Submissions for variant NM_000532.5(PCCB):c.82C>G (p.Leu28Val)

gnomAD frequency: 0.00026  dbSNP: rs141137691

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000405424	SCV000441242	uncertain significance	Propionic acidemia	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000405424	SCV001421447	uncertain significance	Propionic acidemia	2022-09-01	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 28 of the PCCB protein (p.Leu28Val). This variant is present in population databases (rs141137691, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with PCCB-related conditions. ClinVar contains an entry for this variant (Variation ID: 343457). 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 not expected to disrupt PCCB protein function. 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.
GeneDx	RCV001795957	SCV002496238	uncertain significance	not provided	2024-07-23	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis indicates that this missense variant does not alter protein structure/function
Ambry Genetics	RCV002520085	SCV003633844	uncertain significance	Inborn genetic diseases	2021-09-15	criteria provided, single submitter	clinical testing	The c.82C>G (p.L28V) alteration is located in exon 1 (coding exon 1) of the PCCB gene. This alteration results from a C to G substitution at nucleotide position 82, causing the leucine (L) at amino acid position 28 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV000405424	SCV004235727	uncertain significance	Propionic acidemia	2023-04-06	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001795957	SCV002034061	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001795957	SCV002037624	likely benign	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000405424	SCV002081462	uncertain significance	Propionic acidemia	2019-10-28	no assertion criteria provided	clinical testing