ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.2350A>T (p.Ile784Phe)

gnomAD frequency: 0.00001  dbSNP: rs794728729
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color Diagnostics, LLC DBA Color Health RCV001177216 SCV001341391 uncertain significance Cardiomyopathy 2023-10-26 criteria provided, single submitter clinical testing This missense variant replaces isoleucine with phenylalanine at codon 784 of the RYR2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has shown this variant causes significant increase in calcium oscillation frequency and an enhanced store overload-induced calcium release in response to cAMP treatment in transfected HEK293 cells (PMID: 33664309). This study also showed that this variant causes a conformational change which impacts channel gating and also affects thermal stability resulting in a strong destabilizing effect. This variant has been reported in one individual who experienced sudden cardiac death after experiencing short-coupled torsade de pointes (PMID: 33664309). This variant has been identified in 2/249286 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Invitae RCV002516873 SCV003517831 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 1 2022-01-11 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 784 of the RYR2 protein (p.Ile784Phe). This variant is present in population databases (rs794728729, gnomAD 0.006%). This missense change has been observed in individual(s) with RYR2-related conditions (PMID: 33664309). ClinVar contains an entry for this variant (Variation ID: 201228). 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) performed at Invitae indicates that this missense variant is not expected to disrupt RYR2 protein function. Experimental studies have shown that this missense change affects RYR2 function (PMID: 33664309). 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.
All of Us Research Program, National Institutes of Health RCV003996747 SCV004814632 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2023-12-13 criteria provided, single submitter clinical testing This missense variant replaces isoleucine with phenylalanine at codon 784 of the RYR2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has shown this variant causes significant increase in calcium oscillation frequency and an enhanced store overload-induced calcium release in response to cAMP treatment in transfected HEK293 cells (PMID: 33664309). This study also showed that this variant causes a conformational change which impacts channel gating and also affects thermal stability resulting in a strong destabilizing effect. This variant has been reported in one individual who experienced sudden cardiac death after experiencing short-coupled torsade de pointes (PMID: 33664309). This variant has been identified in 2/249286 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

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