ClinVar Miner

Submissions for variant NM_000532.5(PCCB):c.683C>T (p.Pro228Leu) (rs374722096)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000507200 SCV000604601 pathogenic not specified 2016-09-12 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000413250 SCV000232071 pathogenic not provided 2015-04-20 criteria provided, single submitter clinical testing
GeneDx RCV000413250 SCV000490698 pathogenic not provided 2016-06-10 criteria provided, single submitter clinical testing The P228L variant in the PCCB gene has been reported previously in association with propionic acidemia (Gravel et al. 1994). Expression analysis of P228L found that this variants results in an increased alpha/beta subunit ratio compared to wild-type propionyl-CoA carboxylase indicating that P228L interferes with the correct assembly and/or subsequent stability of the assembled propionyl-CoA carboxylase holoenyzme (Chloupkova et al. 2002). Furthermore, P228L was not observed with any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, it occurs at a position that is conserved across species, and in silico analysis predicts that P228L is probably damaging to the protein structure/function.. In summary, we interpret P228L to be a pathogenic variant.
Invitae RCV000179767 SCV000631918 pathogenic Propionyl-CoA carboxylase deficiency 2018-12-31 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 228 of the PCCB protein (p.Pro228Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs374722096, ExAC 0.009%). This variant has been reported in individuals affected with propionic acidemia (PMID: 8023851, 12007220, 15949719, Invitae). Skin fibroblasts from these patients showed 1-5% residual PCCB enzymatic activity compared with WT controls. Experimental studies using protein extracted from bacterial cultures show that this variant reduces PCCB enzymatic activity (PMID: 12007220). For these reasons, this variant has been classified as Pathogenic.

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