ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.5294C>G (p.Ser1765Cys) (rs564806219)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001084797 SCV000541688 likely benign Catecholaminergic polymorphic ventricular tachycardia 2020-11-25 criteria provided, single submitter clinical testing
GeneDx RCV000756606 SCV000565510 uncertain significance not provided 2019-01-21 criteria provided, single submitter clinical testing The S1765C variant of uncertain significance in the RYR2 gene has been reported in one individual with HCM who was screened by a panel of greater than 40 cardiac-associated genes (Lopes et al., 2015). In addition, S1765C was reported in a patient with unexplained cardiac arrest and suspected CPVT, however, this individual did not meet CPVT diagnostic criteria (Jimenez-Jaimez et al., 2015). Brion et al. (2014) additionally reported S1765C in a case of sudden unexplained death. However, none of the publications reported segregation data or performed functional studies. Similarly, this variant has been seen in multiple unrelated individuals referred for cardiac testing at GeneDx, though, segregation data is either unavailable or uninformative to date. The S1765C 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. Moreover, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Nevertheless, the S1765C variant is 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). Finally, the S1765C variant is observed in 25/34,412 (0.07%) Latino alleles, and 17/126,410 (0.01%) European (non-Finnish) alleles in large population cohorts (Lek et al., 2016), indicating it may be a rare benign variant. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Ambry Genetics RCV000620181 SCV000736423 uncertain significance Cardiovascular phenotype 2017-05-30 criteria provided, single submitter clinical testing The p.S1765C variant (also known as c.5294C>G), located in coding exon 37 of the RYR2 gene, results from a C to G substitution at nucleotide position 5294. The serine at codon 1765 is replaced by cysteine, an amino acid with dissimilar properties. This alteration was reported in a case of sudden cardiac death (Brion M et al. Electrophoresis, 2014 Nov;35:3111-6), and in an individual with unexplained cardiac arrest who did not meet the diagnostic criteria of catecholaminergic polymorphic ventricular tachycardia (Jiménez-Jáimez J et al. Am. J. Cardiol., 2015 Sep;116:894-9). In addition, this alteration has been reported in a hypertrophic cardiomyopathy cohort; however, clinical details were limited (Lopes LR et al. Heart, 2015 Feb;101:294-301). This amino acid position is well 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.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000756606 SCV000884473 uncertain significance not provided 2017-06-08 criteria provided, single submitter clinical testing The p.Ser1765Cys variant (rs564806219) has been observed in an individual included in a cohort of hypertrophic cardiomyopathy patients (Lopes 2015), an individual with a suspected diagnosis of catecholaminergic polymorphic ventricular tachycardia who did not meet full diagnostic criteria (Jimenez-Jaimez 2015), and in a case of sudden unexplained death (Brion 2014). However, so co-segregation data is available for this variant, and it is listed in the Genome Aggregation Database (gnomAD) browser with an overall frequency of 0.017% (identified in 48 out of 276,878 chromosomes). This variant is also listed in the ClinVar database as a variant of uncertain significance (Variation ID: 404210). The serine at codon 1765 is highly conserved considering 10 species up to chicken (Alamut software v2.9), although computational analyses return mixed results regarding the effect of this variant on RYR2 protein structure/function (SIFT: damaging, PolyPhen2: benign, and Mutation Taster: disease causing). Therefore, based on the available information, the clinical significance of the p.Ser1765Cys variant cannot be determined with certainty.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769785 SCV000901210 uncertain significance Cardiomyopathy 2015-12-11 criteria provided, single submitter clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health,University of California San Diego RCV000852597 SCV000995300 likely benign Arrhythmogenic right ventricular cardiomyopathy 2017-02-02 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001099048 SCV001255457 uncertain significance Arrhythmogenic right ventricular dysplasia, familial, 2 2018-09-26 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Clinical Services Laboratory,Illumina RCV001099049 SCV001255458 likely benign Catecholaminergic polymorphic ventricular tachycardia type 1 2018-09-26 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Color Health, Inc RCV000769785 SCV001348912 likely benign Cardiomyopathy 2018-11-09 criteria provided, single submitter clinical testing

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