ClinVar Miner

Submissions for variant NM_000532.5(PCCB):c.337C>T (p.Arg113Ter) (rs186031457)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000255741 SCV000322302 pathogenic not provided 2018-10-01 criteria provided, single submitter clinical testing The R113X variant in the PCCB gene has been reported previously as heterozgyous with a second heterozygous PCCB variant in multiple individuals with proprionic acidemia (Kraus et al., 2012). Functional studies of the R113X variant in fibroblasts did not detect any full-length PCCB protein (Sánchez-Alcudia et al. 2012). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Although not observed as homozygous, the R113X variant is observed in 2/17248 (0.012%) alleles from individuals of East Asian background and 7/246256 (0.0028%) total alleles in large population cohorts (Lek et al., 2016). We interpret R113X as a pathogenic variant.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000613658 SCV000711738 pathogenic Propionic acidemia 2015-12-08 criteria provided, single submitter clinical testing The p.Arg113X variant in PCCB has been reported in one individual with propionic acidemia (Brosch 2008) and has been identified in 3/66722 of European chromosom es by the Exome Aggregation Consortium (ExAC,; db SNP rs186031457). This nonsense variant leads to a premature termination codon a t position 113, which is predicted to lead to a truncated or absent protein. Los s of function of the PCCB gene is an established disease mechanism in individual s with propionic acidemia. In summary, this variant meets our criteria to be cla ssified as pathogenic for propionic acidemia in an autosomal recessive manner ba sed upon its predicted impact on protein function.
Counsyl RCV000613658 SCV000796994 pathogenic Propionic acidemia 2018-01-08 criteria provided, single submitter clinical testing
Baylor Genetics RCV000613658 SCV001162958 pathogenic Propionic acidemia criteria provided, single submitter clinical testing
Invitae RCV000613658 SCV001218029 pathogenic Propionic acidemia 2019-07-12 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg113*) in the PCCB gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs186031457, ExAC 0.02%). This variant has been observed in several individuals affected with propionic acidemia (PMID: 22033733). ClinVar contains an entry for this variant (Variation ID: 265422). Loss-of-function variants in PCCB are known to be pathogenic (PMID: 15464417). For these reasons, this variant has been classified as Pathogenic.
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000613658 SCV001251866 pathogenic Propionic acidemia 2020-05-03 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000613658 SCV001360761 pathogenic Propionic acidemia 2019-01-07 criteria provided, single submitter clinical testing Variant summary: PCCB c.337C>T (p.Arg113X) 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 2.8e-05 in 246256 control chromosomes (gnomAD). c.337C>T has been reported in the literature in multiple individuals affected with Propionic Acidemia (Brosch_2008, Cheng_2017, Kraus_2012, Sanchez-Alcudia_2012). 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 (Kraus_2012, Sanchez-Alcudia_2012). The most pronounced variant effect results in <10% of normal activity. Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Natera, Inc. RCV000613658 SCV001454517 pathogenic Propionic acidemia 2020-09-16 no assertion criteria provided clinical testing

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