Submissions for variant NM_001035.3(RYR2):c.1973A>G (p.Asn658Ser)

gnomAD frequency: 0.00005  dbSNP: rs2009813

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182693	SCV000235072	uncertain significance	not provided	2023-04-27	criteria provided, single submitter	clinical testing	Identified in one patient with HCM in published literature (Robyns et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not 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); This variant is associated with the following publications: (PMID: 19926015, 31513939)
Invitae	RCV002516872	SCV000541726	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2024-01-26	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 658 of the RYR2 protein (p.Asn658Ser). This variant is present in population databases (rs2009813, gnomAD 0.007%). This missense change has been observed in individual(s) with clinical features of RYR2-related conditions (PMID: 31513939; Invitae). ClinVar contains an entry for this variant (Variation ID: 201225). 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 with a positive predictive value of 95%. 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.
Ambry Genetics	RCV000618396	SCV000736711	uncertain significance	Cardiovascular phenotype	2021-06-01	criteria provided, single submitter	clinical testing	The p.N658S variant (also known as c.1973A>G), located in coding exon 20 of the RYR2 gene, results from an A to G substitution at nucleotide position 1973. The asparagine at codon 658 is replaced by serine, an amino acid with highly similar properties. This variant has been reported in one individual from a catecholaminergic polymorphic ventricular tachycardia (CPVT) genetic testing cohort and in one individual from a hypertrophic cardiomyopathy cohort; however, clinical details were limited for both cases (Kapplinger JD et al. Circ Genom Precis Med, 2018 02;11:e001424; Robyns T et al. Eur J Med Genet, 2020 Mar;63:103754). This amino acid position is highly 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.
Center for Human Genetics, University of Leuven	RCV000768527	SCV000886846	uncertain significance	Hypertrophic cardiomyopathy	2018-10-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001188651	SCV001355742	uncertain significance	Cardiomyopathy	2023-07-31	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with serine at codon 658 of the RYR2 protein. Computational prediction suggests that this variant may have a 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 been reported in an individual affected with catecholaminergic polymorphic ventricular tachycardia (PMID: 31155924) and in an individual suspected to be affected with catecholaminergic polymorphic ventricular tachycardia (PMID: 29453246). It has also been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 31513939), in an individual affected with cardiomyopathy (PMID: 37477868), and in an individual affected with stillbirth (PMID: 30615648). This variant has been identified in 11/280302 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.