ClinVar Miner

Submissions for variant NM_000282.4(PCCA):c.1899+4_1899+7del (rs794727334)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000176154 SCV000227764 pathogenic not provided 2014-12-02 criteria provided, single submitter clinical testing
Invitae RCV001066663 SCV001231679 likely pathogenic Propionic acidemia 2019-12-15 criteria provided, single submitter clinical testing This sequence change falls in intron 21 of the PCCA gene. It does not directly change the encoded amino acid sequence of the PCCA protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with propionic acidemia (PMID: 10780784, 9385377). This variant is also known as 1824IVS+3del4 and IVS21+3del4 in the literature. ClinVar contains an entry for this variant (Variation ID: 195560). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 15235904, 9385377). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001066663 SCV001431999 likely pathogenic Propionic acidemia 2020-08-14 criteria provided, single submitter clinical testing Variant summary: PCCA c.1899+4_1899+7delAGTA alters a 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, in functional studies, the variant resulted in increased exon skipping (Richard_1997, Clavero_2004). Clavero et al also report that small levels of (3-16%) of correctly spliced transcript were also seen in patient homozygous for the variant, which was sufficient to permit the development of a mild phenotype (Clavero_2004). The variant allele was found at a frequency of 5.9e-05 in 152424 control chromosomes (gnomAD). c.1899+4_1899+7delAGTA has been reported in the literature in individuals affected with Propionic Acidemia (Richard_1997, Kraus_2012). These data indicate that the variant is likely to be associated with disease. One ClinVar submitter (evaluation after 2014) cite the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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