chr12-40310434-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM5PP3_StrongPP5_Very_Strong

The NM_198578.4(LRRK2):c.4321C>T(p.Arg1441Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000242 in 1,612,956 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1441G) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000040 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

LRRK2
NM_198578.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10O:1

Conservation

PhyloP100: 3.73

Variant links:

Genes affected

LRRK2 (HGNC:18618): (leucine rich repeat kinase 2) This gene is a member of the leucine-rich repeat kinase family and encodes a protein with an ankryin repeat region, a leucine-rich repeat (LRR) domain, a kinase domain, a DFG-like motif, a RAS domain, a GTPase domain, a MLK-like domain, and a WD40 domain. The protein is present largely in the cytoplasm but also associates with the mitochondrial outer membrane. Mutations in this gene have been associated with Parkinson disease-8. [provided by RefSeq, Jul 2008]

LRRK2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a domain Roc (size 183) in uniprot entity LRRK2_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_198578.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr12-40310434-C-G is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.941

PP5

Variant 12-40310434-C-T is Pathogenic according to our data. Variant chr12-40310434-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 1938.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-40310434-C-T is described in Lovd as [Pathogenic]. Variant chr12-40310434-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRRK2	NM_198578.4 link	c.4321C>T	p.Arg1441Cys	missense_variant	Exon 31 of 51	ENST00000298910.12	NP_940980.4	Q5S007Q17RV3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRRK2	ENST00000298910.12 link	c.4321C>T	p.Arg1441Cys	missense_variant	Exon 31 of 51	1	NM_198578.4	ENSP00000298910.7		Q5S007

Frequencies

GnomAD3 genomes

AF:

0.0000397

AC:

AN:

151268

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000486

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00637

Gnomad NFE

AF:

0.0000295

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251116

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135702

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000226

AC:

AN:

1461570

Hom.:

Cov.:

AF XY:

0.0000275

AC XY:

AN XY:

727100

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000189

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000396

AC:

AN:

151386

Hom.:

Cov.:

AF XY:

0.0000271

AC XY:

AN XY:

73904

show subpopulations

Gnomad4 AFR

AF:

0.0000484

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000295

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00000776

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal dominant Parkinson disease 8

Pathogenic:5Other:1

Oct 17, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: LRRK2 c.4321C>T (p.Arg1441Cys) results in a non-conservative amino acid change located in the Small GTP-binding protein domain (IPR005225) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251116 control chromosomes. c.4321C>T has been reported in the literature in multiple individuals affected with Autosomal Dominant Parkinson Disease (example, Zimprich_2004, DiFonzo_2006). It has also been observed to segregate with disease in related individuals (Zimprich_2004). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. Decreased LRRK2 autophosphorylation, increased formation of inclusion bodies, cell death of neurons and neuronal cell lines after expression of this variant have been reported (Greggio_2006). The following publications have been ascertained in the context of this evaluation (PMID: 16633828, 16750377, 15541309). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Oct 01, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1441 of the LRRK2 protein (p.Arg1441Cys). This variant is present in population databases (rs33939927, gnomAD 0.01%). This missense change has been observed in individuals with Parkinson's disease (PMID: 15541309, 21538529, 24565865). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1938). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on LRRK2 protein function. Experimental studies have shown that this missense change affects LRRK2 function (PMID: 16750377, 17200152, 21494637, 21658387, 23241745). For these reasons, this variant has been classified as Pathogenic. -

Apr 20, 2017

Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 31, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 25, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided

Pathogenic:5

Aug 05, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect; the p.R1441C variant reduces GTPase activity and increases kinase activity, leading to increased formation of inclusion bodies, neuronal cell death, production of enlarged lysosomes, and impaired Golgi transport (PMID: 25201882, 16750377, 26251043); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29357897, 24282027, 30796162, 19781641, 17442267, 20642453, 17447891, 22988862, 21658387, 17200152, 19640926, 22080837, 17623048, 19302196, 22004453, 25330418, 18657457, 21538529, 24375786, 24488318, 16750377, 24148854, 25174890, 19029519, 21494637, 23082216, 24351927, 23241745, 26251043, 27794539, 37046401, 35861376, 37750340, 37152446, 37198191, 37201327, 32613234, 17706965, 34914695, 26159606, 20301387, 25201882, 28576705, 15541309, 33818904, 32580205, 32870915, 16333314, 31324919, 23895867, 24470158, 35029295, 28131193, 17089395, 24565865) -

Jul 05, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP1, PM1, PM5, PS3, PS4 -

Jan 03, 2024

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

LRRK2: PP1:Strong, PS3, PM2, PM5, PS4:Moderate -

May 04, 2022

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The frequency of this variant in the general population is consistent with pathogenicity (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org). This variant has been identified in multiple individuals and families with Parkinson disease (PD) and has been reported as one of the most common pathogenic variants in the LRRK2 gene (PMID: 15541309, 18197194, 18337586, 21538529, 24496098, 32580205). This variant has been primarily identified in individuals with PD diagnosed after the age of 50 years. Early-onset cases have also been reported (PMID: 18197194, 18337586, 21538529, 25330418). Numerous individuals with Parkinson disease have been reported with missense changes at codon 1441, suggesting that this residue is important for protein function (PMID: 27111571). Assessment of experimental evidence suggests this variant results in abnormal protein function. Studies have shown that expression of this variant results in a reduction in GTPase activity and increased kinase activity (PMID: 17200152, 17442267, 17623048, 19781641, 21658387, 24351927, 30796162). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.25

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.61

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Uncertain

0.78

LIST_S2

Uncertain

0.95

M_CAP

Uncertain

0.19

MetaRNN

Pathogenic

0.94

MetaSVM

Uncertain

0.25

MutationAssessor

Uncertain

2.5

PrimateAI

Uncertain

0.68

PROVEAN

Pathogenic

-4.5

REVEL

Pathogenic

0.73

Sift

Benign

0.12

Sift4G

Benign

0.12

Polyphen

1.0

Vest4

0.86

MutPred

0.80

Loss of methylation at R1441 (P = 0.0158);

MVP

0.94

MPC

0.55

ClinPred

0.97

GERP RS

4.7

Varity_R

0.58

gMVP

0.64

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over