Submissions for variant NM_001035.3(RYR2):c.10897G>A (p.Glu3633Lys)

gnomAD frequency: 0.00001  dbSNP: rs748501600

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182836	SCV000235223	uncertain significance	not provided	2018-12-06	criteria provided, single submitter	clinical testing	This variant is denoted Glu3633Lys (aka E3633K) at the protein level and c.10897 G>A at the cDNA level. The Glu3633Lys variant in the RYR2 gene has not been reported previously as a disease-causing mutation nor as a benign polymorphism, to our knowledge. Glu3633Lys results in a non-conservative amino acid substitution of a negatively charged Glutamic acid with a positively charged Lysine at a residue that is conserved across species. However, the Glu3633Lys variant does not occur in or near any of the three mutation hot spot regions in the RYR2 gene. We cannot unequivocally determine whether the Glu3633Lys variant is disease-causing mutations or benign variants. The variant is found in CPVT panel(s).
Ambry Genetics	RCV000246010	SCV000319047	uncertain significance	Cardiovascular phenotype	2024-11-23	criteria provided, single submitter	clinical testing	The p.E3633K variant (also known as c.10897G>A), located in coding exon 77 of the RYR2 gene, results from a G to A substitution at nucleotide position 10897. The glutamic acid at codon 3633 is replaced by lysine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002516902	SCV000835074	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2024-05-25	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 3633 of the RYR2 protein (p.Glu3633Lys). This variant is present in population databases (rs748501600, gnomAD 0.004%). 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: 201348). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RYR2 protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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	RCV001190717	SCV001358294	uncertain significance	Cardiomyopathy	2024-03-13	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 3633 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 3/248568 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000182836	SCV001715669	uncertain significance	not provided	2021-01-08	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003996786	SCV004816008	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia	2024-03-24	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 3633 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 3/248568 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.