chr12-40310434-C-A

Position:

• chr12-40310434-C-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Moderate

The NM_198578.4(LRRK2):​c.4321C>A​(p.Arg1441Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely 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)
• Consequence: LRRK2 NM_198578.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 3.73

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 Pathogenic. Variant got 10 ACMG points.

• PM1: In a helix (size 10) in uniprot entity LRRK2_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) 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 ClinVar as [Pathogenic]. Clinvar id is 1938.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.914
• PP5: Variant 12-40310434-C-A is Pathogenic according to our data. Variant chr12-40310434-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 225276.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRRK2	NM_198578.4	c.4321C>A	p.Arg1441Ser	missense_variant	31/51	ENST00000298910.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRRK2	ENST00000298910.12	c.4321C>A	p.Arg1441Ser	missense_variant	31/51	1	NM_198578.4	P1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 30

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Parkinson disease, late-onset Pathogenic:1

Pathogenic, no assertion criteria provided

research

Zabetian_UW Neurogenetics Lab, University of Washington/VAPSHCS

Apr 14, 2016

It segregates with disease in the family, affects a highly conserved amino acid in which other mutations for the same condition have been found -

Autosomal dominant Parkinson disease 8 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Sep 13, 2018

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Arg1441 amino acid residue in LRRK2. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 15541309, 21538529, 24565865), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been observed to segregate with Parkinson’s disease in a family (PMID: 27111571). ClinVar contains an entry for this variant (Variation ID: 225276). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with serine at codon 1441 of the LRRK2 protein (p.Arg1441Ser). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and serine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D
Eigen	Uncertain	0.26
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Uncertain	0.17	D
MutationAssessor	Benign	1.9	M
MutationTaster	Benign	0.87	D
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.2	D
REVEL	Pathogenic	0.66
Sift	Benign	0.36	T
Sift4G	Benign	0.34	T
Polyphen		1.0	D
Vest4		0.94
MutPred		0.71		Loss of methylation at R1441 (P = 0.0158);
MVP		0.92
MPC		0.50
ClinPred		0.98	D
GERP RS		4.7
Varity_R		0.83
gMVP		0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs33939927; hg19: chr12-40704236;