ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.8145G>T (p.Glu2715Asp) (rs200420897)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000171765 SCV000050778 likely benign not provided 2013-06-24 criteria provided, single submitter research
GeneDx RCV000212982 SCV000235151 uncertain significance not specified 2014-12-22 criteria provided, single submitter clinical testing p.Glu2715Asp (GAG>GAT): c.8145 G>T in exon 54 of the RYR2 gene (NM_001035.2). The Glu2715Asp variant in the RYR2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. This variant was not observed with any significant frequency in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Glu2715Asp results in a conservative amino acid substitution of one negatively-charged amino acid for another at a position that is class conserved across species. In silico algorithms are not consistent in their predictions but at least two concur that Glu2715Asp is possibly damaging to the protein structure/function. However, Glu2715Asp is not located in one of the three mutation hot-spot regions in the RYR2 gene, and consequently, mutations in nearby residues have not been reported (Medeiros-Domingo A et al., 2009), indicating this region may tolerate change. We cannot definitively determine if Glu2715Asp is a disease-causing mutation or a rare benign variant. The variant is found in ARVC panel(s).
Invitae RCV000229232 SCV000285749 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2019-12-05 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with aspartic acid at codon 2715 of the RYR2 protein (p.Glu2715Asp). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and aspartic acid. This variant is present in population databases (rs200420897, ExAC 0.01%). This variant has not been reported in the literature in individuals with RYR2-related disease. ClinVar contains an entry for this variant (Variation ID: 180497). 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 disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Ambry Genetics RCV000618062 SCV000734925 uncertain significance Cardiovascular phenotype 2017-05-31 criteria provided, single submitter clinical testing Insufficient evidence
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769797 SCV000901223 uncertain significance Cardiomyopathy 2017-05-10 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001095882 SCV001252059 uncertain significance Arrhythmogenic right ventricular dysplasia, familial, 2 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Clinical Services Laboratory,Illumina RCV001095883 SCV001252060 uncertain significance Catecholaminergic polymorphic ventricular tachycardia type 1 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Color RCV000769797 SCV001355395 uncertain significance Cardiomyopathy 2020-01-15 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000212982 SCV001362240 uncertain significance not specified 2019-06-17 criteria provided, single submitter clinical testing Variant summary: RYR2 c.8145G>T (p.Glu2715Asp) results in a conservative amino acid change located in the Ryanodine receptor Ryr domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 134624 control chromosomes (gnomAD). The observed variant frequency is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in RYR2 causing Arrhythmia phenotype (6e-05), strongly suggesting that the variant is benign. c.8145G>T has been reported in the literature in individuals affected with CPVT, BrS and unexplained death. These reports do not provide unequivocal conclusions about association of the variant with Arrhythmia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS - possibly benign.
Blueprint Genetics RCV000157460 SCV000207204 uncertain significance Primary dilated cardiomyopathy 2014-11-25 no assertion criteria provided clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000171765 SCV000924920 uncertain significance not provided 2017-06-14 no assertion criteria provided provider interpretation p.Glu2715Asp (c.8145G>T; chr1:237657959) in the RYR2 gene (NM_001035.2) Given the lack of association between RYR2 and Brugada syndrome, the weak case data and its frequency in the general population, we consider this variant a variant of uncertain significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). We've seen this variant in 1 patient with Brugada syndrome in our clinic. Testing was done at Invitae. The RYR2 gene is associated with arrhythmogenic right ventricular cardiomyopathy (ARVC) and catecholaminergic polymorphic ventricular tachycardia (CPVT). It has not been associated with Brugada syndrome. There is no case data available on this variant. One paper mentions this variant (Ng et al 2013), in a study that performed exome sequencing on 870 participants not selected for arrhythmia, cardiomyopathy or family history of sudden death. Its purpose was to uncover the potential for incidental findings of inherited cardiovascular diseases on exome sequencing ordered on patients of other reasons. The p.Glu2715Asp variant was found in 1 of 870 of these individuals. Ng and colleagues interpret this variant as being too common in the NHLBI exome sequencing project (MAF=0.1%) compared to the incidence of CPVT (1 in 10,000). This variant is present in ClinVar, with conflicting interpretations: GeneDx, Invitae and Blueprint Genetics all classify this variant as a variant of uncertain significance. The Biesecker Lab at the NIH classifies this variant as likely benign. This variant is not located in the three hot-spot regions in which pathogenic variants in RYR2 cluster. This variant is located within a region of the RYR2 gene which is tolerant to missense variation (Amr et al 2016). Per the test report, "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 disruptive, but these predictions have not been confirmed by published functional studies. The glutamine at codon 2715 is completely conserved across species, as are neighboring amino acids. There are no other pathogenic/likely pathogenic variants listed in ClinVar at nearby codons. The variant was reported online in 22 of 80,578 individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in 15 of 33,604 individuals of European descent (MAF=0.02%), 3 of 9,357 individuals of Latino descent and 2 of 7,469 individuals of African descent. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease.

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