Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000522063 | SCV000616817 | likely pathogenic | not provided | 2017-09-06 | criteria provided, single submitter | clinical testing | The K298R variant has previously been reported in an individual with propionic acidemia who was also heterozygous for a large deletion of PCCA, although the phase of these variants was not reported (Gallego-Villar et al., 2013). Functional analysis of K298R found that it is associated with 1.6% residual enzyme activity compared to wild-type (Gallego-Villar et al., 2013). The K298R variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. In summary, we interpret K298R to be a likely pathogenic variant. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000664657 | SCV003844841 | pathogenic | Propionic acidemia | 2023-02-16 | criteria provided, single submitter | clinical testing | Variant summary: PCCA c.893A>G (p.Lys298Arg) results in a conservative amino acid change located in the Carbamoyl-phosphate synthetase large subunit-like, ATP-binding domain (IPR005479), the ATP-grasp fold domain (IPR011761), and the Biotin carboxylation domain (IPR011764) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251204 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.893A>G has been reported in the literature in at least one individual affected with Propionic Acidemia (e.g., Gallego-Villar_2013, Cammarata-Scalisi_2019, Shchelochkov_2019). At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant leads to a severe reduction in PCC activity (1.6% of wild-type activity) in vitro (e.g., Gallego-Villar_2013). Three ClinVar submitters (evaluation after 2014) have cited the variant, with two labs classifying the variant as likely pathogenic and one lab classifying it as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic. |
| Baylor Genetics | RCV000664657 | SCV004202875 | pathogenic | Propionic acidemia | 2023-06-17 | criteria provided, single submitter | clinical testing | |
| Counsyl | RCV000664657 | SCV000788657 | uncertain significance | Propionic acidemia | 2017-10-03 | no assertion criteria provided | clinical testing | |
| Natera, |
RCV000664657 | SCV001455847 | likely pathogenic | Propionic acidemia | 2020-09-16 | no assertion criteria provided | clinical testing |