Submissions for variant NM_001035.3(RYR2):c.728A>G (p.Glu243Gly)

dbSNP: rs753663342

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000413004	SCV000492130	uncertain significance	not specified	2016-11-23	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the RYR2 gene. The E243G variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The E243G variant was not observed in approximately 6300 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 E243G 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. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, the G743D 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). Nevertheless, this variant has not been identified in a significant number of affected individuals, and there are no functional studies or segregation data available to clarify the role of this variant in disease.
Invitae	RCV002521426	SCV000833366	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2023-11-02	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 243 of the RYR2 protein (p.Glu243Gly). This variant is present in population databases (rs753663342, gnomAD 0.0009%). 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: 373532). 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. 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	RCV003532096	SCV004358257	uncertain significance	Cardiomyopathy	2023-09-28	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with glycine at codon 243 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 been identified in 1/249096 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.