Submissions for variant NM_001035.3(RYR2):c.13351G>A (p.Glu4451Lys)

gnomAD frequency: 0.00001  dbSNP: rs780734342

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001175873	SCV001339659	uncertain significance	Cardiomyopathy	2023-12-11	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 4451 of the RYR2 protein. Computational prediction tools indicate that this variant has a neutral impact on protein structure and function. 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 7/255258 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	RCV003293921	SCV003999090	uncertain significance	Cardiovascular phenotype	2023-05-26	criteria provided, single submitter	clinical testing	The p.E4451K variant (also known as c.13351G>A), located in coding exon 92 of the RYR2 gene, results from a G to A substitution at nucleotide position 13351. The glutamic acid at codon 4451 is replaced by lysine, an amino acid with similar properties. This alteration was reported in a reportedly healthy exome cohort from India (Bajaj A et al. Hum Genomics, 2022 Aug;16:30). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003526036	SCV004281503	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2023-10-28	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 4451 of the RYR2 protein (p.Glu4451Lys). This variant is present in population databases (rs780734342, gnomAD 0.005%). This variant has not been reported in the literature in individuals affected with RYR2-related conditions. ClinVar contains an entry for this variant (Variation ID: 918329). 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 not expected to disrupt RYR2 protein function with a negative predictive value of 95%. 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.
All of Us Research Program, National Institutes of Health	RCV004000300	SCV004816438	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia	2024-09-23	criteria provided, single submitter	clinical testing	This variant is located in 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 7/255258 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.