Submissions for variant NM_000282.4(PCCA):c.782A>G (p.Glu261Gly)

gnomAD frequency: 0.00004  dbSNP: rs1169861687

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000538185	SCV000631908	likely pathogenic	Propionic acidemia	2024-11-04	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 261 of the PCCA protein (p.Glu261Gly). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individual(s) with autosomal recessive propionic acidemia and/or clinical features of PCCA-related conditions (PMID: 17051315, 27776753; internal data). ClinVar contains an entry for this variant (Variation ID: 459939). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt PCCA protein function with a positive predictive value of 95%. 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.
Counsyl	RCV000538185	SCV000793220	uncertain significance	Propionic acidemia	2017-08-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003230533	SCV003928912	uncertain significance	not specified	2023-04-24	criteria provided, single submitter	clinical testing	Variant summary: PCCA c.782A>G (p.Glu261Gly) 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 was absent in 250162 control chromosomes (gnomAD). c.782A>G has been reported in the literature in individuals affected with Propionic Acidemia (examples: Desviat_2006 and McCrory_2017). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=2) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Baylor Genetics	RCV000538185	SCV004202870	likely pathogenic	Propionic acidemia	2024-03-29	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000538185	SCV005630473	likely pathogenic	Propionic acidemia	2024-01-05	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000538185	SCV002094967	uncertain significance	Propionic acidemia	2021-06-04	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003942761	SCV004758442	likely pathogenic	PCCA-related disorder	2023-12-31	no assertion criteria provided	clinical testing	The PCCA c.782A>G variant is predicted to result in the amino acid substitution p.Glu261Gly. This variant has been reported in the compound heterozygous state with a second pathogenic variant in two presumably unrelated propionic acidemia patients (Table 2, Desviat et al., 2006. PubMed ID: 17051315; Table1, McCrory et al., 2017. PubMed ID: 27776753). This variant is reported in 0.0065% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as likely pathogenic.