12-40310434-C-G

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_198578.4(LRRK2):c.4321C>G(p.Arg1441Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,570 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. R1441C) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

LRRK2
NM_198578.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5O: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 18 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

PM2

Very rare variant in population databases, with high coverage;

PM5

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

PP3

MetaRNN computational evidence supports a deleterious effect, 0.987

PP5

Variant 12-40310434-C-G is Pathogenic according to our data. Variant chr12-40310434-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 1936.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-40310434-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRRK2	NM_198578.4 link	c.4321C>G	p.Arg1441Gly	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>G	p.Arg1441Gly	missense_variant	Exon 31 of 51	1	NM_198578.4	ENSP00000298910.7		Q5S007

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251116

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135702

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461570

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727100

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal dominant Parkinson disease 8

Pathogenic:3Other:1

Mar 12, 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 glycine, which is neutral and non-polar, at codon 1441 of the LRRK2 protein (p.Arg1441Gly). This variant is present in population databases (rs33939927, gnomAD 0.003%). This missense change has been observed in individuals with Parkinson disease (PMID: 15541308, 17095157, 19308469, 19735093, 24357540, 24973808, 25127457). It has also been observed to segregate with disease in related individuals. This variant is also known as R1396G. ClinVar contains an entry for this variant (Variation ID: 1936). Advanced 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 at Invitae 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: 17200152, 20642453). This variant disrupts the p.Arg1441 amino acid residue in LRRK2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15541309, 17200152, 21538529, 21658387, 23241745, 24565865, 27111571). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Mar 28, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Oct 01, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided

Pathogenic:2

Oct 28, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect of altering phosphorylation (Muda et al., 2014) and increasing GTPase binding and kinase activity, which is hypothesized to lead a pathogenic gain-of-function that may contribute to cellular toxicity (West et al., 2007); Not observed at significant frequency in large population cohorts (gnomAD); 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: 21885347, 24211199, 20642453, 17447891, 17200152, 22080837, 24470158, 17623048, 22004453, 25330418, 24488318, 20721916, 24357540, 17095157, 19308469, 22342962, 21390248, 24351927, 23764467, 25127457, 23600457, 23241745, 15541308, 24360742, 27013965, 19503083, 15925109, 24973808, 30796162, 20301387, 29800472, 19735093, 32398759, 33763016, 31589614) -

Dec 16, 2020

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 (http://gnomad.broadinstitute.org). In some published literature, this variant is referred to as PARK8 p.R1396G. This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. The variant is a common founder originating from Basque Country of Northern Spain (PMID: 16991141, 19308469). Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant causes a significant reduction in GTP hydrolysis activity (PMID: 30796162, 27013965). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.44

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.24

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.61

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Benign

0.66

LIST_S2

Uncertain

0.90

M_CAP

Uncertain

0.17

MetaRNN

Pathogenic

0.99

MetaSVM

Uncertain

0.22

MutationAssessor

Uncertain

2.7

PrimateAI

Uncertain

0.58

PROVEAN

Uncertain

-4.3

REVEL

Pathogenic

0.70

Sift

Benign

0.25

Sift4G

Benign

0.31

Polyphen

1.0

Vest4

0.94

MutPred

0.93

Loss of methylation at R1441 (P = 0.0158);

MVP

0.94

MPC

0.53

ClinPred

0.98

GERP RS

4.7

Varity_R

0.91

gMVP

0.67

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