PS3, PS4, PP3 The PINK1 c.1040T>C variant is a single nucleotide change from a thymine to a cytosine at position 1040 which is predicted to change the leucine at position 347 in the protein to proline. This variant has been reported in multiple unrelated families with early onset parkinsonism (PMID:15349870; PMID: 17055324) (PS4). Multiple functional studies have demonstrated that this variant destabilizes PINK1, reduces its kinase activity and affects its function (PMID: 15824318; PMID: 18359116) (PS3). This variant is thought to be a founder mutation in the Filipino population (PMID: 22644621). The variant is in dbSNP (rs28940285) and has been reported in population databases (gnomAD 5/282826, 0 homozygotes) (PM2 not applied as PS4 applied already). The variant has been reported in the ClinVar database as pathogenic by another diagnostic laboratory (Variation ID 2408). It has been reported in the HGMD database (CM042452). Computational predictions support a deleterious effect on the gene or gene product (PP3).
ClinVar Genomic variation as it relates to human health
NM_032409.3(PINK1):c.1040T>C (p.Leu347Pro)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(7)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic
7
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_032409.3(PINK1):c.1040T>C (p.Leu347Pro)
Variation ID: 2408 Accession: VCV000002408.14
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 1p36.12 1: 20645640 (GRCh38) [ NCBI UCSC ] 1: 20972133 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Sep 21, 2018 Feb 28, 2024 Oct 29, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_032409.3:c.1040T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_115785.1:p.Leu347Pro missense NR_046507.1:n.3926A>G non-coding transcript variant NC_000001.11:g.20645640T>C NC_000001.10:g.20972133T>C NG_008164.1:g.17186T>C Q9BXM7:p.Leu347Pro - Protein change
- L347P
- Other names
- -
- Canonical SPDI
- NC_000001.11:20645639:T:C
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00003
The Genome Aggregation Database (gnomAD) 0.00004
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| PINK1 | - | - |
GRCh38 GRCh37 |
141 | 424 | |
| PINK1-AS | - | - | - | GRCh38 | - | 259 |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Oct 29, 2023 | RCV000002509.19 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Mar 24, 2023 | RCV002223750.5 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Apr 27, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive early-onset Parkinson disease 6
Affected status: yes
Allele origin:
germline
|
Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002556504.2
First in ClinVar: Aug 04, 2022 Last updated: Dec 17, 2022 |
Comment:
PS3, PS4, PP3 The PINK1 c.1040T>C variant is a single nucleotide change from a thymine to a cytosine at position 1040 which is predicted to … (more)
PS3, PS4, PP3 The PINK1 c.1040T>C variant is a single nucleotide change from a thymine to a cytosine at position 1040 which is predicted to change the leucine at position 347 in the protein to proline. This variant has been reported in multiple unrelated families with early onset parkinsonism (PMID:15349870; PMID: 17055324) (PS4). Multiple functional studies have demonstrated that this variant destabilizes PINK1, reduces its kinase activity and affects its function (PMID: 15824318; PMID: 18359116) (PS3). This variant is thought to be a founder mutation in the Filipino population (PMID: 22644621). The variant is in dbSNP (rs28940285) and has been reported in population databases (gnomAD 5/282826, 0 homozygotes) (PM2 not applied as PS4 applied already). The variant has been reported in the ClinVar database as pathogenic by another diagnostic laboratory (Variation ID 2408). It has been reported in the HGMD database (CM042452). Computational predictions support a deleterious effect on the gene or gene product (PP3). (less)
|
|
|
Pathogenic
(Jan 25, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV004225802.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
PP3, PM2, PS3, PS4
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Jun 07, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive early-onset Parkinson disease 6
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV001150212.1
First in ClinVar: Feb 03, 2020 Last updated: Feb 03, 2020 |
Zygosity: Homozygote
Sex: female
Tissue: blood
|
|
|
Pathogenic
(Feb 24, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: yes
Allele origin:
germline
|
AiLife Diagnostics, AiLife Diagnostics
Accession: SCV002502116.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Number of individuals with the variant: 1
Secondary finding: no
|
|
|
Pathogenic
(Mar 24, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Athena Diagnostics
Accession: SCV004229841.1
First in ClinVar: Jan 26, 2024 Last updated: Jan 26, 2024 |
Comment:
The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical … (more)
The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 15824318, 17579517, 19242547, 19880420, 20798600, 23303188) In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. (less)
|
|
|
Pathogenic
(Oct 29, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive early-onset Parkinson disease 6
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000934807.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 347 of the PINK1 protein (p.Leu347Pro). … (more)
This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 347 of the PINK1 protein (p.Leu347Pro). This variant is present in population databases (rs28940285, gnomAD 0.03%). This missense change has been observed in individuals with early-onset Parkinson disease (PMID: 15349870, 17055324, 22956510). It is commonly reported in individuals of Filipino ancestry (PMID: 15349870, 17055324, 22956510). ClinVar contains an entry for this variant (Variation ID: 2408). 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 expected to disrupt PINK1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PINK1 function (PMID: 15824318, 17579517, 18359116, 23303188). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Apr 19, 2005)
|
no assertion criteria provided
Method: literature only
|
PARKINSON DISEASE 6, AUTOSOMAL RECESSIVE EARLY-ONSET
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000022667.3
First in ClinVar: Apr 04, 2013 Last updated: Sep 21, 2018 |
Comment on evidence:
In 3 affected members of a Filipino family with Parkinson disease (PARK6; 605909), Hatano et al. (2004) identified a homozygous 1040T-C transition in exon 5 … (more)
In 3 affected members of a Filipino family with Parkinson disease (PARK6; 605909), Hatano et al. (2004) identified a homozygous 1040T-C transition in exon 5 of the PINK1 gene, resulting in a leu347-to-pro (L347P) substitution. Rogaeva et al. (2004) identified the homozygous L347P mutation in 1 of 289 North American patients with either early- or late-onset PD. The patient was Filipino, had disease onset in the fourth decade of life, and reportedly had 2 affected sibs. The authors noted that the L347P mutation occurs in a conserved residue within the kinase domain of the protein. Three of 50 Filipino control individuals were heterozygous for the L347P mutation, suggesting an allelic frequency of 3% in this population. In mammalian cells, Beilina et al. (2005) found that the L347P mutation resulted in significantly decreased protein stability and in a drastic reduction of kinase activity. The mutation was predicted to occur in a helical segment that forms part of the cyclin binding surface. (less)
|
Comment:
Comment:
PP3, PM2, PS3, PS4
Comment:
The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 15824318, 17579517, 19242547, 19880420, 20798600, 23303188) In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic.
Comment:
This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 347 of the PINK1 protein (p.Leu347Pro). This variant is present in population databases (rs28940285, gnomAD 0.03%). This missense change has been observed in individuals with early-onset Parkinson disease (PMID: 15349870, 17055324, 22956510). It is commonly reported in individuals of Filipino ancestry (PMID: 15349870, 17055324, 22956510). ClinVar contains an entry for this variant (Variation ID: 2408). 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 expected to disrupt PINK1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PINK1 function (PMID: 15824318, 17579517, 18359116, 23303188). For these reasons, this variant has been classified as Pathogenic.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
PS3, PS4, PP3 The PINK1 c.1040T>C variant is a single nucleotide change from a thymine to a cytosine at position 1040 which is predicted to change the leucine at position 347 in the protein to proline. This variant has been reported in multiple unrelated families with early onset parkinsonism (PMID:15349870; PMID: 17055324) (PS4). Multiple functional studies have demonstrated that this variant destabilizes PINK1, reduces its kinase activity and affects its function (PMID: 15824318; PMID: 18359116) (PS3). This variant is thought to be a founder mutation in the Filipino population (PMID: 22644621). The variant is in dbSNP (rs28940285) and has been reported in population databases (gnomAD 5/282826, 0 homozygotes) (PM2 not applied as PS4 applied already). The variant has been reported in the ClinVar database as pathogenic by another diagnostic laboratory (Variation ID 2408). It has been reported in the HGMD database (CM042452). Computational predictions support a deleterious effect on the gene or gene product (PP3).
Comment:
PP3, PM2, PS3, PS4
Comment:
The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 15824318, 17579517, 19242547, 19880420, 20798600, 23303188) In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic.
Comment:
This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 347 of the PINK1 protein (p.Leu347Pro). This variant is present in population databases (rs28940285, gnomAD 0.03%). This missense change has been observed in individuals with early-onset Parkinson disease (PMID: 15349870, 17055324, 22956510). It is commonly reported in individuals of Filipino ancestry (PMID: 15349870, 17055324, 22956510). ClinVar contains an entry for this variant (Variation ID: 2408). 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 expected to disrupt PINK1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PINK1 function (PMID: 15824318, 17579517, 18359116, 23303188). For these reasons, this variant has been classified as Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Genetic screening of Filipinos suspected with familial Parkinson's disease: A pilot study. | Caritativo ECA | Parkinsonism & related disorders | 2023 | PMID: 36774704 |
| Recurrent Biallelic p.L347P PINK1 Variant in Polynesians with Parkinsonism and Isolated Dopa-Responsive Dystonia. | Morales-Briceno H | Movement disorders clinical practice | 2022 | PMID: 35844286 |
| Potential PINK1 Founder Effect in Polynesia Causing Early-Onset Parkinson's Disease. | Patel SG | Movement disorders : official journal of the Movement Disorder Society | 2021 | PMID: 34159639 |
| A genetic analysis of a Spanish population with early onset Parkinson's disease. | Cristina TP | PloS one | 2020 | PMID: 32870915 |
| PINK1 p.Leu347Pro mutations in Malays: Prevalence and illustrative cases. | Tan AH | Parkinsonism & related disorders | 2020 | PMID: 32861104 |
| Defining neurodegeneration on Guam by targeted genomic sequencing. | Steele JC | Annals of neurology | 2015 | PMID: 25558820 |
| The genetic landscape of high-risk neuroblastoma. | Pugh TJ | Nature genetics | 2013 | PMID: 23334666 |
| Characterization of PINK1 (PTEN-induced putative kinase 1) mutations associated with Parkinson disease in mammalian cells and Drosophila. | Song S | The Journal of biological chemistry | 2013 | PMID: 23303188 |
| Systematic review and UK-based study of PARK2 (parkin), PINK1, PARK7 (DJ-1) and LRRK2 in early-onset Parkinson's disease. | Kilarski LL | Movement disorders : official journal of the Movement Disorder Society | 2012 | PMID: 22956510 |
| Analysis of the regulatory and catalytic domains of PTEN-induced kinase-1 (PINK1). | Sim CH | Human mutation | 2012 | PMID: 22644621 |
| The PINK1/Parkin-mediated mitophagy is compromised by PD-associated mutations. | Geisler S | Autophagy | 2010 | PMID: 20798600 |
| Phosphorylation of parkin by Parkinson disease-linked kinase PINK1 activates parkin E3 ligase function and NF-kappaB signaling. | Sha D | Human molecular genetics | 2010 | PMID: 19880420 |
| PINK1 defect causes mitochondrial dysfunction, proteasomal deficit and alpha-synuclein aggregation in cell culture models of Parkinson's disease. | Liu W | PloS one | 2009 | PMID: 19242547 |
| L347P PINK1 mutant that fails to bind to Hsp90/Cdc37 chaperones is rapidly degraded in a proteasome-dependent manner. | Moriwaki Y | Neuroscience research | 2008 | PMID: 18359116 |
| PINK1 protects against oxidative stress by phosphorylating mitochondrial chaperone TRAP1. | Pridgeon JW | PLoS biology | 2007 | PMID: 17579517 |
| Novel features in a patient homozygous for the L347P mutation in the PINK1 gene. | Doostzadeh J | Parkinsonism & related disorders | 2007 | PMID: 17055324 |
| Mutations in PTEN-induced putative kinase 1 associated with recessive parkinsonism have differential effects on protein stability. | Beilina A | Proceedings of the National Academy of Sciences of the United States of America | 2005 | PMID: 15824318 |
| Analysis of the PINK1 gene in a large cohort of cases with Parkinson disease. | Rogaeva E | Archives of neurology | 2004 | PMID: 15596610 |
| Novel PINK1 mutations in early-onset parkinsonism. | Hatano Y | Annals of neurology | 2004 | PMID: 15349870 |
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Text-mined citations for rs28940285 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Sep 29, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.