ClinVar Miner

Submissions for variant NM_000284.4(PDHA1):c.483C>T (p.Tyr161=) (rs398123300)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000078557 SCV000110413 pathogenic not provided 2012-07-18 criteria provided, single submitter clinical testing
GeneDx RCV000078557 SCV000582183 pathogenic not provided 2019-12-20 criteria provided, single submitter clinical testing In vitro transcription assays demonstrate this variant disrupts an exonic splice enhancer (ESE), leading to skipping of exon 5 and introducing a frameshift starting with codon Arginine 141, changing this amino acid to an Alanine residue, and creating a premature Stop codon at position 11 of the new reading frame. This framshift is predicted to cause loss of normal protein function through protein truncation (Boichard et al., 2007).; Not observed in large population cohorts (Lek et al., 2016; McVean et al., 2012; Exome Variant Server); This variant is associated with the following publications: (PMID: 20002125, 18023225)
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001218777 SCV001366976 pathogenic Pyruvate dehydrogenase E1-alpha deficiency 2019-10-03 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS2,PS3,PM2.
Invitae RCV001218777 SCV001390679 pathogenic Pyruvate dehydrogenase E1-alpha deficiency 2019-06-09 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 5 of the PDHA1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with PDHE1α deficiency (PMID: 20002125, 24718837) and has been observed to be de novo in individuals affected with PDHE1α deficiency (PMID: 18023225). ClinVar contains an entry for this variant (Variation ID: 92770). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 18023225). For these reasons, this variant has been classified as Pathogenic.

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