ClinVar Genomic variation as it relates to human health
NM_000284.4(PDHA1):c.1142_1145dup (p.Trp383fs)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000284.4(PDHA1):c.1142_1145dup (p.Trp383fs)
Variation ID: 10880 Accession: VCV000010880.49
- Type and length
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Duplication, 4 bp
- Location
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Cytogenetic: Xp22.12 X: 19359619-19359620 (GRCh38) [ NCBI UCSC ] X: 19377737-19377738 (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 Oct 11, 2015 May 12, 2024 May 6, 2021 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000284.4:c.1142_1145dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000275.1:p.Trp383fs frameshift NM_001173454.2:c.1256_1259dup NP_001166925.1:p.Trp421fs frameshift NM_001173455.2:c.1163_1166dup NP_001166926.1:p.Trp390fs frameshift NM_001173456.2:c.1049_1052dup NP_001166927.1:p.Trp352fs frameshift NC_000023.11:g.19359622_19359625dup NC_000023.10:g.19377740_19377743dup NG_016781.1:g.20730_20733dup NG_021184.1:g.160639_160642dup - Protein change
- W390fs, W352fs, W383fs, W421fs
- Other names
- NM_000284.4(PDHA1):c.1142_1145dup
- p.Trp383fs
- Canonical SPDI
- NC_000023.11:19359619:CAATCA:CAATCAATCA
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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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- Comment on variant
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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Pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Aug 1, 2022 | RCV000011627.19 | |
Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Dec 17, 2022 | RCV000199126.23 | |
Pathogenic (1) |
criteria provided, single submitter
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May 11, 2017 | RCV000624104.5 | |
Pathogenic (1) |
reviewed by expert panel
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May 6, 2021 | RCV001753411.4 |
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
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
(May 06, 2021)
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reviewed by expert panel
Method: curation
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Pyruvate dehydrogenase complex deficiency
(X-linked inheritance)
Affected status: unknown
Allele origin:
germline
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ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen
FDA Recognized Database
Accession: SCV001994852.1 First in ClinVar: Nov 06, 2021 Last updated: Nov 06, 2021 |
Comment:
The c.1142_c.1145dup variant in the PDHA1 gene is a frameshift variant in the final exon of PDHA1, which is predicted to escape nonsense mediated decay … (more)
The c.1142_c.1145dup variant in the PDHA1 gene is a frameshift variant in the final exon of PDHA1, which is predicted to escape nonsense mediated decay and result in amino acid truncation that removes less than 10% of the predicted protein product (PVS1_moderate PMID: 30192042). This variant is absent from population databases (PM2). This variant has been reported in several patients with presentations consistent with PDHA1-related disease in the literature. While this variant has been reported several times before, only five cases met criteria for scoring, including four assumed de novo cases in PMID: 10679936 and PMID: 20002461, and one maternity confirmed de novo case in PMID: 26865159. Several commercial testing laboratories (GeneDx, Illumina, and Ambry) have identified this variant was harbored by maternity confirmed de novo probands with presentations consistent with PDHA1-related disease (minimum of 3 and maximum of 6 probands- SCV001251622.1, SCV000252046.3, SCV000742395.2). Upon further review, the expert panel determined that while unable to confirm the identity of these patients, taken together these data in conjunction with the cases reported in the literature were sufficient to support elevating scoring to PS2_Very Strong per SVI de novo variant scoring criteria v1.0. PMID: 1779625 and PMID: 8504309 reported elevated pyruvate in the blood, and blood and CSF of the respective probands. PMID: 23021068 performed PDC activity assays < 3rd percentile in fibroblasts (PP4). In summary, this variant meets criteria to be classified as a pathogenic of PDHA1- related pyruvate dehydrogenase deficiency in an X-linked manner. PDHA1-specific ACMG/AMP criteria applied: (PVS1_moderate, PM2, PS2_Very Strong, PP4). This was reviewed with the PDHA1 expert panel on 4/6/2021 and approved on 4/18/2021. (less)
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Pathogenic
(Dec 17, 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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Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital
Accession: SCV002818269.1
First in ClinVar: Jan 07, 2023 Last updated: Jan 07, 2023 |
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Pathogenic
(Feb 04, 2020)
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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:
unknown
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Illumina Laboratory Services, Illumina
Accession: SCV001251622.2
First in ClinVar: May 31, 2020 Last updated: Mar 04, 2023 |
Comment:
The PDHA1 c.1142_1145dupATCA (p.Trp383SerfsTer6) variant results in a frameshift and is predicted to result in premature termination of the protein. Across a selection of the … (more)
The PDHA1 c.1142_1145dupATCA (p.Trp383SerfsTer6) variant results in a frameshift and is predicted to result in premature termination of the protein. Across a selection of the available literature, the p.Trp383SerfsTer6 variant has been identified in at least 10 individuals in a heterozygous state with variable phenotypes related to pyruvate dehydrogenase deficiency. Phenotypes include brain abnormalities (thin corpus callosum, cerebral atrophy, or cerebellar malformations), microcephaly, intellectual disability, hypotonia, elevated lactate and pyruvate levels, and epilepsy (Endo et al. 1991; Lissens et al. 2000; Quintata et al. 2010; DeBrosse et al. 2012). At least four of these individuals carried the p.Trp383SerfsTer6 variant in a de novo state (Lissens et al. 2000; Quintata et al. 2010). Evaluation of patient fibroblasts showed significantly decreased pyruvate dehydrogenase complex and pyruvate dehydrogenase E1 activity levels compared to controls (Endo et al. 1991; Lissens et al. 2000; Quintata et al. 2010). The p.Trp383SerfsTer6 variant is not found in the Genome Aggregation Database and is in a region of good sequencing coverage, so the variant is presumed to be rare. This variant occurs in the last exon and may escape nonsense mediated decay. Based on the collective evidence, the p.Trp383SerfsTer6 variant is classified as pathogenic for pyruvate dehydrogenase deficiency. (less)
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Pathogenic
(Aug 01, 2022)
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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: SCV003444629.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the PDHA1 protein in which other variant(s) (p.Ser388*) have … (more)
For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the PDHA1 protein in which other variant(s) (p.Ser388*) have been determined to be pathogenic (PMID: 7981697, 21846590, 21914562, 29756269). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 10880). This variant is also known as c.1256_1259dup, p.Try421Serfs*6. This premature translational stop signal has been observed in individual(s) with clinical features of pyruvate dehydrogenase E1-alpha deficiency (PMID: 1779625, 24718837, 26865159). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp383Serfs*6) in the PDHA1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 8 amino acid(s) of the PDHA1 protein. (less)
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Pathogenic
(Jun 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: SCV001249126.21
First in ClinVar: May 12, 2020 Last updated: May 12, 2024 |
Number of individuals with the variant: 4
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Pathogenic
(Jun 04, 2013)
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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: SCV000252046.3
First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015 |
Comment:
c.1142_1145dupATCA: p.Trp383SerfsX6 (W383SfsX6) in exon 11 of the PDHA1 gene (NM_000284.3). The normal sequence with the bases that are duplicated in braces is: GCCA{ATCA}GTGG. The … (more)
c.1142_1145dupATCA: p.Trp383SerfsX6 (W383SfsX6) in exon 11 of the PDHA1 gene (NM_000284.3). The normal sequence with the bases that are duplicated in braces is: GCCA{ATCA}GTGG. The c.1142_1145dupATCA mutation in the PDHA1 gene has been reported previously in association with pyruvate dehydrogenase complex (PDHc) deficiency (Endo et al., 1991). The duplication causes a frameshift starting with codon Tryptophan 383, changes this amino acid to a Serine residue and creates a premature Stop codon at position 6 of the new reading frame, denoted p.Trp383SerfsX6. This mutation is predicted to cause loss of normal protein function through protein truncation. The variant is found in MITONUC-MITOP panel(s). (less)
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Pathogenic
(May 15, 2020)
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criteria provided, single submitter
Method: research
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Pyruvate dehydrogenase E1-alpha deficiency
Affected status: yes
Allele origin:
de novo
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HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology
Study: CSER-SouthSeq
Accession: SCV001364304.1 First in ClinVar: Jun 26, 2020 Last updated: Jun 26, 2020 |
Comment:
ACMG codes: PVS1, PS2, PS4M, PM2, PP5
Number of individuals with the variant: 1
Clinical Features:
Polyhydramnios (present) , Hydrops fetalis (present) , Corpus callosum, agenesis of (present) , Abnormality of brain morphology (present) , Muscular hypotonia (present) , Hypospadias, penile … (more)
Polyhydramnios (present) , Hydrops fetalis (present) , Corpus callosum, agenesis of (present) , Abnormality of brain morphology (present) , Muscular hypotonia (present) , Hypospadias, penile (present) , Hydronephrosis (present) , Short chin (present) , Sacral dimple (present) , Congenital cerebellar hypoplasia (present) , Ventriculomegaly (present) , Redundant skin (present) (less)
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Likely pathogenic
(Jun 17, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
(X-linked dominant inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001762076.1
First in ClinVar: Jul 30, 2021 Last updated: Jul 30, 2021 |
Clinical Features:
Global developmental delay (present) , Intellectual disability (present) , Seizure (present)
Sex: female
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Pathogenic
(May 11, 2017)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: yes
Allele origin:
germline
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Ambry Genetics
Accession: SCV000742395.3
First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023 |
Observation 1:
Number of individuals with the variant: 1
Sex: male
Observation 2:
Number of individuals with the variant: 1
Sex: female
Ethnicity/Population group: Hispanic
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Pathogenic
(Apr 01, 1993)
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no assertion criteria provided
Method: literature only
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PYRUVATE DEHYDROGENASE E1-ALPHA DEFICIENCY
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000031859.4
First in ClinVar: Apr 04, 2013 Last updated: Mar 23, 2018 |
Comment on evidence:
Huq et al. (1991) described a female Japanese patient with pyruvate dehydrogenase E1-alpha deficiency (PDHAD; 312170) with early clinical presentation and rapid degradation of the … (more)
Huq et al. (1991) described a female Japanese patient with pyruvate dehydrogenase E1-alpha deficiency (PDHAD; 312170) with early clinical presentation and rapid degradation of the alpha and beta subunits of pyruvate dehydrogenase. In this patient, Ito et al. (1992) identified a 4-bp insertion in exon 11 of the PDHA1 gene, resulting in a frameshift. The same 4-bp insertion was found in an unrelated female patient with E1-alpha deficiency (Endo et al., 1991). The patient was heterozygous for the normal and mutant alleles; however, in most of the cultured skin fibroblasts, the mutant allele was expressed. The mutant alpha subunit failed to form a stable pyruvate dehydrogenase structure so that both alpha and beta subunits were degraded rapidly. Ito et al. (1992) noted that short deletions or duplications in the E1-alpha gene of patients with E1-alpha deficiency have been found only in exons 10 and 11, which may be hotspots for mutations by a recombinational event. Takakubo et al. (1993) reported an independent case with the same mutation, an insertion of ATCA after nucleotide 1251 creating a truncated form of protein after glutamine-382 (E382). The patient of Takakubo et al. (1993) was a 4-day-old female who was found to have agenesis of the corpus callosum and gray/white matter heterotopia. Her lactate and pyruvate levels were elevated in both serum and cerebrospinal fluid. PDHC activity in cultured skin fibroblasts was 46% of the normal control value. (less)
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Pathogenic
(Apr 01, 2023)
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no assertion criteria provided
Method: clinical testing
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Pyruvate dehydrogenase E1-alpha deficiency
Affected status: yes
Allele origin:
germline
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Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)
Accession: SCV003927824.1
First in ClinVar: Sep 16, 2023 Last updated: Sep 16, 2023 |
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Likely pathogenic
(Sep 26, 2019)
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no assertion criteria provided
Method: clinical testing
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Pyruvate dehydrogenase E1-alpha deficiency
Affected status: yes
Allele origin:
germline
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Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City
Accession: SCV001133088.1
First in ClinVar: Jan 04, 2020 Last updated: Jan 04, 2020 |
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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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Genetic and clinical features of Chinese patients with mitochondrial ataxia identified by targeted next-generation sequencing. | Dong HL | CNS neuroscience & therapeutics | 2019 | PMID: 29756269 |
Phenotypic and Neuropathological Characterization of Fetal Pyruvate Dehydrogenase Deficiency. | Pirot N | Journal of neuropathology and experimental neurology | 2016 | PMID: 26865159 |
Thiamine-Responsive and Non-responsive Patients with PDHC-E1 Deficiency: A Retrospective Assessment. | van Dongen S | JIMD reports | 2015 | PMID: 24718837 |
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 |
Molecular characterization of 82 patients with pyruvate dehydrogenase complex deficiency. Structural implications of novel amino acid substitutions in E1 protein. | Imbard A | Molecular genetics and metabolism | 2011 | PMID: 21914562 |
Increased superoxide accumulation in pyruvate dehydrogenase complex deficient fibroblasts. | Glushakova LG | Molecular genetics and metabolism | 2011 | PMID: 21846590 |
Mutational study in the PDHA1 gene of 40 patients suspected of pyruvate dehydrogenase complex deficiency. | Quintana E | Clinical genetics | 2010 | PMID: 20002461 |
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 |
Pyruvate dehydrogenase deficiency caused by a four-nucleotide insertion in the E1 alpha subunit gene. | Naito E | Human molecular genetics | 1994 | PMID: 7981697 |
A four-nucleotide insertion hotspot in the X chromosome located pyruvate dehydrogenase E1 alpha gene (PDHA1). | Takakubo F | Human molecular genetics | 1993 | PMID: 8504309 |
Mutation of E1 alpha gene in a female patient with pyruvate dehydrogenase deficiency due to rapid degradation of E1 protein. | Ito M | Journal of inherited metabolic disease | 1992 | PMID: 1338114 |
Demonstration of an unstable variant of pyruvate dehydrogenase protein (E1) in cultured fibroblasts from a patient with congenital lactic acidemia. | Huq AH | Pediatric research | 1991 | PMID: 1909778 |
A four-nucleotide insertion at the E1 alpha gene in a patient with pyruvate dehydrogenase deficiency. | Endo H | Journal of inherited metabolic disease | 1991 | PMID: 1779625 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/4e0dd4ad-0ca9-40b8-8164-554f50b09a61 | - | - | - | - |
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Text-mined citations for rs606231189 ...
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.
NCBI staff reviewed the sequence information reported in PubMed 1338114 Fig. 2 to determine the location of this insertion on the current reference sequence.