Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV001266517 | SCV001444692 | likely pathogenic | Inborn genetic diseases | 2020-01-21 | criteria provided, single submitter | clinical testing | The alteration results in an amino acid change:_x000D_ _x000D_ The c.499G>A (p.V167M) alteration is located in coding exon 5 of the PDHA1 gene. This alteration results from a G to A substitution at nucleotide position 499, causing the valine (V) at amino acid position 167 to be replaced by a methionine (M). The alteration is not observed in population databases: _x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the PDHA1 c.499G>A alteration was not observed, with coverage at this position. The alteration has been observed in affected individuals: _x000D_ _x000D_ This alteration was reported in two affected sisters with pyruvate dehydrogenase deficiency (Dahl, 1992). They had enzyme activity in fibroblasts at 1% and 7% of normal. The altered amino acid is conserved throughout evolution:_x000D_ _x000D_ The p.V167 amino acid is conserved in available vertebrate species. Functional analysis reveals a damaging effect of the amino acid alteration: _x000D_ _x000D_ In vitro functional analysis demonstrated that the p.V167M alteration had 2-4% of wild-type NADH activity. X ray crystallography found that this alteration results in displacement of the diphosphate tail of its coenzyme thiamine diphosphate and disordering of phosphorylation loops, resulting in loss of E1 catalytic efficiency (Whitley, 2018). The alteration is predicted deleterious by in silico modeling:_x000D_ _x000D_ The p.V167M alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. |
| Gene |
RCV001586100 | SCV001811041 | pathogenic | not provided | 2019-08-13 | criteria provided, single submitter | clinical testing | The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 29970614, 10679936, 1301207) |
| Centre de Biologie Pathologie Génétique, |
RCV002274173 | SCV002559017 | pathogenic | Neurodevelopmental delay | criteria provided, single submitter | clinical testing |