ClinVar Miner

Submissions for variant NM_198578.4(LRRK2):c.683G>C (p.Cys228Ser) (rs56108242)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneReviews RCV000032505 SCV000056168 unknown Parkinson disease 8, autosomal dominant 2012-09-13 no assertion criteria provided curation Converted during submission to Uncertain significance.
Invitae RCV000032505 SCV000640139 uncertain significance Parkinson disease 8, autosomal dominant 2017-07-10 criteria provided, single submitter clinical testing This sequence change replaces cysteine with serine at codon 228 of the LRRK2 protein (p.Cys228Ser). The cysteine residue is weakly conserved and there is a moderate physicochemical difference between cysteine and serine. This variant is present in population databases (rs56108242, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in the literature in 2 individuals affected with Parkinson's disease and in 2 unaffected control individuals (PMID: 21885347). ClinVar contains an entry for this variant (Variation ID: 39231). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, this variant has uncertain impact on LRRK2 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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