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

dbSNP: rs121964957

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000032112	SCV002243651	pathogenic	Propionic acidemia	2023-05-21	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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. Experimental studies have shown that this missense change affects PCCA function (PMID: 20493181). 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. ClinVar contains an entry for this variant (Variation ID: 38869). This missense change has been observed in individual(s) with propionic acidemia (PMID: 20493181). This variant is present in population databases (rs121964957, gnomAD 0.0009%). 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).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000032112	SCV003922615	likely pathogenic	Propionic acidemia	2023-03-24	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 (gnomAD). c.862A>G has been reported in the literature in at least one homozygous individual affected with Propionic Acidemia (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 (Lianou_2010, Gallego-Villar_2013). One ClinVar submitter has assessed the variant since 2014: the variant was classified as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics	RCV000032112	SCV004202846	likely pathogenic	Propionic acidemia	2023-09-26	criteria provided, single submitter	clinical testing
GeneReviews	RCV000032112	SCV000055652	not provided	Propionic acidemia		no assertion provided	literature only