ClinVar Miner

Submissions for variant NM_000282.4(PCCA):c.1284+1G>A (rs752761437)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000382350 SCV000329454 pathogenic not provided 2018-07-19 criteria provided, single submitter clinical testing The c.1284+1G>A pathogenic variant in the PCCA gene has been reported previously in the homozygous state in an individual with propionic acidemia (Vatanavicharn et al., 2014). This splice site variant destroys the canonical splice donor site in intron 14. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. The c.1284+1G>A variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.1284+1G>A as a pathogenic variant.
Illumina Clinical Services Laboratory,Illumina RCV000670117 SCV000914607 likely pathogenic Propionic acidemia 2018-10-25 criteria provided, single submitter clinical testing The PCCA c.1284+1G>A variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. The c.1284+1G>A variant has been reported in four studies in which it is found in four individuals with propionic academia, including in one in a homozygous state, in two in a compound heterozygous state, and in one in a heterozygous state (Campeau et al. 2001; Vatanavicharn et al. 2014; Cappuccio et al. 2016; Longo et al. 2017). Control data are unavailable for this variant, which is reported at a frequency of 0.00006 in the European (non-Finnish) population of the Genome Aggregation Database. RT-PCR analysis indicated that the c.1284+1G>A variant results in the skipping of exons 13 and 14 (Campeau et al. 2001). Based on the evidence and the potential impact of splice donor variants, the c.1284+1G>A variant is classified as likely pathogenic for propionic academia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000670117 SCV001201116 pathogenic Propionic acidemia 2020-10-14 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 14 of the PCCA gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs752761437, ExAC 0.001%). This variant has been observed in several individuals affected with propionic acidemia (PMID: 24464666, 27900673, 28712602). ClinVar contains an entry for this variant (Variation ID: 279863). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000670117 SCV001362340 pathogenic Propionic acidemia 2020-12-07 criteria provided, single submitter clinical testing Variant summary: PCCA c.1284+1G>A 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 canonical 5' splicing donor site. At least one publication confirmed this prediction by reporting RT-PCR analysis of patient derived mRNA that revealed skipping of exons 13 and 14 (V356_G428del73) (Campeau_2001). The variant allele was found at a frequency of 3.6e-05 in 251288 control chromosomes. c.1284+1G>A has been reported in the literature in individuals affected with Propionic Acidemia (example, Campeau_2001, Vatanavicharn_2014, Cappuccio_2016, Longo_2017). These data indicate that the variant is likely to 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 propionyl-CoA carboxylase activity in a patient with a compound heterozygous genotype (Longo_2017). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=3)/likely pathogenic(n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Counsyl RCV000670117 SCV000794933 pathogenic Propionic acidemia 2017-10-19 no assertion criteria provided clinical testing

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