VCV000039198.27 - ClinVar

NM_198578.4(LRRK2):c.4883G>C (p.Arg1628Pro)

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.

(12)

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.

Conflicting classifications of pathogenicity
Uncertain significance(1); Benign(3); Likely benign(3)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_198578.4(LRRK2):c.4883G>C (p.Arg1628Pro)

Variation ID: 39198 Accession: VCV000039198.27

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 12q12 12: 40320043 (GRCh38) [ NCBI UCSC ] 12: 40713845 (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	Apr 4, 2013	Dec 22, 2024	Nov 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_198578.4:c.4883G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_940980.4:p.Arg1628Pro	missense
NC_000012.12:g.40320043G>C
NC_000012.11:g.40713845G>C
NG_011709.1:g.100033G>C
	Q5S007:p.Arg1628Pro

... more HGVS ... less HGVS

Protein change

R1628P

Other names

Canonical SPDI

NC_000012.12:40320042:G: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.

0.00639 (C)

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

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00092

Trans-Omics for Precision Medicine (TOPMed) 0.00187

1000 Genomes Project 30x 0.00562

1000 Genomes Project 0.00639

Links

ClinGen: CA343606 UniProtKB: Q5S007#VAR_024951 dbSNP: rs33949390 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.
LRRK2		-	-	GRCh38 GRCh37	3868	3893

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 dominant Parkinson disease 8	Conflicting interpretations of pathogenicity (6)	criteria provided, conflicting classifications	Mar 26, 2024	RCV000032472.26
Early onset Alzheimer disease with behavioral disturbance	no classifications from unflagged records (1)	no classifications from unflagged records	Nov 29, 2023	RCV000984891.4
Spinocerebellar atrophy	no classifications from unflagged records (1)	no classifications from unflagged records	Nov 29, 2023	RCV000984892.4
Autosomal dominant Parkinson disease 8 Klippel-Feil syndrome 1, autosomal dominant	no classifications from unflagged records (1)	no classifications from unflagged records	Nov 29, 2023	RCV000984893.4
not provided	Benign/Likely benign (2)	criteria provided, multiple submitters, no conflicts	Nov 1, 2024	RCV001705623.2
Parkinson disease	Benign (1)	criteria provided, single submitter	May 4, 2023	RCV003993756.1

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.
Benign (Sep 01, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001825827.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021	Comment: This variant is associated with the following publications: (PMID: 27812003, 25511328, 27133195, 24997548, 29209554, 29029963, 30954774, 30917570, 24095219, 26311745, 26930193, 18412265, 25761573, 22575234, 18716801, 20018409, … (more) This variant is associated with the following publications: (PMID: 27812003, 25511328, 27133195, 24997548, 29209554, 29029963, 30954774, 30917570, 24095219, 26311745, 26930193, 18412265, 25761573, 22575234, 18716801, 20018409, 19672984, 24488318, 21885347, 20571044, 20186690, 23421816, 19699188, 25243190, 20642453) (less)
Benign (Oct 14, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Autosomal dominant Parkinson disease 8 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001014940.6 First in ClinVar: Dec 17, 2019 Last updated: Feb 20, 2024
Likely benign (Nov 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: SCV005433491.1 First in ClinVar: Dec 22, 2024 Last updated: Dec 22, 2024	Comment: LRRK2: BS1 Number of individuals with the variant: 1
Likely benign (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Autosomal dominant Parkinson disease 8 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000378612.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Publications: PubMed (9) PubMed: 26930193‚ 18688798‚ 18412265‚ 25243190‚ 19699188‚ 18781329‚ 18716801‚ 20642453‚ 21885347 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 (Jan 08, 2024)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Autosomal dominant Parkinson disease 8 Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001138691.3 First in ClinVar: Jan 09, 2020 Last updated: Jan 26, 2024
Uncertain significance (Mar 26, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Autosomal dominant Parkinson disease 8 Affected status: unknown Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV004807246.1 First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024
Benign (May 04, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Parkinson disease Affected status: yes Allele origin: germline	Molecular Genetics, Royal Melbourne Hospital Additional submitter: Shariant Australia, Australian Genomics Accession: SCV004812816.1 First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024	Comment: East Asian population allele frequency is 1.844% (rs33949390, 413/19,932 alleles, 3 homozygotes in gnomAD v2.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.5.1, … (more) East Asian population allele frequency is 1.844% (rs33949390, 413/19,932 alleles, 3 homozygotes in gnomAD v2.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.5.1, this variant is classified as BENIGN. Following criteria are met: BA1 (less)
not provided (-)	no classification provided Method: literature only	Autosomal dominant Parkinson disease 8 Affected status: not provided Allele origin: unknown	GeneReviews Accession: SCV000056132.2 First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022	Publications: PubMed (2) PubMed: 18412265‚ 20301387 BookShelf: NBK1208 BookShelf: NBK1208
Pathogenic (Feb 28, 2019)	Flagged submission flagged submission Method: provider interpretation Reason: Outlier claim with insufficient supporting evidence Source: ClinGen	Parkinson disease 8, autosomal dominant Affected status: yes Allele origin: germline	Codex Genetics Limited Accession: SCV000996007.1 First in ClinVar: Jan 06, 2020 Last updated: Jan 06, 2020	Publications: PubMed (2) PubMed: 20301387‚ 18412265 Age: 39-62 years Sex: mixed
Likely pathogenic (Feb 28, 2019)	Flagged submission flagged submission Method: provider interpretation Reason: Outlier claim with insufficient supporting evidence Source: ClinGen	Early onset Alzheimer disease with behavioral disturbance Affected status: yes Allele origin: germline	Codex Genetics Limited Accession: SCV000996008.1 First in ClinVar: Jan 06, 2020 Last updated: Jan 06, 2020	Publications: PubMed (2) PubMed: 20301387‚ 18412265 Age: 40-49 years Sex: female
Pathogenic (Feb 28, 2019)	Flagged submission flagged submission Method: provider interpretation Reason: Outlier claim with insufficient supporting evidence Source: ClinGen	Spinocerebellar atrophy Affected status: yes Allele origin: germline	Codex Genetics Limited Accession: SCV000996009.1 First in ClinVar: Jan 06, 2020 Last updated: Jan 06, 2020	Publications: PubMed (2) PubMed: 20301387‚ 18412265 Age: 30-39 years Sex: female
Pathogenic (Feb 28, 2019)	Flagged submission flagged submission Method: provider interpretation Reason: Outlier claim with insufficient supporting evidence Source: ClinGen	Parkinson disease 8, autosomal dominant Klippel-Feil syndrome 1, autosomal dominant Affected status: yes Allele origin: germline	Codex Genetics Limited Accession: SCV000996010.1 First in ClinVar: Jan 06, 2020 Last updated: Jan 06, 2020	Publications: PubMed (2) PubMed: 20301387‚ 18412265 Age: 60-69 years Sex: male
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Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more

Comment:

This variant is associated with the following publications: (PMID: 27812003, 25511328, 27133195, 24997548, 29209554, 29029963, 30954774, 30917570, 24095219, 26311745, 26930193, 18412265, 25761573, 22575234, 18716801, 20018409, 19672984, 24488318, 21885347, 20571044, 20186690, 23421816, 19699188, 25243190, 20642453)

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:

East Asian population allele frequency is 1.844% (rs33949390, 413/19,932 alleles, 3 homozygotes in gnomAD v2.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.5.1, this variant is classified as BENIGN. Following criteria are met: BA1

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
LRRK2 Parkinson Disease.	Adam MP	-	2023	PMID: 20301387
Parkinson-Related LRRK2 Mutation R1628P Enables Cdk5 Phosphorylation of LRRK2 and Upregulates Its Kinase Activity.	Shu Y	PloS one	2016	PMID: 26930193
LRRK2 G2385R and R1628P mutations are associated with an increased risk of Parkinson's disease in the Malaysian population.	Gopalai AA	BioMed research international	2014	PMID: 25243190
Association of LRRK2 exonic variants with susceptibility to Parkinson's disease: a case-control study.	Ross OA	The Lancet. Neurology	2011	PMID: 21885347
14-3-3 binding to LRRK2 is disrupted by multiple Parkinson's disease-associated mutations and regulates cytoplasmic localization.	Nichols RJ	The Biochemical journal	2010	PMID: 20642453
LRRK2 R1628P contributes to Parkinson's disease susceptibility in Chinese Han populations from mainland China.	Yu L	Brain research	2009	PMID: 19699188
LRRK2 R1628P increases risk of Parkinson's disease: replication evidence.	Tan EK	Human genetics	2008	PMID: 18781329
The LRRK2 Arg1628Pro variant is a risk factor for Parkinson's disease in the Chinese population.	Lu CS	Neurogenetics	2008	PMID: 18716801
Lrrk2 R1628P in non-Chinese Asian races.	Tan EK	Annals of neurology	2008	PMID: 18688798
Analysis of Lrrk2 R1628P as a risk factor for Parkinson's disease.	Ross OA	Annals of neurology	2008	PMID: 18412265

Text-mined citations for rs33949390 ...

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 Jan 13, 2025

ClinVar Genomic variation as it relates to human health

NM_198578.4(LRRK2):c.4883G>C (p.Arg1628Pro)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs33949390 ...