Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV003153700 | SCV000637522 | uncertain significance | Catecholaminergic polymorphic ventricular tachycardia 1 | 2023-03-08 | criteria provided, single submitter | clinical testing | This variant is present in population databases (rs745576995, gnomAD 0.006%). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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: 463575). This variant has not been reported in the literature in individuals affected with RYR2-related conditions. This sequence change affects a donor splice site in intron 98 of the RYR2 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), however the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in RYR2 cause disease. |
| Ambry Genetics | RCV000617593 | SCV000736619 | uncertain significance | Cardiovascular phenotype | 2016-07-13 | criteria provided, single submitter | clinical testing | The c.14151+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 98 of the RYR2 gene. Based on data from ExAC, the A allele has an overall frequency of less than 0.01% (1/103038). This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice donor site; however, direct evidence is unavailable. 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. However, loss of function of RYR2 has not been clearly established as a mechanism of disease. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |