ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.4445G>A (p.Arg1482His) (rs373024059)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000171763 SCV000050703 likely benign not provided 2013-06-24 criteria provided, single submitter research
Color RCV000773225 SCV000906837 likely benign Cardiomyopathy 2018-04-26 criteria provided, single submitter clinical testing
GeneDx RCV000171763 SCV000235103 uncertain significance not provided 2016-11-15 criteria provided, single submitter clinical testing The R1482H variant of uncertain significance in the RYR2 gene has not been published as a pathogenic or benign variant to our knowledge. This variant has been identified independently and in conjunction with additional cardiogenetic variants in individuals referred for cardiomyopathy and arrhythmia genetic testing at GeneDx; however, thus far, segregation data is absent for these individuals due to the lack of clinical information provided and insufficient participation by informative family members. This variant was not observed with any significant frequency in approximately 6,200 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. Although this substitution occurs at a position that is conserved through mammals, the R1482H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Furthermore, the R1482H 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). Nevertheless, in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV000461968 SCV000541696 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2017-12-06 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 1482 of the RYR2 protein (p.Arg1482His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs373024059, ExAC 0.03%) but has not been reported in the literature in individuals with a RYR2-related disease. ClinVar contains an entry for this variant (Variation ID: 191544). 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 C25"). In summary, this variant is a rare missense change with uncertain impact on protein function. Because it is found in the population at an appreciable frequency, this variant is not anticipated to cause disease. However, the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000212979 SCV000272388 likely benign not specified 2018-04-10 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory

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