NM_198578.3:c.4229C>T

LRRK2 · NP_940980.3:p.(Thr1410Met) · NM_198578.3

GRCh37: chr12:40702947 C>T · GRCh38: chr12:40309145 C>T

Gene: LRRK2 Transcript: NM_198578.3

Final call

Benign

BA1 stand-alone benign BS1 strong benign BS2 supporting benign BP4 supporting benign BP6 supporting benign

Variant details

Gene

LRRK2

Transcript

NM_198578.3

Protein

NP_940980.3:p.(Thr1410Met)

gnomAD AF

0.001158833284170709 (v4.1)

ClinVar

Benign

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

BA1 (stand-alone benign) is met: NM_198578.3:c.4229C>T (p.Thr1410Met) has an allele frequency of 2.12% in the African/African American population in gnomAD v2.1 (528/24,960 alleles, 6 homozygotes) and 2.07% in v4.1 (1,552/74,966 alleles, 17 homozygotes), which far exceeds the prevalence of autosomal dominant LRRK2-related Parkinson's disease and meets the >1% BA1 threshold.

BS1 (strong benign) is independently met: the overall gnomAD v2.1 allele frequency of 0.21% and the African subpopulation frequency of 2.12% exceed the >0.3% BS1 threshold. This frequency is inconsistent with a pathogenic role in Parkinson's disease.

BS2 (supporting benign) is met: 6 homozygous individuals are observed in gnomAD v2.1 and 18 in v4.1, consistent with a benign variant tolerated in the homozygous state.

BP4 (supporting benign) is met: computational predictors REVEL (0.466), BayesDel (-0.172832), and SpliceAI (max delta 0.15) do not predict a damaging effect.

BP6 (supporting benign) is met: ClinVar reports the variant as Benign (3 clinical laboratories) and Likely benign (2 clinical laboratories).

Final classification: Benign. BA1 alone is sufficient for a Benign classification per ACMG/AMP 2015 rules. Additional supporting benign criteria (BS1, BS2, BP4, BP6) reinforce this determination.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Benign classification because either BA1 is met or at least two strong 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.4229C>T is a missense substitution (p.Thr1410Met) and does not fall into a null-variant category (nonsense, frameshift, or canonical ±1,2 splice consensus). The generic PVS1 framework (PMC6185798) does not apply.	pvs1_generic_framework pvs1_variant_assessment
PS1	Not assessed	No information available about a different nucleotide change at the same amino acid position (Thr1410) with an established pathogenic classification.
PS2	Not met	No confirmed de novo occurrence of NM_198578.3:c.4229C>T has been reported in the literature. PMID:23279440 is an EFNS/MDS-ES diagnostic guideline document, not a de novo case report.
PS3	Not met	No well-established in vitro or in vivo functional studies demonstrate a damaging effect specific to the T1410M variant. PMID:21060682 studied T1410A (an artificial alanine substitution), not the patient-observed T1410M change. T1410A reduced GTPase activity but did not affect kinase activity; these findings cannot be extrapolated to T1410M without dedicated functional evaluation.	PMID:21060682
PS4	Not met	The variant is common in population databases, with allele frequencies inconsistent with a pathogenic role in Parkinson's disease. PMID:20443975 identified p.T1410M in a cohort of 204 Brazilian PD patients, but without control data or statistical enrichment, this does not constitute evidence for pathogenicity. The variant's high frequency in the general population strongly argues against a pathogenic effect.	gnomad_v2 gnomad_v4 PMID:20443975
PS5	Not met	PS5 requires a different pathogenic missense change at the same amino acid residue (Thr1410). No pathogenic missense variant has been established at residue 1410 of LRRK2.
PM1	Not met	While position 1410 is within the ROC/GTPase domain of LRRK2 and is the autophosphorylation site (PMID:21060682), the variant's high population frequency (AF >2% in African ancestry) and benign ClinVar classification are inconsistent with a pathogenic interpretation. The LRRK2 VCEP has not defined a critical domain or mutational hotspot for PM1 application.	PMID:21060682 gnomad_v2 gnomad_v4
PM2	Not met	This variant is present in gnomAD at frequencies exceeding the PM2 threshold of <0.1%. gnomAD v2.1: overall AF=0.21% (593/282,506 alleles, 6 homozygotes), grpmax FAF=2.07%. gnomAD v4.1: overall AF=0.12% (1,870/1,613,692 alleles, 18 homozygotes), grpmax FAF=1.98%. The high homozygote count is inconsistent with a rare pathogenic variant.	gnomad_v2 gnomad_v4
PM5	N/A	No same-residue pathogenic missense comparator variants were identified. The pm5_candidates.json confirms no candidate comparator variants at residue 1410.	pm5_candidates
PM6	Not met	No confirmed de novo occurrence of this variant has been reported. PMID:23279440 is the EFNS/MDS-ES diagnostic guideline for Parkinson's disease, which does not contain de novo case data.
PP1	Not assessed	No segregation data are available for this variant.
PP2	Not met	LRRK2 has a high rate of benign missense variation in population databases; this variant itself is common (AF >2% in African ancestry). PP2 is intended for genes where missense variants are a common mechanism of disease AND the gene has a low rate of benign missense variation — conditions not met here given the high population frequency of this and other LRRK2 missense variants.	gnomad_v2 gnomad_v4
PP3	Not met	Multiple in silico tools predict a benign effect: REVEL score 0.466 (below commonly used 0.5 damaging threshold), BayesDel score -0.172832 (below 0.13 damaging threshold), and SpliceAI max delta 0.15 (no predicted splice impact). The aggregate computational evidence does not support a pathogenic interpretation.	revel bayesdel spliceai
PP4	Not assessed	No detailed phenotype data specific to patients carrying this variant are available.
PP5	Not met	ClinVar classifies this variant as Benign (3 clinical laboratories) and Likely benign (2 clinical laboratories) (ClinVar variation ID 39179). PP5 requires a reputable source to report the variant as pathogenic, which is not the case. The GeneReviews entries (PMID:20301387, PMID:20301402) are general overviews and do not classify this variant as pathogenic.	clinvar PMID:20301387 PMID:20301402
BA1	Met	This variant has an allele frequency >1% in the African/African American population of gnomAD. gnomAD v2.1: AF=2.12% (528/24,960 alleles, 6 homozygotes). gnomAD v4.1: AF=2.07% (1,552/74,966 alleles, 17 homozygotes). This frequency far exceeds the prevalence of autosomal dominant LRRK2-related Parkinson's disease, meeting BA1 (stand-alone benign).	gnomad_v2 gnomad_v4
BS1	Met	This variant has an allele frequency >0.3% in the general gnomAD v2.1 population (0.21%) and substantially exceeds this threshold in the African/African American subpopulation (2.12%). The variant's frequency is greater than expected for an autosomal dominant Parkinson's disease-causing variant. BS1 is superseded by BA1 in the classification but is independently met.	gnomad_v2 gnomad_v4
BS2	Met	This variant is observed in 6 apparently healthy homozygous individuals in gnomAD v2.1 and 18 homozygotes in gnomAD v4.1. While Parkinson's disease is late-onset, the presence of multiple homozygotes in a population database without reported early-onset parkinsonism is consistent with a benign interpretation.	gnomad_v2 gnomad_v4
BS3	Not met	No well-established in vitro or in vivo functional studies demonstrate a benign effect specific to the T1410M variant. PMID:21060682 studied T1410A (alanine substitution), showing reduced GTPase activity without affecting kinase activity. These findings cannot be directly extrapolated to T1410M (threonine to methionine substitution), which may have different structural and functional consequences. No variant-specific benign functional evidence exists.	PMID:21060682
BS4	Not assessed	No formal segregation data demonstrating lack of cosegregation with Parkinson's disease are available.
BP1	N/A	BP1 applies to missense variants in genes where truncating/loss-of-function is the primary pathogenic mechanism. LRRK2-related Parkinson's disease is a gain-of-function disorder (e.g., G2019S increases kinase activity); pathogenic variants are predominantly missense. BP1 does not apply.
BP2	Not met	BP2 requires observation of the variant in trans with a pathogenic variant for a fully penetrant dominant disorder. No such observation is documented. LRRK2-related Parkinson's disease is autosomal dominant, but co-occurrence in trans with a known pathogenic LRRK2 variant has not been reported for c.4229C>T.
PM3	N/A	PM3 is specific to recessive disorders (variant in trans with a pathogenic variant). LRRK2-related Parkinson's disease is autosomal dominant.
PM4	N/A	PM4 is specific to protein-length-altering variants (in-frame deletions/insertions, stop-loss). NM_198578.3:c.4229C>T is a substitution.
BP3	N/A	Variant is a substitution, not an in-frame deletion/insertion in a repetitive region. BP3 is specific to in-frame indels.
BP4	Met	Multiple lines of computational evidence support a benign interpretation: REVEL score 0.466 (below 0.5 threshold), BayesDel score -0.172832 (below 0.13 damaging threshold), and SpliceAI max delta 0.15 (no predicted splice impact). The aggregate in silico evidence does not predict a damaging effect on the gene product.	revel bayesdel spliceai
BP5	Not assessed	No documentation available of this variant being found in a case with an alternative molecular basis for Parkinson's disease.
BP6	Met	This variant has been classified as Benign by 3 clinical laboratories and Likely benign by 2 clinical laboratories in ClinVar (ClinVar variation ID 39179). Multiple submitters with consistent benign classifications constitute a reputable source for BP6. Submitting laboratories include Labcorp Genetics (formerly Invitae), Illumina Laboratory Services, and Breakthrough Genomics.	clinvar
BP7	N/A	NM_198578.3:c.4229C>T is a missense variant (p.Thr1410Met), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact.

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