ClinVar Miner

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

gnomAD frequency: 0.00004  dbSNP: rs552050895
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Total submissions: 6
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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, this alteration is predicted to be tolerated by in silico analysis. 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.
Invitae RCV003153462 SCV001507980 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 1 2022-08-22 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). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65"). 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

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