Submissions for variant NM_001035.3(RYR2):c.2374G>A (p.Val792Ile)

gnomAD frequency: 0.00002  dbSNP: rs764485892

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002535510	SCV000960212	likely benign	Catecholaminergic polymorphic ventricular tachycardia 1	2024-10-07	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001183108	SCV001348763	uncertain significance	Cardiomyopathy	2023-03-21	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 792 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 4/280668 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.
PreventionGenetics, part of Exact Sciences	RCV004538125	SCV004121178	uncertain significance	RYR2-related disorder	2022-09-14	criteria provided, single submitter	clinical testing	The RYR2 c.2374G>A variant is predicted to result in the amino acid substitution p.Val792Ile. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0083% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-237664181-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
All of Us Research Program, National Institutes of Health	RCV004002815	SCV004814676	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia	2024-09-23	criteria provided, single submitter	clinical testing	Variant of Uncertain Significance due to insufficient evidence: This missense variant replaces valine with isoleucine at codon 792 of the RYR2 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact 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 4/280668 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively.
Ambry Genetics	RCV004029010	SCV005037062	uncertain significance	Cardiovascular phenotype	2023-11-21	criteria provided, single submitter	clinical testing	The p.V792I variant (also known as c.2374G>A), located in coding exon 21 of the RYR2 gene, results from a G to A substitution at nucleotide position 2374. The valine at codon 792 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is well 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.