Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Center for Human Genetics Laboratory, |
RCV000770934 | SCV000853289 | pathogenic | Pyruvate dehydrogenase complex deficiency | 2018-11-28 | criteria provided, single submitter | clinical testing | Functional Studies: Activity of the pyruvate dehydrogenase complex (PDC) in patient's cultured skin fibroblasts was below the reference range of concurrent and prior controls, corresponding to 15% of the control mean. Activity of dihydrolipoamide dehydrogenase (the E3 component of PDC and another mitochondrial reference enzyme) was within the reference range (135% of prior control mean). The ratio of PDC/E3 was below the reference range (12% of the control mean). Protein yield was at the low end of the reference range. These results were consistent with PDC deficiency. Summary of ACMG/AMP VUS Evidence: PM2: Absent from controls: Variant not found in gnomAD database. PP3: Multiple lines of computational evidence support a deleterious effect on the gene or gene product: In-silico predictor results are summarized here: 1)SIFT, PROVEAN, LRT, MetaLR, MetaSVM, FATHMM: Deleterious. 2)Mutation Assessor: Medium Impact. 3)MutationTaster: Disease Causing. 4)PolyPhen-2 HDIV & HVAR: Probably damaging. 5)REVEL ensemble pathogenicity score: 0.853 [Sensitivity 0.38, Specificity 0.98] PM5: Novel missense change at the same amino acid residue where a different missense change determined to be pathogenic has been seen before: An adult patient with PDC deficiency and peripheral neuropathy with a different mutation at the same amino acid (p.E75A) was shown to also have decreased activity in cultured fibroblasts, and patient was reported to be partially responsive to thiamine supplementation clinically and also in vitro by using cultured fibroblasts. (PMID: 18559466) PS3: Well-established functional studies show a deleterious effect: Patient's PDC assay results are reported as "Patient #80" in supplementary table 1 of published sensitivity and variability in various PDC enzyme assays from the Center for Inherited Disorders of Energy Metabolism (CIDEM) (PMID: 28918066) PS2: De novo (paternity and maternity confirmed): Both parents confirmed to be negative for this PDHA1 variant. In summary, the PDHA1:c.225G>T meets ACMG/AMP criteria to be classified as pathogenic, based on absence from controls, computational and predictive data, functional and de novo evidence. (PP3, PM5, PS3, PS2) |