Submissions for variant NM_001035.3(RYR2):c.1069G>A (p.Gly357Ser)

dbSNP: rs1401116572

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000620678	SCV000738218	pathogenic	Cardiovascular phenotype	2021-07-21	criteria provided, single submitter	clinical testing	The p.G357S pathogenic mutation (also known as c.1069G>A), located in coding exon 13 of the RYR2 gene, results from a G to A substitution at nucleotide position 1069. The glycine at codon 357 is replaced by serine, an amino acid with similar properties. This mutation has been previously described in patients with catecholaminergic polymorphic ventricular tachycardia (CPVT) (Medeiros-Domingo A et al. J. Am. Coll. Cardiol., 2009 Nov;54:2065-74; Heiner JD et al. Pediatr Emerg Care, 2011 Nov;27:1065-8). This mutation was identified in a very large family with multiple cases of CPVT, including sudden cardiac death in youth, and strong segregation with the disease was demonstrated (Wangüemert F et al. Heart Rhythm, 2015 Jul;12:1636-43). In vitro studies suggested that this mutation resulted in reduced protein expression and increased release of calcium from intracellular stores under conditions that mimic beta-adrenergic stimulation (Wangüemert F et al. Heart Rhythm, 2015 Jul;12:1636-43; Liu Y et al. PLoS ONE, 2017 Sep;12:e0184177). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002470934	SCV000813564	pathogenic	Catecholaminergic polymorphic ventricular tachycardia 1	2023-12-12	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 357 of the RYR2 protein (p.Gly357Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant RYR2-related conditions (PMID: 22068070, 25814417; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 519533). 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. Experimental studies have shown that this missense change affects RYR2 function (PMID: 25814417, 28961276). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001529699	SCV001817325	pathogenic	not provided	2023-10-18	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect as this variant results in an increase in caffeine sensitivity and store overload-induced calcium release activity compared to wild-type while under conditions that mimic catecholaminergic stress (PMID: 25814417); Located in one of the three hot-spot regions of the RYR2 gene, where the majority of pathogenic missense variants occur (PMID: 19926015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24025405, 24136861, 28961276, 28789916, 30847666, 31112425, 30063211, 19926015, 35176171, 30763784, 35135837, 22068070, 25814417)
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002470934	SCV002768104	pathogenic	Catecholaminergic polymorphic ventricular tachycardia 1	2021-05-06	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 (CPVT) (MIM#604772) (PMID: 12459180, PMID: 27646203, PMID: 29477366). (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 glycine to serine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (4 heterozygotes, 0 homozygotes). (I) 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. This variant is found within an established missense variant hotspot within the N-terminal domain (PMID: 19926015). (SP) 0710 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. This variant (p.Gly357Asp) was classified as a VUS, and identified in an individual as an incidental finding (PMID: 28404607). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic (LOVD, ClinVar), and observed in multiple families with incomplete penetrance, with either an unspecific arrhythmia, or catecholaminergic polymorphic ventricular tachycardia (PMID: 19926015, PMID: 22068070, PMID: 25814417, PMID: 30763784, PMID: 30847666). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Transfected HEK293 cells demonstrated a greater sensitivity to caffeine and forskolin, mimicking catecholaminergic stress conditions (PMID: 25814417). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Color Diagnostics, LLC DBA Color Health	RCV003532205	SCV004358270	pathogenic	Cardiomyopathy	2022-04-07	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with serine at codon 357 in the cytoplasmic MIR domain of the RYR2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant causes instability of the N-terminal region and increased propensity for spontaneous calcium release from the sarcoplasmic reticulum in conditions that mimic beta-adrenergic stimulations (PMID: 25814417, 28961276). This variant has been identified in about 180 individuals from a large, multi-generational pedigree affected with catecholaminergic polymorphic ventricular tachycardia (CPVT), including 9 individuals affected with sudden cardiac death during youth and 40 individuals who received an implantable cardioverter defibrillator (PMID: 25814417). In the serial exercise treadmill test, 74% of the carriers exhibited complex ventricular arrhythmias. This variant has also been reported in another 12 individuals affected with CPVT from at least 8 different families (PMID: 19926015, 22068070, 24136861, 29453246, 30763784, 31112425, 32091590, communication with an external laboratory, ClinVar SCV001817325.1). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001529699	SCV001743606	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV001529699	SCV001925620	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001529699	SCV001929870	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001529699	SCV001970846	pathogenic	not provided		no assertion criteria provided	clinical testing