NM_198578.3:c.2300G>A

LRRK2 · NP_940980.3:p.(Arg767His) · NM_198578.3

GRCh37: chr12:40677735 G>A · GRCh38: chr12:40283933 G>A

Gene: LRRK2 Transcript: NM_198578.3

Final call

Likely Benign

PS3 supporting PM2 supporting BP4 supporting benign BP6 supporting benign

Variant details

Gene

LRRK2

Transcript

NM_198578.3

Protein

NP_940980.3:p.(Arg767His)

gnomAD AF

ClinVar

likely benign

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Benign classification because either one strong benign criterion plus one supporting benign criterion, or at least two supporting benign criteria, are present.

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	NM_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).	pvs1_variant_assessment
PS1	Not assessed	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.
PS2	Not assessed	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.
PS3	Met	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.	PMID:35950872 PMID:27423549
PS4	Not met	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.	PMID:24339985
PS5	Not met	No reputable source classifies this variant as pathogenic. ClinVar classification is likely benign (single clinical laboratory submitter).	clinvar
PM1	Not met	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.
PM2	Met	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.	gnomad_canada
PM5	N/A	No 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.	pm5_candidates
PM6	Not assessed	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.
PP1	Not met	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).'	PMID:24339985
PP2	Not assessed	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.
PP3	Not met	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.	revel bayesdel spliceai
PP4	Not assessed	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.
PP5	Not met	No reputable source classifies this variant as pathogenic. ClinVar classification is likely benign by a single clinical laboratory. No expert panel classification is available.	clinvar
BA1	Not met	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.	gnomad_canada
BS1	Not met	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.	gnomad_canada
BS2	Not assessed	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.
BS3	Not met	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.	PMID:35950872
BS4	Not assessed	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.
BP1	N/A	LRRK2-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.
BP2	Not assessed	No observation of this variant in trans with a known pathogenic LRRK2 variant was identified. BP2 cannot be assessed without such data.
BP4	Met	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.	revel bayesdel spliceai
BP5	Not assessed	No alternate molecular basis for disease was reported in the single case carrying this variant. Insufficient data to assess BP5.
BP6	Met	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.	clinvar
BP7	N/A	NM_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.

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