ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.5657dup (p.Lys1887fs)

dbSNP: rs786205273
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health RCV000171566 SCV000050830 uncertain significance Polymorphic ventricular tachycardia 2018-04-05 criteria provided, single submitter research
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV001248999 SCV001422843 uncertain significance not specified 2020-01-22 criteria provided, single submitter curation The p.Lys1887Glnfs17 variant in RYR2 has not been previously reported in individuals with RYR2-related disease but was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 1887 and leads to a premature termination codon 17 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. It is of note that loss of function of RYR2 in an autosomal dominant disease has not yet been established based on the criteria laid out in Tayoun, 2018 (PMID: 30192042). The number of missense variants reported in RYR2 in the general population is lower than expected, suggesting there is little benign variation in this gene and slightly increasing the possibility that a missense variant in this gene may not be tolerated. In summary, the clinical significance of the p.Lys1887Glnfs17 variant is uncertain. ACMG/AMP Criteria applied: PM2, PP2 (Richards 2015).
Fulgent Genetics, Fulgent Genetics RCV002478544 SCV002779739 uncertain significance Arrhythmogenic right ventricular dysplasia 2; Catecholaminergic polymorphic ventricular tachycardia 1; Ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome 2021-11-16 criteria provided, single submitter clinical testing
GeneDx RCV003319327 SCV004023640 uncertain significance not provided 2023-02-01 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene or region of a gene for which loss of function is not a well-established mechanism of disease; Has not been previously published as pathogenic or benign to our knowledge

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