ClinVar Miner

Submissions for variant NM_000282.4(PCCA):c.937C>T (p.Arg313Ter) (rs138149179)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000032113 SCV000792407 pathogenic Propionyl-CoA carboxylase deficiency 2017-06-27 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000790683 SCV000225504 pathogenic not provided 2013-07-03 criteria provided, single submitter clinical testing
GeneReviews RCV000032113 SCV000055653 pathologic Propionyl-CoA carboxylase deficiency 2012-05-17 no assertion criteria provided curation Converted during submission to Pathogenic.
Institute of Medical Genetics and Genomics,Sir Ganga Ram Hospital RCV000032113 SCV000256838 pathogenic Propionyl-CoA carboxylase deficiency 2012-01-01 criteria provided, single submitter research
Integrated Genetics/Laboratory Corporation of America RCV000032113 SCV000919956 pathogenic Propionyl-CoA carboxylase deficiency 2018-05-25 criteria provided, single submitter clinical testing Variant summary: PCCA c.937C>T (p.Arg313X) 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 3.2e-05 in 276992 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in PCCA causing Propionic Acidemia (3.2e-05 vs 3.40e-03), allowing no conclusion about variant significance. The variant, c.937C>T, has been reported in the literature in multiple individuals affected with Propionic Acidemia (Kraus_2012, Gupta_2016). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, with complete absence of PCCA and very low levels of PCCB in a cultured liver cells homozygous for this variant (Chapman_PCCA_HMG_2016). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000032113 SCV000959042 pathogenic Propionyl-CoA carboxylase deficiency 2018-11-07 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg313*) in the PCCA gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs138149179, ExAC 0.02%). This variant has been observed in several individuals affected with PCCA-related conditions (PMID: 9887338, 22033733, 10101253, 27227689). ClinVar contains an entry for this variant (Variation ID: 38870). Loss-of-function variants in PCCA are known to be pathogenic (PMID: 15464417). For these reasons, this variant has been classified as Pathogenic.

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