Submissions for variant NM_001035.3(RYR2):c.8590+4A>G

gnomAD frequency: 0.00010  dbSNP: rs778964264

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000619950	SCV000736091	uncertain significance	Cardiovascular phenotype	2022-06-07	criteria provided, single submitter	clinical testing	The c.8590+4A>G intronic variant results from an A to G substitution 4 nucleotides after coding exon 58 in the RYR2 gene. This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV002531748	SCV000943493	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change falls in intron 58 of the RYR2 gene. It does not directly change the encoded amino acid sequence of the RYR2 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs778964264, gnomAD 0.02%). 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: 518737). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. 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, LLC DBA Color Health	RCV001526110	SCV001736395	uncertain significance	Cardiomyopathy	2023-06-15	criteria provided, single submitter	clinical testing	This variant causes an A to G nucleotide substitution at the +4 position of intron 58 of the RYR2 gene. Splice prediction tools are inconclusive regarding the impact of this variant on RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 3/198192 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.
GeneDx	RCV001637103	SCV001850789	uncertain significance	not provided	2021-01-28	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 is inconclusive as to whether the variant alters gene splicing; in the absence of RNA/functional studies, the actual effect of this sequence change is unknown; Reported in ClinVar but additional evidence is not available (ClinVar Variant ID#518737; Landrum et al., 2016)
Fulgent Genetics, Fulgent Genetics	RCV002506494	SCV002815224	uncertain significance	Arrhythmogenic right ventricular dysplasia 2; Catecholaminergic polymorphic ventricular tachycardia 1; Ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome	2021-12-05	criteria provided, single submitter	clinical testing