Submissions for variant NM_001035.3(RYR2):c.2828T>C (p.Leu943Ser)

gnomAD frequency: 0.00009  dbSNP: rs373665895

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182703	SCV000235083	uncertain significance	not provided	2017-04-13	criteria provided, single submitter	clinical testing	The L943S variant of uncertain significance in the RYR2 gene has previously been reported in association with HCM (Lopes et al., 2015). The L943S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, L943S is not located in one of the three hot spots regions in the RYR2 gene, where the majority of pathogenic missense variants occur (Medeiros-Domingo et al., 2009). Furthermore, the Exome Aggregation Consortium (ExAC) reports L943S was observed in 12/35,496 alleles from individuals of European (Non-Finnish) ancestry and 3/4,056 alleles from individuals of European (Finnish) ancestry (Lek et al., 2016).
Invitae	RCV002516876	SCV000760601	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2024-01-02	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 943 of the RYR2 protein (p.Leu943Ser). This variant is present in population databases (rs373665895, gnomAD 0.02%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy and catecholaminergic polymorphic ventricular tachycardia (PMID: 25351510, 31112425). ClinVar contains an entry for this variant (Variation ID: 201232). 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. 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	RCV001189148	SCV001356373	uncertain significance	Cardiomyopathy	2023-04-26	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with serine at codon 943 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 been reported in two individuals with catecholaminergic polymorphic ventricular tachycardia (PMID: 31112425), in two individuals affected with atrioventricular nodal reentry tachycardia (PMID: 29396561, 32508047), in one individual affected with hypertrophic cardiomyopathy (PMID: 25351510), and in one infant with sudden death (PMID: 32152366). This variant occurs at an elevated frequency in the general population and has been identified in 30/268806 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001797667	SCV002041607	likely benign	not specified	2021-11-01	criteria provided, single submitter	clinical testing	Variant summary: RYR2 c.2828T>C (p.Leu943Ser) results in a non-conservative amino acid change located in the Ryanodine receptor, Ryr domain (IPR003032) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 237416 control chromosomes. The observed variant frequency is approximately 3.0 fold of the estimated maximal expected allele frequency for a pathogenic variant in RYR2 causing Catecholaminergic Polymorphic Ventricular Tachycardia phenotype (3.4e-05), strongly suggesting that the variant is benign. c.2828T>C has been reported in the literature as a VUS in settings of multigene panel testing in cohorts of individuals with a variety of cardiac conditions such as SIDS/Atrioventricular nodal reentry tachycardia (AVNRT) (example, Neubauer_2017, Giudicessi_2019, Olubando_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Catecholaminergic Polymorphic Ventricular Tachycardia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Ambry Genetics	RCV002433804	SCV002752577	uncertain significance	Cardiovascular phenotype	2022-01-07	criteria provided, single submitter	clinical testing	The p.L943S variant (also known as c.2828T>C), located in coding exon 25 of the RYR2 gene, results from a T to C substitution at nucleotide position 2828. The leucine at codon 943 is replaced by serine, an amino acid with dissimilar properties. This alteration has been reported in a hypertrophic cardiomyopathy cohort, whole exome sequencing cohort, atrioventricular nodal reentry tachycardia cohort, and catecholaminergic polymorphic ventricular tachycardia cohort; however, clinical details were limited (Lopes LR et al. Heart, 2015 Feb;101:294-301; Landstrom AP et al. Circ Arrhythm Electrophysiol, 2017 Apr;10:[ePub ahead of print]; Andreasen L et al. Eur J Hum Genet, 2018 05;26:660-668; Giudicessi JR et al. Circ Genom Precis Med, 2019 05;12:e002510). This amino acid position is highly 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.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003227702	SCV003924146	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1; Ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome	2021-03-30	criteria provided, single submitter	clinical testing	RYR2 NM_001035.2 exon 25 p.Leu943Ser (c.2828T>C): This variant has been reported in the literature in one individual with HCM (Lopes 2015 PMID:25351510). This variant is also present in 0.01% (22/122756) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/1-237693732-T-C) and is present in ClinVar (Variation ID:201232). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000182703	SCV000924925	uncertain significance	not provided	2017-08-16	no assertion criteria provided	provider interpretation