Submissions for variant NM_198578.4(LRRK2):c.2378G>T (p.Arg793Met)

gnomAD frequency: 0.00085  dbSNP: rs35173587

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000032423	SCV000378584	likely benign	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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000032423	SCV001019104	benign	Autosomal dominant Parkinson disease 8	2024-01-08	criteria provided, single submitter	clinical testing
Mendelics	RCV000032423	SCV001138688	uncertain significance	Autosomal dominant Parkinson disease 8	2019-05-28	criteria provided, single submitter	clinical testing
GeneDx	RCV001354528	SCV001949509	benign	not provided	2021-03-15	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 17914064, 31733655, 20177695, 21885347, 24470158, 17803033, 33494262, 24488318, 17523199, 20642453, 22988870, 25401511, 16251215, 27393345, 31996268, 17078063, 19006185)
GeneReviews	RCV000032423	SCV000056079	not provided	Autosomal dominant Parkinson disease 8		no assertion provided	literature only
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354528	SCV001549169	uncertain significance	not provided		no assertion criteria provided	clinical testing	The LRRK2 p.Arg793Met variant was identified in 6 of 1844 proband chromosomes (frequency: 0.00325) from individuals or families with Parkinson disease (PD) or neurodegenerative disease (Chen-Plotnik_2008_PMID: 17914064; Berg_2005_ PMID: 16251215; Covy_2009_ PMID: 19006185). The variant was also identified in a 60 year old male patient with akinetic rigid PD as well as his unaffected son, however his son was below the age of disease onset (Breit_2010_PMID: 20177695). The variant was identified in dbSNP (ID: rs35173587) and ClinVar (classified as likely benign‚Äã by Illumina) but was not identified in Cosmic or LOVD 3.0. The variant was identified in control databases in 299 of 282754 chromosomes (1 homozygous) at a frequency of 0.001057 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (Finnish) in 126 of 25118 chromosomes (freq: 0.005016), Other in 14 of 7220 chromosomes (freq: 0.001939), Latino in 53 of 35434 chromosomes (freq: 0.001496), European (non-Finnish) in 100 of 129090 chromosomes (freq: 0.000775), South Asian in 5 of 30616 chromosomes (freq: 0.000163) and African in 1 of 24968 chromosomes (freq: 0.00004); it was not observed in the Ashkenazi Jewish, and East Asian populations. The p.Arg793 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.