Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV002526388 | SCV000541681 | uncertain significance | Catecholaminergic polymorphic ventricular tachycardia 1 | 2022-12-02 | criteria provided, single submitter | clinical testing | 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RYR2 protein function. ClinVar contains an entry for this variant (Variation ID: 404205). This variant has not been reported in the literature in individuals affected with RYR2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with asparagine, which is neutral and polar, at codon 2960 of the RYR2 protein (p.Ile2960Asn). |
| Ambry Genetics | RCV002446770 | SCV002682783 | uncertain significance | Cardiovascular phenotype | 2023-05-30 | criteria provided, single submitter | clinical testing | The p.I2960N variant (also known as c.8879T>A), located in coding exon 61 of the RYR2 gene, results from a T to A substitution at nucleotide position 8879. The isoleucine at codon 2960 is replaced by asparagine, an amino acid with dissimilar properties. This alteration has been reported in a pediatric cardiomyopathy cohort (Ware SM et al. Am J Hum Genet, 2022 Feb;109:282-298). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Stanford Center for Inherited Cardiovascular Disease, |
RCV000786204 | SCV000924923 | uncertain significance | not provided | 2016-07-27 | no assertion criteria provided | provider interpretation | p.Ile2960Asn (c.8879T>A) in RYR2 (NM_001035.2) Seen in a patient in our center with recurrent unexplained ventricular tachycardia and ventricular fibrillation as well as intellectual disability. Given the novel nature of this variant and the incomplete data on population frequency, we consider this missense variant to be a variant of uncertain significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant appears to be novel. This c.8879T>C (p.Ile2960Thr) variant has not been reported in ClinVar or in published studies. It has not been reported in ExAC, ClinVar, or published studies. The variant is not listed in ExAC. However ExAC includes this warning: “This variant is only covered in 41445 individuals (adjusted allele number = 82890). This means that the site is covered in fewer than 80% of the individuals in ExAC, which may indicate a low-quality site.†Another variant at the same location, c.8879T>C (p.Ile2960Thr), has been reported in 1 individual in ExAC. Specifically, the variant has been observed in the following ethnicity: African: 1/3,601. The population frequency of the c.8879T>C (p.Ile2960Thr) variant is 0.001%. The phenotype of this individual is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in datasets like this so this does not necessarily rule out pathogenicity (Pan et al 2012). |