| DLD mutation | Nucleotide change / alias | Structural / biochemical effect | Reported clinical phenotype | Key notes / population context |
|---|---|---|---|---|
| G194C | c.685G>T; historically also reported as p.G229C in precursor numbering | Common pathogenic variant; relatively minor local structural changes near substitution site, with nearby cofactor-binding residues largely preserved compared with more disruptive variants | Often associated with comparatively milder disease and later presentation; recurrent hepatic failure/liver-predominant phenotype reported; DLD deficiency overall can include lactic acidosis and neurologic involvement | Ashkenazi Jewish founder mutation; carrier frequency reported as ~1:94 in Ashkenazi Jews; also reported in Arab Muslim patients (pqac-00000022, pqac-00000025, pqac-00000027, pqac-00000028) |
| D444V | mature-protein numbering; interface-domain variant | Dimer-interface mutation; enhanced ROS-generating and proteolytic/diaphorase moonlighting activities; promotes oxidative damage to mitochondrial targets | Severe DLD deficiency presentations, including liver disease and metabolic decompensation; contributes to severe clinical course through oxidative injury mechanisms | Reported in Ashkenazi Jewish patients; widely studied as a pathogenic interface mutation (pqac-00000030, pqac-00000031, pqac-00000033, pqac-00000027) |
| R460G | — | Dimer-interface mutation; enhances diaphorase activity and ROS production | Severe multisystem disorder of infancy | Included among severe interface mutations linked to oxidative damage and profound infantile disease (pqac-00000022, pqac-00000030, pqac-00000033) |
| R447G | — | Dimer-interface mutation; perturbs solvent-accessible channel leading to active site; enhances ROS, and in some studies proteolytic activity | Severe multisystem disorder / severe infantile disease | Structural and functional evidence supports interface destabilization as pathogenic mechanism (pqac-00000022, pqac-00000030, pqac-00000033) |
| E340K | — | Mutation associated with altered cryptic activities; enhanced diaphorase activity and ROS production | Severe multisystem disorder of infancy | Disease severity likely reflects both enzyme deficiency and oxidative-damage mechanisms (pqac-00000028, pqac-00000030, pqac-00000033) |
| P453L | — | Most deleterious structural change among analyzed variants; active site extensively compromised | Severe phenotype expected/associated with markedly impaired enzyme function | Identified as especially disruptive in crystallographic analysis (pqac-00000002, pqac-00000022) |
| G426E | — | Dimer-interface variant; alters local charge distribution and introduces dynamics at substitution site; minor structural changes but functionally important | Pathogenic DLD deficiency; severity variable | Illustrates that even subtle structural changes at interface can impair multienzyme-complex function (pqac-00000002, pqac-00000022) |
| I445M | — | Dimer-interface variant; perturbs H+/H2O channel to active site | Pathogenic DLD deficiency; associated with impaired catalysis | Channel perturbation provides a structural explanation for dysfunction (pqac-00000002, pqac-00000004) |
| I12T | — | Unstable protein retaining dimeric form but with markedly compromised forward/reverse LADH activity and reduced FAD affinity | Pathogenic DLD deficiency | N-terminal variant showing severe biochemical impairment without the same structural class as interface mutants (pqac-00000004, pqac-00000022) |
| M326V | — | Protein instability, functional dimer disassembly, significant FAD loss, virtually undetectable catalytic activity | Pathogenic DLD deficiency | Demonstrates loss-of-stability mechanism (pqac-00000004, pqac-00000022) |
| G101del | — | Protein instability, dimer disassembly, significant FAD loss, virtually undetectable catalytic activity | Pathogenic DLD deficiency; reported in myopathic / Leigh-related clinical literature | Strong example of instability-driven deficiency (pqac-00000004, pqac-00000027, pqac-00000028) |
| I318T | — | Minor conformational perturbations with residual enzymatic activity retained | Pathogenic DLD deficiency with residual function | Supports genotype–biochemistry gradient rather than uniform complete loss of function (pqac-00000004, pqac-00000022) |
| I358T / I353T | I358T in structural literature; I353T reported clinically in one case | Minor conformational perturbations / residual activity for I358T; I353T reported as disease-causing in Leigh syndrome case report | I353T associated with episodic encephalopathy, lactic acidosis, hypoglycemia, learning disability, and Leigh syndrome; I358T supports a residual-activity model | Numbering may differ between reports due to precursor vs mature protein conventions (pqac-00000004, pqac-00000023, pqac-00000024) |
| R482G | c.1444A>G | Novel pathogenic variant in highly conserved region | Neurological deterioration beginning at birth/early infancy, hyperlactatemia, hypotonia/rigidity/choreoathetoid movements, early death | Reported in siblings with atypical α-ketoglutarate dehydrogenase deficiency / DLD deficiency phenotype (pqac-00000025, pqac-00000029) |
| G136del | — | Previously reported pathogenic deletion | Reported with DLD deficiency; in compound heterozygosity with I353T in a patient with episodic encephalopathy, lactic acidosis, hypoglycemia, and Leigh syndrome | Established disease-causing mutation in prior literature (pqac-00000023, pqac-00000024) |


*Table: This table summarizes disease-causing human DLD variants, linking structural/biochemical effects to reported clinical phenotypes. It is useful for functional annotation because it connects specific residues and mechanistic defects to recognizable metabolic and neurologic presentations.*