Submissions for variant NM_001035.3(RYR2):c.8879T>A (p.Ile2960Asn)

dbSNP: rs759048462

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002526388	SCV000541681	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2025-01-29	criteria provided, single submitter	clinical testing	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). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with RYR2-related conditions. ClinVar contains an entry for this variant (Variation ID: 404205). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt RYR2 protein function with a positive predictive value of 80%. 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.
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, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000786204	SCV005333001	uncertain significance	not provided	2023-04-11	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); Not located in one of the three hot-spot regions of the RYR2 gene, where the majority of pathogenic missense variants occur (Medeiros-Domingo et al., 2009); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19926015)
Stanford Center for Inherited Cardiovascular Disease, Stanford University	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).