ClinVar Genomic variation as it relates to human health

A Homozygote Missense variant c.494G>A in Exon 5 of the PCCB gene that results in the amino acid substitution p.Arg165Gln was identified. The observed variant has a maximum allele frequency of 0.00001/0.00 % in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic/LikelyPathogenic (ClinVar ID: 551146). This variant has previously been reported for Propionic acidemia by Stanescu S et al., 2021. Furthermore, functional studies demonstrate that this variant has a damaging effect on the gene or gene product (Pérez-Cerdá C et al., 2003). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines.

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 165 of the PCCB protein (p.Arg165Gln). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with propionic acidemia (PMID: 11749052, 12757933). ClinVar contains an entry for this variant (Variation ID: 551146). 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). This variant disrupts the p.Arg165 amino acid residue in PCCB. Other variant(s) that disrupt this residue have been observed in individuals with PCCB-related conditions (PMID: 8295402, 11749052, 12757933, 15949719, 20549364), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

Variant summary: PCCB c.494G>A (p.Arg165Gln) results in a conservative amino acid change located in the Acetyl-coenzyme A carboxyltransferase, N-terminal domain (IPR011762) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.9e-06 in 169706 control chromosomes (gnomAD). c.494G>A has been reported in the literature in individuals affected with Propionic Acidemia (e.g. Muro_2001, Perez-Cerda_2003). These data indicate that the variant is likely to be associated with disease. A different variant affecting the same codon has been classified as pathogenic by our lab (c.493C>T, p.Arg165Trp), supporting the critical relevance of codon 165 to PCCB protein function. At least one publication reports experimental evidence evaluating an impact on enzymatic function, finding that the variant results in <1% of wild type PCC activity (Perez-Cerda_2003). The following publications have been ascertained in the context of this evaluation (PMID: 11749052, 12559849). ClinVar contains an entry for this variant (Variation ID: 551146). Based on the evidence outlined above, the variant was classified as pathogenic.