Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Illumina Laboratory Services, |
RCV000372794 | SCV000353518 | uncertain significance | Autosomal recessive early-onset Parkinson disease 6 | 2017-04-28 | criteria provided, single submitter | clinical testing | The PINK1 c.1196C>T (p.Pro399Leu) missense variant has been reported in one study in which it is found in a heterozygous state in two siblings with early-onset Parkinson disease, both of whom also carried a missense variant in the PARK7 gene (Tang et al. 2006). The variant was additionally found in a heterozygous state in their unaffected mother; their father was not tested. Although early-onset Parkinson disease typically manifests before 40 years of age, a 42-year-old unaffected family member was also shown to carry both variants suggesting incomplete penetrance. The p.Pro399Leu variant was absent from 568 control chromosomes but is reported at a frequency of 0.00006 in the South Asian population of the Exome Aggregation Consortium based on one allele in a region of good sequencing coverage, so the variant is presumed to be rare. The Pro399 residue is highly conserved. Functional studies by multiple groups and in multiple cell types suggest that the p.Pro399Leu variant impairs protein stability and antioxidative neuroprotective function, Parkin ubiquitination, degradation, and recruitment to mitochondria (Tang et al. 2006; Xiong et al. 2009; Narendra et al. 2013). Based on the evidence, the p.Pro399Leu variant is classified as a variant of unknown significance, but suspicious for pathogenicity of Parkinson disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. |
| OMIM | RCV000002518 | SCV000022676 | pathogenic | Parkinson disease, autosomal recessive early-onset, digenic, PINK1/DJ1 | 2006-06-01 | no assertion criteria provided | literature only |