Submissions for variant NM_004562.3(PRKN):c.719C>T (p.Thr240Met) (rs137853054)

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics	RCV000419390	SCV000511468	uncertain significance	not provided	2016-07-06	criteria provided, single submitter	clinical testing	Converted during submission to Uncertain significance.
Athena Diagnostics Inc	RCV000419390	SCV000614408	likely pathogenic	not provided	2017-02-03	criteria provided, single submitter	clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000625845	SCV000746413	pathogenic	Neoplasm of ovary	2017-12-03	criteria provided, single submitter	clinical testing
Invitae	RCV000007470	SCV000766631	pathogenic	Parkinson disease 2	2018-08-09	criteria provided, single submitter	clinical testing	This sequence change replaces threonine with methionine at codon 240 of the PARK2 protein (p.Thr240Met). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs137853054, ExAC 0.1%). This variant has been reported in multiple individuals affected with early onset Parkinson's disease (PMID: 26274610, 12764050, 18973255, 23275044, 19205068, 18519021). It has also been reported to segregate with autosomal recessive Parkinson's disease in a family (PMID: 16476817). ClinVar contains an entry for this variant (Variation ID: 7054). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. For these reasons, this variant has been classified as Pathogenic.
Illumina Clinical Services Laboratory,Illumina	RCV000007470	SCV000916134	pathogenic	Parkinson disease 2	2017-10-20	criteria provided, single submitter	clinical testing	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.
OMIM	RCV000007470	SCV000027670	pathogenic	Parkinson disease 2	2006-02-01	no assertion criteria provided	literature only