ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.12667_12669del (p.Lys4223del) (rs794728838)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182901 SCV000235290 uncertain significance not provided 2017-06-16 criteria provided, single submitter clinical testing The c.12667_12669delAAG variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. c.12667_12669delAAG results in the deletion of a moderately conserved Lysine residue at position 4223 and does not cause a shift in reading frame. Other in-frame deletion/duplication mutations in the RYR2 have been reported in association with CPVT. Additionally, c.12667_12669delAAG is located in the channel region hot spot" of the RYR2 gene (Medeiros-Domingo et al., 2009). However, the NHLBI Exome Sequencing Project reports c.12667_12669delAAG was observed at a low frequency in 1/7990 alleles from individuals of European background and 4/3824 alleles from individuals of African American background, including one individual homozygous for c.12667_12669delAAG. Therefore, it is unclear whether this variant is a pathogenic mutation or a rare benign variant."
Integrated Genetics/Laboratory Corporation of America RCV000781826 SCV000920174 likely benign not specified 2018-07-16 criteria provided, single submitter clinical testing Variant summary: RYR2 c.12667_12669delAAG (p.Lys4223del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 7.6e-05 in 276480 control chromosomes (gnomAD). The observed variant frequency is approximately 1.27 fold of the estimated maximal expected allele frequency for a pathogenic variant in RYR2 causing Arrhythmia phenotype (6e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.12667_12669delAAG in individuals affected with Arrhythmia and no experimental evidence demonstrating its impact on protein function have been reported. One ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as "uncertian significance." Based on the evidence outlined above, the variant was classified as likely benign.
Color RCV001177598 SCV001341835 uncertain significance Cardiomyopathy 2020-02-19 criteria provided, single submitter clinical testing
Invitae RCV001220668 SCV001392673 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2019-05-23 criteria provided, single submitter clinical testing This variant, c.12667_12669delAAG, results in the deletion of 1 amino acid(s) of the RYR2 protein (p.Lys4223del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs780366391, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with RYR2-related disease. ClinVar contains an entry for this variant (Variation ID: 201411). Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the deleted amino acid(s) is currently unknown. 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.

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.