ClinVar Miner

Submissions for variant NM_004562.3(PRKN):c.1289G>A (p.Gly430Asp) (rs191486604)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000269607 SCV000461686 likely pathogenic Parkinson disease 2 2017-04-28 criteria provided, single submitter clinical testing The PARK2 c.1289G>A (p.Gly430Asp) missense variant has been reported in at least four studies in which it was found in a total of five individuals with Parkinson disease with onset of disease under the age of 40 years, including one who was homozygous for the variant and four who were compound heterozygous (Scherfler et al. 2004; Mellick et al. 2009; Haylett et al. 2012; Angeli et al. 2013). The p.Gly430Asp variant was absent from 212 ethnically-matched control chromosomes but is reported at a frequency of 0.00035 in the European American population of the Exome Sequencing Project. Fiesel et al. (2015) demonstrated through molecular dynamic simulations that the p.Gly430Asp variant alters the active site of the enzyme through the introduction of a negative charge. In addition, the in vitro E3 ligase activity of the variant protein on a model substrate was reduced and mitochondrial relocalization was hampered in cells transfected with variant PARK2, as compared to wild type (Sriram et al. 2005; Okatsu et al. 2010; Fiesel et al. 2015). Based on the collective evidence, the p.Gly430Asp variant is classified as pathogenic for the juvenile form of Parkinson disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000269607 SCV000946454 pathogenic Parkinson disease 2 2018-08-06 criteria provided, single submitter clinical testing This sequence change replaces glycine with aspartic acid at codon 430 of the PARK2 protein (p.Gly430Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is present in population databases (rs191486604, ExAC 0.02%). This variant has been observed to be homozygous or in combination with another PARK2 variant in individuals and families affected with early-onset Parkinson's disease (PMID: 11179010, 12764051, 15090472, 18486522), and has also been observed to segregate with disease in an affected family (PMID: 12764051). This variant is also known as 1390G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 356016). Experimental studies have shown that this missense change impairs the function of the PARK2 protein (PMID: 16049031, 16339143, 20404107, 20604804, 20798600, 23751051). For these reasons, this variant has been classified as Pathogenic.

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