Submissions for variant NM_001035.3(RYR2):c.10640C>T (p.Thr3547Met)

gnomAD frequency: 0.00004  dbSNP: rs552050895

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182789	SCV000235175	uncertain significance	not provided	2012-07-18	criteria provided, single submitter	clinical testing	p.Thr3547Met (ACG>ATG): c.10640 C>T in exon 74 of the RYR2 gene (NM_001035.2). The Thr3547Met variant in the RYR2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Thr3547Met results in a non-conservative amino acid substitution of a polar Threonine residue with a non-polar Methionine residue at a position that is conserved across species. In silico analysis predicts Thr3547Met is possibly damaging to the protein structure/function. Furthermore, the NHLBI ESP Exome Variant Server reports Thr3547Met was not observed in approximately 9,500 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. Nevertheless, no mutations in surrounding residues have been reported, indicating this region of the protein may be tolerant of change. We cannot definitively determine if Thr3547Met is a disease-causing mutation or a rare benign variant. The variant is found in POSTMORTEM panel(s).
Ambry Genetics	RCV000620260	SCV000735779	uncertain significance	Cardiovascular phenotype	2023-07-05	criteria provided, single submitter	clinical testing	The p.T3547M variant (also known as c.10640C>T), located in coding exon 74 of the RYR2 gene, results from a C to T substitution at nucleotide position 10640. The threonine at codon 3547 is replaced by methionine, an amino acid with similar properties. This alteration has been reported in a whole exome sequencing cohort (Landstrom AP et al. Circ Arrhythm Electrophysiol, 2017 Apr;10:). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000852417	SCV000995101	uncertain significance	Congestive heart failure	2018-01-17	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001190680	SCV001358242	uncertain significance	Cardiomyopathy	2023-05-10	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with methionine at codon 3547 of the RYR2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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 been identified in 15/280260 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003153462	SCV001507980	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2025-01-01	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 3547 of the RYR2 protein (p.Thr3547Met). This variant is present in population databases (rs552050895, gnomAD 0.03%). 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: 201305). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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.
Fulgent Genetics, Fulgent Genetics	RCV002485214	SCV002791953	uncertain significance	Arrhythmogenic right ventricular dysplasia 2; Catecholaminergic polymorphic ventricular tachycardia 1; Ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome	2021-09-29	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003996776	SCV004815852	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia	2024-04-10	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with methionine at codon 3547 of the RYR2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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 been identified in 15/280260 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.