ClinVar Genomic variation as it relates to human health
NM_001386393.1(PANK2):c.1253C>T (p.Thr418Met)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001386393.1(PANK2):c.1253C>T (p.Thr418Met)
Variation ID: 4556 Accession: VCV000004556.37
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 20p13 20: 3918717 (GRCh38) [ NCBI UCSC ] 20: 3899364 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Aug 8, 2014 May 1, 2024 Dec 30, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001386393.1:c.1253C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001373322.1:p.Thr418Met missense NM_001324191.2:c.710C>T NP_001311120.1:p.Thr237Met missense NM_001324193.2:c.275C>T NP_001311122.1:p.Thr92Met missense NM_024960.6:c.710C>T NP_079236.3:p.Thr237Met missense NM_153638.4:c.1583C>T NP_705902.2:p.Thr528Met missense NM_153640.4:c.710C>T NP_705904.1:p.Thr237Met missense NR_136715.2:n.1154C>T non-coding transcript variant NC_000020.11:g.3918717C>T NC_000020.10:g.3899364C>T NG_008131.3:g.34879C>T LRG_1016:g.34879C>T LRG_1016t1:c.1583C>T LRG_1016p1:p.Thr528Met LRG_1016t2:c.1253C>T LRG_1016p2:p.Thr418Met Q9BZ23:p.Thr528Met - Protein change
- T237M, T528M, T92M
- Other names
- T418M
- 1253C>T
- Thr418Met
- Canonical SPDI
- NC_000020.11:3918716:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- variation affecting protein Variation Ontology [VariO:0002]
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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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00003
The Genome Aggregation Database (gnomAD), exomes 0.00001
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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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. |
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MIR103A2 | - | - |
GRCh38 GRCh37 |
- | 46 | |
MIR103B2 | - | - | - | GRCh38 | - | 16 |
PANK2 | - | - |
GRCh38 GRCh37 |
475 | 735 |
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. |
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Pathogenic (7) |
criteria provided, multiple submitters, no conflicts
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Dec 30, 2023 | RCV000004816.20 | |
Pathogenic (2) |
criteria provided, single submitter
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Feb 11, 2019 | RCV000132733.4 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Oct 3, 2022 | RCV001310448.19 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 6, 2022 | RCV002512773.3 |
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. |
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Pathogenic
(Jul 01, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001500248.17
First in ClinVar: Mar 14, 2021 Last updated: Apr 15, 2024 |
Number of individuals with the variant: 1
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Pathogenic
(Jul 06, 2022)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV003718310.2
First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024 |
Comment:
The c.1583C>T (p.T528M) alteration is located in exon 6 (coding exon 6) of the PANK2 gene. This alteration results from a C to T substitution … (more)
The c.1583C>T (p.T528M) alteration is located in exon 6 (coding exon 6) of the PANK2 gene. This alteration results from a C to T substitution at nucleotide position 1583, causing the threonine (T) at amino acid position 528 to be replaced by a methionine (M). Based on data from gnomAD, the T allele has an overall frequency of <0.01% (4/282880) total alleles studied. The highest observed frequency was <0.01% (1/25122) of European (Finnish) alleles. This alteration has been detected in the homozygous state and as compound heterozygous in trans with other pathogenic PANK2 alterations in numerous unrelated individuals with pantothenate kinase-associated neurodegeneration (Golanska, 2015; Wu, 2013; Hartig, 2006; Hayflick, 2003; Zhou, 2001). This amino acid position is highly conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. (less)
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Pathogenic
(Jun 07, 2019)
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criteria provided, single submitter
Method: clinical testing
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Pigmentary pallidal degeneration
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV001149860.1
First in ClinVar: Feb 03, 2020 Last updated: Feb 03, 2020 |
Sex: female
Tissue: blood
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Pathogenic
(Feb 11, 2019)
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criteria provided, single submitter
Method: clinical testing
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Pigmentary pallidal degeneration
Affected status: yes
Allele origin:
unknown
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001366582.2
First in ClinVar: Jul 04, 2020 Last updated: Dec 12, 2020 |
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PP4,PP3,PP2,PP1. This variant was detected in homozygous state.
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Pathogenic
(Jul 01, 2020)
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criteria provided, single submitter
Method: clinical testing
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Pigmentary pallidal degeneration
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Laboratory for Molecular Genetic Diagnostic of Neurological Diseases, University of Belgrade, School of Medicine
Accession: SCV001481972.1
First in ClinVar: Mar 07, 2021 Last updated: Mar 07, 2021 |
Number of individuals with the variant: 8
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Pathogenic
(Oct 03, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV002578829.2
First in ClinVar: Oct 15, 2022 Last updated: Mar 04, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant … (more)
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31589614, 28113101, 32705819, 30363918, 23968566, 27185474, 33098801, 34272103, 30838286, 12510040, 16437574, 32043823, 28781879, 25724846, 11479594) (less)
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Pathogenic
(Nov 14, 2023)
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criteria provided, single submitter
Method: clinical testing
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Pigmentary pallidal degeneration
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV004101802.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Clinical Features:
Iron accumulation in brain (present) , Stuttering (present)
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Pathogenic
(Dec 30, 2023)
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criteria provided, single submitter
Method: clinical testing
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Pigmentary pallidal degeneration
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001412852.4
First in ClinVar: Jul 16, 2020 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 528 of the PANK2 protein (p.Thr528Met). … (more)
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 528 of the PANK2 protein (p.Thr528Met). This variant is present in population databases (rs137852967, gnomAD 0.004%). This missense change has been observed in individual(s) with clinical features of Hallervorden-Spatz syndrome (HSS) and is associated with both classical and atypical HSS (PMID: 11479594, 15565311, 16437574, 23968566, 25802776, 26087139, 27185474, 28781879). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.1283C>T, T418M. ClinVar contains an entry for this variant (Variation ID: 4556). 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 PANK2 protein function with a positive predictive value of 95%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on PANK2 function (PMID: 15659606, 16272150, 16437574). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jan 02, 2003)
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no assertion criteria provided
Method: literature only
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NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 1
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000024992.2
First in ClinVar: Apr 04, 2013 Last updated: Jul 22, 2017 |
Comment on evidence:
In individuals with both typical and atypical pantothenate kinase-associated neurodegeneration (NBIA1; 234200), Zhou et al. (2001) identified a C-to-T transition at nucleotide 1283 of the … (more)
In individuals with both typical and atypical pantothenate kinase-associated neurodegeneration (NBIA1; 234200), Zhou et al. (2001) identified a C-to-T transition at nucleotide 1283 of the PANK2 gene, resulting in a threonine-to-methionine substitution at codon 418 (T418M). This mutation was found in homozygosity in 2 patients with classical PKAN, and in compound heterozygosity with the G411R mutation (606157.0002) in an individual with atypical PKAN. Hayflick et al. (2003) found the T418M mutation on 10 alleles in 6 of 66 families with PANK2 mutations causing Hallervorden-Spatz syndrome. (less)
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Pathogenic
(Jul 29, 2021)
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no assertion criteria provided
Method: research
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Pigmentary pallidal degeneration
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Human Genetics Research Lab, Central University of Jammu
Accession: SCV001762284.1
First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021 |
Comment:
The variant NM_153638.3(PANK2):c.1583C>T (p.Thr528Met) was found to be segregating with the disease in the family in autosomal recessive mode of inheritance. Two of the affected … (more)
The variant NM_153638.3(PANK2):c.1583C>T (p.Thr528Met) was found to be segregating with the disease in the family in autosomal recessive mode of inheritance. Two of the affected sibs were found homozygous for the variant whereas both healthy parents were found to be heterozygous for the variant. Source: OMIM 234200 Neurodegeneration with brain iron accumulation-1 (NBIA1), also known as Hallervorden-Spatz disease, is caused by homozygous or compound heterozygosity mutation in the pantothenate kinase-2 gene (PANK2; 606157) (less)
Number of individuals with the variant: 2
Sex: mixed
Ethnicity/Population group: JAMMU AND KASHMIR-MUSLIM
Geographic origin: India
Comment on evidence:
variant found segregating with the disease in the family.
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pathogenic
(-)
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no assertion criteria provided
Method: not provided
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Hypoprebetalipoproteinemia, acanthocytosis, retinitis pigmentosa, and pallidal degeneration
Affected status: not provided
Allele origin:
inherited
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Undiagnosed Diseases Program Translational Research Laboratory, National Institutes of Health
Accession: SCV000187662.1
First in ClinVar: Aug 08, 2014 Last updated: Aug 08, 2014 |
Comment:
Converted during submission to Pathogenic.
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not provided
(-)
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no classification provided
Method: literature only
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Pigmentary pallidal degeneration
Affected status: unknown
Allele origin:
germline
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GeneReviews
Accession: SCV002014771.2
First in ClinVar: Nov 20, 2021 Last updated: Oct 01, 2022 |
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Germline Functional Evidence
Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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variation affecting protein
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Human Genetics Research Lab, Central University of Jammu
Accession: SCV001762284.1
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Novel PANK2 mutation in the first Greek compound heterozygote patient with pantothenate-kinase-associated neurodegeneration. | Paraskevas GP | SAGE open medical case reports | 2017 | PMID: 28781879 |
Pantothenate Kinase-Associated Neurodegeneration. | Adam MP | - | 2017 | PMID: 20301663 |
A novel gene mutation in PANK2 in a patient with severe jaw-opening dystonia. | Yapici Z | Brain & development | 2016 | PMID: 27185474 |
Screening for THAP1 Mutations in Polish Patients with Dystonia Shows Known and Novel Substitutions. | Golanska E | PloS one | 2015 | PMID: 26087139 |
Deep brain stimulation for pantothenate kinase-associated neurodegeneration. | Garcia-Ruiz PJ | Case reports in neurological medicine | 2015 | PMID: 25802776 |
Idiopathic basal ganglia calcifications: an atypical presentation of PKAN. | Wu YW | Pediatric neurology | 2013 | PMID: 23968566 |
Genotypic and phenotypic spectrum of PANK2 mutations in patients with neurodegeneration with brain iron accumulation. | Hartig MB | Annals of neurology | 2006 | PMID: 16437574 |
Biochemical properties of human pantothenate kinase 2 isoforms and mutations linked to pantothenate kinase-associated neurodegeneration. | Zhang YM | The Journal of biological chemistry | 2006 | PMID: 16272150 |
Altered neuronal mitochondrial coenzyme A synthesis in neurodegeneration with brain iron accumulation caused by abnormal processing, stability, and catalytic activity of mutant pantothenate kinase 2. | Kotzbauer PT | The Journal of neuroscience : the official journal of the Society for Neuroscience | 2005 | PMID: 15659606 |
MR relaxometry and 1H MR spectroscopy for the determination of iron and metabolite concentrations in PKAN patients. | Hájek M | European radiology | 2005 | PMID: 15565311 |
Genetic, clinical, and radiographic delineation of Hallervorden-Spatz syndrome. | Hayflick SJ | The New England journal of medicine | 2003 | PMID: 12510040 |
A novel pantothenate kinase gene (PANK2) is defective in Hallervorden-Spatz syndrome. | Zhou B | Nature genetics | 2001 | PMID: 11479594 |
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Text-mined citations for rs137852967 ...
HelpRecord last updated May 01, 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.