Submissions for variant NM_001035.3(RYR2):c.1354G>A (p.Val452Ile)

gnomAD frequency: 0.00002  dbSNP: rs375218751

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV002528361	SCV000637513	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2023-12-22	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 452 of the RYR2 protein (p.Val452Ile). This variant is present in population databases (rs375218751, gnomAD 0.009%). 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: 463568). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RYR2 protein function with a negative predictive value of 95%. 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769773	SCV000901196	uncertain significance	Cardiomyopathy	2016-02-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000769773	SCV001344336	uncertain significance	Cardiomyopathy	2023-06-21	criteria provided, single submitter	clinical testing	This variant is located in 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 13/279996 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357848	SCV001553437	uncertain significance	not provided		no assertion criteria provided	clinical testing	The RYR2 p.Val452Ile variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0 databases. The variant was identified in dbSNP (ID: rs375218751) as "With Uncertain significance allele" and in ClinVar (classified as VUS by Invitae with associated condition of Catecholaminergic polymorphic ventricular tachycardia). The variant was identified in control databases in 13 of 279996 chromosomes at a frequency of 0.000046 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 11 of 128000 chromosomes (freq: 0.000086) and European (Finnish) in 2 of 25006 chromosomes (freq: 0.00008), while the variant was not observed in the African, Latino, Ashkenazi Jewish, East Asian, Other and South Asian populations. The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (MaxEntScan and NNSplice) predict the loss of a 5' splice site at the site of variation; although this is not very predictive of pathogenicity. The p.Val452 residue is conserved in mammals and distantly related organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.