ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.6284T>C (p.Ile2095Thr)

gnomAD frequency: 0.00002  dbSNP: rs142498105
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV002537392 SCV000955595 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 1 2022-03-18 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 2095 of the RYR2 protein (p.Ile2095Thr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with catecholaminergic polymorphic ventricular tachycardia (CPVT) and hypertrophic cardiomyopathy (PMID: 26189708, 26688388). ClinVar contains an entry for this variant (Variation ID: 658340). 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.
Color Diagnostics, LLC DBA Color Health RCV001188546 SCV001355619 uncertain significance Cardiomyopathy 2023-06-08 criteria provided, single submitter clinical testing This variant is located 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 an individual affected with catecholaminergic polymorphic ventricular tachycardia (PMID: 26189708) and in an individual affected with hypertrophic cardiomyopathy (PMID: 26688388). This variant has been identified in 10/280556 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 RCV002363125 SCV002657072 uncertain significance Cardiovascular phenotype 2023-03-23 criteria provided, single submitter clinical testing The p.I2095T variant (also known as c.6284T>C), located in coding exon 41 of the RYR2 gene, results from a T to C substitution at nucleotide position 6284. The isoleucine at codon 2095 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in a subject with catecholaminergic polymorphic ventricular tachycardia (CPVT) and in a sudden cardiac death cohort (Jiménez-Jáimez J et al. Am. J. Cardiol., 2015 Sep;116:894-9; Chanavat V et al. Clin. Chim. Acta, 2016 Jan;453:80-5). This alteration was also noted as a secondary finding in an exome cohort (Diebold I et al. Hum Mutat, 2020 May;41:1025-1032). This amino acid position is not well conserved in available vertebrate species, and threonine is the reference amino acid in other 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.
Fulgent Genetics, Fulgent Genetics RCV002487791 SCV002777673 uncertain significance Arrhythmogenic right ventricular dysplasia 2; Catecholaminergic polymorphic ventricular tachycardia 1; Ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome 2021-10-08 criteria provided, single submitter clinical testing

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