Submissions for variant NM_001035.3(RYR2):c.4990G>T (p.Val1664Phe)

dbSNP: rs749434532

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000766717	SCV000235114	uncertain significance	not provided	2021-06-28	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not located in one of the three hot-spot regions of the RYR2 gene, where the majority of pathogenic missense variants occur (Medeiros-Domingo et al., 2009); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 201253; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 27535533)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000182730	SCV000272390	uncertain significance	not specified	2015-04-10	criteria provided, single submitter	clinical testing	The p.Val1664Phe variant in RYR2 has not been previously identified in individua ls with cardiomyopathy, but has been identified in 1/66670 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org). Comp utational prediction tools and conservation analysis suggest that this variant m ay impact the protein, though this information is not predictive enough to deter mine pathogenicity. In summary, the clinical significance of the p.Val1664Phe va riant is uncertain.
Invitae	RCV002515327	SCV000831868	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2023-10-15	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 1664 of the RYR2 protein (p.Val1664Phe). This variant is present in population databases (rs749434532, gnomAD 0.004%). This missense change has been observed in individual(s) with left ventricular non-compaction (PMID: 33500567). ClinVar contains an entry for this variant (Variation ID: 201253). 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 expected to disrupt RYR2 protein function. 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.
Color Diagnostics, LLC DBA Color Health	RCV001182512	SCV001347978	uncertain significance	Cardiomyopathy	2023-04-07	criteria provided, single submitter	clinical testing	This variant is located in 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 been reported in an individual affected with catecholaminergic polymorphic ventricular tachycardia (PMID: 29453246) and in an individual with left ventricular noncompaction (PMID: 33500567). This variant has been identified in 5/248998 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	RCV002336456	SCV002642299	uncertain significance	Cardiovascular phenotype	2020-12-18	criteria provided, single submitter	clinical testing	The p.V1664F variant (also known as c.4990G>T), located in coding exon 37 of the RYR2 gene, results from a G to T substitution at nucleotide position 4990. The valine at codon 1664 is replaced by phenylalanine, an amino acid with highly similar properties. This variant was reported in a catecholaminergic polymorphic ventricular tachycardia (CPVT) genetic testing cohort; however, clinical details were limited (Kapplinger JD et al. Circ Genom Precis Med, 2018 02;11:e001424). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV000766717	SCV003820587	uncertain significance	not provided	2023-01-23	criteria provided, single submitter	clinical testing