Reported previously in individuals with Parkinson disease; however, the R1325Q variant was also observed in healthy control individuals in published literature (Zhang et al., 2018; Foo et al., 2014; Lesage et al., 2009); Reported as heterozygous in an individual with Parkinson disease and as homozygous in the individual's mother with tremor in published literature (Nuytemans et al., 2008); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 19405094, 19472409, 31161537, 21885347, 18197194, 34426522, 20301387, 18973807, 30598256, 33272183, 33454605, 30049590, 24565865, 19357115, Kalogeropulou2022[functionalstudy])
ClinVar Genomic variation as it relates to human health
NM_198578.4(LRRK2):c.3974G>A (p.Arg1325Gln)
Germline
Classification
Help
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)
Help
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
Likely pathogenic(1); Uncertain significance(4)
Likely pathogenic(1); Uncertain significance(4)
6
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.3974G>A (p.Arg1325Gln)
Variation ID: 39175 Accession: VCV000039175.12
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 12q12 12: 40308481 (GRCh38) [ NCBI UCSC ] 12: 40702283 (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 Nov 24, 2024 Jan 25, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_198578.4:c.3974G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_940980.4:p.Arg1325Gln missense NC_000012.12:g.40308481G>A NC_000012.11:g.40702283G>A NG_011709.1:g.88471G>A - Protein change
- R1325Q
- Other names
-
p.Arg1325Gln
- Canonical SPDI
- NC_000012.12:40308480:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe 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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Trans-Omics for Precision Medicine (TOPMed) 0.00015
Exome Aggregation Consortium (ExAC) 0.00018
The Genome Aggregation Database (gnomAD), exomes 0.00019
The Genome Aggregation Database (gnomAD) 0.00021
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00023
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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 |
3559 | 3584 | |
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. |
|---|---|---|---|---|
| Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
|
Jan 25, 2024 | RCV000032449.11 | |
| Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Dec 6, 2023 | RCV001731324.4 |
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. |
|
|---|---|---|---|---|---|
|
Uncertain significance
(Aug 05, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001982910.3
First in ClinVar: Oct 30, 2021 Last updated: Mar 04, 2023 |
Comment:
Reported previously in individuals with Parkinson disease; however, the R1325Q variant was also observed in healthy control individuals in published literature (Zhang et al., 2018; … (more)
Reported previously in individuals with Parkinson disease; however, the R1325Q variant was also observed in healthy control individuals in published literature (Zhang et al., 2018; Foo et al., 2014; Lesage et al., 2009); Reported as heterozygous in an individual with Parkinson disease and as homozygous in the individual's mother with tremor in published literature (Nuytemans et al., 2008); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 19405094, 19472409, 31161537, 21885347, 18197194, 34426522, 20301387, 18973807, 30598256, 33272183, 33454605, 30049590, 24565865, 19357115, Kalogeropulou2022[functionalstudy]) (less)
|
|
|
Uncertain significance
(Sep 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal dominant Parkinson disease 8
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000826589.3
First in ClinVar: Oct 10, 2018 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1325 of the LRRK2 protein (p.Arg1325Gln). … (more)
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1325 of the LRRK2 protein (p.Arg1325Gln). This variant is present in population databases (rs72546338, gnomAD 0.03%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Parkinson disease (PMID: 18197194, 19405094, 21885347, 30598256). ClinVar contains an entry for this variant (Variation ID: 39175). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
|
|
|
Uncertain significance
(Jan 25, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal dominant Parkinson disease 8
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV005049897.1
First in ClinVar: Jun 09, 2024 Last updated: Jun 09, 2024 |
|
|
|
Likely pathogenic
(Apr 21, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal dominant Parkinson disease 8
Affected status: no
Allele origin:
germline
|
Centogene AG - the Rare Disease Company
Accession: SCV002059832.1
First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022 |
|
|
|
Uncertain significance
(Dec 06, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV005408306.1
First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024 |
Comment:
BS2
Number of individuals with the variant: 1
|
|
|
not provided
(-)
|
no classification provided
Method: literature only
|
Autosomal dominant Parkinson disease 8
Affected status: not provided
Allele origin:
unknown
|
GeneReviews
Accession: SCV000056106.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022 |
|
Comment:
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1325 of the LRRK2 protein (p.Arg1325Gln). This variant is present in population databases (rs72546338, gnomAD 0.03%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Parkinson disease (PMID: 18197194, 19405094, 21885347, 30598256). ClinVar contains an entry for this variant (Variation ID: 39175). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Comment:
BS2
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:
Reported previously in individuals with Parkinson disease; however, the R1325Q variant was also observed in healthy control individuals in published literature (Zhang et al., 2018; Foo et al., 2014; Lesage et al., 2009); Reported as heterozygous in an individual with Parkinson disease and as homozygous in the individual's mother with tremor in published literature (Nuytemans et al., 2008); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 19405094, 19472409, 31161537, 21885347, 18197194, 34426522, 20301387, 18973807, 30598256, 33272183, 33454605, 30049590, 24565865, 19357115, Kalogeropulou2022[functionalstudy])
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1325 of the LRRK2 protein (p.Arg1325Gln). This variant is present in population databases (rs72546338, gnomAD 0.03%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Parkinson disease (PMID: 18197194, 19405094, 21885347, 30598256). ClinVar contains an entry for this variant (Variation ID: 39175). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Comment:
BS2
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| LRRK2 Parkinson Disease. | Adam MP | - | 2023 | PMID: 20301387 |
| Impact of 100 LRRK2 variants linked to Parkinson's disease on kinase activity and microtubule binding. | Kalogeropulou AF | The Biochemical journal | 2022 | PMID: 35950872 |
| The genetic structure of the Turkish population reveals high levels of variation and admixture. | Kars ME | Proceedings of the National Academy of Sciences of the United States of America | 2021 | PMID: 34426522 |
| Systematically analyzing rare variants of autosomal-dominant genes for sporadic Parkinson's disease in a Chinese cohort. | Yang N | Neurobiology of aging | 2019 | PMID: 30598256 |
| Genetic analysis of LRRK2 in Parkinson's disease in Han Chinese population. | Zhang JR | Neurobiology of aging | 2018 | PMID: 30049590 |
| LRRK2 protective haplotype and full sequencing study in REM sleep behavior disorder. | Ouled Amar Bencheikh B | Parkinsonism & related disorders | 2018 | PMID: 29576439 |
| Motor and nonmotor heterogeneity of LRRK2-related and idiopathic Parkinson's disease. | Marras C | Movement disorders : official journal of the Movement Disorder Society | 2016 | PMID: 27091104 |
| Association of LRRK2 exonic variants with susceptibility to Parkinson's disease: a case-control study. | Ross OA | The Lancet. Neurology | 2011 | PMID: 21885347 |
| Relative contribution of simple mutations vs. copy number variations in five Parkinson disease genes in the Belgian population. | Nuytemans K | Human mutation | 2009 | PMID: 19405094 |
| Molecular analyses of the LRRK2 gene in European and North African autosomal dominant Parkinson's disease. | Lesage S | Journal of medical genetics | 2009 | PMID: 19357115 |
| Founder mutation p.R1441C in the leucine-rich repeat kinase 2 gene in Belgian Parkinson's disease patients. | Nuytemans K | European journal of human genetics : EJHG | 2008 | PMID: 18197194 |
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Text-mined citations for rs72546338 ...
HelpThese 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 Nov 25, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.