Submissions for variant NM_001035.3(RYR2):c.2613+4C>G

gnomAD frequency: 0.00021  dbSNP: rs371880082

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001182013	SCV001347324	likely benign	Cardiomyopathy	2019-08-21	criteria provided, single submitter	clinical testing
Invitae	RCV002559008	SCV001390354	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2023-12-19	criteria provided, single submitter	clinical testing	This sequence change falls in intron 22 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 (rs371880082, gnomAD 0.05%). 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: 922133). 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 may disrupt the consensus splice site. 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	RCV002429814	SCV002744551	uncertain significance	Cardiovascular phenotype	2021-10-29	criteria provided, single submitter	clinical testing	The c.2613+4C>G intronic variant results from a C to G substitution 4 nucleotides after coding exon 22 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003987795	SCV004804318	uncertain significance	not specified	2024-01-09	criteria provided, single submitter	clinical testing	Variant summary: RYR2 c.2613+4C>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant weakens a 5' donor site. One predict the variant no significant impact on splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 5.6e-05 in 248830 control chromosomes, predominantly at a frequency of 0.00052 within the African or African-American subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2613+4C>G in individuals affected with Catecholaminergic Polymorphic Ventricular Tachycardia and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 922133). Based on the evidence outlined above, the variant was classified as uncertain significance.