ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.3163C>T (p.Arg1055Cys) (rs754181384)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000523211 SCV000617993 uncertain significance not provided 2017-08-01 criteria provided, single submitter clinical testing The R1055C variant of uncertain significance in the RYR2 gene has been reported previously in association with hypertophic cardiomyopathy (HCM); however, no clinical or segregation information was provided (Lopes et al., 2015). This variant has also been identified independently of additional cardiogenetic variants in one other individual referred for cardiomyopathy genetic testing at GeneDx; however, thus far, segregation data is limited or absent due to the lack of clinical information provided and/or insufficient participation by informative family members. The R1055C variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R1055C 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. Furthermore, this substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Nevertheless, the R1055C 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).
Invitae RCV000639044 SCV000760603 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2017-12-06 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 1055 of the RYR2 protein (p.Arg1055Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs754181384, ExAC 0.005%). 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 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.

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