ClinVar Miner

Submissions for variant NM_000532.5(PCCB):c.1495C>T (p.Arg499Ter) (rs202247820)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000032127 SCV000794409 pathogenic Propionyl-CoA carboxylase deficiency 2017-09-26 criteria provided, single submitter clinical testing
GeneReviews RCV000032127 SCV000055682 pathologic Propionyl-CoA carboxylase deficiency 2012-05-17 no assertion criteria provided curation Converted during submission to Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000032127 SCV000697270 pathogenic Propionyl-CoA carboxylase deficiency 2017-05-23 criteria provided, single submitter clinical testing Variant summary: The PCCB c.1495C>T (p.Arg499X) variant results in a premature termination codon, predicted to cause a truncated or absent PCCB protein due to nonsense mediated decay, which are commonly known mechanisms for disease. A functional study, Chloupkova_2000 indicates that the variant impedes protein function and stability. This variant is absent in 121316 control chromosomes (ExAC). Multiple publications have cited the variant in affected compound heterozygous individuals, predominantly of Japan origin. In addition, multiple databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000032127 SCV000960094 pathogenic Propionyl-CoA carboxylase deficiency 2018-10-29 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the PCCB gene (p.Arg499*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 41 amino acids of the PCCB protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with propionic acidemia (PMID: 8295402, 12007220, 12189489). ClinVar contains an entry for this variant (Variation ID: 38878). Experimental studies have shown that this truncation leads to PCCB protein instability and loss of enzymatic activity (PMID: 11136555). For these reasons, this variant has been classified as Pathogenic.

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