Submissions for variant NM_001035.3(RYR2):c.1346T>G (p.Ile449Arg)

gnomAD frequency: 0.00001  dbSNP: rs373331669

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002543657	SCV001505490	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2023-11-17	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 449 of the RYR2 protein (p.Ile449Arg). This variant is present in population databases (rs373331669, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of RYR2-related conditions (PMID: 29037160, 30975432). ClinVar contains an entry for this variant (Variation ID: 1015998). 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 not expected to disrupt RYR2 protein function with a negative 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.
Color Diagnostics, LLC DBA Color Health	RCV001526171	SCV001736468	uncertain significance	Cardiomyopathy	2023-05-24	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with arginine at codon 449 of the RYR2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in three individuals from a family affected with Jervell and Lange-Nielsen syndrome. However, a homozygous pathogenic variant in the KCNQ1 gene was identified in this family and could explain the observed phenotype (PMID: 29037160). This variant has also been reported in a sudden cardiac arrest survivor without cardiac phenotype (PMID: 30975432). This variant has been identified in 5/248594 chromosomes 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.
Dept of Medical Biology, Uskudar University	RCV003318401	SCV004022075	uncertain significance	Long QT syndrome	2024-01-08	criteria provided, single submitter	research	Criteria: PM2, PP2, PP3
All of Us Research Program, National Institutes of Health	RCV004005077	SCV004844455	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia	2024-09-23	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with arginine at codon 449 of the RYR2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in three individuals from a family affected with Jervell and Lange-Nielsen syndrome. However, a homozygous pathogenic variant in the KCNQ1 gene was identified in this family and could explain the observed phenotype (PMID: 29037160). This variant has also been reported in a sudden cardiac arrest survivor without cardiac phenotype (PMID: 30975432). This variant has been identified in 5/248594 chromosomes 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.
Ambry Genetics	RCV004987061	SCV005496941	uncertain significance	Cardiovascular phenotype	2024-08-29	criteria provided, single submitter	clinical testing	The p.I449R variant (also known as c.1346T>G), located in coding exon 15 of the RYR2 gene, results from a T to G substitution at nucleotide position 1346. The isoleucine at codon 449 is replaced by arginine, an amino acid with similar properties. This alteration has been reported in a sudden cardiac arrest cohort (Asatryan B et al. Am J Cardiol, 2019 Jun;123:2031-2038). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.