ClinVar Miner

Submissions for variant NM_000532.5(PCCB):c.990dup (p.Glu331Ter) (rs786200983)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000153647 SCV000700506 pathogenic not provided 2017-03-02 criteria provided, single submitter clinical testing
GeneDx RCV000153647 SCV000239123 pathogenic not provided 2017-02-24 criteria provided, single submitter clinical testing The c.990dupT variant in the PCCB gene has been reported previously in both the homozygous state and compound heterozygous state with another PCCB gene variant in individuals with propionic acidemia (Pérez et al., 2010; Kraus et al., 2012). The duplication results in the replacement of a Glutamic acid codon with a Stop codon at position 331, denoted p.Glu331Ter. The c.990dupT variant is not observed at a significant frequency in the NHLBI Exome Sequencing Project (Exome Variant Server). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. In summary, we interpret c.990dupT as pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000173704 SCV000697273 pathogenic Propionyl-CoA carboxylase deficiency 2017-07-24 criteria provided, single submitter clinical testing Variant summary: The PCCB c.990dupT (p.Glu331X) 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.This variant was found in 6/121406 control chromosomes at a frequency of 0.0000494, which does not exceed the estimated maximal expected allele frequency of a pathogenic PCCB variant (0.0025). Multiple publications have cited the variant in affected compound heterozygote and homozygote individuals. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000173704 SCV000631920 pathogenic Propionyl-CoA carboxylase deficiency 2018-09-04 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Glu331*) in the PCCB gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs763069936, ExAC 0.06%). This variant has been reported in the homozygous state or in combination with other known pathogenic variants in the PCCB gene in individuals affected with propionic aciduria (PMID: 12559849, 22033733, 23430860, 24516753). ClinVar contains an entry for this variant (Variation ID: 167423). Loss-of-function variants in PCCB are known to be pathogenic (PMID: 15464417). For these reasons, this variant has been classified as Pathogenic.

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