ClinVar Genomic variation as it relates to human health
NM_005391.5(PDK3):c.473G>A (p.Arg158His)
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.
Pathogenic(2); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_005391.5(PDK3):c.473G>A (p.Arg158His)
Variation ID: 60682 Accession: VCV000060682.35
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xp22.11 X: 24503479 (GRCh38) [ NCBI UCSC ] X: 24521596 (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 23, 2013 Feb 14, 2024 Apr 27, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_005391.5:c.473G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005382.1:p.Arg158His missense NM_001142386.3:c.473G>A NP_001135858.1:p.Arg158His missense NC_000023.11:g.24503479G>A NC_000023.10:g.24521596G>A NG_016762.1:g.43253G>A Q15120:p.Arg158His - Protein change
- R158H
- Other names
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- Canonical SPDI
- NC_000023.11:24503478:G:A
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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
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The frequency of the allele represented by this VCV record.
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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
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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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PDK3 | - | - |
GRCh38 GRCh37 |
200 | 362 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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 (3) |
criteria provided, multiple submitters, no conflicts
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Apr 27, 2023 | RCV000054495.19 | |
Uncertain significance (1) |
criteria provided, single submitter
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Dec 2, 2022 | RCV002513712.8 |
Submissions - Germline
Classification
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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
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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
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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
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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
(May 07, 2019)
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criteria provided, single submitter
Method: clinical testing
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Charcot-Marie-Tooth disease X-linked dominant 6
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001388698.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant has been reported to affect PDK3 protein function (PMID: 23297365). This variant has … (more)
For these reasons, this variant has been classified as Pathogenic. This variant has been reported to affect PDK3 protein function (PMID: 23297365). This variant has been observed to segregate with X-linked Charcot-Marie-Tooth disease in families (PMID: 23297365, 26801680). ClinVar contains an entry for this variant (Variation ID: 60682). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with histidine at codon 158 of the PDK3 protein (p.Arg158His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. (less)
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Uncertain significance
(Dec 02, 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: SCV003538333.1
First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023 |
Comment:
The c.473G>A (p.R158H) alteration is located in exon 4 (coding exon 4) of the PDK3 gene. This alteration results from a G to A substitution … (more)
The c.473G>A (p.R158H) alteration is located in exon 4 (coding exon 4) of the PDK3 gene. This alteration results from a G to A substitution at nucleotide position 473, causing the arginine (R) at amino acid position 158 to be replaced by a histidine (H). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been reported to co-segregate with Charcot-Marie-Tooth disease in two families with different haplotypes (Kennerson, 2013; Kennerson, 2016). This amino acid position is highly conserved in available vertebrate species. Functional studies show a gain of function affect (Kennerson, 2013; Perez-Siles, 2016; Perez-Siles, 2020; Narayanan, 2021). This alteration is predicted to be deleterious by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. (less)
Number of individuals with the variant: 1
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Pathogenic
(Apr 27, 2023)
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criteria provided, single submitter
Method: research
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Charcot-Marie-Tooth disease X-linked dominant 6
Affected status: yes
Allele origin:
germline
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Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL)
Accession: SCV003920788.1
First in ClinVar: Nov 04, 2023 Last updated: Nov 04, 2023 |
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Pathogenic
(Apr 01, 2013)
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no assertion criteria provided
Method: literature only
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CHARCOT-MARIE-TOOTH DISEASE, X-LINKED DOMINANT, 6 (1 family)
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000082973.3
First in ClinVar: Aug 23, 2013 Last updated: Aug 23, 2013 |
Comment on evidence:
In affected members of a family with X-linked dominant Charcot-Marie-Tooth disease-6 (CMTX6; 300905), Kennerson et al. (2013) identified a c.473G-A transition in exon 4 of … (more)
In affected members of a family with X-linked dominant Charcot-Marie-Tooth disease-6 (CMTX6; 300905), Kennerson et al. (2013) identified a c.473G-A transition in exon 4 of the PDK3 gene, resulting in an arg158-to-his (R158H) substitution at a highly conserved residue. The mutation, which was found by linkage analysis combined with whole-exome sequencing and was confirmed by Sanger sequencing, segregated with the disorder in the family and was not present in 1,200 control chromosomes or published control databases. In vitro functional expression studies showed that the mutation conferred a gain of function, resulting in hyperactivity of PDK3. The R158H mutant protein showed a 10-fold higher dissociation constant for ATP binding compared to wildtype. The reduced affinity for nucleotides of R158H facilitates the removal of product inhibition by ADP, resulting in increased kinase activity. The mutant protein had a higher affinity than wildtype for the E2 subunit of the pyruvate dehydrogenase complex (PDC). Kennerson et al. (2013) postulated that the mutation shifts the equilibrium of the PDK3 enzyme toward the open conformation, resulting in increased activity that locks the PDC in a predominantly phosphorylated inactive state, leading to impaired ATP production and/or lactate accumulation. (less)
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Charcot-Marie-tooth disease causing mutation (p.R158H) in pyruvate dehydrogenase kinase 3 (PDK3) affects synaptic transmission, ATP production and causes neurodegeneration in a CMTX6 C. elegans model. | Narayanan RK | Human molecular genetics | 2021 | PMID: 34387338 |
Energy metabolism and mitochondrial defects in X-linked Charcot-Marie-Tooth (CMTX6) iPSC-derived motor neurons with the p.R158H PDK3 mutation. | Perez-Siles G | Scientific reports | 2020 | PMID: 32504000 |
Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. | Smith ED | Human mutation | 2017 | PMID: 28106320 |
Pathogenic mechanisms underlying X-linked Charcot-Marie-Tooth neuropathy (CMTX6) in patients with a pyruvate dehydrogenase kinase 3 mutation. | Perez-Siles G | Neurobiology of disease | 2016 | PMID: 27388934 |
A new locus for X-linked dominant Charcot-Marie-Tooth disease (CMTX6) is caused by mutations in the pyruvate dehydrogenase kinase isoenzyme 3 (PDK3) gene. | Kennerson ML | Human molecular genetics | 2013 | PMID: 23297365 |
Text-mined citations for rs397515323 ...
HelpRecord last updated Feb 14, 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.