ClinVar Miner

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

gnomAD frequency: 0.00006  dbSNP: rs121964959
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000012791 SCV000631912 pathogenic Propionic acidemia 2024-01-28 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 410 of the PCCB protein (p.Arg410Trp). This variant is present in population databases (rs121964959, gnomAD 0.006%). This missense change has been observed in individuals with propionic acidemia (PMID: 8411997, 12007220, 22033733). ClinVar contains an entry for this variant (Variation ID: 12011). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PCCB protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects PCCB function (PMID: 12757933, 15890657, 15949719). 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
Baylor Genetics RCV000012791 SCV004205186 pathogenic Propionic acidemia 2023-10-16 criteria provided, single submitter clinical testing
OMIM RCV000012791 SCV000033031 pathogenic Propionic acidemia 1999-01-01 no assertion criteria provided literature only
GeneReviews RCV000012791 SCV000055678 not provided Propionic acidemia no assertion provided literature only
Natera, Inc. RCV000012791 SCV002081489 pathogenic Propionic acidemia 2021-01-15 no assertion criteria provided clinical testing

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