About LRRK2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
LRRK2 c.4229C>T, p.(Thr1410Met)
Classification
Benign
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is benign. Select a step to read what it means.
Benign.A benign classification under the recorded framework.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
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: 0
Benign evidence criteria: 5
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 5
BA1Stand alone
BA1 · stand alone
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).
BS1Strong
BS1 · strong
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 BS1 is superseded by BA1 in the classification but is independently met.
BS2Supporting
BS2 · supporting
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.
BP4Supporting
BP4 · supporting
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.
BP6Supporting
BP6 · supporting
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.
Recorded classification: 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: BA1 stand-alone benign, BS1 strong benign, BS2 supporting benign, BP4 supporting benign, BP6 supporting benign; combination = 1 stand-alone benign + 1 strong benign + 3 supporting benign, which maps to Benign.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
1,870 / 1,613,692 alleles
gnomAD v4.1: 1,870 / 1,613,692 alleles. Recorded AF 0.00115883. Recorded homozygote count 18.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.00209907; MAF= 0.20991%, 593/282506 alleles, homozygotes = 6) and has highest observed frequency in the African/African American population (AF= 0.0211538; MAF= 2.11538%, 528/24960 alleles, homozygotes = 6); grpmax FAF= 0.020734.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.0014115092290988057, 26/18420 alleles, homozygotes = 0).
SpliceAI score
0.150 maximum delta
Recorded SpliceAI maximum delta score: 0.150. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
5 reported laboratory submissions
3 Benign · 2 Likely benign.
No screenshot for this evidence
Functional evidence
Not recorded
No standalone functional evidence summary is recorded in evidence_summary.functional.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
1 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV114383285, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under ClinGen LRRK2 VCEP v1.0.0, with the data and sources behind each one.
29 criteria with recorded statuses: 5 met · 12 not met · 5 not assessed · 7 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
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.
No criteria match.
Met · 5
BA1 Stand aloneThis 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). Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 African AF=2.12% (>1% BA1 threshold)
- v4.1 African AF=2.07% (>1% BA1 threshold)
- multiple homozygotes observed
Sources
BS1 StrongThis 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. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 overall AF=0.21%
- African AF=2.12% (>>0.3% BS1 threshold)
- v4.1 overall AF=0.12%
- African AF=2.07%
Sources
BS2 SupportingThis 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. Details ▾Hide ▴
Evidence considered
- 6 homozygotes in gnomAD v2.1
- 18 homozygotes in gnomAD v4.1
- observation of homozygotes in a population database supports benign interpretation
Still missing
- Late-onset disease caveat
- formal documentation of healthy clinical status in homozygotes not available
Sources
BP4 SupportingMultiple 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. Details ▾Hide ▴
Evidence considered
- REVEL=0.466
- BayesDel=-0.172832 (benign)
- SpliceAI max delta=0.15 (no splice impact)
Sources
BP6 SupportingThis 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. Details ▾Hide ▴
Evidence considered
- ClinVar classification: Benign (3 labs)
- Likely benign (2 labs)
- ClinVar ID 39179
Sources
Not met · 12 · evaluated, threshold not reached
PS2 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. Details ▾Hide ▴
Evidence considered
- No de novo case reports identified
Still missing
- No de novo testing has been reported for this variant
PS3 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. Details ▾Hide ▴
Evidence considered
- PMID:21060682 studied T1410A
- not T1410M
- functional data for the specific amino acid substitution are absent
Still missing
- No variant-specific functional assay for T1410M
Sources
PS4 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. Details ▾Hide ▴
Evidence considered
- gnomAD AF >2% in African ancestry
- PMID:20443975 reported variant in PD patients without control comparison
Still missing
- No case-control study demonstrating enrichment in affected individuals
Sources
PM1 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. Details ▾Hide ▴
Evidence considered
- Thr1410 is in the ROC/GTPase domain and is an autophosphorylation site
- but high population frequency contradicts a pathogenic role
Still missing
- No VCEP-defined mutational hotspot for LRRK2 PM1
Sources
PM2 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. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF=0.21%
- v4.1 AF=0.12%
- both exceed PM2 threshold of <0.1%
Sources
PM6 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. Details ▾Hide ▴
Evidence considered
- No de novo case reports identified
Still missing
- No de novo testing reported
PP2 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. Details ▾Hide ▴
Evidence considered
- The variant is common in population databases
- inconsistent with PP2 application
Sources
PP3 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. Details ▾Hide ▴
Evidence considered
- REVEL=0.466 (benign)
- BayesDel=-0.172832 (benign)
- SpliceAI max delta=0.15 (no splice impact)
Sources
PP5 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. Details ▾Hide ▴
Evidence considered
- ClinVar classification: Benign/Likely benign
- GeneReviews does not classify as pathogenic
Sources
BS3 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. Details ▾Hide ▴
Evidence considered
- PMID:21060682 studied T1410A
- not T1410M
- no direct functional evidence for T1410M benign effect
Still missing
- No variant-specific functional assay for T1410M showing no damaging effect
Sources
BP2 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. Details ▾Hide ▴
Evidence considered
- No observation in trans with a pathogenic LRRK2 variant reported
Still missing
- No allelic data with known pathogenic LRRK2 variants
PS5 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. Details ▾Hide ▴
Evidence considered
- No established pathogenic missense at residue 1410
Still missing
- No pathogenic comparator at residue 1410
Not assessed · 5 · no assessment recorded
PS1 No information available about a different nucleotide change at the same amino acid position (Thr1410) with an established pathogenic classification. Details ▾Hide ▴
Evidence considered
- No same-residue pathogenic comparator identified
Still missing
- No established pathogenic variant at residue 1410
PP1 No segregation data are available for this variant. Details ▾Hide ▴
Still missing
- No family segregation studies reported
PP4 No detailed phenotype data specific to patients carrying this variant are available. Details ▾Hide ▴
Still missing
- No patient-specific phenotype data available
BS4 No formal segregation data demonstrating lack of cosegregation with Parkinson's disease are available. Details ▾Hide ▴
Still missing
- No family-based segregation studies reported
BP5 No documentation available of this variant being found in a case with an alternative molecular basis for Parkinson's disease. Details ▾Hide ▴
Still missing
- No observation with alternate molecular basis reported
Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_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. Details ▾Hide ▴
Evidence considered
- Missense variant
- no null-variant criteria satisfied
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PM3 N/APM3 is specific to recessive disorders (variant in trans with a pathogenic variant). LRRK2-related Parkinson's disease is autosomal dominant. Details ▾Hide ▴
Evidence considered
- Autosomal dominant disorder
- PM3 not applicable
PM4 N/APM4 is specific to protein-length-altering variants (in-frame deletions/insertions, stop-loss). NM_198578.3:c.4229C>T is a substitution. Details ▾Hide ▴
Evidence considered
- Substitution
- not a protein-length-altering variant
PM5 N/ANo same-residue pathogenic missense comparator variants were identified. The pm5_candidates.json confirms no candidate comparator variants at residue 1410. Details ▾Hide ▴
Evidence considered
- No pathogenic comparator at the same amino acid residue
Sources
pm5_candidates
BP1 N/ABP1 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. Details ▾Hide ▴
Evidence considered
- LRRK2-PD is gain-of-function
- pathogenic variants are missense
BP3 N/AVariant is a substitution, not an in-frame deletion/insertion in a repetitive region. BP3 is specific to in-frame indels. Details ▾Hide ▴
Evidence considered
- Not an in-frame indel
BP7 N/ANM_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. Details ▾Hide ▴
Evidence considered
- Missense variant
- not synonymous
Identifiers
- Gene
- LRRK2
- Transcript
- NM_198578.3
- Coding (HGVS c.)
- NM_198578.3:c.4229C>T
- Protein (HGVS p.)
- NP_940980.3:p.(Thr1410Met)
- GRCh38
- chr12:40309145 C>T
- GRCh37
- chr12:40702947 C>T
- ClinVar
- 39179
- COSMIC
- COSV114383285
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…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in LRRK2
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
1,870 / 1,613,692 alleles
AF 0.00116 · 18 homozygotes · FAF 0.0198
gnomAD v2.1
593 / 282,506 alleles
AF 0.0021 · 6 homozygotes · FAF 0.0207
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 0.0012 · 1870 / 1,613,692 alleles · 18 hom · FAF 0.02
| African/African American1552 / 74,966 | 0.02117 hom |
| Remaining individuals97 / 62,480 | 0.00161 hom |
| Admixed American79 / 59,978 | 0.0013 |
| Middle Eastern3 / 6,058 | 0.0005 |
| South Asian40 / 91,060 | 0.00044 |
| European (non-Finnish)97 / 1,179,816 | 8.2e-05 |
| East Asian2 / 44,868 | 4.5e-05 |
0 alternate alleles recorded in 3 other groups: European (Finnish), Amish, Ashkenazi Jewish.
gnomAD v2.1
AF 0.0021 · 593 / 282,506 alleles · 6 hom · FAF 0.021
| African/African American528 / 24,960 | 0.0216 hom |
| Admixed American30 / 35,404 | 0.00085 |
| Remaining individuals6 / 7,204 | 0.00083 |
| South Asian15 / 30,610 | 0.00049 |
| European (non-Finnish)13 / 128,886 | 0.0001 |
| East Asian1 / 19,952 | 5e-05 |
0 alternate alleles recorded in 2 other groups: Ashkenazi Jewish, European (Finnish).
gnomAD-Canada
AF not recorded · ? / ? alleles
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0.00115883; MAF= 0.11588%, 1870/1613692 alleles, homozygotes = 18) and has highest observed frequency in the African/African American population (AF= 0.0207027; MAF= 2.07027%, 1552/74966 alleles, homozygotes = 17); grpmax FAF= 0.0198454.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.00209907; MAF= 0.20991%, 593/282506 alleles, homozygotes = 6) and has highest observed frequency in the African/African American population (AF= 0.0211538; MAF= 2.11538%, 528/24960 alleles, homozygotes = 6); grpmax FAF= 0.020734.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.0014115092290988057, 26/18420 alleles, homozygotes = 0).
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.466
- BayesDel
- -0.173
How the predictions were used
BP4 SupportingMultiple 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. Details ▾Hide ▴
Evidence considered
- REVEL=0.466
- BayesDel=-0.172832 (benign)
- SpliceAI max delta=0.15 (no splice impact)
Sources
PP3 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. Details ▾Hide ▴
Evidence considered
- REVEL=0.466 (benign)
- BayesDel=-0.172832 (benign)
- SpliceAI max delta=0.15 (no splice impact)
Sources
BP7 N/ANM_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. Details ▾Hide ▴
Evidence considered
- Missense variant
- not synonymous
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.15). REVEL score = 0.466. BayesDel score = -0.172832.
7 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Recorded publications
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PMID 20443975 ↗Genetic analysis of LRRK2 functional domains in Brazilian patients with Parkinson's disease.Abdalla-Carvalho CB et al. · 2010Abdalla-Carvalho et al. (2010) sequenced LRRK2 exons 29-31 and 38-44 (ROC and MAPKKK domains) in 204 Brazilian Parkinson's disease patients. Among the identified variants was p.T1410M. The study identified this as one of four substitutions detected but did not provide functional characterization or case-control analysis.Names this variant
Quoted passage
We identified four polymorphisms, a novel silent variant p.R1398R and four substitutions: p.T1410
Abstract
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PMID 21060682 ↗Identification and characterization of a leucine-rich repeat kinase 2 (LRRK2) consensus phosphorylation motif.Pungaliya PP et al. · 2010Pungaliya et al. (2010) identified the LRRK2 autophosphorylation consensus motif and demonstrated that Thr1410 within the ROC/GTPase domain is a site of autophosphorylation. The study functionally characterized T1410A (alanine substitution), showing reduced GTPase activity but no effect on kinase activity, GTP binding, or dimerization. The patient-observed T1410M variant was not studied. This paper establishes functional importance of the Thr1410 residue but does not provide variant-specific evidence for T1410M.Does not name this variant
Quoted passage
Interestingly, the phosphomotif was also identified within LRRK2 itself. Autophosphorylation was detected by mass spectrometry and biochemical means at the only F-x-T-x-R site (Thr 1410) within LRRK2.
Abstract; Results sections on autophosphorylation, GTPase activity
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PMID 23279440 ↗EFNS/MDS-ES/ENS [corrected] recommendations for the diagnosis of Parkinson's disease.Berardelli A et al. · 2013Berardelli et al. (2013) is the EFNS/MDS-ES/ENS consensus recommendations for the diagnosis of Parkinson's disease. The paper provides diagnostic criteria and investigation guidelines. NM_198578.3:c.4229C>T is not mentioned in this document.Does not name this variant
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PMID 25741868 ↗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.Richards S et al. · 2015Richards et al. (2015) provide the ACMG/AMP standards and guidelines for sequence variant interpretation. The paper does not mention LRRK2, NM_198578.3:c.4229C>T, or T1410M. It serves as the framework document for variant classification methodology.Does not name this variant
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PMID 20301387 ↗LRRK2-Related Parkinson Disease.Adam MP et al. · 1993This GeneReviews entry (LRRK2-Related Parkinson Disease) provides an overview of LRRK2 genetics and clinical management. It discusses known pathogenic LRRK2 variants including G2019S, R1441C, and others, but NM_198578.3:c.4229C>T (p.Thr1410Met) is not specifically discussed or classified.Does not name this variant
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PMID 20301402 ↗Monogenic Parkinson Disease Overview.Adam MP et al. · 1993This GeneReviews entry (Monogenic Parkinson Disease Overview) provides a broad review of monogenic PD genes. It does not contain specific information about NM_198578.3:c.4229C>T or p.Thr1410Met.Does not name this variant
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PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.Nykamp K et al. · 2017Nykamp et al. (2017) present the Sherloc classification framework, a refinement of ACMG-AMP criteria. The paper does not discuss LRRK2 or NM_198578.3:c.4229C>T specifically.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
1,870 / 1,613,692 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.150
Open source ↗
ClinVar
3 Benign · 2 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
- ClinGen CSpec ↗cspec.genome.network/cspec/ui/svi/doc/1612839626
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/39179/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/12-40702947-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr12-40309145-C-T?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/12-40309145-C-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_198578.3%3Ac.4229…
- OncoKB ↗www.oncokb.org/gene/LRRK2/T1410M
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=122506420
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0.00115883; MAF= 0.11588%, 1870/1613692 alleles, homozygotes = 18) and has highest observed frequency in the African/African American population (AF= 0.0207027; MAF= 2.07027%, 1552/74966 alleles, homozygotes = 17); grpmax FAF= 0.0198454.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.00209907; MAF= 0.20991%, 593/282506 alleles, homozygotes = 6) and has highest observed frequency in the African/African American population (AF= 0.0211538; MAF= 2.11538%, 528/24960 alleles, homozygotes = 6); grpmax FAF= 0.020734.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.0014115092290988057, 26/18420 alleles, homozygotes = 0).
ClinVar
This variant has been reported in ClinVar as Benign (3 clinical laboratories) and as Likely benign (2 clinical laboratories). (ClinVarID = 39179)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.15). REVEL score = 0.466. BayesDel score = -0.172832.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV114383285, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.