ClinVar

Description

Variant summary: DLD c.1463C>T (p.Pro488Leu) results in a non-conservative amino acid change located in the Pyridine nucleotide-disulphide oxidoreductase, dimerisation domain (IPR004099) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.6e-05 in 251298 control chromosomes. c.1463C>T has been reported in the literature in a compound heterozygous individual affected with Dihydrolipoamide Dehydrogenase Deficiency (MSUD Type 3) whose cells had 6% of the E3 activity of control cells, but normal citrate synthase activity (Liu_1993). This report suggests the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The purified protein results in <10% dihydrolipoamide dehydrogenase activity compared to the WT (e.g. Ambrus_2011). The following publications have been ascertained in the context of this evaluation (PMID: 21558426, 16770810, 8506365, 23290025, 9934985). ClinVar contains an entry for this variant (Variation ID: 11965). Based on the evidence outlined above, the variant was classified as likely pathogenic.