Submissions for variant NM_001035.3(RYR2):c.9295G>C (p.Val3099Leu)

gnomAD frequency: 0.00001  dbSNP: rs745616771

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000392155	SCV000337459	uncertain significance	not provided	2015-11-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781829	SCV000920177	uncertain significance	not specified	2017-09-11	criteria provided, single submitter	clinical testing	Variant summary: The RYR2 c.9295G>C (p.Val3099Leu) variant involves the alteration of a conserved nucleotide and 3/3 in silico tools (SNPsandGO and Mutation Taster not captured here due to low reliability index and p-value, respectively) predict a benign outcome. This variant was found in 5/239622 control chromosomes, predominantly observed in the Latino subpopulation at a frequency of 0.000152 (5/32962). This frequency is about 6 times the estimated maximal expected allele frequency of a pathogenic RYR2 variant (0.000025), suggesting this is likely a benign polymorphism found primarily in population(s) of Latino origin. A publication, Landstrom_2017, cites the variant to have been observed in a cohort of affected and unaffected individuals, however, exact frequency in each cohort is not provided. A clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as a "Variant of Uncertain Significance - Possibly Benign."
Invitae	RCV002519159	SCV001220591	likely benign	Catecholaminergic polymorphic ventricular tachycardia 1	2023-09-29	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001525717	SCV001735899	uncertain significance	Cardiomyopathy	2023-04-24	criteria provided, single submitter	clinical testing	This missense variant replaces valine with leucine at codon 3099 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 cardiovascular disorders in the literature. This variant has been identified in 5/242622 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.
Ambry Genetics	RCV002374463	SCV002686676	uncertain significance	Cardiovascular phenotype	2022-11-23	criteria provided, single submitter	clinical testing	The p.V3099L variant (also known as c.9295G>C), located in coding exon 65 of the RYR2 gene, results from a G to C substitution at nucleotide position 9295. The valine at codon 3099 is replaced by leucine, an amino acid with highly similar properties. This variant was reported in a whole exome testing cohort; however, clinical details were not provided (Landstrom AP et al. Circ Arrhythm Electrophysiol, 2017 Apr;10:[Epub ahead of print]). 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.