Submissions for variant NM_001035.3(RYR2):c.7063G>A (p.Glu2355Lys)

gnomAD frequency: 0.00002  dbSNP: rs754990305

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001183007	SCV001348653	uncertain significance	Cardiomyopathy	2023-03-29	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 2355 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 not been reported in individuals affected with RYR2-related disorders in the literature. This variant has been identified in 8/248914 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.
Invitae	RCV002560838	SCV001374861	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2024-01-03	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 2355 of the RYR2 protein (p.Glu2355Lys). This variant is present in population databases (rs754990305, gnomAD 0.006%). 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: 922765). 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.
GeneDx	RCV001597250	SCV001830656	uncertain significance	not provided	2020-10-23	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Is 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)
Ambry Genetics	RCV002365865	SCV002662143	uncertain significance	Cardiovascular phenotype	2022-05-09	criteria provided, single submitter	clinical testing	The p.E2355K variant (also known as c.7063G>A), located in coding exon 46 of the RYR2 gene, results from a G to A substitution at nucleotide position 7063. The glutamic acid at codon 2355 is replaced by lysine, an amino acid with similar properties. This variant was reported in an exome cohort; however, clinical details were not provided (Landstrom AP et al. Circ Arrhythm Electrophysiol, 2017 Apr;10:[Epub ahead of print]). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.