Submissions for variant NM_000282.4(PCCA):c.231+15C>T

gnomAD frequency: 0.00291  dbSNP: rs202049874

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000323167	SCV000382007	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.
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000514592	SCV000610982	likely benign	not provided	2017-05-11	criteria provided, single submitter	clinical testing
GeneDx	RCV000611978	SCV000730262	benign	not specified	2018-01-16	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000611978	SCV001448481	uncertain significance	not specified	2020-11-16	criteria provided, single submitter	clinical testing	Variant summary: PCCA c.231+15C>T alters a non-conserved nucleotide located close to a 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. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0031 in 250160 control chromosomes in the gnomAD database, including 6 homozygotes. This frequency is somewhat close to the estimated maximal expected allele frequency for a pathogenic PCCA variant causing Propionic Acidemia (0.0031 vs 0.0034), suggesting this variant might represent a benign polymorphism. To our knowledge, no occurrence of c.231+15C>T in individuals affected with Propionic Acidemia and no experimental evidence demonstrating its impact on protein function have been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign (n=2) or uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000323167	SCV001728102	benign	Propionic acidemia	2024-02-01	criteria provided, single submitter	clinical testing