Submissions for variant NM_001035.3(RYR2):c.10142+4T>C

gnomAD frequency: 0.00001  dbSNP: rs397516496

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036646	SCV000060301	uncertain significance	not specified	2012-12-14	criteria provided, single submitter	clinical testing	The 10142+4T>C variant in RYR2 has not been reported in the literature nor previ ously identified by our laboratory. This variant has also not been identified i n large and broad European American and African American populations by the NHLB I Exome Sequencing Project (http://evs.gs.washington.edu/EVS), though it may be common in other populations. This variant is located in the 5' splice region. Co mputational tools do not suggest an impact to splicing. However, this informatio n is not predictive enough to rule out pathogenicity. Additional information is needed to fully assess the clinical significance of the 10142+4T>C variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002513391	SCV000957186	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2023-11-08	criteria provided, single submitter	clinical testing	This sequence change falls in intron 69 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 not present in population databases (gnomAD no frequency). 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: 43696). 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	RCV001192358	SCV001360408	likely benign	Cardiomyopathy	2019-07-11	criteria provided, single submitter	clinical testing
GeneDx	RCV001636621	SCV001850863	benign	not provided	2015-05-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000036646	SCV002500744	uncertain significance	not specified	2022-03-29	criteria provided, single submitter	clinical testing	Variant summary: RYR2 c.10142+4T>C alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 208128 control chromosomes. 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.10142+4T>C in individuals affected with Catecholaminergic Polymorphic Ventricular Tachycardia and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health	RCV003996232	SCV004843691	likely benign	Catecholaminergic polymorphic ventricular tachycardia	2023-10-27	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004018802	SCV004943178	uncertain significance	Cardiovascular phenotype	2022-02-20	criteria provided, single submitter	clinical testing	The c.10142+4T>C intronic alteration consists of a T to C substitution nucleotides after coding exon 69 in the RYR2 gene. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.