ClinVar Miner

Submissions for variant NM_000282.4(PCCA):c.231+1G>C (rs972937270)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000664756 SCV000788766 pathogenic Propionic acidemia 2017-01-03 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000664756 SCV000917965 pathogenic Propionic acidemia 2018-02-19 criteria provided, single submitter clinical testing Variant summary: PCCA c.231+1G>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 5' splicing donor site. One publication reports experimental evidence that this variant determines exons 3-4 skipping (Desviat_2009). The variant allele was found at a frequency of 1.4e-05 in 276520 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in PCCA causing Propionic Acidemia (1.4e-05 vs 0.0034), allowing no conclusion about variant significance. The c.231+1G>C variant has been reported in the literature in individuals affected with Propionic Acidemia (Desviat_2006, Desviat_2009). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity. No 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.
Invitae RCV000664756 SCV001422156 pathogenic Propionic acidemia 2019-11-15 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 3 of the PCCA gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with propionic acidemia (PMID: 22033733, 25047749). ClinVar contains an entry for this variant (Variation ID: 550113). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 17051315). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PCCA are known to be pathogenic (PMID: 15464417). For these reasons, this variant has been classified as Pathogenic.

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