ClinVar Miner

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

dbSNP: rs749908889
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Total submissions: 7
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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 2024-01-22 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg514*) in the PCCB gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 26 amino acid(s) of the PCCB protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individuals with proprionic acidemia (PMID: 11136555, 24059531, 27227689). ClinVar contains an entry for this variant (Variation ID: 217893). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects PCCB 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.
Fulgent Genetics, Fulgent Genetics RCV000235647 SCV002798016 pathogenic Propionic acidemia 2022-05-08 criteria provided, single submitter clinical testing
Baylor Genetics RCV000235647 SCV004205213 pathogenic Propionic acidemia 2023-07-04 criteria provided, single submitter clinical testing
Natera, Inc. RCV000235647 SCV002081500 pathogenic Propionic acidemia 2020-12-18 no assertion criteria provided clinical testing

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