Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV002032886 | SCV002111941 | pathogenic | Pyruvate dehydrogenase E3 deficiency | 2023-08-21 | criteria provided, single submitter | clinical testing | This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 353 of the DLD protein (p.Ile353Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with dihydrolipoamide dehydrogenase deficiency (PMID: 23290025, 27896107, 33306821). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as I318T. ClinVar contains an entry for this variant (Variation ID: 1346904). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt DLD protein function. For these reasons, this variant has been classified as Pathogenic. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV002032886 | SCV003928786 | likely pathogenic | Pyruvate dehydrogenase E3 deficiency | 2023-04-28 | criteria provided, single submitter | clinical testing | Variant summary: DLD c.1058T>C (p.Ile353Thr) results in a non-conservative amino acid change located in the FAD/NAD(P)-binding domain (IPR023753) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251324 control chromosomes. c.1058T>C has been reported in the literature as a biallelic compound heterozygous genotype in individuals affected with Dihydrolipoamide Dehydrogenase Deficiency (MSUD Type 3) (example, Quinonez_2014, Quinonez_2013, Wu_2020, Staretz-Chacham_2021). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 27896107, 23290025, 34684524, 33306821). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| Baylor Genetics | RCV002032886 | SCV004193958 | likely pathogenic | Pyruvate dehydrogenase E3 deficiency | 2024-01-02 | criteria provided, single submitter | clinical testing |