Submissions for variant NM_032409.3(PINK1):c.1474C>T (p.Arg492Ter)

gnomAD frequency: 0.00004  dbSNP: rs34208370

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000497743	SCV000589572	pathogenic	not provided	2022-05-03	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: decreased kinase activity and aberrant Parkin subcellular localization (Guo et al., 2017); Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 90 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; This variant is associated with the following publications: (PMID: 25525159, 15955953, 15349870, 29431110, 20547144, 24513209, 16401616, 17960343, 27094865, 18973254, 28862745, 33045815, 33491134, 18785233, 29255601)
Invitae	RCV000814157	SCV000954558	pathogenic	Autosomal recessive early-onset Parkinson disease 6	2023-10-03	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg492*) in the PINK1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 90 amino acid(s) of the PINK1 protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individuals with early onset Parkinson's disease (EOPD) (PMID: 15349870, 17960343, 18785233). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 431963). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects PINK1 function (PMID: 20547144, 29255601). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000814157	SCV001525058	pathogenic	Autosomal recessive early-onset Parkinson disease 6	2019-11-04	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Centogene AG - the Rare Disease Company	RCV000814157	SCV002059758	pathogenic	Autosomal recessive early-onset Parkinson disease 6	2021-06-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000814157	SCV002782849	pathogenic	Autosomal recessive early-onset Parkinson disease 6	2022-02-09	criteria provided, single submitter	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000497743	SCV001739920	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000497743	SCV001964641	pathogenic	not provided		no assertion criteria provided	clinical testing