The relationship between PCCA and propionic acidemia (autosomal recessive) was evaluated using the ClinGen Clinical Validity Framework as of November 28th, 2018. PCCA encodes the alpha subunit of propionyl-CoA carboxylase (PCC). PCC is composed of 6 alpha-subunit and 6 beta-subunits. The beta subunit is encoded by PCCB. PCC, a mitochondrial biotin-dependent enzyme, catalyzes the carboxylation of propionyl-CoA, which is produced by the catabolism of cholesterol, valine, odd chain fatty acids, methionine, isoleucine and threonine, to methylmalonyl-CoA. Variants in PCCA were first reported in humans with this disease as early as 1996 (Campeau et al, Am J Hum Genet 59 (suppl 59): A1448; Richard et al, 1997, PMID 9385377). At least 9 unique variants (missense, nonsense, frameshift, and splice site) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level and experimental data. Variants in this gene have been reported in at least 8 probands in 4 publications (Richard et al, 1997, PMID 9385377; Yang et al, 2004, PMID 15059621; Vatanavicharn et al, 2014, PMID 24464666; Gupta et al, 2016, PMID 27227689). Many more patients have been reported in the literature, but the maximum score for genetic evidence has been reached. The mechanism for disease is biallelic loss of function. This gene-disease association is supported by the biochemical function of PCCA as a subunit of PCC (see Wongkittichote et al, 2017, PMID 29033250 for review), the finding that variants in the gene encoding the beta subunit of PCC (PCCB) cause propionic acidemia, genetic complementation studies (Gravel et al, 1997, PMID 195466), a null mouse model which recapitulates the biochemical features of propionic acidemia, and rescue of the phenotype in the null mouse model by a Pcca transgene (Miyazaki et al, 2001; PMID 11461925) and AAV8 Pcca gene transfer (Chandler et al, 2011; PMID 20950151). In summary, PCCA is definitively associated with propionic acidemia. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Aminoacidopathy Gene Curation Expert Panel.
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