NM_000284.4:c.1142_1145dupATCA
Variant summary
Our verdict is Pathogenic. Variant got 9 ACMG points: 9P and 0B. PVS1_ModeratePM2PS2PP4
This summary comes from the ClinGen Evidence Repository: 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. LINK:https://erepo.genome.network/evrepo/ui/classification/CA121215/MONDO:0019169/014
Frequency
Consequence
NM_000284.4 frameshift
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| PDHA1 | NM_000284.4 | c.1142_1145dupATCA | p.Trp383SerfsTer6 | frameshift_variant | Exon 11 of 11 | ENST00000422285.7 | NP_000275.1 |
Ensembl
Frequencies
GnomAD3 genomes
GnomAD4 exome Cov.: 30
GnomAD4 genome
ClinVar
Submissions by phenotype
Pyruvate dehydrogenase E1-alpha deficiency Pathogenic:7
ACMG codes: PVS1, PS2, PS4M, PM2, PP5 -
PVS1, PS4, PM2, PS2 -
- -
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. -
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. -
- -
- -
not provided Pathogenic:3
- -
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). -
- -
Inborn genetic diseases Pathogenic:1
- -
Pyruvate dehydrogenase complex deficiency Pathogenic:1
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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at