ClinVar Miner

Submissions for variant NM_000532.5(PCCB):c.1228C>T (p.Arg410Trp) (rs121964959)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000012791 SCV000631912 pathogenic Propionic acidemia 2016-12-13 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 410 of the PCCB protein (p.Arg410Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs121964959, ExAC 0.006%). This variant has been reported in the literature in individuals affected with propionic acidemia as homozygous (PMID: 8411997) and as a compound heterozygous (PMID: 12007220, 22033733). ClinVar contains an entry for this variant (Variation ID: 12011). Experimental studies have shown that this missense change disrupts protein function leading to reduced enzymatic activity (PMID: 15949719, 12757933, 15890657). For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000012791 SCV000789286 likely pathogenic Propionic acidemia 2017-01-17 criteria provided, single submitter clinical testing
Mendelics RCV000012791 SCV001136613 pathogenic Propionic acidemia 2019-05-28 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000012791 SCV001339066 pathogenic Propionic acidemia 2020-03-13 criteria provided, single submitter clinical testing Variant summary: PCCB c.1228C>T (p.Arg410Trp) results in a non-conservative amino acid change located in the Acetyl-coenzyme A carboxyltransferase, C-terminal (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 2.8e-05 in 251032 control chromosomes (gnomAD). c.1228C>T has been reported in the literature in multiple individuals (both homozygous and compound heterozygous) affected with Propionic Acidemia (e.g. Chloupkova_2002, McCrory_2017, Kraus_2012, Gravel_1994). These data indicate that the variant is very likely to be associated with disease. In functional studies, the variant was found to have reduced enzymatic activity (Kraus_2012, Perez-Cedra_2003). Three ClinVar submitters (evaluation after 2014) cite the variant as likely pathogenic/pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic
OMIM RCV000012791 SCV000033031 pathogenic Propionic acidemia 1999-01-01 no assertion criteria provided literature only
GeneReviews RCV000012791 SCV000055678 pathologic Propionic acidemia 2012-05-17 no assertion criteria provided curation Converted during submission to Pathogenic.

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