Submissions for variant NM_032409.3(PINK1):c.1015G>A (p.Ala339Thr)

gnomAD frequency: 0.00074  dbSNP: rs55831733

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000594876	SCV000705966	uncertain significance	not provided	2017-03-01	criteria provided, single submitter	clinical testing
Invitae	RCV000641728	SCV000763376	uncertain significance	Autosomal recessive early-onset Parkinson disease 6	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 339 of the PINK1 protein (p.Ala339Thr). This variant is present in population databases (rs55831733, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Parkinson disease (PMID: 15596610, 16702191, 18330912, 18403612, 19351622, 25466404, 28849312). ClinVar contains an entry for this variant (Variation ID: 500148). 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) performed at Invitae indicates that this missense variant is not expected to disrupt PINK1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects PINK1 function (PMID: 19847793, 24374372). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000594876	SCV000885912	uncertain significance	not provided	2017-08-18	criteria provided, single submitter	clinical testing	The p.Ala339Thr variant (rs55831733) has been reported as a heterozygote in several individuals included in cohorts of Parkinson’s disease (PD) patients while being absent or rare in controls (Abou-Sleiman 2006, Brooks 2009, Gandhi 2006, Marongiu 2008, Petersen 2015, Rogaeva 2004). However, this putative enrichment in patient populations has never been supported statistically and co-segregation of the p.Ala339Thr variant with PD has not been reported. Furthermore, in despite of research efforts, the impact of heterozygous PINK1 variants on the development of PD is not completely understood, and PINK1 variants are classically associated with autosomal recessive inheritance (see link to GeneReviews). None the less, expression of p.Ala339Thr variant protein in cell culture has been shown to sensitize cells to oxidative stress resulting in increased apoptosis compared with expression of wild-type PINK1 (Tan 2009 and Zhou 2014). This variant is listed in the Genome Aggregation Database (gnomAD) browser with an overall frequency of 0.05% (identified in 157 out of 277,112 chromosomes). Taken together, the clinical significance of the p.Ala339Thr variant cannot be determined with certainty.
CeGaT Center for Human Genetics Tuebingen	RCV000594876	SCV001147180	likely pathogenic	not provided	2018-10-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000641728	SCV001254676	uncertain significance	Autosomal recessive early-onset Parkinson disease 6	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
GeneDx	RCV000594876	SCV001767177	uncertain significance	not provided	2021-01-12	criteria provided, single submitter	clinical testing	Reported as a heterozygous variant in patients with Parkinson disease in published literature (Rogaeva et al., 2004; Abou-Sleiman et al., 2006; Gadhi et al., 2006; Peterson et al., 2015); Published functional studies suggest that A339T may have a damaging effect on protein function (Tan et al., 2009); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 16969854, 18330912, 19351622, 22451330, 21412950, 16547921, 16702191, 24374372, 25466404, 15596610, 20981092, 19847793, 22644621, 24441527, 18403612, 28849312)
Molecular Genetics, Royal Melbourne Hospital	RCV000641728	SCV002503753	uncertain significance	Autosomal recessive early-onset Parkinson disease 6	2022-04-22	criteria provided, single submitter	clinical testing	This sequence change is predicted to replace alanine with threonine at codon 339 of the PINK1 protein (p.(Ala339Thr)). The alanine residue is moderately conserved (100 vertebrates, UCSC), and is located in the protein kinase domain. There is a small physicochemical difference between alanine and threonine. The variant is present in a large population cohort at a frequency of 0.06% (rs55831733, 163/282,728 alleles, 0 homozygotes in gnomAD v2.1). The variant has been identified compound heterozygous with a PINK1 variant of uncertain significance in an individual with a dystonia-Parkinsonism phenotype (PMID: 28849312). It has been identified heterozygous in multiple individuals with Parkinson disease, but is not significantly increased compared with the prevalence in controls (PMID: 15596610, 16702191, 16969854, 18330912, 25466404). In vitro functional assays demonstrate the variant causes increased sensitivity to oxidative stress in dopaminergic neurons (PMID: 19847793, 24374372). Multiple lines of computational evidence predict a benign effect for the missense substitution (5/6 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.3.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE . Following criteria are met: PS3_Supporting.