Submissions for variant NM_001035.3(RYR2):c.2510G>C (p.Ser837Thr)

dbSNP: rs375607964

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001188379	SCV001355434	uncertain significance	Cardiomyopathy	2023-12-08	criteria provided, single submitter	clinical testing	This missense variant replaces serine with threonine at codon 837 of the RYR2 protein. Computational prediction tools indicate that this variant has a neutral impact on protein structure and function. 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.
Invitae	RCV002554818	SCV002277307	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2023-12-27	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 837 of the RYR2 protein (p.Ser837Thr). This variant is not present in population databases (gnomAD no frequency). 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: 870976). 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.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV003321800	SCV004026410	uncertain significance	not provided	2023-07-26	criteria provided, single submitter	clinical testing	PM2_SUP, PP2
All of Us Research Program, National Institutes of Health	RCV004000211	SCV004814798	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia	2023-12-18	criteria provided, single submitter	clinical testing	This missense variant replaces serine with threonine at codon 837 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). 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 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.