Submissions for variant NM_198578.4(LRRK2):c.5822G>A (p.Arg1941His)

gnomAD frequency: 0.00022  dbSNP: rs77428810

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000032490	SCV000958744	uncertain significance	Autosomal dominant Parkinson disease 8	2024-10-17	criteria provided, single submitter	clinical testing	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). 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 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.
Mendelics	RCV000032490	SCV001138693	uncertain significance	Autosomal dominant Parkinson disease 8	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000032490	SCV001272087	uncertain significance	Autosomal dominant Parkinson disease 8	2017-04-27	criteria provided, single submitter	clinical testing	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.
Fulgent Genetics, Fulgent Genetics	RCV000032490	SCV002816373	uncertain significance	Autosomal dominant Parkinson disease 8	2021-10-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003317051	SCV004020426	uncertain significance	not specified	2023-06-29	criteria provided, single submitter	clinical testing	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.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV004696643	SCV005198691	uncertain significance	not provided	2022-05-27	criteria provided, single submitter	clinical testing
GeneReviews	RCV000032490	SCV000056151	not provided	Autosomal dominant Parkinson disease 8		no assertion provided	literature only