The relationship between PCCB and propionic acidemia (autosomal recessive) was evaluated using the ClinGen Clinical Validity Framework as of November 28th, 2018. PCCB encodes the beta subunit of propionyl-CoA carboxylase (PCC). PCC is composed of 6 alpha-subunit and 6 beta-subunits. The alpha subunit is encoded by PCCA. 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 PCCB were first reported in humans with this disease as early as 1990 (Tahara et al, PMID 2154743). At least 13 unique variants (missense, nonsense, frameshift, splice site, and large deletion) 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 14 probands in 4 publications (Tahara et al, 1990, PMID 2154743; Tahara et al, 1993, PMID 8411997; Chiu et al, 2014, PMID 24863100; 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 PCCB as a subunit of PCC (see Wongkittichote et al, 2017, PMID 29033250 for review), the finding that variants in the gene encoding the alpha subunit of PCC (PCCA) cause propionic acidemia, genetic complementation studies (Gravel et al, 1997; PMID 195466; RodrÃguez-Pombo et al, 2005, PMID 15949719), and rescue of PCC function in fibroblasts from patients with propionic acidemia by PCCB cDNA (Lamhonwah et al, 1994, PMID 8188292). In summary, PCCB 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.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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