Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000182737 | SCV000235121 | uncertain significance | not provided | 2014-06-30 | criteria provided, single submitter | clinical testing | p.Arg1941Ser (CGT>AGT): c.5821 C>A in exon 38 of the RYR2 gene (NM_001035.2). The R1941S variant has not been published as a mutation or reported as a benign polymorphism to our knowledge. The R1941S variant was not observed in approximately 6200 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Additionally, this substitution occurs at a position that is conserved across species. The R1941S variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties and in silico analysis predicted the variant to be probably damaging to the protein structure/function. However, missense mutations in nearby residues have not been reported in association with arrhythmia. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in ARRHYTHMIA panel(s). |
| Color Diagnostics, |
RCV001189921 | SCV001357306 | uncertain significance | Cardiomyopathy | 2020-02-19 | criteria provided, single submitter | clinical testing | This missense variant replaces arginine with serine at codon 1941 of the RYR2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 2/248956 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. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001193371 | SCV001362142 | uncertain significance | not specified | 2019-08-12 | criteria provided, single submitter | clinical testing | Variant summary: RYR2 c.5821C>A (p.Arg1941Ser) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 248956 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.5821C>A in individuals affected with Arrhythmia and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. |
| Invitae | RCV002516883 | SCV001415284 | likely benign | Catecholaminergic polymorphic ventricular tachycardia 1 | 2023-06-29 | criteria provided, single submitter | clinical testing |