Submissions for variant NM_001035.3(RYR2):c.5570C>T (p.Pro1857Leu)

gnomAD frequency: 0.00003  dbSNP: rs568198475

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000619341	SCV000738249	likely benign	Cardiovascular phenotype	2024-01-25	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002531807	SCV000825781	likely benign	Catecholaminergic polymorphic ventricular tachycardia 1	2023-10-25	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001187319	SCV001354089	uncertain significance	Cardiomyopathy	2023-03-09	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 1857 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 been reported in an individual affected with unexplained cardiac arrest (PMID: 26189708) and in another individual affected with atrioventricular nodal reentry tachycardia (doi: 10.1002/ctm2.25). This variant has been identified in 19/279842 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	RCV001770549	SCV002004508	uncertain significance	not provided	2019-10-16	criteria provided, single submitter	clinical testing	Identified in patients with Long QT syndrome and catecholaminergic polymorphic ventricular tachycardia (CPVT) in published literature (Jimenez-Jaimez et al., 2015; Miyata et al., 2018); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 519547; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; 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); This variant is associated with the following publications: (PMID: 29434162, 26189708)
All of Us Research Program, National Institutes of Health	RCV004002709	SCV004819988	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia	2023-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 1857 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 been reported in an individual affected with unexplained cardiac arrest (PMID: 26189708) and in another individual affected with atrioventricular nodal reentry tachycardia (doi: 10.1002/ctm2.25). This variant has been identified in 19/279842 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV001770549	SCV005411592	uncertain significance	not provided	2024-08-30	criteria provided, single submitter	clinical testing	BS1, BP4, PS4_moderate