Submissions for variant NM_001035.3(RYR2):c.12545A>C (p.Glu4182Ala)

dbSNP: rs794728788

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182822	SCV000235208	likely pathogenic	not provided	2014-06-26	criteria provided, single submitter	clinical testing	p.Glu4182Ala (GAG>GCG): c.12545 A>C in exon 90 of the RYR2 gene (NM_001035.2). The E4182A variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The E4182A variant was not observed in approximately 6200 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 E4182A 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, E4182A is located in the channel region, a mutation hotspot region of the RYR2 gene (Medeiros- Domingo A et al., 2009). Missense mutations in nearby residues (N4178Y, N4178S, E4187Q, L4188P) have been reported in association with CPVT, supporting the functional importance of this region of the protein. Therefore, this variant is a strong candidate for a pathogenic mutation, however the possibility that it is a benign variant cannot be excluded. The variant is found in ARRHYTHMIA panel(s).
Invitae	RCV002516900	SCV000637498	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2017-01-06	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid with alanine at codon 4182 of the RYR2 protein (p.Glu4182Ala). The glutamic acid residue is highly conserved and there is a moderate physicochemical difference between glutamic acid and alanine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a RYR2-related disease. ClinVar contains an entry for this variant (Variation ID: 201335). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. This variant occurs within one of the three regions of the RYR2 gene (N-terminal domain, central domain, or channel region) where other pathogenic variants have been reported to cluster (PMID: 19926015).
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798635	SCV002042890	likely pathogenic	Cardiomyopathy	2020-10-01	criteria provided, single submitter	clinical testing