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

gnomAD frequency: 0.00016  dbSNP: rs137853054

Total submissions: 14

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	likely pathogenic	Neoplasm of ovary	2020-05-03	criteria provided, single submitter	clinical testing
Invitae	RCV000419390	SCV000766631	pathogenic	not provided	2024-01-09	criteria provided, single submitter	clinical testing	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.
Illumina Laboratory Services, Illumina	RCV000007470	SCV000916134	pathogenic	Autosomal recessive juvenile 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.
Institute Of Human Genetics Munich, Klinikum Rechts Der Isar, Tu München	RCV000007470	SCV001430016	pathogenic	Autosomal recessive juvenile Parkinson disease 2	2019-06-07	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV001449638	SCV001652819	pathogenic	Young-onset Parkinson disease	2021-05-03	criteria provided, single submitter	clinical testing
GeneDx	RCV000419390	SCV001778405	pathogenic	not provided	2023-10-27	criteria provided, single submitter	clinical testing	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)
Centogene AG - the Rare Disease Company	RCV000007470	SCV002028314	pathogenic	Autosomal recessive juvenile Parkinson disease 2	2021-08-18	criteria provided, single submitter	clinical testing
AiLife Diagnostics, AiLife Diagnostics	RCV000419390	SCV002502669	likely pathogenic	not provided	2022-03-29	criteria provided, single submitter	clinical testing
Intergen, Intergen Genetics and Rare Diseases Diagnosis Center	RCV000007470	SCV003930287	pathogenic	Autosomal recessive juvenile Parkinson disease 2		criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000419390	SCV004010632	pathogenic	not provided	2023-06-01	criteria provided, single submitter	clinical testing	PRKN: PM3:Very Strong, PM2, PP1, PS3:Supporting
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000007470	SCV004037771	pathogenic	Autosomal recessive juvenile Parkinson disease 2	2023-08-30	criteria provided, single submitter	clinical testing	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.
OMIM	RCV000007470	SCV000027670	pathogenic	Autosomal recessive juvenile Parkinson disease 2	2006-02-01	no assertion criteria provided	literature only