rs606231185
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000284.4(PDHA1):c.934_940delAGTAAGA(p.Ser312fs) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 22)
Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )
Failed GnomAD Quality Control
Consequence
PDHA1
NM_000284.4 frameshift
NM_000284.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 9.51
Genes affected
PDHA1 (HGNC:8806): (pyruvate dehydrogenase E1 subunit alpha 1) The pyruvate dehydrogenase (PDH) complex is a nuclear-encoded mitochondrial multienzyme complex that catalyzes the overall conversion of pyruvate to acetyl-CoA and CO(2), and provides the primary link between glycolysis and the tricarboxylic acid (TCA) cycle. The PDH complex is composed of multiple copies of three enzymatic components: pyruvate dehydrogenase (E1), dihydrolipoamide acetyltransferase (E2) and lipoamide dehydrogenase (E3). The E1 enzyme is a heterotetramer of two alpha and two beta subunits. This gene encodes the E1 alpha 1 subunit containing the E1 active site, and plays a key role in the function of the PDH complex. Mutations in this gene are associated with pyruvate dehydrogenase E1-alpha deficiency and X-linked Leigh syndrome. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Mar 2010]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant X-19358940-GGAAGTAA-G is Pathogenic according to our data. Variant chrX-19358940-GGAAGTAA-G is described in ClinVar as [Pathogenic]. Clinvar id is 10872.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| PDHA1 | NM_000284.4 | c.934_940delAGTAAGA | p.Ser312fs | frameshift_variant | 10/11 | ENST00000422285.7 | NP_000275.1 |
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
22
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1077367Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 345273
GnomAD4 exome
Data not reliable, filtered out with message: AC0
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345273
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GnomAD4 genome
GnomAD4 genome
Cov.:
22
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Pyruvate dehydrogenase E1-alpha deficiency Pathogenic:6
| Pathogenic, criteria provided, single submitter | clinical testing | 3billion, Medical Genetics | Jan 03, 2022 | Frameshift: predicted to result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region (PVS1_S). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000010872, PMID:2378353). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Feb 02, 2022 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Pyruvate dehydrogenase E1-alpha deficiency (MIM#312170). (I) 0110 - This gene is associated with X-linked dominant disease. Affected males have also been reported with variants resulting in partial enzyme deficiency, however severe variants are presumed to be embryonically lethal (PMID: 22142326). (I) 0115 - Variants in this gene are known to have variable expressivity. Depending on the residual enzymatic activity resulting from the PDHA1 variant, the severity of phenotypic presentation can vary. Additionally, the severity in females is dependent on X-chromosome inactivation patterns (OMIM, PMID: 22142326). (I) 0201 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction with less than 1/3 of the protein sequence affected). However functional studies have shown that this variant causes a 30% reduction in detectable PDHA1 protein with no truncated protein observed and has therefore been shown to cause nonsense-mediated decay (PMID: 2378353). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0600 - Variant is predicted to truncate the annotated pyruvate dehydrogenase E1 component domain (DECIPHER). (I) 0701 - Other NMD predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been observed in over five individuals with pyruvate dehydrogenase E1-alpha deficiency (ClinVar, PMIDs: 2378353, 7887409, 25356417, 27144126). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1001- This variant has strong functional evidence supporting abnormal protein function. Functional studies in patient cells showed 22% of residual enzyme activity compared to WT (PMID: 25356417). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 12, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 06, 2024 | This sequence change creates a premature translational stop signal (p.Ser312Valfs*12) in the PDHA1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 79 amino acid(s) of the PDHA1 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with pyruvate dehydrogenase deficiency (PMID: 2378353, 8504306, 27144126). In at least one individual the variant was observed to be de novo. This variant is also known as 7-bp deletion at nucleotide 1032, 7-bp deletion at bp 927. ClinVar contains an entry for this variant (Variation ID: 10872). This variant disrupts a region of the PDHA1 protein in which other variant(s) (p.Glu358Glyfs*12) have been determined to be pathogenic (PMID: 1907799). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Oct 27, 2022 | The PDHA1 c.934_940del variant is classified as Pathogenic (PVS1_Strong, PS4, PM2) This PDHA1 c.934_940del variant is located in exon 10/11 and is predicted to cause a shift in the reading frame at codon 312 with a termination of the protein 12 amino acids downstream. This is not expected to undergo nonsense-mediated decay however this variant disrupts the last 79 amino acids which are critical for protein function (PVS1_Strong). This variant has been reported in at least 15 probands with a clinical presentation consistent with pyruvate dehydrogenase E1-alpha deficiency and has been confirmed denovo in a number of families (PMID#30842224, 33768920, 34863613, 2378353, 8504306, 27144126) (PS4). The variant has been reported in dbSNP (rs606231185), is reported as disease causing in the HGMD database (CD900295) is reported as pathogenic by other diagnostic laboratories (ClinVar#10872) and is absent from population databases (PM2). - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Apr 03, 2020 | - - |
not provided Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | May 01, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 23, 2022 | Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 79 amino acids are lost and replaced with 11 incorrect amino acids; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 8962591, 2378353, 30842224, 25356417, 1301207, 8504306, 27144126, 1907799, 7887408, 33768920, 34863613) - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at