ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: rs746286209
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Total submissions: 5
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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 2022-02-25 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 acceptor site, with three of them also predicting it creates a new cryptic exonic one. 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV000780576 SCV003442241 pathogenic Propionic acidemia 2023-12-07 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 5 of the PCCA gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PCCA are known to be pathogenic (PMID: 15464417). This variant is present in population databases (rs746286209, gnomAD 0.005%). Disruption of this splice site has been observed in individual(s) with propionic acidemia (PMID: 22033733). ClinVar contains an entry for this variant (Variation ID: 632933). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000780576 SCV004202884 pathogenic Propionic acidemia 2024-03-18 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000780576 SCV005630465 pathogenic Propionic acidemia 2024-02-29 criteria provided, single submitter clinical testing
Natera, Inc. RCV000780576 SCV002094961 pathogenic Propionic acidemia 2020-09-22 no assertion criteria provided clinical testing

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