Submissions for variant NM_001035.3(RYR2):c.689G>A (p.Gly230Asp)

dbSNP: rs794728710

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182662	SCV000235041	pathogenic	not provided	2013-10-11	criteria provided, single submitter	clinical testing	p.Gly230Asp (GGT>GAT): c.689 G>A in exon 10 of the RYR2 gene (NM_001035.2). While the Gly230Asp mutation in the RYR2 gene has not been reported to our knowledge, a mutation affecting this same residue, Gly230Cys, has been reported in association with CPVT (Meli A et al., 2011). Additionally, Gly230Asp is located in the N-terminal mutation hot-spot" domain of the RYR2 gene (Medeiros-Domingo A et al., 2009). Gly230Asp results in a non-conservative amino acid substitution of a non-polar Glycine with a negatively charged Aspartic acid at a position that is conserved across species. In silico analysis predicts Gly230Asp is damaging to the protein structure/function. Furthermore, Gly230Asp was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, Gly230Asp in the RYR2 gene is interpreted as a likely disease-causing mutation. Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) is characterized by syncope, typically beginning in the first decade of life, which may be triggered by physical activity or intense emotion. In patients with CPVT, stress-induced release of catecholamines causes a dysfunction of the calcium-ion channel in the myocytes (De La Fuente et al., 2008; Napolitano C et al., 2012; Priori S et al., 2002). CPVT is primarily caused by autosomal dominant mutations in the RYR2 and KCNJ2 genes. Less commonly, CPVT is caused by autosomal recessive mutations in the CASQ2 gene (Napolitano C et al., 2012). Approximately 50% of patients with autosomal dominant CPVT have been reported to have a mutation in the RYR2 gene, while mutations in the RYR2 gene associated with ARVC are rare (McNally E et al., 2009; Napolitano C et al., 2012). The variant is found in CPVT panel(s)."
Invitae	RCV002517787	SCV001536463	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2020-10-24	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. This variant disrupts the p.Gly230 amino acid residue in RYR2. Other variant(s) that disrupt this residue have been observed in individuals with RYR2-related conditions (PMID: 21659649), which suggests that this may be a clinically significant amino acid residue. 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 expected to disrupt RYR2 protein function. This variant has been observed in individual(s) with clinical features of RYR2-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 201197). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with aspartic acid at codon 230 of the RYR2 protein (p.Gly230Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid.