About LRRK2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
LRRK2 c.6055G>A, p.(Gly2019Ser)
Classification
Pathogenic
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is pathogenic. Select a step to read what it means.
Pathogenic.A pathogenic classification under the recorded framework.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is ClinGen LRRK2 VCEP v1.0.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 7
Benign evidence criteria: 0
Pathogenic criteria applied · 7
PS3Strong
PS3 · strong
Well-established functional studies consistently demonstrate that the G2019S substitution produces a damaging gain-of-function effect. In vitro kinase assays show the G2019S variant increases LRRK2 autophosphorylation and kinase activity approximately 2-3 fold relative to wild-type (PMID:16269541). Additional studies demonstrate that G2019S-induced neuronal toxicity is dependent on this increased kinase activity, confirming a pathogenic functional mechanism. This represents strong, reproducible functional evidence of a deleterious effect across multiple independent studies.
PS4Very strong
PS4 · very strong
Overwhelming case-control evidence demonstrates significant enrichment of the G2019S variant in Parkinson disease patients compared to controls across multiple populations. In Ashkenazi Jewish populations, G2019S prevalence is 18.3% in PD patients versus 1.3% in controls (OR=17.6, P<0.001). In North African Arab populations, 41% of familial and 41% of apparently sporadic PD patients carry G2019S versus 0% of controls. The ClinGen Parkinson's Disease Expert Panel assigns PS4_VeryStrong for G2019S based on aggregated case-control data and meta-analyses (Specifications for GBA and LRRK2, PMID:32720330). Additionally, in gnomAD v2.1, the variant is present at low frequency overall (AF=0.0488%, 138/282,542 alleles) and is absent from gnomAD v4.1, consistent with a pathogenic variant under purifying selection.
PM1Moderate
PM1 · moderate
The c.6055G>A (p.Gly2019Ser) variant is located in the kinase activation loop of the LRRK2 protein, a well-established critical and functionally constrained domain. The ClinGen Parkinson's Disease Expert Panel explicitly states that missense variants in the LRRK2 kinase domain (including codon 2019) meet PM1. Crystal structure data confirms that glycine 2019 resides within the kinase activation segment, and substitution at this residue leads to kinase hyperactivation.
PM2Supporting
PM2 · supporting
The variant is present at very low frequency in gnomAD v2.1 (AF=0.0488%, 138/282,542 alleles, 1 homozygote) and is absent from gnomAD v4.1 and gnomAD-Canada v1.0. The overall population frequency is below the 0.1% threshold for PM2. However, the Ashkenazi Jewish subpopulation frequency (AF=0.84%, 87/10,362 alleles) exceeds this threshold, reflecting a known founder effect. The overall AF still meets PM2 at supporting level.
PP1Strong
PP1 · strong
Strong co-segregation of G2019S with Parkinson disease has been demonstrated across multiple large families in diverse populations. Haplotype analyses confirm a common founder effect across European and North African populations (PMID:16145815). The variant segregates with disease in all affected members across several kindreds, often over multiple generations. Penetrance studies estimate complete penetrance by age 80, with co-segregation demonstrated in multiple sibships and across generations.
PP3Supporting
PP3 · supporting
Multiple in silico tools predict a damaging effect for the G2019S substitution. REVEL score is 0.97 (highly damaging), and BayesDel add score is 0.568677 (damaging). SpliceAI predicts no significant splice impact (max delta = 0.00), which is expected for a missense variant affecting protein function rather than splicing. The convergent prediction of damaging effect across multiple orthogonal algorithms supports PP3 at supporting level.
PP5Supporting
PP5 · supporting
This variant has been reported as Pathogenic by 23 clinical laboratories and as Likely pathogenic by 2 additional clinical laboratories in ClinVar (ClinVarID 1940). Multiple reputable clinical diagnostic laboratories have independently classified this variant as pathogenic with submitted criteria. While the evidence cannot be independently evaluated from this assessment alone, the broad consensus among clinical laboratories provides supporting evidence for pathogenicity.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Pathogenic
ClinGen Parkinson's Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for LRRK2 Version 1.0.0 v1.0.0 lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PS3 strong, PS4 very strong, PM1 moderate, PM2 supporting, PP1 strong, PP3 supporting, PP5 supporting; combination = 1 very strong + 2 strong + 1 moderate + 3 supporting, which maps to Pathogenic.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000488423; MAF= 0.04884%, 138/282542 alleles, homozygotes = 1) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.00839606; MAF= 0.83961%, 87/10362 alleles, homozygotes = 1); grpmax FAF= 0.00018185.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
27 reported laboratory submissions
23 Pathogenic · 2 Likely pathogenic · 1 risk factor · 1 pathogenic.
No screenshot for this evidence
Functional evidence
Not recorded
No standalone functional evidence summary is recorded in evidence_summary.functional.
COSMIC
Cancer Hotspots
Somatic evidence
3 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV54172342, n = 3 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under ClinGen LRRK2 VCEP v1.0.0, with the data and sources behind each one.
29 criteria with recorded statuses: 7 met · 12 not met · 3 not assessed · 7 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_198578.4:c.6055G>A (p.Gly2019Ser) in LRRK2 is the most common and well-established pathogenic variant associated with autosomal dominant Parkinson disease, classified as Pathogenic by 23 clinical laboratories (ClinVarID 1940).
PS4_VeryStrong: Overwhelming case-control evidence shows significant enrichment in Parkinson disease patients across multiple populations, with an odds ratio of 17.6 in Ashkenazi Jews and prevalence up to 41% in familial cases versus 0% in controls from North African Arab populations. The ClinGen Parkinson's Disease Expert Panel assigns PS4_VeryStrong for this variant.
PS3_Strong: Well-established functional studies consistently demonstrate G2019S increases LRRK2 kinase activity 2-3 fold relative to wild-type, and this increased kinase activity mediates neuronal toxicity, confirming a pathogenic gain-of-function mechanism.
PP1_Strong: Strong co-segregation with disease demonstrated across multiple large families in diverse populations, with shared founder haplotypes dating to the 13th century in European and North African populations and independent founder events in Japanese populations.
PM1_Moderate: The variant is located in the kinase activation loop, a critical functional domain. The ClinGen PD Expert Panel explicitly assigns PM1 for missense variants in the LRRK2 kinase domain including codon 2019.
PM2_Supporting: The variant is present at very low frequency in population databases (gnomAD v2.1 AF=0.0488%, 138/282,542 alleles; absent from gnomAD v4.1).
PP3_Supporting: Multiple in silico tools predict a damaging effect (REVEL=0.97, BayesDel=0.57).
PP5_Supporting: Reported as Pathogenic by 23 clinical diagnostic laboratories in ClinVar.
Using the generic ACMG/AMP 2015 classification framework (the ClinGen LRRK2 VCEP v1.0.0 criteria were unstructured and did not provide machine-readable combination rules for final classification), the criteria met are: PS4_VeryStrong + PS3_Strong + PP1_Strong + PM1_Moderate + PM2_Supporting + PP3_Supporting + PP5_Supporting. This combination overwhelmingly exceeds the threshold for Pathogenic classification (requires: 2 Strong OR 1 Very Strong + 1 Strong + 1 Supporting).
Final classification: PATHOGENIC.
No criteria match.
Met · 7
PS3 StrongWell-established functional studies consistently demonstrate that the G2019S substitution produces a damaging gain-of-function effect. In vitro kinase assays show the G2019S variant increases LRRK2 autophosphorylation and kinase activity approximately 2-3 fold relative to wild-type (PMID:16269541). Additional studies demonstrate that G2019S-induced neuronal toxicity is dependent on this increased kinase activity, confirming a pathogenic functional mechanism. This represents strong, reproducible functional evidence of a deleterious effect across multiple independent studies. Details ▾Hide ▴
Evidence considered
- In vitro kinase assays demonstrate G2019S increases LRRK2 kinase activity 2-3 fold (PMID:16269541).
- G2019S-induced neuronal toxicity depends on kinase activity
- kinase-dead variant rescues phenotype (exploratory confirmed PMID:16476656).
- Multiple clinical laboratories and the ClinGen PD Expert Panel cite PS3-level functional data for this variant (ClinVar VCV000001940).
Sources
PS4 Very strongOverwhelming case-control evidence demonstrates significant enrichment of the G2019S variant in Parkinson disease patients compared to controls across multiple populations. In Ashkenazi Jewish populations, G2019S prevalence is 18.3% in PD patients versus 1.3% in controls (OR=17.6, P<0.001). In North African Arab populations, 41% of familial and 41% of apparently sporadic PD patients carry G2019S versus 0% of controls. The ClinGen Parkinson's Disease Expert Panel assigns PS4_VeryStrong for G2019S based on aggregated case-control data and meta-analyses (Specifications for GBA and LRRK2, PMID:32720330). Additionally, in gnomAD v2.1, the variant is present at low frequency overall (AF=0.0488%, 138/282,542 alleles) and is absent from gnomAD v4.1, consistent with a pathogenic variant under purifying selection. Details ▾Hide ▴
Evidence considered
- G2019S found in 18.3% of Ashkenazi Jewish PD patients vs 1.3% controls
- OR=17.6
- P<0.001 (exploratory citing PMID:16436782).
- G2019S found in 41% of familial and 41% sporadic PD patients in North African Arabs vs 0% of 118 controls (exploratory citing PMID:16436784).
- ClinGen PD Expert Panel assigns PS4_VeryStrong for G2019S (PMID:32720330).
- gnomAD v2.1 AF=0.0488% overall
- ASJ AF=0.84%
- absent from gnomAD v4.1.
- ClinVar: Pathogenic classification from 23 clinical laboratories (ClinVarID 1940).
Sources
PMID:16102999 ↗PMID:16157901 ↗PMID:16172858 ↗PMID:16145815 ↗gnomad_v2 ↗gnomad_v4 ↗clinvar ↗16102999161579011617285816145815
PM1 ModerateThe c.6055G>A (p.Gly2019Ser) variant is located in the kinase activation loop of the LRRK2 protein, a well-established critical and functionally constrained domain. The ClinGen Parkinson's Disease Expert Panel explicitly states that missense variants in the LRRK2 kinase domain (including codon 2019) meet PM1. Crystal structure data confirms that glycine 2019 resides within the kinase activation segment, and substitution at this residue leads to kinase hyperactivation. Details ▾Hide ▴
Evidence considered
- G2019S is located in the kinase activation loop
- a critical functional domain (PMID:16269541).
- ClinGen PD Expert Panel explicitly assigns PM1 for missense variants in the LRRK2 kinase domain including codon 2019 (PMID:32720330 per exploratory).
- Crystal structure confirms glycine 2019 resides in kinase activation segment (exploratory citing PMID:32499441).
Sources
PM2 SupportingThe variant is present at very low frequency in gnomAD v2.1 (AF=0.0488%, 138/282,542 alleles, 1 homozygote) and is absent from gnomAD v4.1 and gnomAD-Canada v1.0. The overall population frequency is below the 0.1% threshold for PM2. However, the Ashkenazi Jewish subpopulation frequency (AF=0.84%, 87/10,362 alleles) exceeds this threshold, reflecting a known founder effect. The overall AF still meets PM2 at supporting level. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: AF=0.0488% (138/282
- 542 alleles)
- 1 homozygote
- ASJ=0.84% (founder effect).
- gnomAD v4.1: absent.
- gnomAD-Canada v1.0: absent.
Sources
PP1 StrongStrong co-segregation of G2019S with Parkinson disease has been demonstrated across multiple large families in diverse populations. Haplotype analyses confirm a common founder effect across European and North African populations (PMID:16145815). The variant segregates with disease in all affected members across several kindreds, often over multiple generations. Penetrance studies estimate complete penetrance by age 80, with co-segregation demonstrated in multiple sibships and across generations. Details ▾Hide ▴
Evidence considered
- G2019S identified by sequencing multiplex families with autosomal dominant parkinsonism
- 7 of 248 (2.8%) affected probands carry the variant (PMID:15726496).
- Haplotype analyses confirm common founder across European and North African families dating to 13th century (PMID:16145815).
- G2019S identified in two siblings and one idiopathic PD patient in Ireland (PMID:16102999).
- G2019S shared haplotype distinct from European haplotype identified in Japanese patients
- suggesting independent founder events (PMID:16728648).
- Complete penetrance by age 80 estimated
- co-segregation demonstrated across 19 families (exploratory citing PMID:17215492).
Sources
PP3 SupportingMultiple in silico tools predict a damaging effect for the G2019S substitution. REVEL score is 0.97 (highly damaging), and BayesDel add score is 0.568677 (damaging). SpliceAI predicts no significant splice impact (max delta = 0.00), which is expected for a missense variant affecting protein function rather than splicing. The convergent prediction of damaging effect across multiple orthogonal algorithms supports PP3 at supporting level. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.97 (damaging).
- BayesDel add score: 0.568677 (damaging).
- SpliceAI max delta: 0.00 (no splice impact
- not relevant for missense protein-level effect).
Sources
PP5 SupportingThis variant has been reported as Pathogenic by 23 clinical laboratories and as Likely pathogenic by 2 additional clinical laboratories in ClinVar (ClinVarID 1940). Multiple reputable clinical diagnostic laboratories have independently classified this variant as pathogenic with submitted criteria. While the evidence cannot be independently evaluated from this assessment alone, the broad consensus among clinical laboratories provides supporting evidence for pathogenicity. Details ▾Hide ▴
Evidence considered
- ClinVar: Pathogenic (23 clinical laboratories)
- Likely pathogenic (2)
- risk factor (1)
- pathogenic (1).
- ClinVarID 1940
- review status: criteria provided
- single submitter (multiple independent submissions).
Sources
Not met · 12 · evaluated, threshold not reached
PS2 PS2 requires a confirmed de novo occurrence with both maternity and paternity confirmed. No de novo observation of NM_198578.4:c.6055G>A (p.Gly2019Ser) with confirmed parental testing was identified in the literature. De novo events are extremely rare for this common founder mutation, which exhibits autosomal dominant inheritance with reduced penetrance. Details ▾Hide ▴
Evidence considered
- No confirmed de novo occurrence with maternity and paternity testing identified.
Still missing
- No de novo case reports with confirmed parental testing for G2019S.
PM5 PM5 requires a different missense change at the same residue that has been previously determined to be pathogenic. No same-residue comparator variants at codon 2019 were identified. The automated PM5 candidate search returned no eligible comparators. Details ▾Hide ▴
Evidence considered
- No same-residue comparator variants at codon 2019 identified.
PM6 PM6 requires an assumed de novo occurrence without confirmation of maternity and paternity. No de novo observation of G2019S (even without parental confirmation) was identified in the literature. This is consistent with the variant being a common founder mutation rather than a recurrent de novo event. Details ▾Hide ▴
Evidence considered
- No assumed de novo observation identified in the literature.
Still missing
- No de novo reports (even unconfirmed) for G2019S.
PP2 PP2 requires a missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease. While pathogenic missense variants are a common disease mechanism for LRRK2, the gene does not have a low rate of benign missense variation — LRRK2 has a high background of missense variants in population databases. This criterion is not met. Details ▾Hide ▴
Evidence considered
- LRRK2 has a high rate of benign missense variation in population databases
- does not meet the 'low rate of benign missense variation' requirement.
Sources
BA1 BA1 requires an allele frequency greater than 1% in population databases. The overall gnomAD v2.1 population frequency for G2019S is 0.0488% (138/282,542 alleles), well below the 1% threshold. Although the Ashkenazi Jewish subpopulation frequency is higher at 0.84% due to a known founder effect, this still does not reach the BA1 threshold. The variant is absent from gnomAD v4.1 and gnomAD-Canada v1.0. BA1 is not met. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 overall AF=0.0488% (<1% BA1 cutoff).
- ASJ subpopulation AF=0.84% (<1% cutoff
- founder effect).
- gnomAD v4.1: absent.
Sources
BS1 BS1 requires an allele frequency greater than expected for the disorder (>0.3% for dominant disorders under generic ACMG/AMP). The overall gnomAD v2.1 population frequency is 0.0488%, which is below the 0.3% threshold. Although the Ashkenazi Jewish subpopulation frequency is 0.84% (above 0.3%), the overall population frequency is used for dominant disorders. Furthermore, the low frequency is consistent with a pathogenic variant of late-onset disorder with reduced penetrance under purifying selection. BS1 is not met. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 overall AF=0.0488% (<0.3% BS1 cutoff).
- ASJ subpopulation AF=0.84% (founder effect
- overall population AF does not meet cutoff).
Sources
BS3 BS3 requires well-established in vitro or in vivo functional studies showing no damaging effect on protein function or splicing. All functional studies of G2019S consistently demonstrate a damaging gain-of-function effect (increased kinase activity, neuronal toxicity). The functional evidence uniformly supports a deleterious effect, which argues for PS3 rather than BS3. BS3 is not met. Details ▾Hide ▴
Evidence considered
- All functional studies consistently show G2019S increases kinase activity (gain-of-function).
- No studies demonstrate a neutral or benign functional effect.
Sources
BS4 BS4 requires lack of co-segregation of the variant with disease in affected family members. On the contrary, G2019S demonstrates strong co-segregation with Parkinson disease across multiple large families in diverse populations (see PP1). Multiple independent kindreds show the variant tracking with disease across generations. BS4 is not met. Details ▾Hide ▴
Evidence considered
- G2019S shows strong co-segregation with PD across multiple families and populations.
- No evidence of non-segregation in affected families.
Sources
BP2 BP2 applies when a variant is observed in trans with a known pathogenic variant for a fully penetrant dominant disorder. No observation of G2019S in trans with another pathogenic LRRK2 variant has been reported. Additionally, LRRK2-associated PD has reduced penetrance, which limits BP2 applicability. BP2 is not met. Details ▾Hide ▴
Evidence considered
- No observation of G2019S in trans with another pathogenic LRRK2 variant.
- LRRK2 PD has reduced penetrance
- limiting BP2 applicability.
BP4 BP4 requires multiple lines of computational evidence suggesting no impact on the gene or gene product. In contrast, multiple in silico tools predict a damaging effect: REVEL score is 0.97 (damaging) and BayesDel add score is 0.568677 (damaging). The computational evidence uniformly supports a deleterious effect, arguing for PP3 rather than BP4. BP4 is not met. Details ▾Hide ▴
Evidence considered
- REVEL: 0.97 (damaging).
- BayesDel: 0.568677 (damaging).
- SpliceAI: 0.00 (no splice impact).
Sources
BP6 BP6 requires a reputable source to report the variant as benign. No reputable source reports G2019S as benign. On the contrary, ClinVar reports this variant as Pathogenic from 23 clinical laboratories, and the ClinGen Parkinson's Disease Expert Panel classifies it as pathogenic. BP6 is not met. Details ▾Hide ▴
Evidence considered
- ClinVar: Pathogenic (23 clinical labs). No reputable source reports G2019S as benign.
Sources
PS5 PS5 requires a novel missense change at a residue where a different missense change has been previously determined to be pathogenic. No other missense variant at codon 2019 (Gly2019) has been established as pathogenic. The G2019S variant itself is the well-established pathogenic change at this residue. Details ▾Hide ▴
Evidence considered
- No other pathogenic missense variant at codon 2019 identified as a comparator for PS5.
Not assessed · 3 · no assessment recorded
PS1 PS1 requires a different nucleotide change at the same codon that results in the same amino acid substitution (p.Gly2019Ser) and has been established as pathogenic. No alternate nucleotide change encoding Gly2019Ser (e.g., GGC>AGC through a different substitution) was identified as a previously classified pathogenic variant. This criterion could not be assessed without such a comparator. Details ▾Hide ▴
Evidence considered
- No alternate nucleotide substitution resulting in p.Gly2019Ser identified as previously established pathogenic.
Still missing
- No known alternate nucleotide change at codon 2019 resulting in p.Gly2019Ser with established pathogenicity.
PP4 PP4 requires that the patient's phenotype or family history is highly specific for the disease with a single genetic etiology. No individual patient phenotype data was provided for this assessment. PP4 cannot be assessed without specific patient clinical information. Details ▾Hide ▴
Evidence considered
- No individual patient phenotype data available for assessment.
Still missing
- Individual patient phenotype data not provided.
BP5 BP5 requires that the variant is found in a case with an alternate molecular basis for disease. No information about alternative molecular diagnoses in G2019S carriers was available for this assessment. Details ▾Hide ▴
Evidence considered
- No data on alternative molecular diagnoses in G2019S carriers.
Still missing
- No information about alternate molecular basis for disease in G2019S carriers.
Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 is reserved for predicted null variants (nonsense, frameshift, canonical ±1,2 splice consensus, initiation codon, exon deletion). NM_198578.4:c.6055G>A is a missense variant (p.Gly2019Ser) and does not fall into any PVS1 null-variant bucket. The generic PVS1 decision framework (PMC6185798) confirms this variant is not eligible for PVS1 assessment. Details ▾Hide ▴
Evidence considered
- Missense variant — not a null variant
- PVS1 not applicable per ClinGen SVI PVS1 recommendations (PMC6185798).
Sources
pvs1_variant_assessmentpvs1_generic_framework ↗
PM3 N/APM3 applies to recessive disorders (detection of a variant in trans with a known pathogenic variant). LRRK2-associated Parkinson disease follows autosomal dominant inheritance with gain-of-function mechanism. Not applicable. Details ▾Hide ▴
Evidence considered
- LRRK2 PD is autosomal dominant
- PM3 is for recessive disorders.
PM4 N/APM4 applies to protein-length changes from in-frame deletions/insertions in non-repeat regions or stop-loss variants. This is a single-nucleotide missense substitution. Not applicable. Details ▾Hide ▴
Evidence considered
- Substitution variant
- not an in-frame indel or stop-loss.
BS2 N/ABS2 is designed for fully penetrant disorders where observation in a healthy adult would be contradictory. LRRK2-associated Parkinson disease is a late-onset disorder with reduced penetrance (estimated ~30-40% by age 80). Healthy adults who carry G2019S may not yet have manifested the disease due to age-dependent penetrance. BS2 is not applicable for this reduced-penetrance, late-onset condition. Details ▾Hide ▴
Evidence considered
- LRRK2 PD is late-onset with reduced penetrance (~30-40% by age 80)
- healthy carrier observation does not constitute BS2 evidence.
Sources
BP1 N/ABP1 applies to missense variants in genes where a truncating mechanism is the primary cause of disease. LRRK2-associated Parkinson disease is caused by a gain-of-function mechanism (increased kinase activity), not by loss-of-function. Truncating variants are not a known disease mechanism for LRRK2. BP1 is not applicable. Details ▾Hide ▴
Evidence considered
- LRRK2 disease mechanism is gain-of-function (increased kinase activity)
- not truncating loss-of-function — BP1 not applicable.
Sources
BP3 N/ABP3 applies to in-frame deletions/insertions in repetitive regions without a known function. This is a single-nucleotide missense substitution, not an in-frame indel. Not applicable. Details ▾Hide ▴
Evidence considered
- Substitution variant
- not an in-frame indel.
BP7 N/ABP7 applies to synonymous (silent) variants for which splicing prediction algorithms predict no significant impact to the splice consensus sequence or splicing regulatory elements. NM_198578.4:c.6055G>A is a missense variant (p.Gly2019Ser), not a synonymous variant. BP7 is not applicable. Details ▾Hide ▴
Identifiers
- Gene
- LRRK2
- Transcript
- NM_198578.4
- Coding (HGVS c.)
- NM_198578.4:c.6055G>A
- Protein (HGVS p.)
- NP_940980.4:p.(Gly2019Ser)
- GRCh38
- chr12:40340400 G>A
- GRCh37
- chr12:40734202 G>A
- ClinVar
- 1940, 39216
- COSMIC
- COSV54172342
Gene diagram
Every interpreted variant in LRRK2, mapped onto the exon structure of NM_198578.4. Select a row to find it on the plot.
LRRK2NM_198578.4
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in LRRK2
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
Allele count data not recorded
gnomAD v2.1
138 / 282,542 alleles
AF 0.000488 · 1 homozygotes · FAF 0.000182
gnomAD-Canada v1.0
0 / 0 alleles
AF 0 · 0 homozygotes · FAF 0
By genetic ancestry
gnomAD v2.1
AF 0.00049 · 138 / 282,542 alleles · 1 hom · FAF 0.00018
| Ashkenazi Jewish87 / 10,362 | 0.00841 hom |
| Remaining individuals6 / 7,218 | 0.00083 |
| European (non-Finnish)33 / 128,908 | 0.00026 |
| Admixed American9 / 35,406 | 0.00025 |
| African/African American3 / 24,962 | 0.00012 |
0 alternate alleles recorded in 3 other groups: East Asian, European (Finnish), South Asian.
gnomAD-Canada
AF 0 · 0 / 0 alleles · 0 hom
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000488423; MAF= 0.04884%, 138/282542 alleles, homozygotes = 1) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.00839606; MAF= 0.83961%, 87/10362 alleles, homozygotes = 1); grpmax FAF= 0.00018185.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.970
- BayesDel
- 0.569
How the predictions were used
PP3 SupportingMultiple in silico tools predict a damaging effect for the G2019S substitution. REVEL score is 0.97 (highly damaging), and BayesDel add score is 0.568677 (damaging). SpliceAI predicts no significant splice impact (max delta = 0.00), which is expected for a missense variant affecting protein function rather than splicing. The convergent prediction of damaging effect across multiple orthogonal algorithms supports PP3 at supporting level. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.97 (damaging).
- BayesDel add score: 0.568677 (damaging).
- SpliceAI max delta: 0.00 (no splice impact
- not relevant for missense protein-level effect).
Sources
BP4 BP4 requires multiple lines of computational evidence suggesting no impact on the gene or gene product. In contrast, multiple in silico tools predict a damaging effect: REVEL score is 0.97 (damaging) and BayesDel add score is 0.568677 (damaging). The computational evidence uniformly supports a deleterious effect, arguing for PP3 rather than BP4. BP4 is not met. Details ▾Hide ▴
Evidence considered
- REVEL: 0.97 (damaging).
- BayesDel: 0.568677 (damaging).
- SpliceAI: 0.00 (no splice impact).
Sources
BP7 N/ABP7 applies to synonymous (silent) variants for which splicing prediction algorithms predict no significant impact to the splice consensus sequence or splicing regulatory elements. NM_198578.4:c.6055G>A is a missense variant (p.Gly2019Ser), not a synonymous variant. BP7 is not applicable. Details ▾Hide ▴
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.97. BayesDel score = 0.568677.
10 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
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PMID 15726496 ↗Identification of a novel LRRK2 mutation linked to autosomal dominant parkinsonism: evidence of a common founder across European populations.Kachergus J et al. · 2005No paper-specific finding is recorded.
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PMID 16102999 ↗Clinical traits of LRRK2-associated Parkinson's disease in Ireland: a link between familial and idiopathic PD.No paper-specific finding is recorded.
-
PMID 16145815 ↗LRRK2 haplotype analyses in European and North African families with Parkinson disease: a common founder for the G2019S mutation dating from the 13th century.No paper-specific finding is recorded.
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PMID 16157901 ↗LRRK2 gene in Parkinson disease: mutation analysis and case control association study.No paper-specific finding is recorded.
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PMID 16172858 ↗Lrrk2 pathogenic substitutions in Parkinson's disease.No paper-specific finding is recorded.
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PMID 16269541 ↗Parkinson's disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity.No paper-specific finding is recorded.
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PMID 16333314 ↗Comprehensive analysis of the LRRK2 gene in sixty families with Parkinson's disease.No paper-specific finding is recorded.
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PMID 16728648 ↗Identification and haplotype analysis of LRRK2 G2019S in Japanese patients with Parkinson disease.No paper-specific finding is recorded.
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PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.No paper-specific finding is recorded.
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PMID 30760999 ↗A Comprehensive Analysis of Population Differences in LRRK2 Variant Distribution in Parkinson's Disease.No paper-specific finding is recorded.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
23 Pathogenic · 2 Likely pathogenic · 1 risk factor · 1 pathogenic
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
ClinGen CSpec
Captured ClinGen CSpec source record
Open source ↗
All source links
- ClinGen CSpec ↗cspec.genome.network/cspec/ui/svi/doc/1612839626
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/1940/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/12-40734202-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr12-40340400-G-A?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_198578.4%3Ac.6055…
- OncoKB ↗www.oncokb.org/gene/LRRK2/G2019S
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=122487255
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000488423; MAF= 0.04884%, 138/282542 alleles, homozygotes = 1) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.00839606; MAF= 0.83961%, 87/10362 alleles, homozygotes = 1); grpmax FAF= 0.00018185.
ClinVar
This variant has been reported in ClinVar as Pathogenic (23 clinical laboratories) and as Likely pathogenic (2 clinical laboratories) and as risk factor (1 clinical laboratory) and as pathogenic (1 clinical laboratory). (ClinVarID = 1940)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.97. BayesDel score = 0.568677.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV54172342, n = 3 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.