Submissions for variant NM_000532.5(PCCB):c.1309G>A (p.Gly437Ser)

gnomAD frequency: 0.00001  dbSNP: rs1349202366

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001037425	SCV001200836	pathogenic	Propionic acidemia	2023-09-10	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 836321). This missense change has been observed in individual(s) with propionic acidemia (PMID: 22033733; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (no rsID available, gnomAD 0.009%). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 437 of the PCCB protein (p.Gly437Ser).
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV001037425	SCV003920312	pathogenic	Propionic acidemia	2022-08-15	criteria provided, single submitter	clinical testing	This variant has been reported in the literature in the homozygous or compound heterozygous state in at least 2 individuals with propionic acidemia (Kraus 2012 PMID: 22033733; Adhikari 2020 PMID: 32778825); it has also been identified to be in trans with a pathogenic variant in at least 1 affected individual at an external laboratory (Invitae data, ClinVar Variation ID: 836321). This variant is present in the Genome Aggregation Database (Highest reported MAF: 0.009% [3/34588]; https://gnomad.broadinstitute.org/variant/3-136046485-G-A?dataset=gnomad_r2_1); please note, disease-causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status, and/or variable expressivity. Evolutionary conservation and computational predictive tools strongly suggest that this variant may impact the protein. In summary, this variant is classified as pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003413821	SCV004114485	uncertain significance	PCCB-related condition	2023-09-07	criteria provided, single submitter	clinical testing	The PCCB c.1309G>A variant is predicted to result in the amino acid substitution p.Gly437Ser. This variant was reported in the homozygous state in a suspected propionic acidemia patient (Kraus et al 2012. PubMed ID: 22033733). This variant was also reported in a set of individuals with inborn errors of metabolism; however, no clinical information was provided and the variant zygosity or presence of another variant was not specified (Table S5, Adhikari et al. 2020. PubMed ID: 32778825). We have also observed this variant internally, in the heterozygous state, in an individual who was also heterozygous for a PCCB loss-of-function variant (Internal Data). This variant is reported in 0.0087% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-136046485-G-A). In ClinVar, this variant has been interpreted as likely pathogenic and pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/836321/). This variant is interpreted as likely pathogenic.
Baylor Genetics	RCV001037425	SCV004205206	likely pathogenic	Propionic acidemia	2023-07-26	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001037425	SCV001454529	likely pathogenic	Propionic acidemia	2020-09-16	no assertion criteria provided	clinical testing