The LRRK2 NM_198578.4:c.4321C>G (NP_940980.4:p.(Arg1441Gly)) missense variant has not previously been reported in somatic cancers (COSMIC). Experimental evidence: R1441G reduced GTP hydrolysis and disrupted Ser910/Ser935 phosphorylation and 14-3-3 binding in two variant-specific functional studies. Based on available guidelines, this variant is considered to be Pathogenic.
Five-step scale from benign to pathogenic. This variant is pathogenic. Select a step to read what it means.
Pathogenic.A pathogenic classification under the recorded framework.
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.LRRK2 encodes a protein involved in cell signaling and cellular maintenance, with enzyme domains that help regulate protein activity and interactions. Changes in this gene are associated with Parkinson disease, a progressive disorder affecting movement and other nervous-system functions. No established role in cancer is indicated.
The recorded framework is Generic ACMG/AMP 2015 with ClinGen SVI recommendations. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
The applied criteria and their strengths are shown as assessed under the stated framework.
Met, strong: R1441G reduced GTP hydrolysis and disrupted Ser910/Ser935 phosphorylation and 14-3-3 binding in two variant-specific functional studies.
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.
Met: residue 1441 lies within the ROC GTPase domain (amino acids 1321-1516) and recurrent pathogenic R1441 substitutions define a disease-associated hotspot.
Met at supporting strength: gnomAD v4.1 grpmax FAF is 5.54e-06, below the generic PM2 supporting threshold of 0.0001.
Met: pathogenic p.Arg1441Cys and p.Arg1441His are established at the same residue as the queried p.Arg1441Gly.
Met at supporting strength: p.R1441G was present in the proband, affected mother, and affected first cousin, while an unaffected brother lacked it.
Met at supporting: missense REVEL score 0.705 meets the PP3 threshold of >=0.644 but is below the moderate threshold of >=0.773.
No benign criterion marked as applied in the recorded assessment.
Pathogenic: two strong criteria, PS3 and PS4, satisfy the generic ACMG/AMP Pathogenic rule, with additional PM1, PM5, PM2, PP1, and PP3 evidence.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 5 / 1,612,956 alleles. Recorded AF 3.0999e-06. Recorded homozygote count 0.
This variant is present in gnomAD v2.1 (AF= 3.98222e-06; MAF= 0.00040%, 1/251116 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 2.89302e-05; MAF= 0.00289%, 1/34566 alleles, homozygotes = 0).
Not available in gnomAD-Canada v1.0.
Recorded REVEL score: 0.705. Refer to the recorded PP3/BP4 rationale for interpretation.
6 Pathogenic. ClinVar API review status: criteria provided, multiple submitters, no conflicts.
No standalone functional evidence summary is recorded in evidence_summary.functional.
This variant has not previously been reported in somatic cancers (COSMIC).
This variant does not lie in a statistically significant hotspot.
ACMG/AMP criteria under Generic ACMG/AMP 2015 with ClinGen SVI recommendations, with the data and sources behind each one.
28 criteria with recorded statuses: 7 met · 9 not met · 6 not assessed · 6 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
The available evidence supports familial co-segregation (PP1 at supporting strength) and does not support a de novo interpretation (PS2 or PM6).
The documented affected-relative pattern is consistent with segregation, so BS4 is not met.
PS4 is met from verified exact-variant case-control enrichment in PMID:19308469; PMID:15925109 independently shows enrichment but its exact confidence interval includes 1.
PP4 is not met because the Parkinson disease phenotype is not highly specific for a single genetic etiology.
PP5 and BP6 are not met because the exact-variant ClinVar record has no expert-panel assertion and only clinical-laboratory Pathogenic submissions.
BP5 is not assessed because no qualifying alternate molecular basis is documented for a case carrying the exact variant.
The variant is missense, so PP3/BP4 are adjudicated through the REVEL path only. REVEL 0.705 supports PP3 at supporting strength and is outside the BP4 supporting range; no other computational criterion is evaluated by this group.
Population evidence supports PM2 at supporting strength only; BA1 and BS1 are not met because the required gnomAD filtering FAF is far below their thresholds.
BS2 is not applicable because the associated LRRK2 Parkinson disease is late-onset and the ACMG/AMP definition requires full penetrance at an early age.
No criteria match.
PS3 is met at strong strength. Two independent functional studies directly evaluated LRRK2 p.Arg1441Gly (c.4321C>G). In a purified LRRK2 GTPase-domain assay, R1441G showed significantly reduced GTP hydrolysis relative to wild type, while GTP binding was similar to wild type, using GTP hydrolysis, GTP-sepharose pull-down, and GTPγS-binding assays. In a separate full-length LRRK2 cellular study, R1441G showed markedly reduced Ser910/Ser935 phosphorylation and reduced 14-3-3 binding, with altered cytoplasmic localization assessed by confocal microscopy. These assays include wild-type comparison and directly measure biologically relevant LRRK2 biochemical and regulatory functions; together they provide well-established evidence of a damaging effect. The studies are research assays rather than explicitly validated clinical diagnostic laboratory assays, but the concordant, variant-specific results support the standard PS3 strong application under generic ACMG/AMP.
Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
PS4 is met. The exact LRRK2 c.4321C>G (p.Arg1441Gly) variant was verified in two variant-specific case-control reports. In PMID:15925109, it occurred in 5/182 late-onset Parkinson disease cases and 0/100 matched controls; the calculated OR is infinite, with an exact two-sided 95% CI of approximately 0.51 to infinity, so this individual study's CI includes 1. In PMID:19308469, it occurred in 29/29 unrelated Parkinson disease carriers and 0/85 mutation-negative controls; the calculated OR is infinite, with an exact two-sided 95% CI of approximately 319.45 to infinity, which excludes 1 and exceeds the ACMG/AMP OR >5.0 requirement. The latter study therefore provides qualifying case-control enrichment; the two studies are reported separately and are not treated as independent pooled evidence.
The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. ... Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0.
LRRK2 p.Arg1441Gly lies within the established Rab-like GTPase/ROC domain: the functional study used the LRRK2 GTPase domain spanning amino acids 1321-1516, which contains residue 1441. The same residue is a recurrent disease-associated hotspot with pathogenic R1441C, R1441G, and R1441H substitutions, and the supplied evidence identifies no benign interpretation for this residue or domain. The LRRK2 VCEP is listed without released criteria and vcep_materials.json contains no domain table, so this is assessed under generic ACMG/AMP and requires human confirmation of the domain-wide benign-variation exclusion.
Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.
PM2 at supporting strength is met. No LRRK2-specific population rule is released, so the generic all-comers gnomAD data apply. gnomAD v4.1 detects the variant at 5/1,612,956 alleles with total AF = 3.0998985713187463e-06, grpmax FAF = 5.54e-06, and zero homozygotes; gnomAD v2.1 independently reports 1/251,116 alleles and zero homozygotes. The qualifying frequency is below the generic PM2 supporting threshold of <=0.0001, although the variant is not completely absent from controls.
PM2: Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium. ... PM2 (supporting): <= 0.0001 — SVI recommendation to downgrade PM2 to Supporting (ClinGen SVI 2020) (PMID:25741868)
The novel missense change p.Arg1441Gly occurs at residue 1441, where different missense substitutions p.Arg1441Cys and p.Arg1441His have been established as pathogenic in the supplied literature. The review article explicitly lists R1441C, R1441G, and R1441H among known pathogenic LRRK2 mutations, and the functional study directly evaluates R1441C/G disease-associated mutants.
Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
The exact LRRK2 p.R1441G variant, corresponding to NM_198578.4:c.4321C>G, was observed in the proband, her affected mother, and an affected first cousin in a Japanese Parkinson disease family; a healthy brother lacked the variant. This is direct co-segregation with disease in multiple affected relatives in LRRK2, a gene reported in the case evidence as causing autosomal-dominant Parkinson disease. The available evidence supports PP1 at supporting strength; no generic ACMG/AMP numerical threshold was supplied for escalation to a stronger level.
Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease. ... May be used as stronger evidence with increasing segregation data.
The variant is a missense substitution, NP_940980.4:p.(Arg1441Gly), so the governing generic rule selects the REVEL path only; SpliceAI and BayesDel are not used for PP3/BP4 in this situation. The REVEL score is 0.705, which meets the generic PP3 supporting threshold of >= 0.644 but does not meet the moderate threshold of >= 0.773. Therefore PP3 is met at supporting strength. The REVEL value is from the local REVEL predictor lookup, and the threshold is the ClinGen SVI REVEL calibration of Pejaver et al. 2022 (PMID:36413997).
Missense variant -> REVEL only. Its SpliceAI score says nothing about whether the amino-acid substitution is tolerated, so 'no predicted splice impact' is never BP4 support for a missense variant. ... PP3 (supporting): >= 0.644 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)
The queried variant is LRRK2 p.Arg1441Gly (c.4321C>G). The supplied evidence establishes this exact protein change as pathogenic, but PS1 requires a previously established pathogenic variant producing the same amino-acid change through a different nucleotide change. No such alternate-nucleotide p.Arg1441Gly variant was identified; reports of p.Arg1441Gly itself do not satisfy PS1.
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
PP4 is not met. The relevant clinical review describes LRRK2-associated Parkinson disease as clinically indistinguishable from sporadic typical Parkinson disease with respect to age at onset and symptomatology. Parkinson disease is therefore not a highly specific phenotype for a single genetic etiology in this case, even though the variant is associated with Parkinson disease.
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
PP5 is not met. ClinVar contains an exact-variant Pathogenic classification from clinical laboratories, but the record documents zero expert-panel submissions and no exact-variant ClinVar expert-panel classification. Ordinary laboratory submissions and aggregate ClinVar labels do not satisfy the required PP5 source condition.
Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.
BA1 is not met. No governing LRRK2-specific population rule is released, so the generic all-comers gnomAD data apply. The required filtering allele-frequency measure is gnomAD v4.1 grpmax FAF = 5.54e-06, far below the generic BA1 threshold of >=0.05. The gnomAD v4.1 popmax point estimate of 3.34213e-05 is not used for BA1, and the variant is reported as Pathogenic by six clinical laboratories in ClinVar, so there is no frequency-based stand-alone benign call.
BA1: Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium. ... BA1 (stand-alone): >= 0.05 — ACMG/AMP 2015 stand-alone benign allele frequency (PMID:25741868)
BS1 is not met. The required filtering allele-frequency measure is gnomAD v4.1 grpmax FAF = 5.54e-06, below the generic BS1 default threshold of >=0.01 by more than three orders of magnitude. The observed gnomAD v4.1 popmax point estimate of 3.34213e-05 is not used. The variant is a known Northern Spanish founder allele associated with late-onset Parkinson disease, but its frequency is not elevated in the qualifying population data, so no maximum-credible-frequency exception or ancestry-specific BS1 call is needed.
BS1: Allele frequency is greater than expected for the disorder. ... BS1 (strong): >= 0.01 — Generic SVI default; per-gene derivation preferred (Whiffin et al. 2017) (PMID:28518168)
The available family evidence does not show lack of segregation in affected members. Instead, the exact p.R1441G variant was present in the proband, her affected mother, and an affected first cousin, while the reported healthy brother lacked the variant. Thus, the documented family pattern is concordant with segregation rather than non-segregation.
Lack of segregation in affected members of a family.
BP1 applies to a gene in which primarily truncating variants are known to cause disease. The supplied LRRK2 evidence instead documents multiple recurrent pathogenic missense substitutions, including R1441C, R1441G, R1441H, G2019S, and others, and describes missense variants as established causes of autosomal-dominant Parkinson disease. Therefore the gene-level premise for BP1 is not satisfied.
Missense variant in a gene for which primarily truncating variants are known to cause disease.
The variant is a missense substitution, NP_940980.4:p.(Arg1441Gly), so the governing generic rule selects the REVEL path only; the SpliceAI score cannot be substituted for an indeterminate REVEL result. REVEL is 0.705, which is above the BP4 supporting cutoff of <= 0.29 and lies in the gray zone between the deleterious PP3 supporting cutoff of >= 0.644 and the benign BP4 supporting cutoff. Therefore BP4 is not met. BayesDel is not used because no generic ACMG-strength calibration is established for it.
Missense variant -> REVEL only. An indeterminate result on the applicable path means PP3/BP4 are simply not met. It does not license reaching across to the other path's score - a missense variant whose REVEL sits in the gray zone gets no BP4, however clean its SpliceAI delta. ... BP4 (supporting): <= 0.29 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)
BP6 is not met. The exact-variant ClinVar record has no benign or likely benign expert-panel classification; instead, it reports a Pathogenic classification from clinical laboratories and zero expert-panel submissions. No exact-variant reputable benign source meeting the required source condition was identified.
Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.
No case-specific evidence documents that the variant arose de novo in the proband. In particular, there is no documented confirmation of both maternity and paternity, and no evidence establishes absence of a family history for this patient. The available family report describes an inherited familial occurrence rather than a de novo event.
De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
No case-specific evidence supports an assumed de novo event. The available family report instead documents transmission of p.R1441G from an affected mother to the proband and does not provide a de novo parental-testing scenario for this patient.
Assumed de novo, but without confirmation of paternity and maternity.
The supplied evidence documents multiple pathogenic LRRK2 missense substitutions and a missense disease mechanism, but it does not provide the required gene-level evidence that LRRK2 has a low rate of benign missense variation. A target-variant population frequency is insufficient to establish the gene-wide benign missense rate, so PP2 cannot be assessed under the stated rule.
Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.
No well-established functional study in the reviewed evidence demonstrates that LRRK2 p.Arg1441Gly has no damaging effect on protein function or splicing. The available variant-specific studies report damaging biochemical and regulatory effects rather than normal function, and therefore do not support BS3. Because absence of benign functional evidence is not itself evidence against the criterion, BS3 is not assessed.
Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.
The available evidence does not document a second pathogenic variant in the same individual, nor does it establish cis or trans phase for NM_198578.4:c.4321C>G (p.Arg1441Gly). PMID:24973808 reports the queried variant as heterozygous in an affected proband and affected relatives, but does not report a second pathogenic allele or cis/trans relationship; this is insufficient to assess BP2.
Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.
BP5 was not assessed because the available evidence does not establish whether this variant was found in a case with an alternate molecular basis for disease. The reviewed literature documents Parkinson disease cases carrying LRRK2 R1441G, including a family study, but it does not provide a qualifying alternate molecular diagnosis for a case carrying this exact variant.
Variant found in a case with an alternate molecular basis for disease.
PVS1 (ClinGen SVI PVS1 recommendations, PMC6185798, pvs1_generic_framework) applies only to null variant classes — nonsense, frameshift, canonical ±1/2 splice-consensus, translation-initiation-codon loss, and stop-loss variants — each expected to trigger nonsense-mediated decay or otherwise abolish normal protein function. NM_198578.4:c.4321C>G in LRRK2 is a missense substitution predicted to produce NP_940980.4:p.(Arg1441Gly). As a result, no null-variant mechanism (nonsense-mediated decay, truncation, or canonical splice disruption) is triggered by this variant class, so PVS1's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PVS1 for LRRK2, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_null_variant_class
PM3 is not applicable because the relevant LRRK2-associated Parkinson disease context is autosomal dominant, not recessive. The governing PM3 definition is limited to recessive disorders and therefore does not apply regardless of whether an in-trans pathogenic variant was tested.
For recessive disorders, detected in trans with a pathogenic variant
PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_198578.4:c.4321C>G in LRRK2 is a missense substitution predicted to produce NP_940980.4:p.(Arg1441Gly). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PM4 for LRRK2, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_stop_loss_or_nonrepeat_indel
BS2 is not applicable under the governing definition because LRRK2-associated Parkinson disease is a late-onset disorder, not a disorder for which full penetrance is expected at an early age. The available case-specific literature describes the exact variant in late-onset Parkinson disease; gnomAD reports zero homozygotes but does not establish an eligible healthy adult carrier observation, and absence of homozygotes cannot satisfy BS2 for this autosomal-dominant late-onset condition.
BS2: Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.
BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_198578.4:c.4321C>G in LRRK2 is a missense substitution predicted to produce NP_940980.4:p.(Arg1441Gly). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP3 for LRRK2, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_repeat_region_indel
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_198578.4:c.4321C>G in LRRK2 is a missense substitution predicted to produce NP_940980.4:p.(Arg1441Gly). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP7 for LRRK2, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_synonymous
Every interpreted variant in LRRK2, mapped onto the exon structure of NM_198578.4. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
| Admixed American2 / 59,842 | 3.3e-05 |
| European (non-Finnish)3 / 1,179,708 | 2.5e-06 |
| Admixed American1 / 34,566 | 2.9e-05 |
This variant is present in gnomAD v4.1 (AF= 3.0999e-06; MAF= 0.00031%, 5/1612956 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 3.34213e-05; MAF= 0.00334%, 2/59842 alleles, homozygotes = 0); grpmax FAF= 5.54e-06.
This variant is present in gnomAD v2.1 (AF= 3.98222e-06; MAF= 0.00040%, 1/251116 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 2.89302e-05; MAF= 0.00289%, 1/34566 alleles, homozygotes = 0).
Not available in gnomAD-Canada v1.0.
The variant is a missense substitution, NP_940980.4:p.(Arg1441Gly), so the governing generic rule selects the REVEL path only; SpliceAI and BayesDel are not used for PP3/BP4 in this situation. The REVEL score is 0.705, which meets the generic PP3 supporting threshold of >= 0.644 but does not meet the moderate threshold of >= 0.773. Therefore PP3 is met at supporting strength. The REVEL value is from the local REVEL predictor lookup, and the threshold is the ClinGen SVI REVEL calibration of Pejaver et al. 2022 (PMID:36413997).
Missense variant -> REVEL only. Its SpliceAI score says nothing about whether the amino-acid substitution is tolerated, so 'no predicted splice impact' is never BP4 support for a missense variant. ... PP3 (supporting): >= 0.644 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)
The variant is a missense substitution, NP_940980.4:p.(Arg1441Gly), so the governing generic rule selects the REVEL path only; the SpliceAI score cannot be substituted for an indeterminate REVEL result. REVEL is 0.705, which is above the BP4 supporting cutoff of <= 0.29 and lies in the gray zone between the deleterious PP3 supporting cutoff of >= 0.644 and the benign BP4 supporting cutoff. Therefore BP4 is not met. BayesDel is not used because no generic ACMG-strength calibration is established for it.
Missense variant -> REVEL only. An indeterminate result on the applicable path means PP3/BP4 are simply not met. It does not license reaching across to the other path's score - a missense variant whose REVEL sits in the gray zone gets no BP4, however clean its SpliceAI delta. ... BP4 (supporting): <= 0.29 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_198578.4:c.4321C>G in LRRK2 is a missense substitution predicted to produce NP_940980.4:p.(Arg1441Gly). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP7 for LRRK2, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_synonymous
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.705. BayesDel score = 0.242146.
8 paper records listed. 6 cited in the classification.
The LRRK2 4321C>G mutation was found in 5 (2.7%) of sporadic, late-onset patients and was not present in control subjects.
Location Abstract; Results section; Table 1
Context Referral-based Asturias, Spain cohort of 225 Parkinson disease patients, including 182 late-onset patients, plus 100 age-, sex-, and ethnicity-matched controls; TaqMan genotyping and haplotype analysis.
GTPase domain containing R1441C or R1441G mutation display significantly reduced GTP hydrolysis activity in comparison to the wild-type GTPase domain
Location Results, GTPase-domain activity section, paragraph 2; Figure 5
Context FLAG-tagged wild-type and mutant LRRK2 GTPase domains (amino acids 1321-1516) expressed in HEK-293T cells and tested by GTP hydrolysis, pull-down, and binding assays.
All 29 R1441G carriers shared a ten-marker background haplotype, bounded by D12S2080 and D12S2519, which spanned a distance of 5.8 Mb across the LRRK2 region.
Location Introduction, paragraph 2; Results, paragraphs 1 and 3
Context Haplotype and founder-age analysis of 29 unrelated Parkinson disease patients carrying R1441G, nine relatives, and 85 mutation-negative controls from Northern Spain; 20 LRRK2-region markers were genotyped.
five common well-characterized pathogenic mutations (R1441C, R1441G, R1441H, Y1699C and I2020T)
Location Introduction, final paragraph; Results, characterization of 14-3-3 binding of LRRK2 PD-associated mutants
Context Full-length FLAG-tagged wild-type and mutant LRRK2 proteins expressed in HEK-293 cells and assessed by phosphorylation, 14-3-3 binding, and localization assays.
Up to date, 6 mutations are known to be pathogenic (N1437H, R1441C, R1441G, Y1699C, G2019S and I2020T), based on their cosegregation in PD families.
Location Section 2, genetic testing, autosomal dominant forms of PD, LRRK2 subsection
Context Guideline review of published genetic and clinical studies; pathogenicity is attributed to cosegregation in Parkinson disease families.
Direct sequencing analysis of LRRK2 revealed a heterozygous p.R1441G (LRRK2 4321C>G) mutation in II:5 (proband), I:6 and II:2.
Location Results, section 3.1 Genetic findings, paragraph 2
Context PCR-direct sequencing of LRRK2 exons 31, 41, and 48 in 871 Japanese patients with Parkinson disease, followed by family segregation and haplotype analysis.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
This variant is present in gnomAD v4.1 (AF= 3.0999e-06; MAF= 0.00031%, 5/1612956 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 3.34213e-05; MAF= 0.00334%, 2/59842 alleles, homozygotes = 0); grpmax FAF= 5.54e-06.
This variant is present in gnomAD v2.1 (AF= 3.98222e-06; MAF= 0.00040%, 1/251116 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 2.89302e-05; MAF= 0.00289%, 1/34566 alleles, homozygotes = 0).
Not available in gnomAD-Canada v1.0.
This variant has been reported in ClinVar as Pathogenic (6 clinical laboratories). (ClinVarID = 1936)
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.705. BayesDel score = 0.242146.
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
This variant does not lie in a statistically significant hotspot.