ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.13291G>A (p.Glu4431Lys) (rs571985775)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000151775 SCV000200200 uncertain significance not specified 2018-11-16 criteria provided, single submitter clinical testing Disclaimer: This variant has not undergone full assessment. The following are pr eliminary notes: All ClinVar submissions are recent (2017). HGMD: 3 more publica tions which will probably not increase the classification. ClinVar: VUS by sever al labs (all recent, 2017)
GeneDx RCV000766733 SCV000235219 uncertain significance not provided 2018-10-18 criteria provided, single submitter clinical testing The E4431K variant of uncertain significance in the RYR2 gene was first reported in one Norwegian individual with a history of syncope and a prolonged QT interval (Berge et al., 2008), and was also found in a 25-year-old male with autopsy-negative sudden unexplained death, who had a history of palpitations and negative family history (Wang et al., 2014). The E4431K variant has been observed both independently of and in conjunction with additional cardiogenetic variants in other individuals referred for cardiomyopathy and/or arrhythmia genetic testing at GeneDx. In one proband referred for CPVT genetic testing, this variant did not segregate with CPVT in one affected relative, however, no other informative segregation data is available for this family, or the remaining cases at GeneDx, to further clarify the role of this variant in disease.The E4431K variant is observed in 49/104,610 (0.05%) alleles from individuals of European (non-Finnish) ancestry in large population cohorts (Lek et al., 2016). In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Nevertheless, the E4431K 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. Furthermore, E4431K is 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).
Invitae RCV000458521 SCV000541718 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2018-11-26 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 4431 of the RYR2 protein (p.Glu4431Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs571985775, ExAC 0.07%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in one individual affected with long QT syndrome (LQTS) and in one case of sudden unexplained death (PMID: 18752142, 24631775), as well as in individuals not diagnosed with RYR2-related diseases (PMID: 28404607, 26633542). ClinVar contains an entry for this variant (Variation ID: 165128). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. 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.
Phosphorus, Inc. RCV000577997 SCV000679818 uncertain significance Arrhythmogenic right ventricular dysplasia, familial, 2 2017-08-01 criteria provided, single submitter clinical testing
Phosphorus, Inc. RCV000578054 SCV000679819 uncertain significance Catecholaminergic polymorphic ventricular tachycardia type 1 2017-08-01 criteria provided, single submitter clinical testing
Phosphorus, Inc. RCV000577938 SCV000679820 uncertain significance Left ventricular noncompaction 2017-08-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV000620731 SCV000735762 uncertain significance Cardiovascular phenotype 2018-08-17 criteria provided, single submitter clinical testing Insufficient evidence
Ambry Genetics RCV000622853 SCV000742577 uncertain significance Inborn genetic diseases 2016-02-03 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: UNCERTAIN: Alteration(s) of Uncertain Clinical Significance Detected
Color RCV000777878 SCV000913886 uncertain significance Cardiomyopathy 2018-10-03 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the calcium ion channel pore-forming region of the RYR2 protein. Computational prediction tools and conservation analyses suggest that this variant may not impact the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in an individual affected with long QT syndrome (PMID: 18752142), in an individual with sudden unexplained death and history of heart palpitation (PMID: 24631775), as well as in two individuals with unknown phenotypes (PMID: 28404607, 26633542). This variant has also been identified in 51/239208 chromosomes (49/104610 non-Finnish European chromosomes) in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
Integrated Genetics/Laboratory Corporation of America RCV000151775 SCV000918175 uncertain significance not specified 2017-12-26 criteria provided, single submitter clinical testing Variant summary: The c.13291G>A (p.Glu4431Lys) in RYR2 gene is a missense variant involves a mildly conserved nucleotide located within Ryanodine Receptor TM 4-6 domain (InterPro). The 3/4 in silico tools used predict benign outcome for this variant, however no functional studies supporting these predictions were published at the time of evaluation. The c.13291G>A was identified in the control population dataset of gnomAD at a low frequency of 0.00021 (51/ 239208 chrs tested), predominantly in individuals of European (N-F) descent (0.0004684; 49/104610). The observed frequency significantly exceeds the maximum expected allele frequency for a pathogenic variant of 0.00003, although arrhythmic phenotype in these individuals cannot be ruled out. The variant has been reported in at least three individuals with clinical findings suggestive of arrhythmia and or CPVT, however without strong evidence for causality (eg. segregation, co-occurrence information was not provided). Multiple diagnostic centers have classified the variant as VUS. Taking all evidence into consideration, the variant was classified as VUS-possibly benign, until new information becomes available.
Center for Advanced Laboratory Medicine, UC San Diego Health,University of California San Diego RCV000852418 SCV000995102 uncertain significance Hypertrophic cardiomyopathy 2017-07-26 criteria provided, single submitter clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000151775 SCV000280443 uncertain significance not specified 2015-09-17 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Glu4431Lys (E4431K; c.13291 G>A) in the RYR2 gene: Based on the limited data available about this variant (reviewed below), we consider this a variant of unknown significance (VUS). Most reported disease-causing variants in this gene are missense variants associated with catecholaminergic polymorphic ventricular tachycardia (CPVT) according to HGMD. The RYR2 gene is also associated, rarely, with arrhythmogenic right ventricular cardiomyopathy (ARVC) type 2. However, this variant has not been reported in a patient with CPVT or ARVC, and instead has been reported in one individual with a history of prolonged QTc and syncope (Berge et al. 2008), in one individual with HCM and polymorphic VT who also carried a pathogenic variant for HCM in another gene (Kellen 2012-abstract), and in a 25-year-old Caucasian male with autopsy-negative sudden cardiac death and a history of palpitations but no family history (Wang et al. 2014). Yano et al. (2006) reported that disease-causing variants in RYR2 cluster within 3 hot-spot regions: the N-terminal domain (residues 77-433), the central domain (residues 2246-2534), and the C-terminal domain (residues 3778-4959). This variant does fall within the C-terminal disease-causing hotspot. This is a non-conservative amino acid substitution from a negatively-charged glutamic acid to a positively-charged lysine at a residue that is conserved across vertebrate species. This glutamic acid is not conserved across paralog proteins (RYR1-RYR3) according to cardiodb: ( In silico analysis with PolyPhen-2 predicts this variant to be “benign” with a score of 0.09. There are no missense variants at nearby residues (+/-10) listed in HGMD in association with disease (as of January, 2014). The variant has not been seen in ~6000 individuals from published controls and publicly available population datasets. Berge et al. (2008) did not detect it in 94 controls. It is absent from the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~4100 Caucasian and ~1800 African American individuals. The phenotype of those individuals is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension. There is also no variation at this codon listed in 1000 Genomes (as of November 3, 2014).

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