Submissions for variant NM_001035.3(RYR2):c.727G>A (p.Glu243Lys)

dbSNP: rs794728712

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182665	SCV000235044	uncertain significance	not provided	2018-03-16	criteria provided, single submitter	clinical testing	The E243K variant in the RYR2 gene has been reported in one individual with definitive CPVT and one individual with either strong or possible CPVT (Hayashi et al., 2009; Medeiros-Domingo et al., 2009). The E243K variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The E243K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties, and this substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. The E243K variant is located in one of the three hot-spot regions of the RYR2 gene, where the majority of pathogenic missense mutations occur (Medeiros-Domingo et al., 2009). Although this region is not a channel functional domain and there are no nearby definitively pathogenic variants, a handful of individuals identified by GeneDx to harbor this variant reported syncope and/or sudden cardiac arrest and at least one individual had syncope with exertion, suggesting that this variant may be pathogenic, but segregation data is limited or absent for these individuals due to the lack of clinical information provided and/or insufficient participation by informative family members. Furthermore, no individual carrying this variant reported a clearly strong clinical diagnosis of CPVT or ARVC, and some individuals harbored additional cardiogenetic variants of uncertain significance. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant
Ambry Genetics	RCV000618334	SCV000737687	uncertain significance	Cardiovascular phenotype	2016-09-02	criteria provided, single submitter	clinical testing	The p.E243K variant (also known as c.727G>A), located in coding exon 10 of the RYR2 gene, results from a G to A substitution at nucleotide position 727. The glutamic acid at codon 243 is replaced by lysine, an amino acid with similar properties. This variant has been described in association with catecholaminergic polymorphic ventricular tachycardia (CPVT) and exertional syncope (Medeiros-Domingo A et al. J Am Coll Cardiol. 2009;54:2065-74; Hayashi M et al. Circulation. 2009;119:2426-34). This variant was previously reported in the SNPDatabase as rs794728712, but was absent from population-based cohorts in the NHLBI Exome Sequencing Project (ESP) and 1000 Genomes Project databases. In the ESP, this variant was not observed in 6265 samples (12530 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV002516867	SCV000819451	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2023-03-26	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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RYR2 protein function. ClinVar contains an entry for this variant (Variation ID: 201200). This missense change has been observed in individual(s) with catecholaminergic polymorphic ventricular tachycardia (CPVT) or RYR2-related clinical features (PMID: 19398665, 19926015, 21954897, 29453246). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 243 of the RYR2 protein (p.Glu243Lys).