Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Blueprint Genetics | RCV000208294 | SCV000264187 | uncertain significance | Primary familial hypertrophic cardiomyopathy | 2015-06-01 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV002517404 | SCV003469440 | uncertain significance | Catecholaminergic polymorphic ventricular tachycardia 1 | 2023-05-15 | criteria provided, single submitter | clinical testing | 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on RYR2 function (PMID: 27756708). 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. ClinVar contains an entry for this variant (Variation ID: 222791). This missense change has been observed in individual(s) with clinical features of RYR2-related conditions (PMID: 27756708). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2673 of the RYR2 protein (p.Ala2673Val). |
| 3billion | RCV002517404 | SCV003841431 | likely pathogenic | Catecholaminergic polymorphic ventricular tachycardia 1 | 2023-02-23 | criteria provided, single submitter | clinical testing | The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Missense changes are a common disease-causing mechanism. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 27756708). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.71; 3Cnet: 0.11). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with RYR2 related disorder (PMID: 27756708). However, the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. |