Variant classification summary

NM_198578.4:c.4321C>G

LRRK2 · NP_940980.4:p.(Arg1441Gly) · NM_198578.4

GRCh37: chr12:40704236 C>G · GRCh38: chr12:40310434 C>G

Gene: LRRK2 Transcript: NM_198578.4

Final call

Pathogenic

PS3 strong PS4 strong PM1 moderate PM2 supporting PM5 moderate PP1 supporting PP3 supporting

Variant details

Gene

LRRK2

Transcript

NM_198578.4

Protein

NP_940980.4:p.(Arg1441Gly)

gnomAD AF

3.0998985713187463e-06 (v4.1)

ClinVar

Pathogenic

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Pathogenic: PS3 strong showed damaging biochemical and cellular effects.

2

Pathogenic: PS4 strong showed qualifying case-control enrichment.

3

Pathogenic: PM1 moderate identified a pathogenic ROC GTPase-domain hotspot.

4

Pathogenic: PM2 supporting showed an extremely low gnomAD frequency.

5

Pathogenic: PM5 moderate identified pathogenic substitutions at Arg1441.

6

Pathogenic: PP1 supporting showed familial co-segregation.

7

Pathogenic: PP3 supporting was met by the adjudicated REVEL result.

Final determination: Under generic ACMG/AMP 2015 fallback rules, two strong pathogenic criteria (PS3 and PS4) satisfy Pathogenic; no benign rule is satisfied, so the evidence is not conflicting.

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	Not applicable: PVS1 requires a null variant (nonsense, frameshift, canonical splice, start-loss or stop-loss), and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not met	Not met: available reports establish p.Arg1441Gly itself, but no different-nucleotide variant producing the same amino-acid change was identified.	clinvar PMID:15925109 PMID:24973808
PS2	Not assessed	Not assessed: no documented de novo observation with confirmation of both maternity and paternity is available for this patient.
PS3	Met	Met, strong: R1441G reduced GTP hydrolysis and disrupted Ser910/Ser935 phosphorylation and 14-3-3 binding in two variant-specific functional studies.	PMID:17623048 PMID:20642453
PS4	Met	Met: 29/29 Parkinson disease cases versus 0/85 controls gives OR infinite with exact 95% CI approximately 319.45 to infinity, exceeding the OR >5.0 threshold and excluding 1.	PMID:15925109 PMID:19308469
PM1	Met	Met: residue 1441 lies within the ROC GTPase domain (amino acids 1321-1516) and recurrent pathogenic R1441 substitutions define a disease-associated hotspot.	PMID:17623048 PMID:20642453 PMID:23279440 cspec
PM2	Met	Met at supporting strength: gnomAD v4.1 grpmax FAF is 5.54e-06, below the generic PM2 supporting threshold of 0.0001.	gnomad_v4 gnomad_v2 cspec
PM3	N/A	Not applicable: LRRK2-associated Parkinson disease is autosomal dominant, whereas PM3 applies only to recessive disorders.	clinvar
PM4	N/A	Not applicable: PM4 requires a protein-length change, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Met	Met: pathogenic p.Arg1441Cys and p.Arg1441His are established at the same residue as the queried p.Arg1441Gly.	PMID:23279440 PMID:20642453 PMID:17623048
PM6	Not assessed	Not assessed: no assumed de novo observation without parental confirmation is documented for this patient.
PP1	Met	Met at supporting strength: p.R1441G was present in the proband, affected mother, and affected first cousin, while an unaffected brother lacked it.	PMID:24973808
PP2	Not assessed	Not assessed: missense disease mechanism is supported, but no gene-wide measure establishes a low rate of benign LRRK2 missense variation.	PMID:23279440 PMID:20642453 gnomad_v4
PP3	Met	Met at supporting: missense REVEL score 0.705 meets the PP3 threshold of >=0.644 but is below the moderate threshold of >=0.773.	revel
PP4	Not met	Not met: LRRK2-associated Parkinson disease is clinically indistinguishable from sporadic typical Parkinson disease, so the phenotype is not highly specific for one genetic etiology.	PMID:23279440
PP5	Not met	Not met: ClinVar has no exact-variant expert-panel classification; its Pathogenic label comes from clinical laboratories and cannot trigger PP5.	clinvar
BA1	Not met	Not met: gnomAD v4.1 grpmax FAF is 5.54e-06, far below the generic BA1 threshold of 0.05.	gnomad_v4 gnomad_v2 clinvar cspec
BS1	Not met	Not met: gnomAD v4.1 grpmax FAF is 5.54e-06, below the generic BS1 threshold of 0.01 despite the variant's founder and late-onset context.	gnomad_v4 gnomad_v2 PMID:15925109 PMID:19308469
BS2	N/A	Not applicable: LRRK2-associated Parkinson disease is late-onset, whereas BS2 requires full penetrance expected at an early age.	PMID:15925109 gnomad_v4 gnomad_v2
BS3	Not assessed	Not assessed: available R1441G functional studies report reduced GTP hydrolysis and disrupted 14-3-3 regulation, with no normal-function result supporting BS3.
BS4	Not met	Not met: all three reported affected relatives carried p.R1441G, while the healthy brother lacked the variant.	PMID:24973808
BP1	Not met	Not met: LRRK2 disease is established through recurrent pathogenic missense substitutions, not primarily truncating variants.	PMID:23279440 PMID:20642453 PMID:17623048
BP2	Not assessed	Not assessed: no documented pathogenic second allele or cis/trans phase is available for NM_198578.4:c.4321C>G.	PMID:24973808
BP3	N/A	Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: missense REVEL score 0.705 exceeds the BP4 supporting cutoff of <=0.29 and is therefore indeterminate for benign computational evidence.	revel
BP5	Not assessed	Not assessed: no qualifying case is documented with both this exact variant and an alternate molecular basis for the disease.	PMID:15925109 PMID:19308469 PMID:24973808
BP6	Not met	Not met: no exact-variant benign expert-panel report exists, while ClinVar records Pathogenic clinical-laboratory submissions and zero expert-panel submissions.	clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a missense variant.	generic_acmg_combination_rules

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