ClinVar Miner

Submissions for variant NM_000532.5(PCCB):c.1534C>T (p.Arg512Cys) (rs186710233)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000032128 SCV000943118 pathogenic Propionic acidemia 2019-12-16 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 512 of the PCCB protein (p.Arg512Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs186710233, ExAC 0.001%). This variant has been observed to occur as homozygous or in combination with other PCCB variants in several individuals affected with propionic acidemia (PMID: 9683601, 23053474, 22033733, 24863100, 15059621). This variant has also been observed to segregate with propionic acidemia in a family (PMID: 22033733). ClinVar contains an entry for this variant (Variation ID: 38879). This variant has been reported to affect PCCB protein stability and assembly (PMID: 12757933, 11136555, 11749052). For these reasons, this variant has been classified as Pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV001090671 SCV001246347 pathogenic not provided 2018-08-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000032128 SCV001554544 pathogenic Propionic acidemia 2021-03-31 criteria provided, single submitter clinical testing Variant summary: PCCB c.1534C>T (p.Arg512Cys) results in a non-conservative amino acid change located in the Acetyl-coenzyme A carboxyltransferase, C-terminal domain (IPR011763) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251254 control chromosomes. c.1534C>T has been reported in the literature in multiple individuals affected with Propionic Acidemia (example, Chloupkova_2000, Yang_2004, Kraus_2012, Chiu_2014). These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal enzyme specific activity (example, Chloupkova_2000, Perez-Cedra_2003). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. At-least one submitters cites overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneReviews RCV000032128 SCV000055683 pathologic Propionic acidemia 2012-05-17 no assertion criteria provided curation Converted during submission to Pathogenic.
Natera, Inc. RCV000032128 SCV001454530 pathogenic Propionic acidemia 2020-09-16 no assertion criteria provided clinical testing

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