ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.3356G>A (p.Arg1119His) (rs201312753)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color RCV000771974 SCV000904928 uncertain significance Cardiomyopathy 2018-10-27 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the cytoplasmic SPRY domain 2 of the RYR2 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 41/277124 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 RCV000724470 SCV000228609 uncertain significance not provided 2015-02-09 criteria provided, single submitter clinical testing
GeneDx RCV000724470 SCV000235093 uncertain significance not provided 2018-11-26 criteria provided, single submitter clinical testing The R1119H variant of uncertain significance in the RYR2 gene has not been published in association with arrhythmia to our knowledge. R1119H has been identified in several patients with varying cardiac phenotypes referred for genetic testing at GeneDx. This variant was observed in 30/126,640 (0.02%) alleles from individuals of European (non-Finnish) ancestry in large population cohorts (Lek et al., 2016). Although the R1119H variant is a conservative amino acid substitution, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Nevertheless, the R1119H 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). Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV000463788 SCV000541690 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2018-10-24 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 1119 of the RYR2 protein (p.Arg1119His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs201312753, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with RYR2-related disease. 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.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000724470 SCV000924919 uncertain significance not provided 2017-06-08 no assertion criteria provided provider interpretation We consider the c.3356G>A (p.Arg1119His) variant to be a variant of uncertain significance, probably benign. It was found in our patient along with a de novo Likely Pathogenic variant in the RYR2 gene that explains the patient’s phenotype. The p.Arg1119His variant is present in population-based cohorts but has not been reported in the literature in association with disease. The variant was reported in 41 / 277,124 (0. 015%) alleles in the gnomAD dataset (http://gnomad.broadinstitute.org), which includes variant calls from 123,136 exome sequences and 15,496 genome sequences from unrelated individuals of non-Finnish European, Finnish, African, Latino, Ashkenazi Jewish, East Asian, and South Asian descent. The highest ethnicity-specific minor allele frequency is 0.024% in non-Finnish Europeans. The gnomAD dataset is comprised of multiple cohorts, some of which were recruited from the general population and others that include individuals sequenced as part of various disease-specific and population genetic studies; the phenotypes of individuals are not publicly available. This is a conservative amino acid change from a positively-charged Arginine to a positively-charged Histidine. According to the Invitae report, in silico 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: "Probably Damaging"; Align-GVGD: "Class C25"). The arginine at codon 1119 is highly conserved across vertebrate evolution. However, the variant does not occur within one of the three “hotspots” in the RYR2 gene, where other pathogenic variants have been reported to cluster (Medeiros-Domingo et al., 2009). Furthermore, pathogenic variants have not been reported to ClinVar in association with arrhythmia at nearby residues (+/- 10), indicating this region of the protein may tolerate change. In summary, we consider this variant to be a rare missense change with uncertain impact on protein function. In light of this evidence, we consider it to be a variant of uncertain significance, likely benign.

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