ClinVar Miner

Submissions for variant NM_000282.4(PCCA):c.862A>G (p.Arg288Gly)

dbSNP: rs121964957
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000032112 SCV002243651 pathogenic Propionic acidemia 2024-02-12 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 288 of the PCCA protein (p.Arg288Gly). This variant is present in population databases (rs121964957, gnomAD 0.0009%). This missense change has been observed in individual(s) with propionic acidemia (PMID: 20493181). ClinVar contains an entry for this variant (Variation ID: 38869). 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 PCCA protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PCCA function (PMID: 20493181). This variant disrupts the p.Arg288 amino acid residue in PCCA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 27227689; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000032112 SCV003922615 likely pathogenic Propionic acidemia 2024-06-21 criteria provided, single submitter clinical testing Variant summary: PCCA c.862A>G (p.Arg288Gly) results in a non-conservative amino acid change located in the Carbamoyl-phosphate synthetase large subunit-like, ATP-binding domain (IPR005479) 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 251350 control chromosomes. c.862A>G has been reported in the literature in at least 1 homozygous individual affected with Propionic Acidemia (example, Lianou_2010). These data indicate that the variant may be associated with disease. The variant was found to result in reduced enzymatic activity, with the most pronounced effect reported as 3.2% residual activity (example, Lianou_2010, Gallego-Villar_2013). The following publications have been ascertained in the context of this evaluation (PMID: 23053474, 20493181). ClinVar contains an entry for this variant (Variation ID: 38869). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics RCV000032112 SCV004202846 likely pathogenic Propionic acidemia 2023-11-29 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000032112 SCV005630475 likely pathogenic Propionic acidemia 2024-06-23 criteria provided, single submitter clinical testing
GeneReviews RCV000032112 SCV000055652 not provided Propionic acidemia no assertion provided literature only

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