Submissions for variant NM_000532.5(PCCB):c.1172T>C (p.Phe391Ser)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002646825	SCV002979249	pathogenic	Propionic acidemia	2024-10-15	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 391 of the PCCB protein (p.Phe391Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of propionic acidemia and/or propionic acidemia (PMID: 33981581; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1942487). 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 PCCB protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002646825	SCV004020708	likely pathogenic	Propionic acidemia	2023-06-05	criteria provided, single submitter	clinical testing	Variant summary: PCCB c.1172T>C (p.Phe391Ser) results in a non-conservative amino acid change to a highly conserved residue (HGMD) located in the Acetyl-coenzyme A carboxyltransferase, C-terminal (IPR011763) of the encoded protein sequence. Another missense variant affecting this residue (p.Phe391Cys) has been classified as likely pathogenic by a ClinVar submitter. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251416 control chromosomes (gnomAD). c.1172T>C has been reported in the literature in individuals affected with Propionic Acidemia who were compound heterozygous with another pathogenic variant (Mobarak_2021). These data indicate that the variant is likely associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 33981581). One clinical diagnostic laboratory has submitted a clinical-significance assessment for this variant to ClinVar after 2014, and classified it as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.