Submissions for variant NM_000282.4(PCCA):c.223G>C (p.Ala75Pro)

gnomAD frequency: 0.00001  dbSNP: rs794727479

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000177029	SCV000228841	uncertain significance	not provided	2014-12-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000674930	SCV000800346	uncertain significance	Propionic acidemia	2018-06-04	criteria provided, single submitter	clinical testing
Invitae	RCV000674930	SCV003442163	uncertain significance	Propionic acidemia	2022-05-28	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 75 of the PCCA protein (p.Ala75Pro). This variant is present in population databases (rs794727479, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of propionic acidemia (PMID: 10329019, 27900673). This variant is also known as 148G->C (A50P). ClinVar contains an entry for this variant (Variation ID: 196245). 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. Experimental studies have shown that this missense change affects PCCA function (PMID: 12385775). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003230436	SCV003928913	uncertain significance	not specified	2023-04-05	criteria provided, single submitter	clinical testing	Variant summary: PCCA c.223G>C (p.Ala75Pro) results in a non-conservative amino acid change located in the N-terminal domain (IPR005481) 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 250608 control chromosomes (gnomAD). The variant, c.223G>C (aka c.148G>C / A50P) has been reported in the literature in at least two compound heterozygous individuals who were affected with a milder form of Propionic Acidemia (Campeau_1999, Cappuccio_2016). These data indicate that the variant may be associated with disease. A publication reported experimental evidence evaluating an impact on protein function, and demonstrated decreased enzyme activity (likely as a result of increased degradation), with a relatively high residual activity (15-30%) in a PCCA-deficient fibroblast system (Clavero_2002). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.