Submissions for variant NM_000282.4(PCCA):c.415-2A>C (rs746286209)

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780576	SCV000917967	pathogenic	Propionic acidemia	2021-02-16	criteria provided, single submitter	clinical testing	Variant summary: PCCA c.415-2A>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 3-prime acceptor site. Three predict the variant creates a new 3-prime acceptor site. The variant allele was found at a frequency of 8e-06 in 250414 control chromosomes (gnomAD). c.415-2A>C has been reported in the literature in compound heterozygosity with another pathogenic variant in at least one individual affected with Propionic Acidemia (e.g. Kraus_2012). This study also reported that the allele bearing c.415-2A>C is either not transcribed or the mRNA is degraded, and the authors measured approximately 2% of wild-type PCC activity in the patient's cells. No other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.