Variant summary: PANK2 c.700A>G (p.Thr234Ala) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251292 control chromosomes. c.700A>G has been reported in the literature as a biallelic compound heterozygous genotyp in individuals affected with Pantothenate Kinase-Associated Neurodegeneration (example, Zhou_2001, cited in Hayflick_2003 and Thomas_2004; Egan_2005). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Kotzbauer_2005). These results showed no damaging effect of this variant. The following publications have been ascertained in the context of this evaluation (PMID: 28113101, 16023068, 12510040, 15659606, 16450344, 27544236, 14743358, 26547561, 16272150, 11479594). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
ClinVar Genomic variation as it relates to human health
NM_001386393.1(PANK2):c.370A>G (p.Thr124Ala)
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.
(3)
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.
Conflicting classifications of pathogenicity
Likely pathogenic(1); Uncertain significance(1)
Likely pathogenic(1); Uncertain significance(1)
3
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001386393.1(PANK2):c.370A>G (p.Thr124Ala)
Variation ID: 4554 Accession: VCV000004554.6
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 20p13 20: 3907997 (GRCh38) [ NCBI UCSC ] 20: 3888644 (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 Jul 22, 2017 Mar 23, 2024 Dec 21, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001386393.1:c.370A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001373322.1:p.Thr124Ala missense NM_001324191.2:c.-174A>G 5 prime UTR NM_001324192.1:c.700A>G NP_001311121.1:p.Thr234Ala missense NM_001324193.2:c.-466A>G 5 prime UTR NM_024960.6:c.-174A>G 5 prime UTR NM_153638.3:c.700A>G NM_153638.4:c.700A>G NP_705902.2:p.Thr234Ala missense NM_153640.4:c.-174A>G 5 prime UTR NR_136715.2:n.414A>G non-coding transcript variant NC_000020.11:g.3907997A>G NC_000020.10:g.3888644A>G NG_008131.3:g.24159A>G LRG_1016:g.24159A>G LRG_1016t1:c.700A>G LRG_1016p1:p.Thr234Ala LRG_1016t2:c.370A>G LRG_1016p2:p.Thr124Ala Q9BZ23:p.Thr234Ala - Protein change
- T234A
- Other names
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T124A
- Canonical SPDI
- NC_000020.11:3907996:A:G
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
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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
Help
The frequency of the allele represented by this VCV record.
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The Genome Aggregation Database (gnomAD) 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00003
- 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. |
|||
| PANK2 | - | - |
GRCh38 GRCh37 |
481 | 748 | |
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. |
|---|---|---|---|---|
| Uncertain significance (1) |
criteria provided, single submitter
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May 9, 2023 | RCV003234892.1 | |
| Likely pathogenic (2) |
criteria provided, single submitter
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Dec 21, 2023 | RCV001851655.5 |
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. |
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|---|---|---|---|---|---|
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Uncertain significance
(May 09, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003934223.1
First in ClinVar: Jun 24, 2023 Last updated: Jun 24, 2023 |
Comment:
Variant summary: PANK2 c.700A>G (p.Thr234Ala) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging … (more)
Variant summary: PANK2 c.700A>G (p.Thr234Ala) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251292 control chromosomes. c.700A>G has been reported in the literature as a biallelic compound heterozygous genotyp in individuals affected with Pantothenate Kinase-Associated Neurodegeneration (example, Zhou_2001, cited in Hayflick_2003 and Thomas_2004; Egan_2005). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Kotzbauer_2005). These results showed no damaging effect of this variant. The following publications have been ascertained in the context of this evaluation (PMID: 28113101, 16023068, 12510040, 15659606, 16450344, 27544236, 14743358, 26547561, 16272150, 11479594). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. (less)
|
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Likely pathogenic
(Dec 21, 2023)
|
criteria provided, single submitter
Method: clinical testing
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Pigmentary pallidal degeneration
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002162930.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 234 of the PANK2 protein (p.Thr234Ala). … (more)
This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 234 of the PANK2 protein (p.Thr234Ala). This variant is present in population databases (rs137852965, gnomAD 0.004%). This missense change has been observed in individual(s) with clinical features of pantothenate kinase-associated neurodegeneration (PMID: 11479594, 16023068, 26547561). This variant is also known as c.400A>G (p.T124A) or c.370A>G. ClinVar contains an entry for this variant (Variation ID: 4554). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PANK2 protein function. Experimental studies have shown that this missense change does not substantially affect PANK2 function (PMID: 15659606). This variant disrupts the p.Thr234 amino acid residue in PANK2. Other variant(s) that disrupt this residue have been observed in individuals with PANK2-related conditions (PMID: 23166001), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. (less)
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Pathogenic
(Aug 01, 2001)
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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
|
OMIM
Accession: SCV000024990.3
First in ClinVar: Apr 04, 2013 Last updated: Mar 23, 2024 |
Comment on evidence:
In an individual with atypical pantothenate kinase-associated neurodegeneration (NBIA1; 234200), Zhou et al. (2001) identified an A-to-G transition at nucleotide 400 of the PANK2 gene, … (more)
In an individual with atypical pantothenate kinase-associated neurodegeneration (NBIA1; 234200), Zhou et al. (2001) identified an A-to-G transition at nucleotide 400 of the PANK2 gene, resulting in a threonine-to-alanine substitution at codon 124 (T124A). (less)
|
Comment:
Comment:
This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 234 of the PANK2 protein (p.Thr234Ala). This variant is present in population databases (rs137852965, gnomAD 0.004%). This missense change has been observed in individual(s) with clinical features of pantothenate kinase-associated neurodegeneration (PMID: 11479594, 16023068, 26547561). This variant is also known as c.400A>G (p.T124A) or c.370A>G. ClinVar contains an entry for this variant (Variation ID: 4554). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PANK2 protein function. Experimental studies have shown that this missense change does not substantially affect PANK2 function (PMID: 15659606). This variant disrupts the p.Thr234 amino acid residue in PANK2. Other variant(s) that disrupt this residue have been observed in individuals with PANK2-related conditions (PMID: 23166001), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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:
Variant summary: PANK2 c.700A>G (p.Thr234Ala) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251292 control chromosomes. c.700A>G has been reported in the literature as a biallelic compound heterozygous genotyp in individuals affected with Pantothenate Kinase-Associated Neurodegeneration (example, Zhou_2001, cited in Hayflick_2003 and Thomas_2004; Egan_2005). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Kotzbauer_2005). These results showed no damaging effect of this variant. The following publications have been ascertained in the context of this evaluation (PMID: 28113101, 16023068, 12510040, 15659606, 16450344, 27544236, 14743358, 26547561, 16272150, 11479594). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Comment:
This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 234 of the PANK2 protein (p.Thr234Ala). This variant is present in population databases (rs137852965, gnomAD 0.004%). This missense change has been observed in individual(s) with clinical features of pantothenate kinase-associated neurodegeneration (PMID: 11479594, 16023068, 26547561). This variant is also known as c.400A>G (p.T124A) or c.370A>G. ClinVar contains an entry for this variant (Variation ID: 4554). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PANK2 protein function. Experimental studies have shown that this missense change does not substantially affect PANK2 function (PMID: 15659606). This variant disrupts the p.Thr234 amino acid residue in PANK2. Other variant(s) that disrupt this residue have been observed in individuals with PANK2-related conditions (PMID: 23166001), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Clinical and genetic features of PKAN patients in a tertiary centre in Turkey. | Akcakaya NH | Clinical neurology and neurosurgery | 2017 | PMID: 28113101 |
| Exploring Missense Mutations in Tyrosine Kinases Implicated with Neurodegeneration. | Sami N | Molecular neurobiology | 2017 | PMID: 27544236 |
| Pallidal neuronal apolipoprotein E in pantothenate kinase-associated neurodegeneration recapitulates ischemic injury to the globus pallidus. | Woltjer RL | Molecular genetics and metabolism | 2015 | PMID: 26547561 |
| PANK2 and C19orf12 mutations are common causes of neurodegeneration with brain iron accumulation. | Dezfouli MA | Movement disorders : official journal of the Movement Disorder Society | 2013 | PMID: 23166001 |
| Partial deficit of pantothenate kinase 2 catalytic activity in a case of tremor-predominant neurodegeneration with brain iron accumulation. | Liang TW | Movement disorders : official journal of the Movement Disorder Society | 2006 | PMID: 16450344 |
| 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 |
| Neuro-ophthalmologic and electroretinographic findings in pantothenate kinase-associated neurodegeneration (formerly Hallervorden-Spatz syndrome). | Egan RA | American journal of ophthalmology | 2005 | PMID: 16023068 |
| 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 |
| Clinical heterogeneity of neurodegeneration with brain iron accumulation (Hallervorden-Spatz syndrome) and pantothenate kinase-associated neurodegeneration. | Thomas M | Movement disorders : official journal of the Movement Disorder Society | 2004 | PMID: 14743358 |
| 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 rs137852965 ...
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Record last updated Nov 10, 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.