Submissions for variant NM_001035.3(RYR2):c.4747C>T (p.Pro1583Ser)

gnomAD frequency: 0.00014  dbSNP: rs200070226

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000766723	SCV000568207	uncertain significance	not provided	2022-11-03	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on 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); This variant is associated with the following publications: (PMID: 28404607, 30615648, 32048431, 25041964, 31402444, 26383259, 34426522, 19926015)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000766723	SCV000732034	uncertain significance	not provided	2022-10-27	criteria provided, single submitter	clinical testing	The p.Pro1583Ser variant in RYR2 has been reported in the literature in 1 individual with SCD and 1 individual with ARVC. For the patient with ARVC, the variant segregated with disease in 1 affected relative and 1 relative with borderline clinical features (Roux-Buisson 2014, Hertz 2016). The variant has also been identified in 13/34114 Latino chromosomes and 11/125230 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs200070226). This variant has also been reported in ClinVar (Variation ID:419965). Computational prediction tools and conservation analysis suggest that the p.Pro1583Ser variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Pro1583Ser variant is uncertain. The ACMG/AMP Criteria applied: PP3; PS4_Supporting.
Invitae	RCV002526557	SCV000938753	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2022-10-04	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1583 of the RYR2 protein (p.Pro1583Ser). This variant is present in population databases (rs200070226, gnomAD 0.04%). This missense change has been observed in individual(s) with RYR2-related conditions (PMID: 25041964, 26383259, 30615648). ClinVar contains an entry for this variant (Variation ID: 419965). 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. 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001171196	SCV001333892	likely benign	Cardiomyopathy	2018-12-13	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001171196	SCV001351113	uncertain significance	Cardiomyopathy	2023-03-29	criteria provided, single submitter	clinical testing	This variant replaces proline with serine at codon 1583 in 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 been reported in individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 25041964), sudden cardiac death (PMID: 26383259), idiopathic ventricular fibrillation (PMID: 31114860), and Wolff-Parkinson-White syndrome and supraventricular tachycardia (PMID: 32233023). This variant occurs at an elevated frequency in the general population and has been identified in 27/277360 chromosomes 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.
Ambry Genetics	RCV002341136	SCV002635969	likely benign	Cardiovascular phenotype	2022-02-22	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000482205	SCV003934699	uncertain significance	not specified	2023-05-15	criteria provided, single submitter	clinical testing	Variant summary: RYR2 c.4747C>T (p.Pro1583Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 245972 control chromosomes, predominantly at a frequency of 0.00038 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 11.054 fold of the estimated maximal expected allele frequency for a pathogenic variant in RYR2 causing Catecholaminergic Polymorphic Ventricular Tachycardia phenotype (3.4e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.4747C>T has been reported in the literature in individuals from one family affected with Arrhythmogenic right Ventricular Cardiomyopathy (Roux-Buisson_2014), in individuals with Sudden Cardiac Death (Hertz_2016), Long QT syndrome (Coll_2018) and Arrhythmogenic cardiomyopathy (Goudal_2022). However, the current evidence at this time is not sufficient to determine the role of this variant in disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30020974, 35819174, 26383259, 25041964, 30615648). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments: Likely Benign (n=2) and VUS (n-5). Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health	RCV004003317	SCV004823705	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia	2024-02-05	criteria provided, single submitter	clinical testing	This variant replaces proline with serine at codon 1583 in 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 been reported in individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 25041964), sudden cardiac death (PMID: 26383259), idiopathic ventricular fibrillation (PMID: 31114860), and Wolff-Parkinson-White syndrome and supraventricular tachycardia (PMID: 32233023). This variant occurs at an elevated frequency in the general population and has been identified in 27/277360 chromosomes 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.
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	RCV000656153	SCV000678347	uncertain significance	Wolff-Parkinson-White pattern	2017-07-14	no assertion criteria provided	research	This variant was identified in an individual with Wolff-Parkinson-White syndrome