Submissions for variant NM_000532.5(PCCB):c.882C>T (p.Pro294=)

gnomAD frequency: 0.00080  dbSNP: rs142730126

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000281740	SCV000441257	uncertain significance	Propionic acidemia	2018-01-12	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.
GeneDx	RCV001705512	SCV000523275	likely benign	not provided	2020-09-08	criteria provided, single submitter	clinical testing
Invitae	RCV000281740	SCV001013375	likely benign	Propionic acidemia	2024-01-29	criteria provided, single submitter	clinical testing
Laboratory of Inherited Metabolic Diseases, Research centre for medical genetics	RCV000281740	SCV001482013	uncertain significance	Propionic acidemia	2021-02-17	criteria provided, single submitter	research	PM2, BS3
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000439688	SCV001737659	likely benign	not specified	2021-05-30	criteria provided, single submitter	clinical testing	Variant summary: PCCB c.882C>T (p.Pro294Pro) alters a non-conserved nucleotide located in the exonic splice region close to the canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing, although a slight weakening of the canonical splice donor site is predicted. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00093 in 251454 control chromosomes in the gnomAD database, including 2 homozygotes. This frequency is not significantly higher than expected for a pathogenic variant in PCCB causing Propionic Acidemia (0.00093 vs 0.0025), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.882C>T in individuals affected with Propionic Acidemia and no experimental evidence demonstrating its impact on protein function have been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=3, VUS, n=2). Based on the evidence outlined above, the variant was classified as likely benign.
CeGaT Center for Human Genetics Tuebingen	RCV001705512	SCV004155588	likely benign	not provided	2023-05-01	criteria provided, single submitter	clinical testing	PCCB: BP4, BP7, BS2
Natera, Inc.	RCV000281740	SCV001460372	likely benign	Propionic acidemia	2019-12-13	no assertion criteria provided	clinical testing