12-40310434-C-G

Variant names:

• chr12-40310434-C-G
• rs33939927
• NM_198578.4:c.4321C>G

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_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. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. 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. R1441H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: LRRK2 NM_198578.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5 O:1
• Conservation: PhyloP100: 3.73
• Publications: 1140 publications found

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 Gene-Disease associations (from GenCC):

• autosomal dominant Parkinson disease 8

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Genomics England PanelApp
• Parkinson disease

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hereditary late onset Parkinson disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000258167 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 19 uncertain 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 chr12-40310435-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1942.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 VariationId is 1936.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRRK2	NM_198578.4	c.4321C>G	p.Arg1441Gly	missense_variant	Exon 31 of 51	ENST00000298910.12	NP_940980.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRRK2	ENST00000298910.12	c.4321C>G	p.Arg1441Gly	missense_variant	Exon 31 of 51	1	NM_198578.4	ENSP00000298910.7

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251116 AF XY: 0.00000737

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461570 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727100

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33456

American (AMR) AF: 0.0000447 AC: 2 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5688

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111842

Other (OTH) AF: 0.00 AC: 0 AN: 60382

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000233207), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 30

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal dominant Parkinson disease 8 Pathogenic:3 Other:1

Oct 01, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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

- -

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	D
BayesDel_noAF	Pathogenic	0.24
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Benign	0.66	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.22	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		3.7
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-4.3	D
REVEL	Pathogenic	0.70
Sift	Benign	0.25	T
Sift4G	Benign	0.31	T
Polyphen		1.0	D
Vest4		0.94
MutPred		0.93		Loss of methylation at R1441 (P = 0.0158);
MVP		0.94
MPC		0.53
ClinPred		0.98	D
GERP RS		4.7
PromoterAI		0.019	Neutral
Varity_R		0.91
gMVP		0.67
Mutation Taster		=4/96	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs33939927; hg19: chr12-40704236;