ClinVar Genomic variation as it relates to human health
NM_000284.4(PDHA1):c.491A>G (p.Asn164Ser)
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(6); Likely pathogenic(3); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000284.4(PDHA1):c.491A>G (p.Asn164Ser)
Variation ID: 488569 Accession: VCV000488569.35
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xp22.12 X: 19353154 (GRCh38) [ NCBI UCSC ] X: 19371272 (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 Feb 13, 2018 May 12, 2024 Mar 26, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000284.4:c.491A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000275.1:p.Asn164Ser missense NM_001173454.2:c.605A>G NP_001166925.1:p.Asn202Ser missense NM_001173455.2:c.512A>G NP_001166926.1:p.Asn171Ser missense NM_001173456.2:c.491A>G NP_001166927.1:p.Asn164Ser missense NC_000023.11:g.19353154A>G NC_000023.10:g.19371272A>G NG_016781.1:g.14262A>G - Protein change
- N164S, N202S, N171S
- Other names
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- Canonical SPDI
- NC_000023.11:19353153: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
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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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PDHA1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
561 | 774 |
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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Conflicting interpretations of pathogenicity (6) |
criteria provided, conflicting classifications
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Mar 26, 2024 | RCV000578359.14 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 13, 2022 | RCV001824834.2 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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May 25, 2022 | RCV001091316.20 |
Submissions - Germline
Classification
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The submitted germline classification for each SCV record. (Last evaluated) |
Review status
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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
(Jan 13, 2022)
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criteria provided, single submitter
Method: clinical testing
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Pyruvate dehydrogenase complex deficiency
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002074233.1
First in ClinVar: Feb 12, 2022 Last updated: Feb 12, 2022 |
Comment:
Variant summary: PDHA1 c.491A>G (p.Asn164Ser) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging … (more)
Variant summary: PDHA1 c.491A>G (p.Asn164Ser) results in a 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 was absent in 183518 control chromosomes (gnomAD). c.491A>G has been reported in the literature in multiple male individuals affected with Pyruvate Dehydrogenase Deficiency (e.g. Lissens_2000, DeBrosse_2012, Shin_2017). These data indicate that the variant is very likely to be associated with disease. These publications also reported enzymatic measurements from patient derived fibroblasts, and demonstrated low activities (Lissens_2000, Shin_2017). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=3) / likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Likely pathogenic
(Jun 11, 2019)
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criteria provided, single submitter
Method: clinical testing
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Pyruvate dehydrogenase E1-alpha deficiency
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002021650.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Dec 09, 2017)
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criteria provided, single submitter
Method: clinical testing
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Pyruvate dehydrogenase E1-alpha deficiency
(X-linked inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV000680324.1
First in ClinVar: Feb 13, 2018 Last updated: Feb 13, 2018 |
Sex: male
Tissue: blood
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Likely pathogenic
(Aug 02, 2022)
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criteria provided, single submitter
Method: clinical testing
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Pyruvate dehydrogenase E1-alpha deficiency
Affected status: yes
Allele origin:
germline
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MGZ Medical Genetics Center
Accession: SCV002581684.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PS4, PS3_MOD, PM2_SUP, PP3
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Number of individuals with the variant: 2
Sex: female
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Pathogenic
(May 25, 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: SCV002522033.2
First in ClinVar: Jun 05, 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 has a deleterious effect on protein structure/function; … (more)
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25978847, 32445240, 10679936) (less)
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Pathogenic
(May 30, 2023)
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criteria provided, single submitter
Method: clinical testing
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Pyruvate dehydrogenase E1-alpha deficiency
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV004299491.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, … (more)
For these reasons, this variant has been classified as Pathogenic. 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 PDHA1 protein function. ClinVar contains an entry for this variant (Variation ID: 488569). This missense change has been observed in individual(s) with Leigh syndrome and/or pyruvate dehydrogenase deficiency (PMID: 10679936, 32445240). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 164 of the PDHA1 protein (p.Asn164Ser). (less)
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Uncertain significance
(Mar 26, 2024)
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criteria provided, single submitter
Method: clinical testing
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Pyruvate dehydrogenase E1-alpha deficiency
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004807425.1
First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024 |
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Likely pathogenic
(Oct 23, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
(Unknown mechanism)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001446424.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Global developmental delay (present)
Sex: female
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Pathogenic
(May 05, 2020)
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criteria provided, single submitter
Method: clinical testing
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Pyruvate dehydrogenase E1-alpha deficiency
Affected status: yes
Allele origin:
unknown
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Baylor Genetics
Accession: SCV001521299.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
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Pathogenic
(Nov 01, 2019)
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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: SCV001247271.21
First in ClinVar: May 12, 2020 Last updated: May 12, 2024 |
Number of individuals with the variant: 1
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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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Pediatric Leigh Syndrome: Neuroimaging Features and Genetic Correlations. | Alves CAPF | Annals of neurology | 2020 | PMID: 32445240 |
Enzymatic testing sensitivity, variability and practical diagnostic algorithm for pyruvate dehydrogenase complex (PDC) deficiency. | Shin HK | Molecular genetics and metabolism | 2017 | PMID: 28918066 |
Spectrum of neurological and survival outcomes in pyruvate dehydrogenase complex (PDC) deficiency: lack of correlation with genotype. | DeBrosse SD | Molecular genetics and metabolism | 2012 | PMID: 23021068 |
Mutations in the X-linked pyruvate dehydrogenase (E1) alpha subunit gene (PDHA1) in patients with a pyruvate dehydrogenase complex deficiency. | Lissens W | Human mutation | 2000 | PMID: 10679936 |
Text-mined citations for rs1555933963 ...
HelpRecord last updated May 12, 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.