ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.4465T>C (p.Cys1489Arg) (rs200450676)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000768765 SCV000900135 uncertain significance Cardiomyopathy 2017-07-28 criteria provided, single submitter clinical testing
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000678836 SCV000805024 likely pathogenic Long QT syndrome 2017-04-12 no assertion criteria provided clinical testing
Color RCV000768765 SCV000914107 uncertain significance Cardiomyopathy 2018-06-11 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This variant is a missense variant located in the cytoplasmic SPRY domain 3 of the RYR2 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in an individual affected with cardiovascular disorders in the literature. This variant has been identified in 39/275700 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000725016 SCV000333232 uncertain significance not provided 2015-08-10 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515200 SCV000611433 uncertain significance Arrhythmogenic right ventricular dysplasia, familial, 2; Catecholaminergic polymorphic ventricular tachycardia type 1 2017-05-23 criteria provided, single submitter clinical testing
GeneDx RCV000154819 SCV000235104 uncertain significance not specified 2017-05-04 criteria provided, single submitter clinical testing The C1489R variant has been reported inone individual with hypertrophic cardiomyopathy and one individual with sudden unexpected death in epilepsy and ahistory of nocturnal seizures (Lopes et al., 2015; Bagnall et al., 2016). The C1489R variant has also been reported asan incidental finding identified in a cohort referred for clinical whole exome sequencing; authors classified C1489R asa variant of uncertain significance, though did not provide patient-specific clinical data (Landstrom et al., 2017). The C1489R variant is observed in 7/11490 (0.06%) alleles and 11/66650 (0.02%)alleles from individuals of Latino and European (Non-Finnish) ancestry in the ExAC dataset, respectively (Lek et al.,2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).The C1489R variant is a non-conservative amino acid substitution, which is likely to impact secondary proteinstructure as these residues differ in polarity, charge, size and/or other properties. Moreover, this substitution occurs ata position that is conserved through mammals, and in silico analysis predicts this variant is probably damaging tothe protein structure/function. Nonetheless, C1489R is not located in one of the three hot-spot regions of the RYR2gene, where the majority of pathogenic missense variants occur (Medeiros-Domingoet al., 2009). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000556479 SCV000637566 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2018-03-26 criteria provided, single submitter clinical testing This sequence change replaces cysteine with arginine at codon 1489 of the RYR2 protein (p.Cys1489Arg). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and arginine. This variant is present in population databases (rs200450676, ExAC 0.06%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported to occur de novo in an individual that suffered sudden cardiac death and had a history of nocturnal seizures (PMID: 26704558). ClinVar contains an entry for this variant (Variation ID: 178120). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65"). 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000154819 SCV000204500 uncertain significance not specified 2013-05-24 criteria provided, single submitter clinical testing The Cys1489Arg variant in RYR2 has now been identified by our laboratory in 1 Bl ack individual and 1 Caucasian individual with DCM (LMM unpublished data). In ad dition, it has also been identified in 1/8376 European American chromosomes by t he NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs20 0450676). Computational analyses (biochemical amino acid properties, conservatio n, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impact to the protein. Additional information is needed to fully assess the c linical significance of this variant.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000725016 SCV000987636 uncertain significance not provided criteria provided, single submitter clinical testing

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