ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.2545G>A (p.Asp849Asn)

gnomAD frequency: 0.00004  dbSNP: rs372569289
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV002561131 SCV001374889 likely benign Catecholaminergic polymorphic ventricular tachycardia 1 2024-12-24 criteria provided, single submitter clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute RCV001256776 SCV001433220 uncertain significance not provided 2019-12-09 criteria provided, single submitter clinical testing
GeneDx RCV001256776 SCV002008806 uncertain significance not provided 2023-08-22 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter 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 (Medeiros-Domingo et al., 2009); Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 19926015)
Ambry Genetics RCV002429871 SCV002742496 uncertain significance Cardiovascular phenotype 2023-01-24 criteria provided, single submitter clinical testing The p.D849N variant (also known as c.2545G>A), located in coding exon 22 of the RYR2 gene, results from a G to A substitution at nucleotide position 2545. The aspartic acid at codon 849 is replaced by asparagine, an amino acid with highly similar properties. This variant was reported as an incidental finding in an exome cohort; however, clinical details were limited (Landstrom AP et al. Circ Arrhythm Electrophysiol, 2017 Apr;10:[Epub ahead of print]). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics RCV002484100 SCV002790455 uncertain significance Arrhythmogenic right ventricular dysplasia 2; Catecholaminergic polymorphic ventricular tachycardia 1; Ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome 2021-09-30 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV003532891 SCV004360539 uncertain significance Cardiomyopathy 2023-11-28 criteria provided, single submitter clinical testing This missense variant replaces aspartic acid with asparagine at codon 849 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 4/280680 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.
All of Us Research Program, National Institutes of Health RCV004010632 SCV004814865 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2024-05-09 criteria provided, single submitter clinical testing This missense variant replaces aspartic acid with asparagine at codon 849 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 cardiovascular disorders in the literature. This variant has been identified in 4/280680 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.
Juno Genomics, Hangzhou Juno Genomics, Inc RCV004819240 SCV005440618 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 1; Ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome criteria provided, single submitter clinical testing PM2_Supporting

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