Submissions for variant NM_001035.3(RYR2):c.506G>A (p.Arg169Gln)

dbSNP: rs397516539

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036762	SCV000060417	likely pathogenic	Catecholaminergic polymorphic ventricular tachycardia	2013-08-27	criteria provided, single submitter	clinical testing	The Arg169Gln variant in RYR2 has been reported in 3 Asian individuals with CPVT , was reported to occur de novo in one of these individuals, and was absent from 200 control chromosomes (Hsueh 2006, Ge 2012, Kawamura 2013). This variant has been identified by our laboratory in 1 Caucasian individual with LVNC and bidire ctional VT, and was not identified in large population studies. Arginine (Arg) a t position 169 is highly conserved in mammals and across evolutionarily distant species and computational analyses (AlignGVGD, PolyPhen2, and SIFT) suggest that the Arg169Gln variant may impact the protein, which raises the possibility that a change at this position might not be tolerated. Additionally, this variant is located in a conserved domain of the RYR2 protein that may be critical for prot ein interactions and where other variants are clustered (Amador 2009, Lobo 2009) . In summary, this variant is likely to be pathogenic, though additional studies are required to fully establish its clinical significance.
GeneDx	RCV000182658	SCV000235036	pathogenic	not provided	2014-12-12	criteria provided, single submitter	clinical testing	p.Arg169Gln (CGA>CAA):c.506 G>A in exon 8 of the RYR2 gene (NM_001035.2). The Arg169Gln mutation in the RYR2 gene has been reported previously in an 18 year old female with exercised induced ventricular tachycardia and was absent from 100 reference alleles (Hsueh C et al., 2006). In addition, the NHLBI ESP Exome Variant Server reports Arg169Gln was not observed in approximately 6000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. Arg169Gln resides in the N-terminal domain, one of three mutation hot spots, in the RYR2 gene (Medeiros-Domingo A et al., 2009). Structural studies indicate that Arg169Gln leads to destabilization of the beta8-beta9 loop in this region of the protein (Lobo P et al., 2009). Mutations in nearby codons (Pro164Ser, Arg176Gln) have been reported in association with polymorphic ventricular tachycardia and ARVD further supporting the functional importance of this region of the protein. In summary, Arg169Gln in the RYR2 gene is interpreted as a 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 (McNally E et al., 2009; Napolitano C et al., 2012). The variant is found in CPVT panel(s).
Ambry Genetics	RCV000621755	SCV000737675	pathogenic	Cardiovascular phenotype	2019-01-04	criteria provided, single submitter	clinical testing	The p.R169Q pathogenic mutation (also known as c.506G>A), located in coding exon 8 of the RYR2 gene, results from a G to A substitution at nucleotide position 506. The arginine at codon 169 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been detected in patients with suspected or reported catecholaminergic polymorphic ventricular tachycardia (CPVT), and has also been reported as occurring de novo in two pediatric cases from a CPVT cohort who experienced cardiac arrest (Hsueh CH et al. Int J Cardiol. 2006;108:276-8; Kawamura M et al. Circ J. 2013;77:1705-13; Ohno S. PLoS ONE. 2015;10(6):e0131517). Structural analyses have suggested that this alteration occurs in a variant clustering domain and may break ionic interactions (Lobo PA et al. Structure. 2009;17:1505-14; Amador FJ et al. Proc Natl Acad Sci. U.S.A. 2009;106:11040-4). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000182658	SCV001762194	pathogenic	not provided	2021-06-17	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002513428	SCV002239421	pathogenic	Catecholaminergic polymorphic ventricular tachycardia 1	2023-06-18	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 43801). This missense change has been observed in individual(s) with catecholaminergic polymorphic ventricular tachycardia (PMID: 16517285, 23595086, 26114861). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 169 of the RYR2 protein (p.Arg169Gln).
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002513428	SCV003921884	pathogenic	Catecholaminergic polymorphic ventricular tachycardia 1	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and gain of function are known mechanisms of disease in this gene and are associated with catecholaminergic polymorphic ventricular tachycardia 1 (MIM#604772) and left ventricular non-compaction (PMID: 12459180, 27646203, 29477366, 31875585, 33500567). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. Penetrance for CPVT is estimated to be 60-70% (PMID: 23549275). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (DECIPHER). (SP) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. The variant p.(Arg169Leu) has been reported pathogenic in ClinVar, and de novo in a patient with CPVT (PMID: 26114861). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant is multiply reported pathogenic in ClinVar and the literature in individuals with CPVT or LVNC with atypical CPVT, several of whom were de novo (PMID: 16517285, 23595086, 26114861, 29453246, 31875585). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. This variant has been found to result in reduced threshold for overload-induced Ca2+ release from the sarcoplasmic reticulum and increased fractional Ca2+ release, by in vitro studies (PMID: 31875585). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed; by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign