ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.9742C>T (p.Arg3248Cys)

gnomAD frequency: 0.00001  dbSNP: rs1290534109
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000621125 SCV000736750 uncertain significance Cardiovascular phenotype 2020-12-17 criteria provided, single submitter clinical testing The p.R3248C variant (also known as c.9742C>T), located in coding exon 68 of the RYR2 gene, results from a C to T substitution at nucleotide position 9742. The arginine at codon 3248 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health RCV001179340 SCV001343987 uncertain significance Cardiomyopathy 2024-05-02 criteria provided, single submitter clinical testing This missense variant replaces arginine with cysteine at codon 3248 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with RYR2-related disorders in the literature. This variant has been identified in 2/249000 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV002531756 SCV002127589 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 1 2024-06-02 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 3248 of the RYR2 protein (p.Arg3248Cys). This variant is present in population databases (no rsID available, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with RYR2-related conditions. ClinVar contains an entry for this variant (Variation ID: 518975). 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 with a negative predictive value of 95%. 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.
Fulgent Genetics, Fulgent Genetics RCV002477344 SCV002784929 uncertain significance Arrhythmogenic right ventricular dysplasia 2; Catecholaminergic polymorphic ventricular tachycardia 1; Ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome 2021-11-03 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV004002663 SCV004817190 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2024-05-14 criteria provided, single submitter clinical testing This missense variant replaces arginine with cysteine at codon 3248 of the RYR2 protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <=0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 2/249000 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.
GeneDx RCV004794422 SCV005414926 uncertain significance not provided 2024-05-24 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not located in one of the three hot-spot regions of the RYR2 gene, where the majority of pathogenic missense variants occur (PMID: 19926015); Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 34758253, 19926015)
Genomics England Pilot Project, Genomics England RCV001542518 SCV001760028 likely pathogenic Arrhythmogenic right ventricular dysplasia 2 no assertion criteria provided clinical testing

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