Description
Across a selection of the available literature, the PARK2 c.719C>T (p.Thr240Met) missense variant has been reported in a biallelic state in at least six individuals with Parkinson disease (PD) from three families, with age of onset ranging from 22 to 40 years (Madegowda et al. 2005; Deng et al. 2006; Camargos et al. 2009). Two additional siblings with PD onset at age 45 and 55 were heterozygous for the p.Thr240Met variant, a second missense variant, and a deletion of exon three and parts of introns two and three, zygosity unspecified (Al-Mubarak et al. 2015). Notably, one unaffected 56-year-old individual was found to have the same genotype as her four affected compound heterozygous siblings who all displayed symptoms by age 38, suggesting reduced penetrance (Deng et al. 2006). In addition, the p.Thr240Met variant has been reported in a heterozygous state in at least four unrelated affected individuals (onset at age 33, <51, 55, and unspecified) as well as in five unaffected individuals from the same family as the five compound heterozygous individuals described above (Foroud et al. 2003; Deng et al. 2006; Bras et al. 2008; Camargos et al. 2009; Moura et al. 2013). Based on this information, this variant is expected to confer recessive disease although dominant disease implications cannot be completely ruled out. The p.Thr240Met variant was absent from 660 control chromosomes and is reported at a frequency of 0.00172 in the South Asian population of the Genome Aggregation Database. Compared to the wildtype, the parkin protein containing the p.Thr240Met variant, which occurs at a moderately conserved residue in the RING1 protein domain, showed decreased β-catenin ubiquitinating activity when expressed in HEK293T cells (Lin et al. 2015). Two other missense variants at the same position have also been reported in association with PD. Based on the collective evidence, the p.Thr240Met variant is classified as pathogenic for juvenile Parkinson disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
| # | Sample | Method | Observation |
|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences |
|---|
| 1 | germline | unknown | not provided | not provided | not provided | | not provided | not provided | not provided | not provided |
