Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000480543 | SCV000570033 | uncertain significance | not provided | 2020-04-16 | criteria provided, single submitter | clinical testing | Has not been previously published as pathogenic or benign to our knowledge; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not located in one of the three hot-spot regions of the RYR2 gene, where the majority of pathogenic missense variants occur (Medeiros-Domingo et al., 2009) |
| Labcorp Genetics |
RCV002526589 | SCV002258459 | uncertain significance | Catecholaminergic polymorphic ventricular tachycardia 1 | 2021-08-31 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine with tryptophan at codon 76 of the RYR2 protein (p.Arg76Trp). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs542777295, ExAC 0.01%). This variant has not been reported in the literature in individuals affected with RYR2-related conditions. ClinVar contains an entry for this variant (Variation ID: 420977). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RYR2 protein function. 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. |
| Color Diagnostics, |
RCV003532140 | SCV004358244 | uncertain significance | Cardiomyopathy | 2022-10-11 | criteria provided, single submitter | clinical testing | This missense variant replaces arginine with tryptophan at codon 76 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 been reported in an individual suspected of having catecholaminergic polymorphic ventricular tachycardia (PMID: 29453246). This variant has been identified in 3/280598 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. |
| Victorian Clinical Genetics Services, |
RCV002526589 | SCV005087146 | uncertain significance | Catecholaminergic polymorphic ventricular tachycardia 1 | 2023-07-17 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0103 - Dominant negative and gain of function are known mechanisms of disease in this gene and are associated with catecholaminergic polymorphic ventricular tachycardia 1 (MIM#604772) and left ventricular non-compaction (PMIDs: 12459180, 27646203, 29477366, 31875585, 33500567). Loss of function has been reported for ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome (MIM#115000), however dominant negative mechanism has not been excluded (PMID: 33536282). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. Penetrance for CPVT is estimated to be 60-70% (PMID: 23549275). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2 & v3) <0.001 for a dominant condition (3 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated inositol 1,4,5-trisphosphate/ryanodine receptor domain (DECIPHER). (I) 0710 - Other missense variant(s) comparable to the one identified in this case have inconclusive previous evidence for pathogenicity. p.(Arg76Pro) and p.(Arg76Gln) have been reported as VUS by clinical testing laboratories (ClinVar). The p.(Arg76Gln) variant was identified in an individual with cardiomyopathy, and another with DCM and heart failure (ClinVar, personal communication). (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. It has been reported as a VUS by two clinical testing laboratories, including in an individual with chronic systolic (congestive) heart failure (ClinVar, personal communication). In addition, it has been reported as a rare variant in an individual with suspected CPVT (PMID: 29453246). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |