Submissions for variant NM_001035.3(RYR2):c.8366T>C (p.Ile2789Thr)

dbSNP: rs1419719746

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002568164	SCV002153476	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2024-03-04	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 2789 of the RYR2 protein (p.Ile2789Thr). 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: 1174950). 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 with a positive predictive value of 95%. 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.
AiLife Diagnostics, AiLife Diagnostics	RCV001529397	SCV002502435	uncertain significance	not provided	2021-09-29	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002495853	SCV002776888	uncertain significance	Arrhythmogenic right ventricular dysplasia 2; Catecholaminergic polymorphic ventricular tachycardia 1; Ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome	2021-10-18	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV003533009	SCV004360695	uncertain significance	Cardiomyopathy	2023-04-21	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with threonine at codon 2789 of the RYR2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with RYR2-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
All of Us Research Program, National Institutes of Health	RCV004008914	SCV004823320	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia	2024-05-14	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with threonine at codon 2789 of the RYR2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
GeneDx	RCV001529397	SCV005385703	uncertain significance	not provided	2024-01-30	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Not located in one of the three hot-spot regions of the RYR2 gene, where the majority of pathogenic missense variants occur (PMID: 19926015); This variant is associated with the following publications: (PMID: 19926015)
Ambry Genetics	RCV004988676	SCV005496964	uncertain significance	Cardiovascular phenotype	2024-10-29	criteria provided, single submitter	clinical testing	The p.I2789T variant (also known as c.8366T>C), located in coding exon 56 of the RYR2 gene, results from a T to C substitution at nucleotide position 8366. The isoleucine at codon 2789 is replaced by threonine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001529397	SCV001742784	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001529397	SCV001959125	uncertain significance	not provided		no assertion criteria provided	clinical testing