Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000033216 | SCV001406862 | pathogenic | Pyruvate dehydrogenase E3 deficiency | 2024-01-18 | criteria provided, single submitter | clinical testing | This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 479 of the DLD protein (p.Asp479Val). 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: 10448086, 21996136, 23995961). This variant is also known as p.Asp444Val. ClinVar contains an entry for this variant (Variation ID: 40186). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects DLD function (PMID: 17404228, 21558426, 21930696, 27544700). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. |
| Victorian Clinical Genetics Services, |
RCV000033216 | SCV002767867 | pathogenic | Pyruvate dehydrogenase E3 deficiency | 2020-10-19 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from aspartic acid to valine (exon 13). (N) 0252 - Variant is homozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (P) 0600 - Variant is located in an annotated domain or motif (pyridine nucleotide-disulphide oxidoreductase, dimerisation domain; PDB). (N) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as homozygous in multiple patients with deficiency in dihydrolipoamide dehydrogenase (DLD) and/or pyruvate dehydrogenase complex (PDHc) (PMIDs: 10448086, 21996136, 23995961). (P) 1001 - Strong functional evidence supporting abnormal protein function. DLD activity level was reduced in patients (PMIDs: 10448086, 23995961). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign |
| Revvity Omics, |
RCV000033216 | SCV003828918 | likely pathogenic | Pyruvate dehydrogenase E3 deficiency | 2022-09-05 | criteria provided, single submitter | clinical testing | |
| Hadassah Hebrew University Medical Center | RCV000033216 | SCV004099502 | pathogenic | Pyruvate dehydrogenase E3 deficiency | criteria provided, single submitter | clinical testing | ||
| Center for Genomic Medicine, |
RCV000033216 | SCV004804871 | pathogenic | Pyruvate dehydrogenase E3 deficiency | 2024-03-17 | criteria provided, single submitter | research | |
| OMIM | RCV000033216 | SCV000057068 | pathogenic | Pyruvate dehydrogenase E3 deficiency | 2007-04-10 | no assertion criteria provided | literature only |