ClinVar Genomic variation as it relates to human health

Converted during submission to Uncertain significance.

In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32807662, 16367892, 24167364, 12629236, 26274610, 26556299, 12764050, 18973255, 23275044, 18519021, 16476817, 19205068, 30200940, 31409571, 33019779, 32802956, 32849182, 33640967, 18211709, 25877876, 34426522, 32870915, 33045815, 34434164, 16227559, 30994895)

PRKN: PM3:Very Strong, PM2, PP1, PS3:Supporting

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.

Variant summary: PARK2 c.719C>T (p.Thr240Met) results in a non-conservative amino acid change located in the RING/Ubox-like zinc-binding domain (IPR041170) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00037 in 251448 control chromosomes (gnomAD). c.719C>T has been reported in the literature in multiple bi-allelic individuals affected with Autosomal Recessive Juvenile Parkinson Disease (examples: Foroud_2003, Periquet_2003, Madegowda_2005, Camargos_2009) and in at-least one of these families the variant segregated with the disease (Deng_2006). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 19205068 , 12764050, 12629236, 16227559, 16476817). Eleven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic/likely pathogenic (n=10) and VUS (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 240 of the PRKN protein (p.Thr240Met). This variant is present in population databases (rs137853054, gnomAD 0.2%). This missense change has been observed in individual(s) with early onset Parkinson's disease (PMID: 12764050, 16476817, 18519021, 18973255, 19205068, 23275044, 26274610). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 7054). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PRKN protein function. For these reasons, this variant has been classified as Pathogenic.