ClinVar Miner

Submissions for variant NM_000532.5(PCCB):c.562G>A (p.Gly188Arg) (rs746102997)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000674578 SCV000799938 likely pathogenic Propionic acidemia 2018-05-14 criteria provided, single submitter clinical testing
Invitae RCV000674578 SCV000961644 likely pathogenic Propionic acidemia 2018-10-30 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 188 of the PCCB protein (p.Gly188Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs746102997, ExAC 0.01%). This variant has been observed in individuals affected with propionic acidemia (PMID: 12559849, 22033733, 23053474, 27900673). ClinVar contains an entry for this variant (Variation ID: 558327). Experimental studies have shown that this missense change impairs enzymatic activity (PMID: 23053474). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000674578 SCV001360763 pathogenic Propionic acidemia 2019-10-04 criteria provided, single submitter clinical testing Variant summary: PCCB c.562G>A (p.Gly188Arg) results in a non-conservative amino acid change located in the Acetyl-coenzyme A carboxyltransferase, N-terminal domain (IPR011762) 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 4e-06 in 251438 control chromosomes (gnomAD). c.562G>A has been reported in the literature in multiple individuals (compound heterozygotes or homozygotes) affected with Propionic Acidemia (Perez_2003, Desviat_2006, Kraus_2012, Gallego-Villar_2012, Cappuccio_2016, Tummolo_2018). These data indicate that the variant is very likely to be associated with disease. In vitro study showed that this variant had residual activity at 13% of WT levels (Gallego-Villar_2012). Two ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV001268006 SCV001446578 likely pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing

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