Submissions for variant NM_001035.3(RYR2):c.14884T>A (p.Tyr4962Asn)

gnomAD frequency: 0.00001  dbSNP: rs748937501

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182855	SCV000235243	uncertain significance	not provided	2022-07-15	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 (gnomAD); 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); This variant is associated with the following publications: (PMID: 19926015, 26582918)
Color Diagnostics, LLC DBA Color Health	RCV001177416	SCV001341629	uncertain significance	Cardiomyopathy	2023-09-28	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with asparagine at codon 4962 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 2/248080 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.
Invitae	RCV003153463	SCV001516286	likely pathogenic	Catecholaminergic polymorphic ventricular tachycardia 1	2022-09-19	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 4962 of the RYR2 protein (p.Tyr4962Asn). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Tyr4962 amino acid residue in RYR2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22787013, 24025405). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 201366). This variant has not been reported in the literature in individuals affected with RYR2-related conditions. This variant is present in population databases (rs748937501, gnomAD 0.002%).
Ambry Genetics	RCV002390466	SCV002700861	uncertain significance	Cardiovascular phenotype	2020-06-01	criteria provided, single submitter	clinical testing	The p.Y4962N variant (also known as c.14884T>A), located in coding exon 105 of the RYR2 gene, results from a T to A substitution at nucleotide position 14884. The tyrosine at codon 4962 is replaced by asparagine, an amino acid with dissimilar properties. A variant at the same amino acid position has been identified in an individual with a family history of catecholaminergic polymorphic ventricular tachycardia (CPVT); however, clinical details are limited (van der Werf C et al. Circ Arrhythm Electrophysiol, 2012 Aug;5:748-56). This amino acid position is highly 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.