Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Eurofins Ntd Llc |
RCV000407596 | SCV000345972 | uncertain significance | not provided | 2016-09-16 | criteria provided, single submitter | clinical testing | |
| Victorian Clinical Genetics Services, |
RCV003225059 | SCV003922003 | likely pathogenic | Pyruvate dehydrogenase E1-alpha deficiency | 2021-05-06 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely Pathogenic. Following criteria are met: 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 disease. Both males and females can be affected to varying degrees (OMIM). (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. Additionally, the severity in females is dependent on X-chromosome inactivation patterns (OMIM, PMID: 22142326). (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to threonine. (I) 0253 - This variant is hemizygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated dehydrogenase E1 component (NCBI, PDB). (I) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. An alternative change to valine at the same residue has previously been classified as likely pathogenic (ClinVar). (SP) 0808 - Previous reports of pathogenicity for this variant are conflicting. The variant has previously been reported in one hemizygous individual with an intermittant milder form of PDHC deficiency, in whom inheritance information and family history was unobtainable, however it has also been classified as a VUS in ClinVar (PMID: 22142326). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1006 - Clinically accredited laboratory assay shows abnormal function of product not specific to the gene. Pyruvate dehydrogenase activity in cultured fibroblasts from this individual measured moderately below the normal range (Oxford Regional Genetics Laboratories). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |