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rs34637584

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 11P and 5B. PM1PP3PP5_Very_StrongBP4BS2

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

Scores

14
3
2

Clinical Significance

Pathogenic/Likely pathogenic; risk factor criteria provided, multiple submitters, no conflicts P:22O:2

Conservation

PhyloP100: 9.66
Variant links:
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 6 ACMG points.

PM1
In a helix (size 7) in uniprot entity LRRK2_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_198578.4
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 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.
BS2
High AC in GnomAd at 55 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
LRRK2NM_198578.4 linkuse as main transcriptc.6055G>A p.Gly2019Ser missense_variant 41/51 ENST00000298910.12

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
LRRK2ENST00000298910.12 linkuse as main transcriptc.6055G>A p.Gly2019Ser missense_variant 41/511 NM_198578.4 P1

Frequencies

GnomAD3 genomes
AF:
0.000362
AC:
55
AN:
152064
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000725
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000852
Gnomad ASJ
AF:
0.00547
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.0000943
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.000235
Gnomad OTH
AF:
0.000957
GnomAD3 exomes
AF:
0.000526
AC:
132
AN:
251154
Hom.:
1
AF XY:
0.000553
AC XY:
75
AN XY:
135730
show subpopulations
Gnomad AFR exome
AF:
0.000123
Gnomad AMR exome
AF:
0.000260
Gnomad ASJ exome
AF:
0.00854
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000256
Gnomad OTH exome
AF:
0.000978
GnomAD4 exome
AF:
0.000417
AC:
609
AN:
1461622
Hom.:
1
Cov.:
31
AF XY:
0.000413
AC XY:
300
AN XY:
727112
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000403
Gnomad4 ASJ exome
AF:
0.00785
Gnomad4 EAS exome
AF:
0.0000756
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.000274
Gnomad4 OTH exome
AF:
0.00111
GnomAD4 genome
AF:
0.000361
AC:
55
AN:
152182
Hom.:
0
Cov.:
33
AF XY:
0.000336
AC XY:
25
AN XY:
74402
show subpopulations
Gnomad4 AFR
AF:
0.0000723
Gnomad4 AMR
AF:
0.000851
Gnomad4 ASJ
AF:
0.00547
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0000943
Gnomad4 NFE
AF:
0.000235
Gnomad4 OTH
AF:
0.000947
Alfa
AF:
0.000773
Hom.:
0
Bravo
AF:
0.000586
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000581
AC:
5
ExAC
AF:
0.000387
AC:
47
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.000382
EpiControl
AF:
0.000356

ClinVar

Significance: Pathogenic/Likely pathogenic; risk factor
Submissions summary: Pathogenic:22Other:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Autosomal dominant Parkinson disease 8 Pathogenic:12Other:1
Pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsFeb 07, 2022- -
Pathogenic, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaAug 02, 2021The 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. -
Pathogenic, criteria provided, single submitterclinical testingInvitaeJan 26, 2024This 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. -
not provided, no classification providedliterature onlyGeneReviews-- -
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpDec 03, 2021Variant 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 submitterclinical testingGenetics and Molecular Pathology, SA PathologyApr 28, 2022- -
Pathogenic, criteria provided, single submitterclinical testingMendelicsMay 28, 2019- -
Pathogenic, criteria provided, single submitterclinical testingAl Jalila Children's Genomics Center, Al Jalila Childrens Speciality HospitalJan 06, 2020- -
Pathogenic, no assertion criteria providedliterature onlyOMIMNov 22, 2012- -
Likely pathogenic, criteria provided, single submitterclinical testing3billionMay 22, 2022The 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 submitterclinical testingBaylor GeneticsJan 23, 2020This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
Pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics Munich, Klinikum Rechts Der Isar, TU MünchenDec 07, 2017- -
Pathogenic, criteria provided, single submitterclinical testingCourtagen Diagnostics Laboratory, Courtagen Life SciencesMay 14, 2014- -
not provided Pathogenic:6
Pathogenic, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, Amsterdam University Medical Center-- -
Pathogenic, criteria provided, single submitterclinical testingGeneDxMar 12, 2020The 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) -
Pathogenic, criteria provided, single submitterclinical testingAthena DiagnosticsMay 07, 2021This 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, criteria provided, single submitterclinical testingInstitute of Medical Genetics and Applied Genomics, University Hospital TübingenOct 23, 2020- -
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenNov 01, 2022LRRK2: PS4, PM1, PP1, PP3, PP4, PS3:Supporting -
Pathogenic, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Parkinson disease, late-onset Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsMay 03, 2021- -
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsJul 19, 2022The 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 submitterclinical testingMolecular Genetics, Royal Melbourne HospitalMar 30, 2023This 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 condition Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesJan 02, 2024The 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 submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineDec 29, 2017LRRK2 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.94
BayesDel_addAF
Pathogenic
0.35
D
BayesDel_noAF
Pathogenic
0.57
Cadd
Pathogenic
31
Dann
Uncertain
1.0
DEOGEN2
Uncertain
0.47
T
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
1.0
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.96
D
M_CAP
Pathogenic
0.74
D
MetaRNN
Benign
0.16
T
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
3.2
M
MutationTaster
Benign
1.0
A
PrimateAI
Pathogenic
0.90
D
PROVEAN
Pathogenic
-5.1
D
REVEL
Pathogenic
0.97
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.96
MVP
0.98
MPC
1.8
ClinPred
0.18
T
GERP RS
5.7
Varity_R
0.88
gMVP
0.92

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs34637584; hg19: chr12-40734202; COSMIC: COSV54172342; API