Submissions for variant NM_001035.3(RYR2):c.12859T>C (p.Tyr4287His)

gnomAD frequency: 0.00004  dbSNP: rs190009333

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000151774	SCV000200197	uncertain significance	not specified	2014-01-22	criteria provided, single submitter	clinical testing	The Tyr4287His variant in RYR2 has not been previously reported in individuals w ith cardiomyopathy, but has been identified in 1/194 Han Chinese chromosomes by the 1000 Genomes Project (dbSNP rs190009333) and in 1/8238 European American chr omosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS /). Computational analyses (biochemical amino acid properties, conservation, Ali gnGVGD, PolyPhen2, and SIFT) suggest that this variant may impact the protein, t hough this information is not predictive enough to determine pathogenicity. Addi tional information is needed to fully assess the clinical significance of this v ariant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003153435	SCV000541684	likely benign	Catecholaminergic polymorphic ventricular tachycardia 1	2024-12-19	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000777991	SCV000914097	uncertain significance	Cardiomyopathy	2023-12-15	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with histidine at codon 4287 of the RYR2 protein. Computational prediction tools indicate that this variant's impact on protein structure and function is inconclusive. 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 6/280136 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	RCV002381474	SCV002688921	uncertain significance	Cardiovascular phenotype	2024-05-23	criteria provided, single submitter	clinical testing	The p.Y4287H variant (also known as c.12859T>C), located in coding exon 90 of the RYR2 gene, results from a T to C substitution at nucleotide position 12859. The tyrosine at codon 4287 is replaced by histidine, an amino acid with 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.
All of Us Research Program, National Institutes of Health	RCV003998228	SCV004818694	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia	2024-01-03	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with histidine at codon 4287 of the RYR2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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 cardiovascular disorders in the literature. This variant has been identified in 6/280136 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.