ClinVar Miner

Submissions for variant NM_000284.4(PDHA1):c.1159_1162dup (p.Ser388Ter)

dbSNP: rs863224156
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000195575 SCV000252047 pathogenic not provided 2022-07-28 criteria provided, single submitter clinical testing Nonsense variant predicted to result in protein truncation, as the last 3 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29756269, 21846590, 7981697, 21914562, 32472546, 32005694, 32348839)
Labcorp Genetics (formerly Invitae), Labcorp RCV001853190 SCV002183992 pathogenic Pyruvate dehydrogenase E1-alpha deficiency 2021-03-07 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Ser388*) in the PDHA1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 3 amino acid(s) of the PDHA1 protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with pyruvate dehydrogenase complex deficiency (PMID: 7981697, 21914562, 29756269, 21846590). In at least one individual the variant was observed to be de novo. This variant is also known as 1159AAGT. ClinVar contains an entry for this variant (Variation ID: 214947). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV002354555 SCV002620693 pathogenic Inborn genetic diseases 2020-09-11 criteria provided, single submitter clinical testing The c.1159_1162dupAAGT variant, located in coding exon 11 of the PDHA1 gene, results from a duplication of AAGT at nucleotide position 1159, causing a translational frameshift with a predicted alternate stop codon (p.S388*). This alteration has been reported in male subjects with pyruvate dehydrogenase deficiency (Chun K et al. Am. J. Hum. Genet., 1995 Mar;56:558-69; Imbard A et al. Mol. Genet. Metab., 2011 Dec;104:507-16; Cameron JM et al. Am. J. Med. Genet. A, 2004 Nov;131:59-66; Seyda A et al. Hum. Mol. Genet., 2000 Apr;9:1041-8; Naito E et al. Hum. Mol. Genet., 1994 Jul;3:1193-4; Dong HL et al. CNS Neurosci Ther, 2019 01;25:21-29). This alteration occurs at the 3' terminus of thePDHA1 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 3 AA of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Seyda A et al. Hum. Mol. Genet., 2000 Apr;9:1041-8). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

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