Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Eurofins Ntd Llc |
RCV000078557 | SCV000110413 | pathogenic | not provided | 2012-07-18 | criteria provided, single submitter | clinical testing | |
| Gene |
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, |
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. |
| Victorian Clinical Genetics Services, |
RCV001218777 | SCV003921841 | pathogenic | Pyruvate dehydrogenase E1-alpha deficiency | 2022-07-14 | criteria provided, single submitter | clinical testing | 0102 - Loss of function is a known mechanism of disease in this gene and is associated with pyruvate dehydrogenase E1-alpha deficiency (MIM#312170). (I) 0110 - This gene is associated with X-linked dominant disease. Males can also be affected, however severe variants are presumed to be embryonically lethal (PMID: 22142326). (I) 0115 - Variants in this gene are known to have variable expressivity. Depending on the residual enzymatic activity resulting from the PDHA1 variant, the severity of phenotypic presentation can vary (OMIM, PMID: 22142326). (I) 0209 - Splice site variant proven to affect splicing of the transcript with uncertain effect on protein sequence. Functional studies using patient cDNA and in vitro minigene assays, have verified that this variant results in partial exon 5 skipping, where splicing is incomplete leaving residual wildtype transcript. This is predicted to result in a frameshift event and the protein p.(Arg141Alafs*11) (PMID: 18023225). (SP) 0253 - This variant is hemizygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as pathogenic, and observed in two de novo hemizygous individuals with pyruvate dehydrogenase, one of whom was mosaic for the variant. It has also been observed in a heterozygous individual with developmental delay and cerebellar ataxia (ClinVar, PMID: 18023225, PMID: 24718837, PMID: 31069529). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed, by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |