chr1-237657959-G-T
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BS1_SupportingBS2
The NM_001035.3(RYR2):c.8145G>T(p.Glu2715Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000144 in 1,512,072 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E2715K) has been classified as Uncertain significance.
Frequency
Consequence
NM_001035.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| RYR2 | ENST00000366574.7 | c.8145G>T | p.Glu2715Asp | missense_variant | Exon 54 of 105 | 1 | NM_001035.3 | ENSP00000355533.2 | ||
| RYR2 | ENST00000609119.2 | n.8145G>T | non_coding_transcript_exon_variant | Exon 54 of 104 | 5 | ENSP00000499659.2 | ||||
| RYR2 | ENST00000660292.2 | c.8145G>T | p.Glu2715Asp | missense_variant | Exon 54 of 106 | ENSP00000499787.2 | ||||
| RYR2 | ENST00000659194.3 | c.8145G>T | p.Glu2715Asp | missense_variant | Exon 54 of 105 | ENSP00000499653.3 |
Frequencies
GnomAD3 genomes 0.000151 AC: 23AN: 151958Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000104 AC: 14AN: 134624Hom.: 0 AF XY: 0.0000982 AC XY: 7AN XY: 71280
GnomAD4 exome AF: 0.000143 AC: 194AN: 1359994Hom.: 0 Cov.: 25 AF XY: 0.000137 AC XY: 92AN XY: 670584
GnomAD4 genome 0.000151 AC: 23AN: 152078Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13AN XY: 74352
ClinVar
Submissions by phenotype
not provided Uncertain:5Benign:1
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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In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in patients with sudden unexpected death and in a patient with hypertrophic cardiomyopathy (HCM); both of whom harbored additional cardiogenetic variants (PMID: 27930701, 32746448); Not located in one of the three hot-spot regions of the RYR2 gene, where the majority of pathogenic missense variants occur (PMID: 19926015); This variant is associated with the following publications: (PMID: 32268277, 29453246, 32746448, 27930701, 23861362, 19926015) -
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Catecholaminergic polymorphic ventricular tachycardia 1 Uncertain:2Other:1
Variant interpreted as Uncertain significance and reported on 12-06-2018 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 2715 of the RYR2 protein (p.Glu2715Asp). This variant is present in population databases (rs200420897, gnomAD 0.02%). This missense change has been observed in individual(s) with RYR2-related conditions (PMID: 27930701, 29453246, 32152366). ClinVar contains an entry for this variant (Variation ID: 180497). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt RYR2 protein function with a negative predictive value of 95%. 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. -
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. -
Cardiomyopathy Uncertain:2
This variant is located in 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 been reported in an individual with suspected catecholaminergic polymorphic ventricular tachycardia (PMID: 29453246), two individuals with sudden unexplained death (PMID: 27930701, 32268277), and an individual with suspected coronary artery disease (PMID: 23861362). This variant has been identified in 19/165846 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. -
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not specified Uncertain:1
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. -
Catecholaminergic polymorphic ventricular tachycardia Uncertain:1
This variant is located in 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 been reported in an individual with suspected catecholaminergic polymorphic ventricular tachycardia (PMID: 29453246), two individuals with sudden unexplained death (PMID: 27930701, 32268277), and an individual with suspected coronary artery disease (PMID: 23861362). This variant has been identified in 19/165846 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. -
Primary dilated cardiomyopathy Uncertain:1
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Arrhythmogenic right ventricular dysplasia 2 Uncertain:1
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. -
Cardiovascular phenotype Uncertain:1
The p.E2715D variant (also known as c.8145G>T), located in coding exon 54 of the RYR2 gene, results from a G to T substitution at nucleotide position 8145. The glutamic acid at codon 2715 is replaced by aspartic acid, an amino acid with highly similar properties. This alteration has been reported as a secondary cardiac variant in an exome cohort and has been reported in a control subject (Ng D et al. Circ Cardiovasc Genet, 2013 Aug;6:337-46). This variant was also detected in an arrhythmia genetic testing cohort; however, clinical details were limited, and additional cardiac variants were detected in some cases (van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309). This variant has also been reported in pediatric hypertrophic cardiomyopathy (HCM), sudden unexplained death, and catecholaminergic polymorphic ventricular tachycardia (CPVT) cohorts (Kapplinger JD et al. Circ Genom Precis Med, 2018 Feb;11:e001424; Sanchez O et al. PLoS One, 2016 Dec;11:e0167358; Burstein DS et al. Pediatr Res, 2021 May;89:1470-1476). This amino acid position is highly conserved in available vertebrate species; however, aspartic acid is the reference amino acid in other 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at