Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Women's Health and Genetics/Laboratory Corporation of America, |
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 | 2022-10-14 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 550113). Disruption of this splice site has been observed in individuals with propionic acidemia (PMID: 22033733, 25047749). This variant is present in population databases (no rsID available, gnomAD 0.008%). This sequence change affects a donor splice site in intron 3 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). |
Myriad Genetics, |
RCV000664756 | SCV002060237 | likely pathogenic | Propionic acidemia | 2021-11-11 | criteria provided, single submitter | clinical testing | NM_000282.3(PCCA):c.231+1G>C is a canonical splice site variant classified as likely pathogenic in the context of PCCA-related propionic acidemia. c.231+1G>C has been observed in cases with relevant disease (PMID: 22033733, 25047749). Functional assessments of this variant are available in the literature (PMID: 19157943). Internal structural analysis of the variant is supportive of pathogenicity. c.231+1G>C has been observed in population frequency databases (gnomAD: NFE 0.01%). In summary, NM_000282.3(PCCA):c.231+1G>C is a canonical splice site variant that has both functional and internal structural support for pathogenicity and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. |
Baylor Genetics | RCV000664756 | SCV004202849 | pathogenic | Propionic acidemia | 2023-09-21 | criteria provided, single submitter | clinical testing | |
Natera, |
RCV000664756 | SCV002094958 | pathogenic | Propionic acidemia | 2021-09-28 | no assertion criteria provided | clinical testing |