Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV002543657 | SCV001505490 | uncertain significance | Catecholaminergic polymorphic ventricular tachycardia 1 | 2023-11-17 | criteria provided, single submitter | clinical testing | This sequence change replaces isoleucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 449 of the RYR2 protein (p.Ile449Arg). This variant is present in population databases (rs373331669, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of RYR2-related conditions (PMID: 29037160, 30975432). ClinVar contains an entry for this variant (Variation ID: 1015998). 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 not expected to disrupt RYR2 protein function with a negative predictive value of 95%. 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, |
RCV001526171 | SCV001736468 | uncertain significance | Cardiomyopathy | 2023-05-24 | criteria provided, single submitter | clinical testing | This missense variant replaces isoleucine with arginine at codon 449 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 three individuals from a family affected with Jervell and Lange-Nielsen syndrome. However, a homozygous pathogenic variant in the KCNQ1 gene was identified in this family and could explain the observed phenotype (PMID: 29037160). This variant has also been reported in a sudden cardiac arrest survivor without cardiac phenotype (PMID: 30975432). This variant has been identified in 5/248594 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. |
| Dept of Medical Biology, |
RCV003318401 | SCV004022075 | uncertain significance | Long QT syndrome | 2024-01-08 | criteria provided, single submitter | research | Criteria: PM2, PP2, PP3 |
| All of Us Research Program, |
RCV004005077 | SCV004844455 | uncertain significance | Catecholaminergic polymorphic ventricular tachycardia | 2023-10-27 | criteria provided, single submitter | clinical testing | This missense variant replaces isoleucine with arginine at codon 449 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 three individuals from a family affected with Jervell and Lange-Nielsen syndrome. However, a homozygous pathogenic variant in the KCNQ1 gene was identified in this family and could explain the observed phenotype (PMID: 29037160). This variant has also been reported in a sudden cardiac arrest survivor without cardiac phenotype (PMID: 30975432). This variant has been identified in 5/248594 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. |