0%
LRRK2c.2300G>ALikely benign
Print report
Variant interpretation report

LRRK2 c.2300G>A, p.(Arg767His)

NM_198578.3:c.2300G>A NP_940980.3:p.(Arg767His) View identifiers
Classification
Likely benign

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is likely benign. Select a step to read what it means.

Likely benign.A likely benign classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About LRRK2

No gene-level summary was recorded for this case.

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: 2 Benign evidence criteria: 2
Pathogenic criteria applied · 2
PS3Supporting
PS3 · supporting

Functional studies demonstrate that p.Arg767His (R767H) robustly stimulates LRRK2 kinase activity >1.5-fold above wildtype. The variant is located in the ANK domain and structural analysis indicates it disrupts the ANK:C-terminal helix interface by abolishing an ionic interaction with E2516. Charge-reversed double mutation (R767E/E2516R) restores wildtype activity, confirming mechanism. Increased LRRK2 kinase activity is the established pathogenic mechanism in LRRK2-associated Parkinson disease.

PM2Supporting
PM2 · supporting

This variant is present at very low frequency in population databases. In gnomAD-Canada v1.0, the allele frequency is 0.0163% (3/18,414 alleles, 0 homozygotes), which is below the 0.1% PM2 threshold. The variant is absent from African, Admixed American, Ashkenazi Jewish, East Asian, Finnish, Middle Eastern, South Asian, and Other populations; all 3 alleles are in the Non-Finnish European population (AF=0.0256%). gnomAD v2.1 and v4.1 data were not available for this variant.

Benign criteria applied · 2
BP4Supporting
BP4 · supporting

Multiple lines of computational evidence suggest no deleterious impact. REVEL score is 0.157 (below the 0.5 damaging threshold). BayesDel score is -0.0159304 (negative, predicting benign). SpliceAI max delta is 0.01 (predicting no splicing impact). All available in silico tools are concordant in predicting a benign effect.

BP6Supporting
BP6 · supporting

This variant is classified as likely benign in ClinVar (VariationID 3571549) by a clinical diagnostic laboratory (Athena Diagnostics) using criteria provided. Although a single submitter, the classification from a reputable clinical laboratory supports a likely benign assessment.

Recorded classification: Likely benign

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 supporting, PM2 supporting, BP4 supporting benign, BP6 supporting benign; combination = 2 supporting + 2 supporting benign, which maps to Likely Benign.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

SpliceAI score
0.010 maximum delta

Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4 → SpliceAI ↗
No screenshot for this evidence
Functional evidence
Not recorded

No standalone functional evidence summary is recorded in evidence_summary.functional.

Applied · PS3 → OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
3 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV54143918, n = 3 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under ClinGen LRRK2 VCEP v1.0.0, with the data and sources behind each one.

26 criteria with recorded statuses: 4 met · 9 not met · 9 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP4BP5BP6BP7
Met Not met Not assessed Not applicable

This variant has been observed in a single Taiwanese early-onset Parkinson disease patient and was absent from 508 ethnically matched controls (PMID:24339985).

Functional studies demonstrate that p.Arg767His robustly stimulates LRRK2 kinase activity >1.5-fold above wildtype by disrupting the ANK:C-terminal helix interface; this gain-of-function effect is consistent with the established pathogenic mechanism of LRRK2 in Parkinson disease (PMID:35950872).

The variant is present at very low frequency in gnomAD-Canada (AF=0.0163%, 3/18,414 alleles, 0 homozygotes), below the 0.1% PM2 threshold (gnomad_canada).

Multiple in silico tools predict a benign effect: REVEL score 0.157, BayesDel score -0.0159304, and SpliceAI max delta 0.01, all consistent with no deleterious impact (revel, bayesdel, spliceai).

This variant is classified as likely benign in ClinVar by a clinical diagnostic laboratory (VariationID 3571549, criteria provided, single submitter) (clinvar).

Applying generic ACMG/AMP 2015 final classification combination rules (PMID:25741868): two supporting pathogenic criteria (PS3_supporting, PM2_supporting) and two supporting benign criteria (BP4_supporting, BP6_supporting) are present. These offset, resulting in a classification of Variant of Uncertain Significance.

Met · 4

PS3 SupportingFunctional studies demonstrate that p.Arg767His (R767H) robustly stimulates LRRK2 kinase activity >1.5-fold above wildtype. The variant is located in the ANK domain and structural analysis indicates it disrupts the ANK:C-terminal helix interface by abolishing an ionic interaction with E2516. Charge-reversed double mutation (R767E/E2516R) restores wildtype activity, confirming mechanism. Increased LRRK2 kinase activity is the established pathogenic mechanism in LRRK2-associated Parkinson disease. Details ▾Hide ▴
Evidence considered
  • R767H identified as one of 23 LRRK2 variants that robustly stimulate kinase activity in vitro (pRab10 Thr73 phosphorylation >1.5-fold
  • HEK293T cells). Structural analysis shows disruption of ANK:CH interface (ionic interaction with E2516). Rescue by charge-reversed double mutation R767E/E2516R confirms mechanism.
  • PMID:27423549 abstract confirms functional evaluation of R767H in Taiwanese PD cohort
  • but full text unavailable for detailed data extraction.
Still missing
  • Full text of PMID:27423549 not available for detailed functional data extraction
  • single well-established functional study (PMID:35950872) supports supporting strength.
Sources
PMID:35950872 ↗PMID:27423549 ↗
PM2 SupportingThis variant is present at very low frequency in population databases. In gnomAD-Canada v1.0, the allele frequency is 0.0163% (3/18,414 alleles, 0 homozygotes), which is below the 0.1% PM2 threshold. The variant is absent from African, Admixed American, Ashkenazi Jewish, East Asian, Finnish, Middle Eastern, South Asian, and Other populations; all 3 alleles are in the Non-Finnish European population (AF=0.0256%). gnomAD v2.1 and v4.1 data were not available for this variant. Details ▾Hide ▴
Evidence considered
  • gnomAD-Canada v1.0: AF=0.000163 (3/18
  • 414 alleles
  • 0 homozygotes)
  • below PM2 threshold of 0.1%. Restricted to NFE subpopulation (3/11
  • 738).
Still missing
  • gnomAD v2.1 and v4.1 data not available for this variant.
Sources
gnomad_canada ↗
BP4 SupportingMultiple lines of computational evidence suggest no deleterious impact. REVEL score is 0.157 (below the 0.5 damaging threshold). BayesDel score is -0.0159304 (negative, predicting benign). SpliceAI max delta is 0.01 (predicting no splicing impact). All available in silico tools are concordant in predicting a benign effect. Details ▾Hide ▴
Evidence considered
  • REVEL=0.157 (benign)
  • BayesDel=-0.0159304 (benign)
  • SpliceAI max delta=0.01 (no splice impact). All in silico tools concordantly predict benign.
Sources
revelbayesdelspliceai ↗
BP6 SupportingThis variant is classified as likely benign in ClinVar (VariationID 3571549) by a clinical diagnostic laboratory (Athena Diagnostics) using criteria provided. Although a single submitter, the classification from a reputable clinical laboratory supports a likely benign assessment. Details ▾Hide ▴
Evidence considered
  • ClinVar VariationID 3571549: likely benign by Athena Diagnostics
  • criteria provided
  • single submitter.
Still missing
  • No expert panel review in ClinVar
  • single submitter only.
Sources
clinvar ↗

Not met · 9 · evaluated, threshold not reached

PS4 The variant was observed in 1/612 Taiwanese PD patients and 0/508 ethnically matched controls (PMID:24339985). The case count is insufficient to demonstrate statistically significant enrichment in affected individuals. No additional case-control data available. Details ▾Hide ▴
Evidence considered
  • 1/612 PD patients vs 0/508 controls
  • odds ratio not calculable with statistical significance given single observation in cases.
Still missing
  • Larger case-control studies needed to evaluate variant prevalence in PD.
Sources
PMID:24339985 ↗
PM1 Although variant lies in the ANK domain of LRRK2, which is a functional domain, the residue is not in a statistically significant mutational hotspot and the domain contains both pathogenic and benign missense variation. Does not meet PM1 criteria without hotspot enrichment evidence. Details ▾Hide ▴
Evidence considered
  • Hotspot analysis: residue not in a statistically significant hotspot
  • exact variant not listed as hotspot.
PP1 The variant was identified in a single Taiwanese early-onset PD patient. No family segregation data are available. PMID:24339985 explicitly states there is 'insufficient segregation to prove the pathogenicity of the two novel mutations (R767H and S885N).' Details ▾Hide ▴
Evidence considered
  • Single proband identified
  • no co-segregation data. Authors state insufficient segregation to prove pathogenicity.
Still missing
  • Family studies needed to assess segregation.
Sources
PMID:24339985 ↗
PP3 Multiple in silico tools predict a benign effect. REVEL score is 0.157 (below the 0.5 threshold for damaging prediction). BayesDel score is -0.0159304 (negative, predicting benign). SpliceAI max delta score is 0.01 (predicting no splice impact). No computational evidence supports a damaging effect. Details ▾Hide ▴
Evidence considered
  • REVEL=0.157 (benign-range)
  • BayesDel=-0.0159304 (benign)
  • SpliceAI max delta=0.01 (no splice impact).
Sources
revelbayesdelspliceai ↗
PP5 No reputable source classifies this variant as pathogenic. ClinVar classification is likely benign by a single clinical laboratory. No expert panel classification is available. Details ▾Hide ▴
Evidence considered
  • ClinVar VariationID 3571549: likely benign
  • criteria provided
  • single submitter (Athena Diagnostics). Not classified as pathogenic by any source.
Sources
clinvar ↗
BA1 The variant allele frequency in gnomAD-Canada v1.0 is 0.0163% (3/18,414 alleles), which is far below the 1% BA1 threshold for a dominant disorder. This does not support a benign classification on population frequency grounds. Details ▾Hide ▴
Evidence considered
  • gnomAD-Canada AF=0.0163% << 1% BA1 threshold.
Sources
gnomad_canada ↗
BS1 The variant allele frequency in gnomAD-Canada v1.0 is 0.0163% (3/18,414 alleles), which is below the 0.3% BS1 threshold. The variant is not common enough in population databases to support a benign classification. Details ▾Hide ▴
Evidence considered
  • gnomAD-Canada AF=0.0163% < 0.3% BS1 threshold.
Sources
gnomad_canada ↗
BS3 Well-established functional studies (PMID:35950872) demonstrate that R767H activates LRRK2 kinase activity >1.5-fold above wildtype and disrupts the ANK:CH domain interface — effects consistent with a gain-of-function pathogenic mechanism, not a benign effect. BS3 requires functional studies showing no damaging effect, which is contradicted by available data. Details ▾Hide ▴
Evidence considered
  • PMID:35950872: R767H robustly stimulates LRRK2 kinase activity
  • not a benign functional effect. BS3 not supported.
Sources
PMID:35950872 ↗
PS5 No reputable source classifies this variant as pathogenic. ClinVar classification is likely benign (single clinical laboratory submitter). Details ▾Hide ▴
Evidence considered
  • ClinVar VariationID 3571549: likely benign
  • criteria provided
  • single submitter.
Sources
clinvar ↗

Not assessed · 9 · no assessment recorded

PS1 No alternative nucleotide change at the same amino acid position (Arg767) was identified in available data. A different nucleotide substitution producing the same missense change could not be evaluated. Details ▾Hide ▴
Still missing
  • No same-AA alternative nucleotide change identified in ClinVar or literature.
PS2 No de novo occurrence report for this variant was identified in any available source. PMID:23279440 is a clinical diagnostic guideline paper that mentions LRRK2 generally but contains no variant-specific de novo data. Details ▾Hide ▴
Still missing
  • No de novo report for NM_198578.3:c.2300G>A in available literature or databases.
PM6 No de novo occurrence report for this variant was identified in any available source. PMID:23279440 is a clinical guideline paper with no variant-specific de novo data. Details ▾Hide ▴
Still missing
  • No de novo report for NM_198578.3:c.2300G>A.
PP2 No gene-level missense constraint data (e.g., gnomAD missense Z-score or missense o/e metric) were retrieved for LRRK2. PP2 cannot be assessed without this information. Details ▾Hide ▴
Still missing
  • LRRK2 missense constraint metrics not available in retrieved data.
PP4 No patient-specific phenotype data were available for the proband carrying this variant. The single Taiwanese PD patient was described as early-onset (age ≤50) but detailed clinical features are not reported in PMID:24339985. Details ▾Hide ▴
Still missing
  • Detailed phenotype of the single reported carrier not available.
BS2 No data were available on observation of this variant in healthy adults independently of disease phenotype. The 3 gnomAD-Canada alleles come from a population database without linked phenotype information. Details ▾Hide ▴
Still missing
  • No healthy adult carrier data with confirmed unaffected status.
BS4 No segregation data are available for this variant. The single reported carrier was from a case-control study without family analysis. BS4 requires observation of lack of segregation with disease. Details ▾Hide ▴
Still missing
  • No family segregation data available to assess BS4.
BP2 No observation of this variant in trans with a known pathogenic LRRK2 variant was identified. BP2 cannot be assessed without such data. Details ▾Hide ▴
Still missing
  • No data on co-occurrence in trans with pathogenic LRRK2 variants.
BP5 No alternate molecular basis for disease was reported in the single case carrying this variant. Insufficient data to assess BP5. Details ▾Hide ▴
Still missing
  • No data on alternative molecular diagnoses in carriers.
Not applicable · 4· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_198578.3:c.2300G>A is a missense variant (p.Arg767His) and does not fall into the default PVS1 null-variant buckets (nonsense, frameshift, canonical ±1,2 splice consensus). Details ▾Hide ▴
Evidence considered
  • Missense variant
  • not eligible for PVS1 under ClinGen SVI PVS1 decision tree (PMC6185798).
Sources
pvs1_variant_assessment
PM5 N/ANo same-residue pathogenic comparator variant (different amino acid change at Arg767) was identified in ClinVar or literature. PM5 candidate harvesting was unable to confirm classic same-residue semantics. Details ▾Hide ▴
Evidence considered
  • PM5 candidate search returned no eligible comparators.
Sources
pm5_candidates
BP1 N/ALRRK2-associated Parkinson disease is caused by missense gain-of-function variants (e.g., G2019S, R1441C/G/H) that increase kinase activity. Truncating variants are not the primary disease mechanism for LRRK2; therefore BP1, which applies when a gene primarily causes disease through truncating variants, is not applicable. Details ▾Hide ▴
Evidence considered
  • LRRK2 PD mechanism is gain-of-function via missense variants
  • BP1 not applicable.
BP7 N/ANM_198578.3:c.2300G>A is a missense variant (p.Arg767His), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
  • Missense variant
  • BP7 not applicable.

Identifiers

Gene
LRRK2
Transcript
NM_198578.3
Coding (HGVS c.)
NM_198578.3:c.2300G>A
Protein (HGVS p.)
NP_940980.3:p.(Arg767His)
GRCh38
chr12:40283933 G>A
GRCh37
chr12:40677735 G>A
ClinVar
3571549
COSMIC
COSV54143918

Gene diagram

Every interpreted variant in LRRK2, mapped onto the exon structure of NM_198578.3. Select a row to find it on the plot.

LRRK2NM_198578.3
Fetching transcript structure from UCSC…
gnomAD v4.1 Allele count data not recorded
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD-Canada

AF not recorded · ? / ? alleles

Statements

gnomAD-Canada

This variant is present in gnomAD-Canada v1.0 (AF= 0.00016291951775822744, 3/18414 alleles, homozygotes = 0).

Open the gnomAD-Canada detail page →

SpliceAI and Pangolin

SpliceAI acceptor lossat -58 bp
0.000
SpliceAI acceptor gainat +171 bp
0.000
SpliceAI donor lossat +44 bp
0.010
SpliceAI donor gainat +212 bp
0.000
Pangolin splice lossmagnitude shown
-0.010
Pangolin splice gain
0.000

Other predictors

REVEL
0.157
BayesDel
-0.016

How the predictions were used

BP4 SupportingMultiple lines of computational evidence suggest no deleterious impact. REVEL score is 0.157 (below the 0.5 damaging threshold). BayesDel score is -0.0159304 (negative, predicting benign). SpliceAI max delta is 0.01 (predicting no splicing impact). All available in silico tools are concordant in predicting a benign effect. Details ▾Hide ▴
Evidence considered
  • REVEL=0.157 (benign)
  • BayesDel=-0.0159304 (benign)
  • SpliceAI max delta=0.01 (no splice impact). All in silico tools concordantly predict benign.
Sources
revelbayesdelspliceai ↗
PP3 Multiple in silico tools predict a benign effect. REVEL score is 0.157 (below the 0.5 threshold for damaging prediction). BayesDel score is -0.0159304 (negative, predicting benign). SpliceAI max delta score is 0.01 (predicting no splice impact). No computational evidence supports a damaging effect. Details ▾Hide ▴
Evidence considered
  • REVEL=0.157 (benign-range)
  • BayesDel=-0.0159304 (benign)
  • SpliceAI max delta=0.01 (no splice impact).
Sources
revelbayesdelspliceai ↗
BP7 N/ANM_198578.3:c.2300G>A is a missense variant (p.Arg767His), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
  • Missense variant
  • BP7 not applicable.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.157. BayesDel score = -0.0159304.

8 paper records listed. 2 cited in the classification.

Cited in the classification

  • Functional properties of LRRK2 mutations in Taiwanese Parkinson disease.
    Chang KH et al. · 2017 Mar
    Abstract reports evaluation of functional properties of three LRRK2 mutations identified in Taiwanese PD patients: p.R767H, p.S885N, and p.R1441H. Full text unavailable for detailed data extraction.
    → PS3 Names this variant
    PMID 27423549 ↗
    Source detail
    Our previous study found three LRRK2 mutations-p.R767H, p.S885N, and p.R1441H-in Taiwanese patients with Parkinson disease. We evaluated the functional properties of these three LRRK2 mutations

    Location Abstract

    Context Not available (full text not accessible)

  • Impact of 100 LRRK2 variants linked to Parkinson's disease on kinase activity and microtubule binding.
    Kalogeropulou AF et al. · 2022 Sep 16
    R767H identified as one of 23 LRRK2 variants that robustly stimulate kinase activity (>1.5-fold pRab10 Thr73 phosphorylation). Structural analysis reveals disruption of ANK:C-terminal helix interface by abolishing ionic interaction with E2516. Charge-reversed double mutation R767E/E2516R restores wildtype activity.
    → PS3 Names this variant
    PMID 35950872 ↗
    Source detail
    the R767H variant likely destabilizes the ANK:CH interface, as the arginine side chain of the R767 bridges the ANK domain to the C-terminal helix (CH) through hydrophobic and polar interactions with V2513 and E2516

    Location Results; Figures 7G, 7H, 8A, 8C; Supplementary Figures S2, S3

    Context HEK293T cells; pRab10 Thr73 phosphorylation assay; structural modeling of ANK:CH interface

Other recorded publications

  • EFNS/MDS-ES/ENS [corrected] recommendations for the diagnosis of Parkinson's disease.
    Berardelli A et al. · 2013
    EFNS/MDS-ES clinical diagnostic guidelines for Parkinson disease. Lists six known pathogenic LRRK2 mutations (N1437H, R1441C, R1441G, Y1699C, G2019S, I2020T) but does not mention R767H or NM_198578.3:c.2300G>A.
    Does not name this variant
    PMID 23279440 ↗
  • Genetic variants ofLRRK2 in Taiwanese Parkinson's disease.
    Wu YR et al. · 2013
    R767H identified as a novel missense mutation in one Taiwanese early-onset PD patient (age ≤50), absent from 508 ethnically matched controls. Located in the ANK domain of LRRK2. Authors note insufficient segregation to prove pathogenicity.
    Names this variant
    PMID 24339985 ↗
    Quoted passage
    two novel missense mutations (R767H and S885N) regarding LRRK2 in PD patients were identified

    Results; Table 1; Figure 1

  • Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
    ACMG/AMP 2015 standards and guidelines for sequence variant interpretation. General framework document; does not discuss any specific LRRK2 variant including NM_198578.3:c.2300G>A.
    Does not name this variant
    PMID 25741868 ↗
  • A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.
    Karbassi I et al. · 2016
    Describes a standardized DNA variant scoring system (Athena Diagnostics). Does not mention any specific LRRK2 variant including p.Arg767His.
    Does not name this variant
    PMID 26467025 ↗
  • Comprehensive Analysis of Familial Parkinsonism Genes in Rapid-Eye-Movement Sleep Behavior Disorder.
    Mufti K et al. · 2021
    Comprehensive analysis of familial parkinsonism genes in rapid-eye-movement sleep behavior disorder (iRBD). Abstract references LRRK2 generally; R767H is not mentioned in available abstract.
    Does not name this variant
    PMID 33001463 ↗
  • Monogenic Parkinson Disease Overview.
    Adam MP et al. · 1993
    GeneReviews overview of monogenic Parkinson disease. No abstract available for review. This is a general disease overview unlikely to contain variant-specific data for R767H.
    Does not name this variant
    PMID 20301402 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

SpliceAI Lookup Recorded maximum delta 0.010 Open source ↗
ClinVar 1 likely benign 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

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD-Canada

This variant is present in gnomAD-Canada v1.0 (AF= 0.00016291951775822744, 3/18414 alleles, homozygotes = 0).

ClinVar

This variant has been reported in ClinVar as likely benign (1 clinical laboratory). (ClinVarID = 3571549)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.157. BayesDel score = -0.0159304.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV54143918, n = 3 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.