ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.13411G>A (p.Gly4471Arg)

gnomAD frequency: 0.00002  dbSNP: rs794728797
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182834 SCV000235221 uncertain significance not provided 2023-03-30 criteria provided, single submitter clinical testing Identified in at least one case of sudden unexplained death (SUD) in published literature (Wang et al., 2014; Lin et al., 2017); Not observed at significant frequency in large population cohorts (gnomAD); 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); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24631775, 29247119, 31112425, Alvarado2018)
Invitae RCV002517803 SCV001395221 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 1 2023-10-22 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 4471 of the RYR2 protein (p.Gly4471Arg). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with clinical features of RYR2-related conditions (PMID: 24631775, 31112425; Invitae). ClinVar contains an entry for this variant (Variation ID: 201346). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RYR2 protein function. 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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