Submissions for variant NM_001035.3(RYR2):c.640G>A (p.Val214Met)

dbSNP: rs1036926941

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000617302	SCV000738205	uncertain significance	Cardiovascular phenotype	2022-02-10	criteria provided, single submitter	clinical testing	The p.V214M variant (also known as c.640G>A), located in coding exon 9 of the RYR2 gene, results from a G to A substitution at nucleotide position 640. The valine at codon 214 is replaced by methionine, 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 deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
AiLife Diagnostics, AiLife Diagnostics	RCV002223884	SCV002502289	uncertain significance	not provided	2021-08-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003403428	SCV004122799	uncertain significance	not specified	2023-10-12	criteria provided, single submitter	clinical testing	Variant summary: RYR2 c.640G>A (p.Val214Met) results in a conservative amino acid change located in the inositol 1,4,5-trisphosphate/ryanodine receptor domain (IPR014821) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 249166 control chromosomes (gnomAD). 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.640G>A in individuals affected with Catecholaminergic Polymorphic Ventricular Tachycardia or other RYR2-related disorders and no experimental evidence demonstrating its impact on protein function have been reported. Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health	RCV004002706	SCV004819713	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia	2024-05-24	criteria provided, single submitter	clinical testing	This missense variant replaces valine with methionine at codon 214 of the RYR2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, 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 1/249166 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.