ClinVar Miner

Submissions for variant NM_000532.5(PCCB):c.942C>A (p.Tyr314Ter) (rs572246667)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000186088 SCV000239112 pathogenic not provided 2016-10-11 criteria provided, single submitter clinical testing The Y314X nonsense variant in the PCCB gene has been reported previously in association with propionic acidemia (Lévesque et al. 2012). The Y314X variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. In summary, we interpret Y314X to be a pathogenic variant.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000186088 SCV000338743 pathogenic not provided 2016-01-05 criteria provided, single submitter clinical testing
Counsyl RCV000341685 SCV000800299 likely pathogenic Propionic acidemia 2018-06-04 criteria provided, single submitter clinical testing
Invitae RCV000341685 SCV001205750 pathogenic Propionic acidemia 2020-08-20 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Tyr314*) in the PCCB gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs572246667, ExAC 0.003%). This variant has been observed in an individual affected with propionic aciduria (PMID: 23430860). ClinVar contains an entry for this variant (Variation ID: 203882). Loss-of-function variants in PCCB are known to be pathogenic (PMID: 15464417). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000341685 SCV001360762 pathogenic Propionic acidemia 2019-06-03 criteria provided, single submitter clinical testing Variant summary: PCCB c.942C>A (p.Tyr314X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 1.2e-05 in 251454 control chromosomes (gnomAD). The variant, c.942C>A, has been reported in the literature in individuals affected with Propionic Acidemia (Levesque_2011, Sanchez-Alcudia_2012). These data indicate that the variant may be associated with disease. At least one publication, Sanchez-Alcudia_2012, reports PCC activity of this variant from patients fibroblasts treated with readthrough drugs was <10% of normal activity. Three ClinVar submissions from clinical diagnostic laboratories (last evaluation after 2014) cite the variant as likely pathogenic/pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Natera, Inc. RCV000341685 SCV001454522 pathogenic Propionic acidemia 2020-09-16 no assertion criteria provided clinical testing

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