ClinVar Miner

Submissions for variant NM_198578.4(LRRK2):c.5822G>A (p.Arg1941His) (rs77428810)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneReviews RCV000032490 SCV000056151 unknown Parkinson disease 8, autosomal dominant 2012-09-13 no assertion criteria provided curation Converted during submission to Uncertain significance.
Invitae RCV000032490 SCV000958744 uncertain significance Parkinson disease 8, autosomal dominant 2018-11-09 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 1941 of the LRRK2 protein (p.Arg1941His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs77428810, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed in individuals affected with Parkinson's disease and in unaffected control individuals (PMID: 16272164, 21885347). ClinVar contains an entry for this variant (Variation ID: 39216). Experimental studies have shown conflicting results regarding this missense change's effect on LRRK2 protein kinase properties. In one study, it was found that this variant markedly inhibits kinase activity (PMID: 17447891). However, other studies found that the kinase activity as well as cellular localization are similar to wild type (PMID: 20642453, 17584768). 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.

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