ClinVar Miner

Submissions for variant NM_000532.5(PCCB):c.1540C>T (p.Arg514Ter) (rs749908889)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Institute of Medical Genetics and Genomics,Sir Ganga Ram Hospital RCV000235647 SCV000256889 pathogenic Propionic acidemia criteria provided, single submitter research
Counsyl RCV000235647 SCV000797713 likely pathogenic Propionic acidemia 2018-02-07 criteria provided, single submitter clinical testing
Invitae RCV000235647 SCV001219898 pathogenic Propionic acidemia 2019-03-26 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the PCCB gene (p.Arg514*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 26 amino acids of the PCCB protein. This variant is present in population databases (rs749908889, ExAC 0.001%). This variant has been observed in several individuals affected with proprionic acidemia (PMID: 27227689, 11136555, 24059531). ClinVar contains an entry for this variant (Variation ID: 217893). This variant has been reported to affect PCCB protein function (PMID: 11136555). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000235647 SCV001623158 pathogenic Propionic acidemia 2021-05-13 criteria provided, single submitter clinical testing Variant summary: PCCB c.1540C>T (p.Arg514X) 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 4e-06 in 251236 control chromosomes. c.1540C>T has been reported in the literature in individuals affected with Propionic Acidemia (e.g. Sanchez-Alcudia_2012, Al-Jasmi_2016). These data indicate that the variant may be associated with disease. At least one publication reports that full-length protein is not detectable for PCCB with p.Arg514* (Sanchez-Alcudia_2012). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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