Clinical Domain Working Groups

Propionic acidemia (PA) and methylmalonic acidemia (MMA) are inborn errors of branched chain amino acid metabolism; these disorders were combined into VCEP due to overlapping disease characteristics, genetic causes (e.g., autosomal recessive inheritance), and overlapping community of experts. Both conditions result in an inability to break down certain proteins and fats, leading to toxic levels of organic acids in the body. Symptoms most often present in infancy and can include vomiting, hypotonia, lethargy, and failure to thrive. Patients with these organic acidopathies can experience complications such as brain injury, coma, and death. MMA and PA both result from defective metabolism of coenzyme A-activated carboxylic acids by the mitochondria. The current members of the expert panel are experienced in clinical care, biochemical and molecular laboratory interpretation and testing, variant classification, and functional assay development."

The ClinGen PA/MMA VCEP will specify the genes causing propionic acidemia (PA) and methylmalonic acidemia (MMA). The VCEP plans to curate in a tiered approach, in order of frequency and clinical importance, variants associated with propionic acidemia and methylmalonic acidemia due to methylmalonyl-CoA mutase deficiency and genes associated with disorders included in the RUSP (recommended universal (newborn) screening panel), with the same NBS marker C3-carnitine, and in which elevated methylmalonic acid is one of the biochemical features. 

Tier 1: MMUT, MMACHC, PCCA, PCCB
Tier 2: MMAA, MMAB, MMADHC, MCEE