Metabolic Enzymes & Rare Disorders

Intronic variant in the histidine-catabolism gene AMDHD1 that influences circulating 25-hydroxyvitamin D levels through a pathway outside classical vitamin D metabolism

Most common VLCAD deficiency variant in the US, causing mild late-onset disease with exercise-induced rhabdomyolysis and fasting intolerance due to partial loss of mitochondrial fatty acid oxidation

Synonymous variant in the 3′ UTR of ANKRD30A associated with altered circulating sphingolipid levels in a metabolomics genome-wide association study

Pathogenic missense variant in acyl-CoA dehydrogenase family member 9, causing loss of ACAD enzyme activity and impaired mitochondrial complex I assembly; homozygous or compound heterozygous carriers develop ACAD9 deficiency with cardiomyopathy, lactic acidosis, and exercise intolerance; riboflavin-responsive in a subset of patients

Pathogenic missense variant abolishing GALNS enzyme activity; biallelic carriers develop Mucopolysaccharidosis IVA (Morquio syndrome A), a severe skeletal lysosomal storage disorder; heterozygous carriers are clinically unaffected

Pathogenic missense variant in muscle glycogen phosphorylase causing post-translational protein loss; homozygous or compound heterozygous carriers develop McArdle disease (glycogen storage disease type V), the second most common PYGM pathogenic allele in Spanish populations

Pathogenic missense variant in the MCAD enzyme causing a temperature-sensitive reduction in fatty acid oxidation capacity; homozygous individuals retain substantial residual activity and are likely asymptomatic, but compound heterozygotes pairing this allele with a more severe ACADM variant are at risk for MCAD deficiency

Rare pathogenic missense variant in the ACADM gene (p.Ser245Leu) causing medium-chain acyl-CoA dehydrogenase (MCAD) deficiency when inherited in biallelic form — resulting in impaired oxidation of medium-chain fatty acids and risk of hypoketotic hypoglycemia during fasting or illness

Pathogenic missense variant in the MCAD enzyme causing medium-chain acyl-CoA dehydrogenase deficiency — an autosomal recessive disorder of mitochondrial fatty acid oxidation leading to hypoketotic hypoglycemia and metabolic crisis during fasting or illness

Most common European allele for glutaric acidemia type 1; complete loss of GCDH enzyme activity when inherited with a second pathogenic allele, causing striatal necrosis during febrile crises if untreated

Intronic variant in sialyltransferase ST6GALNAC3 associated with higher circulating vitamin D-binding protein levels through altered glycosylation of DBP

Pathogenic missense variant in the y+LAT1 cationic amino acid transporter; homozygosity abolishes intestinal and renal transport of lysine, arginine, and ornithine, causing lysinuric protein intolerance

Most common LCHAD deficiency variant; homozygosity causes severe mitochondrial long-chain fatty acid oxidation failure with cardiomyopathy, rhabdomyolysis, and neuropathy; carrier mothers of affected fetuses risk maternal HELLP syndrome and acute fatty liver of pregnancy

Pathogenic missense variant in D-bifunctional protein (p.Gly16Ser) disrupting peroxisomal fatty acid beta-oxidation; homozygous or compound heterozygous carriers develop either severe neonatal DBP deficiency or the milder Perrault syndrome (sensorineural hearing loss and ovarian insufficiency); heterozygous carriers are unaffected

Missense variant in the enoyl-CoA hydratase domain of D-bifunctional protein; biallelic inheritance causes peroxisomal fatty acid oxidation failure with severe neonatal neurological disease; heterozygous carriers are clinically unaffected but carry reproductive risk

Pathogenic missense variant in glutaryl-CoA dehydrogenase; homozygosity causes glutaric acidemia type 1, an organic acidemia leading to striatal necrosis and movement disorders if untreated; heterozygotes are unaffected carriers relevant for family planning

Finnish founder splice acceptor mutation abolishing y+LAT1 transport activity at the SLC7A7 intron 6 splice site, causing lysinuric protein intolerance when homozygous — a multisystem recessive disorder of cationic amino acid transport

Common missense variant in ACADS encoding short-chain acyl-CoA dehydrogenase; the A allele (Gly209Ser) reduces SCAD enzyme activity and is associated with mildly elevated butyrylcarnitine (C4) on newborn screening, but is classified as benign to likely-benign and is not a cause of clinical SCAD deficiency

Pathogenic missense variant in glucose-6-phosphatase catalytic subunit 1 causing glycogen storage disease type Ia; the most common G6PC1 disease allele in European and Ashkenazi Jewish populations, with complete abolition of enzyme activity when homozygous; heterozygous carriers are clinically unaffected but carry reproductive risk

Likely-pathogenic GCK missense variant (p.Phe316Tyr) causing glucokinase loss of function; heterozygous carriers have a raised glucose set point producing lifelong mild fasting hyperglycemia consistent with maturity-onset diabetes of the young type 2 (MODY2/GCK-MODY)

Pathogenic missense variant in ACADVL encoding VLCAD; heterozygous carriers are asymptomatic, while biallelic carriers develop VLCAD deficiency—a fatty acid oxidation disorder with phenotypes ranging from neonatal cardiomyopathy to exercise-induced rhabdomyolysis

Rare stop-gain variant in CPT2 abolishing carnitine palmitoyltransferase II, the enzyme that shuttles long-chain fatty acids into mitochondria; carriers face elevated risk of exercise-induced rhabdomyolysis

Intronic regulatory variant in IVD (isovaleryl-CoA dehydrogenase) associated with altered IVD expression, isovalerylcarnitine levels, and modest pulmonary fibrosis susceptibility

Intronic variant adjacent to the UGT1A gene cluster; C allele tags elevated serum bilirubin and is associated with lower risk of cardiovascular disease and type 2 diabetes through bilirubin's antioxidant actions.

Rare splice acceptor variant disrupting intron 9 of D-bifunctional protein; biallelic carriers develop peroxisomal fatty acid oxidation failure causing either severe neonatal DBP deficiency or Perrault syndrome; heterozygous carriers are clinically unaffected but carry reproductive risk

Heteroplasmic missense variant in the mitochondrially encoded ND5 subunit of complex I, causing variable-penetrance mitochondrial disease including Leigh syndrome, MELAS, and Leber optic atrophy depending on mutation load.

Pathogenic start-codon variant in muscle glycogen phosphorylase; homozygous or compound heterozygous carriers develop McArdle disease (glycogen storage disease type V), with exercise intolerance, myoglobinuria, and the second-wind phenomenon

Most common alpha-1 antitrypsin deficiency variant causing protein misfolding, lung disease, and liver disease

The most common OTC point mutation, abolishing ornithine transcarbamylase enzyme activity and causing X-linked urea cycle deficiency; hemizygous males face neonatal hyperammonemic crisis while heterozygous females have variable partial deficiency

The most common pathogenic PMM2 variant, causing phosphomannomutase 2 deficiency and PMM2-CDG (congenital disorder of glycosylation type Ia) when inherited in compound heterozygous form; homozygous R141H is embryonic lethal

Nonsense mutation in argininosuccinate lyase introducing a premature stop codon that abolishes the fourth step of the urea cycle; a founder allele in Arab populations causing argininosuccinic aciduria, the second most common urea cycle disorder — homozygotes develop neonatal hyperammonemia and require lifelong arginine supplementation, protein restriction, and hepatic surveillance

Nonsense variant in the aldolase B gene creating a premature stop codon at position 204; pathogenic for hereditary fructose intolerance (HFI), an autosomal recessive disorder causing toxic fructose-1-phosphate accumulation in liver and kidneys when fructose is ingested

Pathogenic missense variant in argininosuccinate lyase that reduces urea cycle enzyme activity to ~12% of normal, causing argininosuccinic aciduria when inherited in biallelic form; heterozygous carriers are typically asymptomatic but carry the allele at reproductive risk

Pathogenic missense variant in the ACAD9 complex I assembly factor causing severe mitochondrial energy failure; the original riboflavin-responsive ACAD9 allele first identified by Gerards et al. 2011, producing hypertrophic cardiomyopathy, exercise intolerance, and lactic acidosis in homozygous or compound heterozygous carriers.

Pathogenic ACADVL frameshift deletion causing premature protein truncation; heterozygous carriers are healthy but carry reproductive risk, while biallelic disruption causes VLCAD deficiency requiring lifelong dietary management

Intronic 5-bp indel (AAAGG) in the IVD regulatory region that is the primary functional variant controlling IVD expression; the derived deletion allele drives higher enzyme activity and lower isovalerylcarnitine, and is enriched in East Asian populations under positive selection

Pathogenic missense in the y+LAT1 cationic amino acid transporter causing lysinuric protein intolerance, a recessive disorder of dibasic amino acid transport with hyperammonemia, protein aversion, and multi-organ complications.

Frameshift deletion in the OTC gene that eliminates ornithine transcarbamylase activity; causes severe neonatal hyperammonemia in hemizygous males and variable hyperammonemia in heterozygous females, the most common urea cycle disorder

Missense variant in CPT2 that destabilizes the carnitine palmitoyltransferase 2 enzyme, impairing mitochondrial uptake of long-chain fatty acids and causing recurrent exercise- and fever-induced rhabdomyolysis in homozygotes; the most common cause of adult myopathic CPT II deficiency in Europeans.

Missense variant in the COPII vesicle coat protein SEC23A, associated with circulating 25-hydroxyvitamin D levels through proposed effects on secretory pathway efficiency

Second most common pathogenic PMM2 allele (p.Phe119Leu); in compound heterozygosity with R141H produces the classic PMM2-CDG phenotype with cerebellar hypoplasia, intellectual disability, and multi-organ glycosylation failure; homozygosity is likely lethal