Submissions for variant NM_001035.3(RYR2):c.8414G>A (p.Arg2805His)

gnomAD frequency: 0.00001  dbSNP: rs1247067433

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000520062	SCV000622093	uncertain significance	not provided	2020-04-10	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Color Diagnostics, LLC DBA Color Health	RCV000772058	SCV000905086	uncertain significance	Cardiomyopathy	2023-09-25	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 2805 of the RYR2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, 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, however, it was detected in one stillbirth case (PMID: 30615648). This variant has been identified in 3/150324 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	RCV002527657	SCV001384149	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2024-04-26	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 2805 of the RYR2 protein (p.Arg2805His). 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 variant has not been reported in the literature in individuals affected with RYR2-related conditions. ClinVar contains an entry for this variant (Variation ID: 453215). 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.
Ambry Genetics	RCV002448582	SCV002679382	uncertain significance	Cardiovascular phenotype	2023-04-26	criteria provided, single submitter	clinical testing	The p.R2805H variant (also known as c.8414G>A), located in coding exon 56 of the RYR2 gene, results from a G to A substitution at nucleotide position 8414. The arginine at codon 2805 is replaced by histidine, an amino acid with highly similar properties. This variant has been detected in a stillbirth cohort (Sahlin E et al. PLoS ONE, 2019 Jan;14:e0210017). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health	RCV004003651	SCV004823398	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia	2023-10-06	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 2805 of the RYR2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, 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, however, it was detected in one stillbirth case (PMID: 30615648). This variant has been identified in 3/150324 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.
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	RCV001254774	SCV001430876	uncertain significance	Sudden cardiac arrest	2020-04-07	no assertion criteria provided	research	This variant has been identified as part of our research program. Refer to the 'condition' field for the phenotype of the proband identified with this variant. For further information please feel free to contact us.