rs34637584
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Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 9P and 1B. PP3PP5_Very_StrongBP4
The NM_198578.4(LRRK2):c.6055G>A(p.Gly2019Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000411 in 1,613,804 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 Likely pathogenic,risk factor (★★).
Frequency
Genomes: 𝑓 0.00036 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00042 ( 1 hom. )
Consequence
LRRK2
NM_198578.4 missense
NM_198578.4 missense
Scores
14
3
2
Clinical Significance
Conservation
PhyloP100: 9.66
Genes affected
LRRK2 (HGNC:18618): (leucine rich repeat kinase 2) This gene is a member of the leucine-rich repeat kinase family and encodes a protein with an ankryin repeat region, a leucine-rich repeat (LRR) domain, a kinase domain, a DFG-like motif, a RAS domain, a GTPase domain, a MLK-like domain, and a WD40 domain. The protein is present largely in the cytoplasm but also associates with the mitochondrial outer membrane. Mutations in this gene have been associated with Parkinson disease-8. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
PP3
Multiple lines of computational evidence support a deleterious effect 11: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Eigen, M_CAP, MutationAssessor, phyloP100way_vertebrate, PrimateAI, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
PP5
Variant 12-40340400-G-A is Pathogenic according to our data. Variant chr12-40340400-G-A is described in ClinVar as [Likely_pathogenic, risk_factor]. Clinvar id is 1940.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-40340400-G-A is described in Lovd as [Pathogenic]. Variant chr12-40340400-G-A is described in Lovd as [Likely_pathogenic].
BP4
Computational evidence support a benign effect (MetaRNN=0.15880463). . Strength limited to SUPPORTING due to the PP5.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| LRRK2 | NM_198578.4 | c.6055G>A | p.Gly2019Ser | missense_variant | 41/51 | ENST00000298910.12 | NP_940980.4 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| LRRK2 | ENST00000298910.12 | c.6055G>A | p.Gly2019Ser | missense_variant | 41/51 | 1 | NM_198578.4 | ENSP00000298910 | P1 |
Frequencies
GnomAD3 genomes 0.000362 AC: 55AN: 152064Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000526 AC: 132AN: 251154Hom.: 1 AF XY: 0.000553 AC XY: 75AN XY: 135730
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GnomAD4 exome AF: 0.000417 AC: 609AN: 1461622Hom.: 1 Cov.: 31 AF XY: 0.000413 AC XY: 300AN XY: 727112
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GnomAD4 genome 0.000361 AC: 55AN: 152182Hom.: 0 Cov.: 33 AF XY: 0.000336 AC XY: 25AN XY: 74402
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ClinVar
Significance: Pathogenic/Likely pathogenic; risk factor
Submissions summary: Pathogenic:24Other:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Autosomal dominant Parkinson disease 8 Pathogenic:14Other:1
| Pathogenic, criteria provided, single submitter | clinical testing | Courtagen Diagnostics Laboratory, Courtagen Life Sciences | May 14, 2014 | - - |
| not provided, no classification provided | literature only | GeneReviews | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 03, 2021 | Variant summary: LRRK2 c.6055G>A (p.Gly2019Ser) results in a non-conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00053 in 251154 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than expected for a pathogenic variant in LRRK2 causing Parkinson Disease 8, Autosomal Dominant, allowing no conclusion about variant significance. c.6055G>A has been widely reported in the literature in multiple individuals affected with Parkinson Disease 8, Autosomal Dominant as a common founder mutation associated with age dependent penetrance among European populations (example, Kachergus_2005) and this association continues to be subsequently acknowledged and cited by others. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (example, Greggio_2006). The most pronounced variant effect results in increased tendency to form inclusion bodies. Secondly, neurons and neuronal cell lines undergo cell death after expression of mutant protein. Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Aug 02, 2021 | The LRRK2 c.6055G>A (p.Gly2019Ser) missense variant is the most common variant reported in individuals with LRRK2-related Parkinson disease (PD) (Saunders-Pullman et al. 2006). Across a selection of available literature, the p.Gly2019Ser variant has been identified in a heterozygous state in 131 individuals and in a homozygous state in two individuals with Parkinson disease (Kachergus et al. 2005; Nichols et al. 2005; Bar-Shira et al. 2009). The p.Gly2019Ser variant was absent from 3487 healthy matched controls in these studies and is reported at a frequency of 0.008396 in the Ashkenazi Jewish population of the Genome Aggregation Database (version 2.1.1). Analysis showed that carriers of the p.Gly2019Ser variant, who were of Ashkenazi Jewish descent, shared a 243 kb haplotype, suggesting a common founder in this population (Bar-Shira et al. 2009). The variant is also noted to exist as a founder variant in North African Berbers (Saunders-Pullman et al. 2006). The p.Gly2019Ser variant is associated with reduced penetrance; penetrance for heterozygotes is age dependent, and varies in different populations ranging from 25% - 42% up to age 80 (Saunders-Pullman et al. 2006). Generally clinical features are indistinguishable between individuals with LRRK2-related PD compared to idiopathic PD. However, studies have shown the p.Gly2019Ser variant results in a slightly milder clinical course than seen in individuals with Parkinson disease (Saunders-Pullman et al. 2006). Mitochondrial dysfunction and lysosomal dysfunction play central roles in PD pathophysiology. Functional studies showed increased mitochondrial DNA damage in iPSC-derived neural cells from patients carrying the p.Gly2019Ser variant than in cells from healthy controls. In patient cells in which the p.Gly2019Ser variant was repaired with zinc finger nuclease, reduced mitochondrial DNA damage was observed at levels seen in healthy control cells (Sanders et al. 2014). The p.Gly2019Ser variant has also been demonstrated to result in enlarged lysosomes, impaired lysosomal function, and increased kinase activity (Henry et al. 2015). Based on the collective evidence, the p.Gly2019Ser variant is classified as pathogenic for LRRK2-related Parkinson disease. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | 3billion | May 22, 2022 | The variant is observed at an allele frequency greater than expected for the associated disorder in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.97; 3Cnet: 0.95). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000001940). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Apr 28, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 26, 2024 | This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 2019 of the LRRK2 protein (p.Gly2019Ser). This variant is present in population databases (rs34637584, gnomAD 0.9%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Parkinson’s disease (PD) and is one of the most common known genetic causes of PD. This variant has been reported to have a reduced penetrance of 25-42.5% in various populations (PMID: 15680455, 15726496, 18986508, 22575234, 26062626, 28639421). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1940). 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) performed at Invitae indicates that this missense variant is not expected to disrupt LRRK2 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects LRRK2 function (PMID: 26251043). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | Dec 07, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital | Jan 06, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Feb 07, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genomics Laboratory, Washington University in St. Louis | Nov 08, 2023 | The LRRK2 c.6055G>A (p.Gly2019Ser) variant is reported as one of the most common alleles in individuals affected with Parkinson’s disease and segregates with disease in families (Saunders-Pullman R et al., PMID: 20301387). The highest population minor allele frequency in the population database genome aggregation database (v.2.1.1) is 0.84% in Ashkenazi Jewish population. Functional studies show increased mitochondrial DNA damage, increased phosphorylation of alpha synuclein, dysregulation of lysosomal function, and kinase-dependent neurodegeneration (Henry G et al., PMID: 26251043; Qing H et al., PMID: 19576176; Sanders LH et al., PMID: 24148854; Vermilyea SC et al., PMID: 29402177), indicating that this variant impacts protein function. This variant resides within a region, amino acids 1879-2138, of LRRK2 that is defined as a critical functional domain (Vermilyea SC et al., PMID: 29402177). Computational predictors indicate that the variant is damaging, evidence that correlates with impact to LRRK2 function. This variant has been reported in the ClinVar database as a pathogenic variant in Parkinson’s disease by 18 submitters, likely pathogenic by one submitter and a risk factor by one submitter. Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic. - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 22, 2012 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Sep 22, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 23, 2020 | This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. - |
not provided Pathogenic:6
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2022 | LRRK2: PS4, PM1, PP1, PP3, PP4, PS3:Supporting - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | May 07, 2021 | This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This variant is reported to exhibit age-dependent penetrance that may be impacted by ethnicity (PMID: 26062626, 25330418, 18986508). This variant appears to be associated with disease in multiple families (PMID: 16240353, 16533964). According to published literature, there is no reported difference in clinical presentation between individuals with this variant in the heterozygous or homozygous state (PMID: 16966502). Assessment of experimental evidence suggests this variant results in abnormal protein function. Studies have shown expression of this variant results in increased kinase activity, dysregulation of lysosomal homeostasis, and age-dependent and kinase-dependent neurodegeneration (PMID: 29402177, 29386392, 26251043, 23472874). - |
| Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 12, 2020 | The G2019S variant is the most common pathogenic substitution in the LRRK2 gene (Lunati et al., 2018); Individuals who are heterozygous for the G2019S variant have more than a 20-fold increase in risk for developing Parkinson disease (Dachsel et al., 2010); Lysosomal dysfunction plays a central role in the pathogenesis of Parkinson disease, and published functional studies have shown that expression of G2019S produces enlarged lysosomes and alters their function (Henry et al., 2015); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 24211199, 19397894, 22080837, 21362567, 15726496, 29357897, 29248340, 30528841, 22736029, 23241358, 23396536, 20232069, 21280089, 20008657, 22914360, 21961647, 20642453, 17447891, 21686713, 22539006, 22773119, 23357204, 23472874, 21658387, 24729340, 19072560, 24652679, 21699405, 17200152, 21972245, 24470158, 21850687, 23227859, 19302196, 22004453, 20626563, 20881132, 25401981, 25330418, 22194196, 17210620, 21885347, 24488318, 24357540, 20818610, 22488887, 21696411, 21883375, 20671708, 23075850, 20096956, 16750377, 24148854, 18675914, 23747310, 25107341, 17095157, 19283415, 21753159, 22323743, 22914834, 25008396, 21494637, 23082216, 21390248, 21799870, 24082139, 22689969, 23764467, 18752982, 19945904, 20933457, 21641848, 22575234, 25434972, 23241745, 25000966, 26251043, 20457952, 18986508, 27692902, 27383589, 27423549, 27393345, 24360742, 24243757, 25962553, 23664753, 26159606, 26282470, 28862745, 29309488, 29800472, 30245141, 30709905, 3066573, 30146349, 16333314, 28487191, 28723952, 16102999, 16001413, 28639421, 18644660, 24123150, 19741132, 30172844, 16966501, 17060589, 29795570, 17116211, 24282027, 30665703, 31077434, 31324919, 31813996, 31605779, 31980526, 32875616, 26600626, 32398759, 33281709, 32353202, 18201824, 33084218, 15852371, 31589614) - |
Parkinson disease, late-onset Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 03, 2021 | - - |
Inborn genetic diseases Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 19, 2022 | The c.6055G>A (p.G2019S) alteration is located in exon 41 (coding exon 41) of the LRRK2 gene. This alteration results from a G to A substitution at nucleotide position 6055, causing the glycine (G) at amino acid position 2019 to be replaced by a serine (S). Based on data from gnomAD, the A allele has an overall frequency of 0.05% (138/282542) total alleles studied. The highest observed frequency was 0.84% (87/10362) of Ashkenazi Jewish alleles. The p.G2019S alteration is the most common disease-causing LRRK2 alteration (Saunders-Pullman, 2019). This amino acid position is highly conserved in available vertebrate species. Functional analysis demonstrated that compared to the wild-type, the p.G2019S alteration significantly increased the phosphorylation of peroxiredoxin 3 (PRDX3), a mitochondrial member of the antioxidant family of thioredoxin peroxidases. Increased PRDX3 phosphorylation was associated with inhibited PRDX3 peroxidase activity and increased death in LRRK2-expressing but not in LRRK2-depleted or vector-transfected neuronal cells (Angeles, 2011). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. - |
Parkinson disease Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Molecular Genetics, Royal Melbourne Hospital | Mar 30, 2023 | This sequence change in LRRK2 is predicted to replace glycine with serine at codon 2019, p.(Gly2019Ser). The glycine residue is highly conserved (100 vertebrates, UCSC), and is located in the protein kinase domain There is a small physicochemical difference between glycine and serine. The highest population minor allele frequency in gnomAD v2.1 is 0.8% (87/10,362 alleles, 1 homozygote) in the Ashkenazi Jewish population, while the highest continental population minor allele frequency is 0.03% (33/128,908 alleles) in the European (non-Finnish) population. This is the most commonly reported pathogenic variant in LRRK2 and is associated with a risk of Parkinson disease (PD) at an estimated age-related penetrance of between 25-42.5% (PMID: 20301387, 28639421). The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (odds ratio 14.98, 95% CI:10.68-21.02) (PMID: 22575234). The variant has been reported to segregate with PD in multiple families (PMID: 15726496 ). A transgenic mouse model for the variant recapitulates the human PD phenotype and brain histopathology (PMID: 22539006). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (6/6 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as PATHOGENIC. Following criteria are met: PS3, PP1_Strong, PS4_Moderate, PP3. - |
LRRK2-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 04, 2024 | The LRRK2 c.6055G>A variant is predicted to result in the amino acid substitution p.Gly2019Ser. This variant has been found in patients with Parkinson disease and is the most common and well-documented pathogenic variant in the LRRK2 gene (Trinh et al. 2016. PubMed ID: 27692902; Biosa et al. 2013. PubMed ID: 23241358; Bonifati et al. 2006. PubMed ID: 16835587). This variant is reported in 0.84% of alleles in individuals of Ashkenazi Jewish descent in gnomAD and it has been reported as a founder mutation in this population (Bar-Shira et al. 2009. PubMed ID: 19283415). Functional studies showed that this variant activated kinase activity, enlarged lysosomes and diminished the lysosomal capacity (Jaleel et al. 2007. PubMed ID: 17447891; West et al. 2007. PubMed ID: 17200152; Henry et al. 2015. PubMed ID: 26251043). This variant is interpreted as pathogenic. - |
Young-onset Parkinson disease Other:1
| risk factor, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 29, 2017 | LRRK2 c.6055G>A (p.Gly2019Ser) has been associated with increased risk for Parkinson's disease. This variant has been observed in multiple ethnic backgrounds with highest frequencies in individuals of Ashkenazi Jewish ancestry (0.86%, Genome Aggregation Database (gnomAD); rs6025) and is present in ClinVar (ID: 1940). A large meta-analysis has reported an odds ratio of 14.98 [95% CI 4.8-10] for developing Parkinson's disease (Wu 2012). In vivo and in vitro functional studies provide some evidence that the p.Gly2019Ser variant may impact protein function (Chen 2012). Therefore, this variant is not expected to cause highly penetrant Mendelian disease. In summary, this variant is an established risk factor for Parkinson's disease. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Benign
T
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
M
MutationTaster
Benign
A
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Pathogenic
D
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at