ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.5774T>C (p.Ile1925Thr)

gnomAD frequency: 0.00003  dbSNP: rs761505396
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 8
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000214458 SCV000272394 uncertain significance not specified 2015-06-25 criteria provided, single submitter clinical testing The p.Ile1925Thr variant in RYR2 has not been previously reported in individuals with cardiomyopathy, but has been identified in 3/64742 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org). Comput ational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Ile1925Thr variant is uncertain.
Labcorp Genetics (formerly Invitae), Labcorp RCV002518197 SCV001219365 likely benign Catecholaminergic polymorphic ventricular tachycardia 1 2025-01-15 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV001190428 SCV001357916 uncertain significance Cardiomyopathy 2023-01-03 criteria provided, single submitter clinical testing This missense variant replaces isoleucine with threonine at codon 1925 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 also been reported in an individual affected with atrioventricular nodal reentrant tachycardia (PMID: 32508047). This variant has been identified in 12/280152 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.
Genetics and Genomics Program, Sidra Medicine RCV001293045 SCV001434025 uncertain significance Hypertrophic cardiomyopathy criteria provided, single submitter research
GeneDx RCV001753649 SCV002005111 uncertain significance not provided 2019-07-01 criteria provided, single submitter clinical testing Has not been reported in association with cardiac disease; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID 229222; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 25925909)
Ambry Genetics RCV002354611 SCV002652104 uncertain significance Cardiovascular phenotype 2023-12-08 criteria provided, single submitter clinical testing The p.I1925T variant (also known as c.5774T>C), located in coding exon 38 of the RYR2 gene, results from a T to C substitution at nucleotide position 5774. The isoleucine at codon 1925 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in a cyclic vomiting syndrome (CVS) cohort, a catecholaminergic polymorphic ventricular tachycardia (CPVT) cohort, and an atrioventricular nodal reentry tachycardia (AVNRT) cohort; however, clinical details were limited for these cohorts (Lee J et al. Neurogastroenterol Motil, 2015 Jul;27:990-6; Landstrom AP et al. Circ Arrhythm Electrophysiol, 2017 Apr;10; Luo R et al. Clin Transl Med, 2020 Jan;10:238-257). This amino acid position is 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.
All of Us Research Program, National Institutes of Health RCV003997752 SCV004820289 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2024-06-11 criteria provided, single submitter clinical testing This missense variant replaces isoleucine with threonine at codon 1925 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 also been reported in an individual affected with atrioventricular nodal reentrant tachycardia (PMID: 32508047). This variant has been identified in 12/280152 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.
Breakthrough Genomics, Breakthrough Genomics RCV001753649 SCV005186372 uncertain significance not provided criteria provided, single submitter not provided

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.