ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.3152G>A (p.Arg1051His) (rs79457258)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000726778 SCV000702976 uncertain significance not provided 2016-11-29 criteria provided, single submitter clinical testing
GeneDx RCV000726778 SCV000235089 uncertain significance not provided 2017-12-13 criteria provided, single submitter clinical testing The R1051H variant of uncertain significance in the RYR2 gene has been previously reported in a 2 month-old female with clinical diagnosis of DCM; however, this individual also harbored variants in several additional cardiomyopathy-associated genes (Pugh et al., 2014). R1051H has been identified in other unrelated individuals referred for genetic testing at GeneDx, yet observation in these individuals, for whom clinical and segregation data is lacking, is not sufficient to determine the absolute pathogenicity of this variant. The R1051H variant has been observed in 20/101,362 (0.02%) alleles from individuals of European (non-Finnish) ancestry in large population cohorts (Lek et al., 2016). In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. However, the R1051H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In addition, R1051H 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). And while a missense variant in the same residue (R1051P) has been reported in the Human Gene Mutation Database (Stenson et al., 2014), the pathogenicity of this variant has not been definitively determined.
Invitae RCV000547335 SCV000637551 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2018-07-31 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 1051 of the RYR2 protein (p.Arg1051His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs79457258, ExAC 0.02%). This variant has been reported in an individual affected with dilated cardiomyopathy (PMID: 24503780). ClinVar contains an entry for this variant (Variation ID: 43765). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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 RCV000036724 SCV000060379 uncertain significance not specified 2018-04-10 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory

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