Submissions for variant NM_001035.3(RYR2):c.8434C>G (p.Gln2812Glu)

gnomAD frequency: 0.00001  dbSNP: rs377285717

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002548052	SCV002121578	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2024-08-08	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with glutamic acid, which is acidic and polar, at codon 2812 of the RYR2 protein (p.Gln2812Glu). This variant is present in population databases (rs377285717, 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: 1362335). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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	RCV004009214	SCV004829981	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia	2024-08-13	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with glutamic acid at codon 2812 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 RYR2-related disorders in the literature. This variant has been identified in 2/107140 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.
Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center	RCV002548052	SCV005397619	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2023-12-27	criteria provided, single submitter	clinical testing	This sequence variant is a single nucleotide substitution (C>G) at position 8434 of the coding sequence of the RYR2 gene that results in a glutamine to glutamic acid amino acid change at residue 2812 of the ryanodine receptor 2 protein. This residue falls in the fourth of 4 RyR repeat domains (UniProt). This is a previously reported variant (ClinVar 1362335) that has not been observed in the literature in individuals affected by RYR2-related disease, to our knowledge. This variant is present in 20 of 1414168 alleles (0.001414%) in the gnomAD v4.0.0 population dataset. Multiple bioinformatic tools predict that this glutamine to glutamic acid amino acid change would be damaging, and the Gln2812 residue at this position is highly conserved across the vertebrate species examined. Studies examining the functional consequence of this variant have not been performed, to our knowledge. At this time, there is insufficient evidence to determine if this variant is pathogenic or benign. Therefore, we consider this a variant of uncertain significance. ACMG Criteria: PM2, PP3