Clinical Domain Working Groups

This expert panel is tasked with curating variants in ACADVL, which encodes very long chain acyl CoA dehydrogenase (VLCAD), by using modified ACMG variant classification rules specific to fatty acid oxidation disorders. VLCAD is a mitochondrial enzyme that catalyzes the first step of β-oxidation of long chain fatty acids (Aoyama et al., 1995).  Autosomal recessive pathological variants in ACADVL cause a condition known as VLCAD deficiency (VLCADD; OMIM #201475)  (Strauss et al., 1995). As a result of this disordered fatty acid metabolism, these patients accumulate high plasma levels of long chain acylcarnitine derivatives (C14:1).  VLCAD deficiency can have a wide clinical presentation that includes: a severe neonatal presentation with cardiomyopathy and a high mortality rate; childhood onset presenting with hypoketotic hypoglycemia with hepatic dysfunction; or as an adult-onset, exercised/ fasting induced myopathy presenting as rhabdomyolysis and myoglobinuria. ACADVL alleles tend to have genotypic/phenotypic correlations (Andresen et al., 1999).  The incidence of VLCADD is now estimated at 1:30,000 to 1:100,000 births (McHugh et al 2011).

Members of the current expert panel are experienced in different aspects of VLCAD deficiency and metabolic disease, including direct patient care, biochemical and molecular laboratory testing, and variant classification/curation.