rs55831733
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_SupportingBS2
The NM_032409.3(PINK1):c.1015G>A(p.Ala339Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00134 in 1,613,680 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. A339A) has been classified as Likely benign.
Frequency
Consequence
NM_032409.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| PINK1 | ENST00000321556.5 | c.1015G>A | p.Ala339Thr | missense_variant | Exon 5 of 8 | 1 | NM_032409.3 | ENSP00000364204.3 | ||
| PINK1 | ENST00000400490.2 | n.108G>A | non_coding_transcript_exon_variant | Exon 1 of 4 | 2 | |||||
| PINK1-AS | ENST00000451424.1 | n.3951C>T | non_coding_transcript_exon_variant | Exon 2 of 3 | 2 | |||||
| PINK1 | ENST00000492302.1 | n.2103G>A | non_coding_transcript_exon_variant | Exon 3 of 5 | 2 |
Frequencies
GnomAD3 genomes 0.000732 AC: 111AN: 151738Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000585 AC: 147AN: 251376Hom.: 0 AF XY: 0.000545 AC XY: 74AN XY: 135888
GnomAD4 exome AF: 0.00140 AC: 2046AN: 1461826Hom.: 3 Cov.: 38 AF XY: 0.00131 AC XY: 954AN XY: 727216
GnomAD4 genome 0.000731 AC: 111AN: 151854Hom.: 0 Cov.: 32 AF XY: 0.000660 AC XY: 49AN XY: 74226
ClinVar
Submissions by phenotype
not provided Uncertain:6
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) -
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PINK1: PS3:Supporting, BP4 -
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. -
Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is higher than would generally be expected for pathogenic variants in this gene. (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)) This variant has been identified in the heterozygous state in multiple individuals with Parkinson disease, however the significance of these occurrences when compared to the population frequency of this variant is uncertain. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 19847793, 24374372, 34893635, 35954270) he variant is located in a region that is considered important for protein function and/or structure. -
BS1, PS3_moderate -
Autosomal recessive early-onset Parkinson disease 6 Uncertain:3
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. -
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. -
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. -
not specified Uncertain:1
Variant summary: PINK1 c.1015G>A (p.Ala339Thr) results in a non-conservative amino acid change located in the protein kinase domain (IPR000719) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00058 in 251376 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in PINK1 causing Autosomal Recessive Early-Onset Parkinson Disease 6, allowing no conclusion about variant significance. c.1015G>A has been reported in the literature in individuals affected with Parkinson Disease (e.g., Brooks_2009, DiFonzo_2023, Gandhi_2006, Junker_2024, Landoulsi_2023, Marongiu_2009, Petersen_2015, Rogaeva_2004, Zech_2017, Schroeder_2008, Abou-Sleiman_2006). These reports do not provide unequivocal conclusions about association of the variant with Autosomal Recessive Early-Onset Parkinson Disease 6. Several publication reports experimental evidence evaluating an impact on protein function (e.g., Tan_2009, Zhou_2014, Broadway_2022). This variant was shown to induce greater apoptosis rate (Tan_2009), to increase cell vulnerability to oxidative stress (Zhou_2014), and was shown to have approximately 75% functional activity compared to wild type (Broadway_2022). The following publications have been ascertained in the context of this evaluation (PMID: 35954270, 19351622, 37750340, 16702191, 38529492, 38173558, 18330912, 25466404, 15596610, 19847793, 28849312, 24374372, 18403612, 16969854). ClinVar contains an entry for this variant (Variation ID: 500148). Based on the evidence outlined above, the variant was classified as uncertain significance. -
PINK1-related disorder Uncertain:1
The PINK1 c.1015G>A variant is predicted to result in the amino acid substitution p.Ala339Thr. This variant has been reported in multiple individuals with Parkinson disease (see for example, Table 3, Rogaeva et al. 2004. PubMed ID: 15596610; Table 4, Brooks et al. 2009. PubMed ID: 19351622; Table 1, Petersen et al. 2014. PubMed ID: 25466404). This variant is reported in 0.088% of alleles in individuals of European (non-Finnish) descent in gnomAD. An in vitro experimental study suggests this variant may increase the rate of cell death (Figure 4, Tan et al. 2009. PubMed ID: 19847793). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at