Variant classification summary

NM_198578.4:c.6055G>A

LRRK2 · NP_940980.4:p.(Gly2019Ser) · NM_198578.4

GRCh37: chr12:40734202 G>A · GRCh38: chr12:40340400 G>A

Gene: LRRK2 Transcript: NM_198578.4

Final call

Pathogenic

PS3 strong PS4 very strong PM1 moderate PM2 supporting PP1 strong PP3 supporting PP5 supporting

Variant details

Gene

LRRK2

Transcript

NM_198578.4

Protein

NP_940980.4:p.(Gly2019Ser)

gnomAD AF

0.0004884229601262822 (v2.1)

ClinVar

Pathogenic

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

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).

2

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.

3

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.

4

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.

5

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.

6

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).

7

PP3_Supporting: Multiple in silico tools predict a damaging effect (REVEL=0.97, BayesDel=0.57).

8

PP5_Supporting: Reported as Pathogenic by 23 clinical diagnostic laboratories in ClinVar.

9

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).

10

Final classification: PATHOGENIC.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Pathogenic classification based on the observed combination of very strong, strong, moderate, and supporting pathogenic criteria.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	PVS1 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.	pvs1_variant_assessment pvs1_generic_framework
PS1	Not assessed	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.
PS2	Not met	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.
PS3	Met	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.	PMID:16269541 PMID:16172858 clinvar
PS4	Met	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.	PMID:16102999 PMID:16157901 PMID:16172858 PMID:16145815 gnomad_v2 gnomad_v4 clinvar
PS5	Not met	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.
PM1	Met	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.	PMID:16269541 cspec
PM2	Met	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.	gnomad_v2 gnomad_v4
PM5	Not met	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.
PM6	Not met	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.
PP1	Met	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.	PMID:15726496 PMID:16145815 PMID:16102999 PMID:16728648
PP2	Not met	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.	gnomad_v2
PP3	Met	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.	revel bayesdel spliceai
PP4	Not assessed	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.
PP5	Met	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.	clinvar
BA1	Not met	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.	gnomad_v2 gnomad_v4
BS1	Not met	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.	gnomad_v2
BS2	N/A	BS2 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.	PMID:15726496
BS3	Not met	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.	PMID:16269541 PMID:16172858
BS4	Not met	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.	PMID:15726496 PMID:16145815 PMID:16102999
BP1	N/A	BP1 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.	PMID:16269541
BP2	Not met	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.
BP4	Not met	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.	revel bayesdel spliceai
BP5	Not assessed	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.
BP6	Not met	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.	clinvar
BP7	N/A	BP7 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.	spliceai
BP3	N/A	BP3 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.
PM3	N/A	PM3 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.
PM4	N/A	PM4 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.

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