ClinVar Miner

Submissions for variant NM_198578.4(LRRK2):c.6055G>A (p.Gly2019Ser) (rs34637584)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Courtagen Diagnostics Laboratory,Courtagen Life Sciences RCV000002017 SCV000236518 pathogenic Parkinson disease 8, autosomal dominant 2014-05-14 criteria provided, single submitter clinical testing
GeneDx RCV000325492 SCV000329408 pathogenic not provided 2019-01-11 criteria provided, single submitter clinical testing The G2019S variant is the most common pathogenic substitution in the LRRK2 gene (Lunati et al., 2018). This variant is associated with approximately 5% of familial Parkinson disease cases and approximately 2% of idiopathic Parkinson disease cases (Dachsel et al., 2010). Individuals who are heterozygous for the G2019S variant have more than a 20-fold increase in risk for developing Parkinson disease (Dachsel et al., 2010). The G2019S variant is associated with reduced penetrance; penetrance for heterozygotes is age dependent, and varies in different studies, ranging from 14% to greater than 90% by age 80 years (Lunati et al., 2018). Affected individuals who are homozygous for the G2019S variant have also been reported, however, they show no difference in the severity of symptoms, age of onset, or disease progression (Kachergus et al., 2005; Latourelle et al., 2008; Dachsel et al., 2010). Lysosomal dysfunction plays a central role in the pathogenesis of Parkinson disease, and functional studies have shown that expression of G2019S produces enlarged lysosomes and diminishes the lysosomal capacity of cells, altering the lysosome function (Henry et al., 2015). The G2019S variant is observed in 87/10144 (0.86%) alleles from individuals of Ashkenazi Jewish background and 136/276858 (0.049%) total alleles, including one homozygous individual, in large population cohorts (Lek et al., 2016). The G2019S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret G2019S as a pathogenic variant.
Invitae RCV000002017 SCV000640135 pathogenic Parkinson disease 8, autosomal dominant 2019-12-19 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 2019 of the LRRK2 protein (p.Gly2019Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs34637584, ExAC 0.06%). This variant is clearly defined as a Parkinson's disease (PD) causative allele and is the most common known genetic cause of PD, having been observed in ~5% of familial and ~1-2% of sporadic PD cases (PMID: 18986508, 15726496, 22575234, 15680455). This variant exhibits age-dependent penetrance, with the probability of becoming affected increasing from 20% at age 50 years to 80% at age 70 years (PMID: 18986508, 15726496). ClinVar contains an entry for this variant (Variation ID: 1940). Experimental studies have shown that this missense change increases kinase activity, enlarges lysosomes and impairs lysosomal function (PMID: 26251043). For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics,Klinikum rechts der Isar RCV000002017 SCV000680283 pathogenic Parkinson disease 8, autosomal dominant 2017-12-07 criteria provided, single submitter clinical testing
Ambry Genetics RCV000622347 SCV000742130 pathogenic Inborn genetic diseases 2017-01-11 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: UNCERTAIN: Alteration(s) of Uncertain Clinical Significance Detected
Athena Diagnostics Inc RCV000325492 SCV000842686 pathogenic not provided 2015-04-22 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000002017 SCV000893982 pathogenic Parkinson disease 8, autosomal dominant 2018-10-31 criteria provided, single submitter clinical testing
Mendelics RCV000002017 SCV001138694 pathogenic Parkinson disease 8, autosomal dominant 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000325492 SCV001250090 pathogenic not provided 2019-05-01 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV001195216 SCV001365523 risk factor Young-onset Parkinson disease 2017-12-29 criteria provided, single submitter clinical testing LRRK2 c.6055G>A (p.Gly2019Ser) has been associated with increased risk for Parkinson's disease. This variant has been observed in multiple ethnic backgrounds with highest frequencies in individuals of Ashkenazi Jewish ancestry (0.86%, Genome Aggregation Database (gnomAD); rs6025) and is present in ClinVar (ID: 1940). A large meta-analysis has reported an odds ratio of 14.98 [95% CI 4.8-10] for developing Parkinson's disease (Wu 2012). In vivo and in vitro functional studies provide some evidence that the p.Gly2019Ser variant may impact protein function (Chen 2012). Therefore, this variant is not expected to cause highly penetrant Mendelian disease. In summary, this variant is an established risk factor for Parkinson's disease.
OMIM RCV000002017 SCV000022175 pathogenic Parkinson disease 8, autosomal dominant 2012-11-22 no assertion criteria provided literature only
GeneReviews RCV000002017 SCV000056154 pathologic Parkinson disease 8, autosomal dominant 2012-09-13 no assertion criteria provided curation Converted during submission to Pathogenic.

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