ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.14845T>C (p.Trp4949Arg) (rs794728810)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 2
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182852 SCV000235240 uncertain significance not provided 2017-07-10 criteria provided, single submitter clinical testing The W4949R variant has not been published as a pathogenic variant nor as benign to our knowledge. The W4949R variant was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The W4949R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved within the cytoplasmic domain across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Variants in nearby residues (R4950K, R4959Q) have been reported in association with CPVT, supporting the functional importance of this region of the protein. Additionally, W4949R is located in the channel region, a hotspot region of the RYR2 gene (Medeiros-Domingo A et al., 2009). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000687362 SCV000814925 likely pathogenic Catecholaminergic polymorphic ventricular tachycardia 2018-06-18 criteria provided, single submitter clinical testing This sequence change replaces tryptophan with arginine at codon 4949 of the RYR2 protein (p.Trp4949Arg). The tryptophan residue is highly conserved and there is a moderate physicochemical difference between tryptophan and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in an individual affected with RYR2-related disease (Invitae). ClinVar contains an entry for this variant (Variation ID: 201363). 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 C0"). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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.