging	2015	PMID: 25174650
An informatics approach to analyzing the incidentalome.	Berg JS	Genetics in medicine : official journal of the American College of Medical Genetics	2013	PMID: 22995991
PARK2 gene mutations in early onset Parkinson's disease patients of South India.	Padmaja MV	Neuroscience letters	2012	PMID: 22766139
Mutations in the parkin gene are a minor cause of Parkinson's disease in the South African population.	Haylett WL	Parkinsonism & related disorders	2012	PMID: 21996382
Impact of autosomal recessive juvenile Parkinson's disease mutations on the structure and interactions of the parkin ubiquitin-like domain.	Safadi SS	Biochemistry	2011	PMID: 21348451
Molecular analysis of the parkin gene in South African patients diagnosed with Parkinson's disease.	Bardien S	Parkinsonism & related disorders	2009	PMID: 18514563
Significance of the parkin and PINK1 gene in Jordanian families with incidences of young-onset and juvenile parkinsonism.	Myhre R	BMC neurology	2008	PMID: 19087301
Molecular pathogenesis of Parkinson's disease: identification of mutations in the Parkin gene in Indian patients.	Biswas A	Parkinsonism & related disorders	2006	PMID: 16793319
Parkin mutations in familial and sporadic Parkinson's disease among Indians.	Chaudhary S	Parkinsonism & related disorders	2006	PMID: 16500134
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Text-mined citations for rs148851677 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_004562.3(PRKN):c.101A>G (p.Gln34Arg)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs148851677 ...