Submissions for variant NM_001035.3(RYR2):c.5917A>G (p.Ile1973Val)

gnomAD frequency: 0.00002  dbSNP: rs780681855

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001182176	SCV001347532	uncertain significance	Cardiomyopathy	2023-02-28	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 1973 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with RYR2-related disorders in the literature. This variant has been identified in 5/246196 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002559798	SCV002198360	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2024-04-26	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1973 of the RYR2 protein (p.Ile1973Val). This variant is present in population databases (rs780681855, gnomAD 0.006%). 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: 922238). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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.
Ambry Genetics	RCV002356843	SCV002653338	uncertain significance	Cardiovascular phenotype	2023-10-25	criteria provided, single submitter	clinical testing	The p.I1973V variant (also known as c.5917A>G), located in coding exon 39 of the RYR2 gene, results from an A to G substitution at nucleotide position 5917. This variant impacts the first base pair of coding exon 39. The isoleucine at codon 1973 is replaced by valine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002483987	SCV002776609	uncertain significance	Arrhythmogenic right ventricular dysplasia 2; Catecholaminergic polymorphic ventricular tachycardia 1; Ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome	2021-10-12	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004008280	SCV004818501	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia	2024-07-29	criteria provided, single submitter	clinical testing	Variant of Uncertain Significance due to insufficient evidence: This variant is located in the cytoplasmic domain of the RYR2 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 6/243346 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center	RCV002559798	SCV005397167	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2023-12-04	criteria provided, single submitter	clinical testing	This sequence variant is a single nucleotide substitution (A>G) at coding nucleotide 5917 of the RYR2 gene that results in a isoleucine to valine amino acid change at residue 1973 of the RYR2 protein. This is a previously reported variant (ClinVar) that has not been observed in individuals with a RYR2-related disorder in the published literature, to our knowledge. This variant is present in 5 of 246,196 alleles in the gnomAD population database (0.002%). Multiple bioinformatic tools predict that this isoleucine to valine amino acid change would be damaging, and the Ile1973 residue is strongly conserved across the vertebrate species examined. Studies examining the functiol consequence of this variant have not been published, to our knowledge. At this time, there is insufficient evidence to determine if this variant is pathogenic or benign. Therefore, we consider this a variant of uncertain significance. ACMG Criteria: PM2, PP2, PP3