ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.11812A>C (p.Ser3938Arg) (rs794728825)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182886 SCV000235275 uncertain significance not provided 2019-01-11 criteria provided, single submitter clinical testing The S3938R variant of uncertain significance in the RYR2 gene has been reported in a 12 year-old Caucasian male with exertional sudden cardiac arrest and no known family history of CPVT; however, the specific nucleotide change was not provided (Roston et al., 2018). S3938R, due to a different nucleotide change (c.11814 C>A), has been published in association with CPVT (Tester et al., 2006). The S3938R variant is not observed in large population cohorts (Lek et al., 2016). S3938R is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Moreover, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Finally, the S3938R variant is 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 RCV001068020 SCV001233107 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2019-01-15 criteria provided, single submitter clinical testing This sequence change replaces serine with arginine at codon 3938 of the RYR2 protein (p.Ser3938Arg). The serine residue is highly conserved and there is a moderate physicochemical difference between serine and arginine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individuals affected with catecholaminergic polymorphic ventricular tachycardia (PMID: 16818210, 30403697); however, one individual had an additional RYR2 variant (PMID: 30403697). ClinVar contains an entry for this variant (Variation ID: 201396). 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.

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