rs77428810

chr12-40335031-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1 BP4 BS2

The NM_198578.4(LRRK2):c.5822G>A(p.Arg1941His) variant causes a missense change. The variant allele was found at a frequency of 0.000201 in 1,614,056 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1941S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: LRRK2 NM_198578.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5 O:1
• Conservation: PhyloP100: 4.58

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]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM1: In a domain Protein kinase (size 259) in uniprot entity LRRK2_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_198578.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.32815164).
• BS2: High AC in GnomAd at 34 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRRK2	NM_198578.4	c.5822G>A	p.Arg1941His	missense_variant	40/51	ENST00000298910.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRRK2	ENST00000298910.12	c.5822G>A	p.Arg1941His	missense_variant	40/51	1	NM_198578.4	P1

Frequencies

GnomAD3 genomes AF: 0.000224 AC: 34 AN: 152098 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.000139 AC: 35 AN: 251386 Hom.: 0 AF XY: 0.000147 AC XY: 20 AN XY: 135858

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000289

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: 0.000211

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000198 AC: 290 AN: 1461840 Hom.: 0 Cov.: 31 AF XY: 0.000179 AC XY: 130 AN XY: 727216

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000403

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: 0.000229

Gnomad4 OTH exome AF: 0.000232

GnomAD4 genome AF: 0.000223 AC: 34 AN: 152216 Hom.: 0 Cov.: 32 AF XY: 0.000255 AC XY: 19 AN XY: 74440

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.000154 Hom.: 0

Bravo AF: 0.000227

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.000123 AC: 15

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal dominant Parkinson disease 8 Uncertain:4 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 06, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 23, 2023	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1941 of the LRRK2 protein (p.Arg1941His). This variant is present in population databases (rs77428810, gnomAD 0.03%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Parkinson disease (PMID: 16272164, 21885347, 33281709). ClinVar contains an entry for this variant (Variation ID: 39216). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on LRRK2 function (PMID: 17447891, 17584768, 20642453, 35950872). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jun 29, 2023

Variant summary: LRRK2 c.5822G>A (p.Arg1941His) results in a non-conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 (i.e., 35 heterozygotes) in 251386 control chromosomes, predominantly at a frequency of 0.00029 within the Latino subpopulation in the gnomAD database (v2.1, Exomes dataset). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5822G>A has been reported in the literature in individuals affected with Parkinson Disease (e.g., Khan_2005, Ross_2011, Lubbe_2016, Muytemans_2020), however without strong evidence for causality (e.g., lack of co-segregation and co-occurrence data). These reports therefore do not provide unequivocal conclusions about association of the variant with Parkinson Disease 8, Autosomal Dominant. A co-occurrence with another pathogenic variant has been reported (LRRK2 c.6055G>A, p.Gly2019Ser; Lubbe_2016), providing supporting evidence for a benign role. Several publications report experimental evidence evaluating an impact on protein function with conflicting findings: two studies found the variant protein resulted in kinase activity similar to the wild-type (e.g., Luzon-Toro_2007, Nichols_2010), while another study found the variant resulted in approximately 33% of wild-type kinase activity (e.g., Jaleel_2007). The following publications have been ascertained in the context of this evaluation (PMID: 17447891, 16272164, 27798102, 17584768, 20642453, 33281709, 21885347). Four submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.077	T
BayesDel_noAF	Uncertain	-0.050
Cadd	Uncertain	24
Dann	Benign	0.95
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.091
Eigen_PC	Benign	0.087
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	1.2	L
MutationTaster	Benign	0.58	N
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.32	N
REVEL	Benign	0.24
Sift	Benign	0.082	T
Sift4G	Benign	0.20	T
Polyphen		0.16	B
Vest4		0.40
MutPred		0.84		Loss of sheet (P = 0.1158);
MVP		0.83
MPC		1.5
ClinPred		0.12	T
GERP RS		4.8
Varity_R		0.15
gMVP		0.48

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

Other links and lift over

dbSNP: rs77428810; hg19: chr12-40728833; COSMIC: COSV54154604;