Submissions for variant NM_000284.4(PDHA1):c.1142_1145dup (p.Trp383fs)

dbSNP: rs606231189

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen	RCV001753411	SCV001994852	pathogenic	Pyruvate dehydrogenase complex deficiency	2021-05-06	reviewed by expert panel	curation	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.
GeneDx	RCV000199126	SCV000252046	pathogenic	not provided	2013-06-04	criteria provided, single submitter	clinical testing	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).
Ambry Genetics	RCV000624104	SCV000742395	pathogenic	Inborn genetic diseases	2017-05-11	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000199126	SCV001249126	pathogenic	not provided	2020-06-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000011627	SCV001251622	pathogenic	Pyruvate dehydrogenase E1-alpha deficiency	2020-02-04	criteria provided, single submitter	clinical testing	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.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000011627	SCV001364304	pathogenic	Pyruvate dehydrogenase E1-alpha deficiency	2020-05-15	criteria provided, single submitter	research	ACMG codes: PVS1, PS2, PS4M, PM2, PP5
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000199126	SCV001762076	likely pathogenic	not provided	2021-06-17	criteria provided, single submitter	clinical testing
Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital	RCV000199126	SCV002818269	pathogenic	not provided	2022-12-17	criteria provided, single submitter	clinical testing
Invitae	RCV000011627	SCV003444629	pathogenic	Pyruvate dehydrogenase E1-alpha deficiency	2022-08-01	criteria provided, single submitter	clinical testing	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.
OMIM	RCV000011627	SCV000031859	pathogenic	Pyruvate dehydrogenase E1-alpha deficiency	1993-04-01	no assertion criteria provided	literature only
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	RCV000011627	SCV001133088	likely pathogenic	Pyruvate dehydrogenase E1-alpha deficiency	2019-09-26	no assertion criteria provided	clinical testing
Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)	RCV000011627	SCV003927824	pathogenic	Pyruvate dehydrogenase E1-alpha deficiency	2023-04-01	no assertion criteria provided	clinical testing