Submissions for variant NM_001035.3(RYR2):c.8617C>T (p.Pro2873Ser)

dbSNP: rs1031049689

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003103764	SCV000541665	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2022-03-18	criteria provided, single submitter	clinical testing	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. 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 expected to disrupt RYR2 protein function. ClinVar contains an entry for this variant (Variation ID: 404193). This variant has not been reported in the literature in individuals affected with RYR2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 2873 of the RYR2 protein (p.Pro2873Ser).
Fulgent Genetics, Fulgent Genetics	RCV000765091	SCV000896300	uncertain significance	Arrhythmogenic right ventricular dysplasia 2; Catecholaminergic polymorphic ventricular tachycardia 1	2018-10-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001189973	SCV001357374	uncertain significance	Cardiomyopathy	2023-09-14	criteria provided, single submitter	clinical testing	This missense variant replaces proline with serine at codon 2873 of the RYR2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 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. This variant has not been identified 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	RCV001775798	SCV002012825	uncertain significance	not provided	2019-07-09	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar but additional evidence is not available (ClinVar Variant ID# 404193; Landrum et al., 2016); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Is 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)
Ambry Genetics	RCV002446769	SCV002681419	uncertain significance	Cardiovascular phenotype	2018-09-12	criteria provided, single submitter	clinical testing	The p.P2873S variant (also known as c.8617C>T), located in coding exon 59 of the RYR2 gene, results from a C to T substitution at nucleotide position 8617. The proline at codon 2873 is replaced by serine, an amino acid with similar properties. 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.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003227749	SCV003924154	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1; Ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome	2021-03-30	criteria provided, single submitter	clinical testing	RYR2 NM_001035.2 exon 59 p.Pro2873Ser (c.8617C>T): This variant has not been reported in the literature and is not present in large control databases. This variant is present in ClinVar (Variation ID:404193). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
All of Us Research Program, National Institutes of Health	RCV004805022	SCV005427982	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia	2024-08-13	criteria provided, single submitter	clinical testing	This missense variant replaces proline with serine at codon 2873 of the RYR2 protein.. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 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 cardiovascular disorders in the literature. This variant has not been identified 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.
Fulgent Genetics, Fulgent Genetics	RCV003227749	SCV005643793	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1; Ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome	2024-01-23	criteria provided, single submitter	clinical testing