Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000619338 | SCV000734940 | pathogenic | Cardiovascular phenotype | 2022-01-31 | criteria provided, single submitter | clinical testing | The c.1511-2A>T intronic pathogenic mutation results from an A to T substitution two nucleotides upstream from coding exon 7 in the PKP2 gene. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. In addition, another alteration impacting the same acceptor site c.1511-2A>G, has been detected in an individual with arrhythmogenic right ventricular cardiomyopathy (ARVC) and shown to result in skipping of exon 7 with a consequent shift in the reading frame (Groeneweg JA et al. Heart Rhythm. 2014;11:2010-7). Based on the supporting evidence, this alteration is classified as a disease-causing mutation. |
| ARUP Laboratories, |
RCV001001115 | SCV001158253 | pathogenic | Arrhythmogenic right ventricular dysplasia 9 | 2019-03-13 | criteria provided, single submitter | clinical testing | The PKP2 c.1511-2A>T variant (rs1453983744), to our knowledge, is not reported in the medical literature, but another variant at this nucleotide has been identified in an individual with arrhythmogenic right ventricular dysplasia/cardiomyopathy and was shown to alter splicing (Groeneweg 2014). The identified variant is reported in ClinVar (Variation ID: 518485) and is found in the general population with an allele frequency of 0.0004% (1/249,604 alleles) in the Genome Aggregation Database. This variant abolishes the canonical splice acceptor site of intron 6, which is likely to disrupt gene function. Based on available information, this variant is considered to be pathogenic. |
| Labcorp Genetics |
RCV001001115 | SCV001224673 | likely pathogenic | Arrhythmogenic right ventricular dysplasia 9 | 2022-09-23 | criteria provided, single submitter | clinical testing | 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. Studies have shown that disruption of this splice site results in skipping of exon 7 and introduces a premature termination codon (PMID: 25087486). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 518485). Disruption of this splice site has been observed in individual(s) with arrythmogenic right ventricular cardiomyopathy (ARVC) (PMID: 25087486). This variant is present in population databases (no rsID available, gnomAD 0.007%). This sequence change affects an acceptor splice site in intron 6 of the PKP2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. |
| Gene |
RCV001565433 | SCV001788774 | pathogenic | not provided | 2019-11-01 | criteria provided, single submitter | clinical testing | Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Has not been previously published as pathogenic or benign to our knowledge |
| Fulgent Genetics, |
RCV001001115 | SCV002811047 | likely pathogenic | Arrhythmogenic right ventricular dysplasia 9 | 2021-10-12 | criteria provided, single submitter | clinical testing |