Submissions for variant NM_000284.4(PDHA1):c.1142_1145dup (p.Trp383fs) (rs606231189)

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
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	Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
CeGaT Praxis fuer Humangenetik Tuebingen	RCV000199126	SCV001249126	pathogenic	not provided	2020-06-01	criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,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
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