Submissions for variant NM_001035.3(RYR2):c.11399G>T (p.Cys3800Phe)

dbSNP: rs1239093704

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001190528	SCV001358032	uncertain significance	Cardiomyopathy	2022-10-24	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with phenylalanine at codon 3800 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 been reported in an individual suspected of having long QT syndrome (PMID: 16188589). This variant has been identified in 1/247738 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.
Ambry Genetics	RCV002320419	SCV002605756	uncertain significance	Cardiovascular phenotype	2021-11-18	criteria provided, single submitter	clinical testing	The p.C3800F variant (also known as c.11399G>T), located in coding exon 83 of the RYR2 gene, results from a G to T substitution at nucleotide position 11399. The cysteine at codon 3800 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This variant has been detected in cohorts with suspected catecholaminergic polymorphic ventricular tachycardia (CPVT) or who were referred for CPVT genetic testing (Tester DJ et al. Heart Rhythm, 2005 Oct;2:1099-105; Kapplinger JD et al. Circ Genom Precis Med, 2018 02;11:e001424). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002560083	SCV003295360	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2022-09-20	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 927314). 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. This missense change has been observed in individual(s) with RYR2-related conditions (PMID: 16188589, 29453246). This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 3800 of the RYR2 protein (p.Cys3800Phe). This variant is present in population databases (no rsID available, gnomAD 0.0009%).
All of Us Research Program, National Institutes of Health	RCV004010441	SCV004824008	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia	2024-08-06	criteria provided, single submitter	clinical testing	Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the cytoplasmic domain of the RYR2 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in an individual referred explicitly for long QT syndrome genetic testing (PMID: 16188589). This variant has been identified in 1/244836 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively.