rs863224150
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_000284.4(PDHA1):c.506C>T(p.Ala169Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. A169A) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 23)
Consequence
PDHA1
NM_000284.4 missense
NM_000284.4 missense
Scores
12
3
1
Clinical Significance
Conservation
PhyloP100: 7.51
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 16 ACMG points.
PM1
?
In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000284.4
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.993
PP5
?
Variant X-19353169-C-T is Pathogenic according to our data. Variant chrX-19353169-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 214941.Status of the report is reviewed_by_expert_panel, 3 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PDHA1 | NM_000284.4 | c.506C>T | p.Ala169Val | missense_variant | 5/11 | ENST00000422285.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PDHA1 | ENST00000422285.7 | c.506C>T | p.Ala169Val | missense_variant | 5/11 | 1 | NM_000284.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 23
GnomAD3 genomes
?
Cov.:
23
GnomAD4 exome Cov.: 27
GnomAD4 exome
Cov.:
27
GnomAD4 genome ? Cov.: 23
GnomAD4 genome
?
Cov.:
23
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Pyruvate dehydrogenase E1-alpha deficiency Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 13, 2018 | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been reported in several individuals affected with PDHA1-related disease, and found to be de novo in one of these cases (PMID: 20002461, 21914562, Invitae). ClinVar contains an entry for this variant (Variation ID: 214941). This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with valine at codon 169 of the PDHA1 protein (p.Ala169Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. - |
Pathogenic, criteria provided, single submitter | clinical testing | Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | Oct 09, 2023 | - - |
Pyruvate dehydrogenase complex deficiency Pathogenic:1
Pathogenic, reviewed by expert panel | curation | ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen | May 06, 2021 | The c.506C>T variant in the PDHA1 gene is a missense variant occurring in a hotspot domain (aa position A169, located in α β heterodimer interface (PM1). This variant is absent from population databases (PM2). This variant has been reported in three individuals in the literature with presentations consistent with PDHA1-related disease. These three cases include two assumed de novo cases (PMID: 20002461 and PMID: 21914562), and one maternity confirmed de novo case via exome sequencing in PMID: 31683770 (PS2). PMID: 20002461 Western Blot studies showed reduced E1a, and Imbard et al 2011 PDC studies indicate activity <3rd percentile in fibroblasts (PP4). In silico predictors suggest a deleterious effect (REVEL score – 0.946; PP3). 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: (PM1, PM2, PS2, PP3, PP4). This was reviewed with the PDHA1 expert panel on 4/6/2021 and approved on 4/6/2021. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 14, 2021 | Not observed in large population cohorts (Lek et al., 2016); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); In silico analysis supports that this variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25525159, 20002461, 29445841, 21914562, 31683770) - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;.;.;H;.;.
MutationTaster
Benign
D;D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;D;D;D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D;D;D;D
Sift4G
Uncertain
D;D;D;D;D;D
Polyphen
1.0
.;.;.;D;.;.
Vest4
MutPred
Loss of helix (P = 0.1299);.;.;Loss of helix (P = 0.1299);.;Loss of helix (P = 0.1299);
MVP
MPC
2.4
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at