rs571985775
Positions:
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP2BS1BS2
The NM_001035.3(RYR2):โc.13291G>Aโ(p.Glu4431Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000558 in 1,591,854 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. E4431E) has been classified as Likely benign.
Frequency
Genomes: ๐ 0.00027 ( 0 hom., cov: 32)
Exomes ๐: 0.00059 ( 0 hom. )
Consequence
RYR2
NM_001035.3 missense
NM_001035.3 missense
Scores
8
10
Clinical Significance
Conservation
PhyloP100: 4.55
Genes affected
RYR2 (HGNC:10484): (ryanodine receptor 2) This gene encodes a ryanodine receptor found in cardiac muscle sarcoplasmic reticulum. The encoded protein is one of the components of a calcium channel, composed of a tetramer of the ryanodine receptor proteins and a tetramer of FK506 binding protein 1B proteins, that supplies calcium to cardiac muscle. Mutations in this gene are associated with stress-induced polymorphic ventricular tachycardia and arrhythmogenic right ventricular dysplasia. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -7 ACMG points.
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), RYR2. . Gene score misZ 5.7809 (greater than the threshold 3.09). Trascript score misZ 6.4158 (greater than threshold 3.09). GenCC has associacion of gene with hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, catecholaminergic polymorphic ventricular tachycardia 1, arrhythmogenic right ventricular dysplasia 2, catecholaminergic polymorphic ventricular tachycardia.
BS1
Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000589 (848/1439580) while in subpopulation NFE AF= 0.000747 (822/1099884). AF 95% confidence interval is 0.000704. There are 0 homozygotes in gnomad4_exome. There are 406 alleles in male gnomad4_exome subpopulation. Median coverage is 29. This position pass quality control queck.
BS2
High AC in GnomAd4 at 41 AD gene.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| RYR2 | NM_001035.3 | c.13291G>A | p.Glu4431Lys | missense_variant | 91/105 | ENST00000366574.7 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| RYR2 | ENST00000366574.7 | c.13291G>A | p.Glu4431Lys | missense_variant | 91/105 | 1 | NM_001035.3 | P1 | |
| RYR2 | ENST00000660292.2 | c.13312G>A | p.Glu4438Lys | missense_variant | 92/106 | ||||
| RYR2 | ENST00000659194.3 | c.13273G>A | p.Glu4425Lys | missense_variant | 91/105 | ||||
| RYR2 | ENST00000609119.2 | c.*4383G>A | 3_prime_UTR_variant, NMD_transcript_variant | 90/104 | 5 |
Frequencies
GnomAD3 genomes 0.000269 AC: 41AN: 152156Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000246 AC: 52AN: 211502Hom.: 0 AF XY: 0.000247 AC XY: 28AN XY: 113584
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GnomAD4 exome AF: 0.000589 AC: 848AN: 1439580Hom.: 0 Cov.: 29 AF XY: 0.000569 AC XY: 406AN XY: 713734
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GnomAD4 genome 0.000269 AC: 41AN: 152274Hom.: 0 Cov.: 32 AF XY: 0.000255 AC XY: 19AN XY: 74444
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:15Benign:3
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:5
| Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2022 | RYR2: PM1 - |
| Uncertain significance, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Dec 05, 2020 | - - |
| Uncertain significance, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 13, 2024 | Identified in one individual with a history of syncope and a prolonged QT interval and in one individual with autopsy-negative sudden unexplained death (PMID: 18752142, 24631775); Reported in a patient with short QT syndrome (SQTS) in the published literature who harbored additional cardiogenetic variants (PMID: 34712558); Located in one of the three hot-spot regions of the RYR2 gene, where the majority of pathogenic missense variants occur (PMID: 19926015); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24631775, 24025405, 27538377, 26633542, 19926015, 28404607, 23022705, 19362677, 34712558, 27535533, 18752142, 37234784, 37937776, 32152366) - |
not specified Uncertain:3
| Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 26, 2017 | 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. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 16, 2018 | 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) - |
| Uncertain significance, no assertion criteria provided | clinical testing | Stanford Center for Inherited Cardiovascular Disease, Stanford University | Sep 17, 2015 | 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: (http://cardiodb.org/Paralogue_Annotation/residue.php?gene=RYR2&position=4431). In silico analysis with PolyPhen-2 predicts this variant to be โbenignโ 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). - |
Catecholaminergic polymorphic ventricular tachycardia 1 Uncertain:1Benign:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Phosphorus, Inc. | Aug 01, 2017 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 03, 2024 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Nov 26, 2018 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Arrhythmogenic right ventricular dysplasia 2 Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Phosphorus, Inc. | Aug 01, 2017 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Nov 26, 2018 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Catecholaminergic polymorphic ventricular tachycardia Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Feb 05, 2024 | This missense variant replaces glutamic acid with lysine at codon 4431 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 been reported in individuals affected with long QT syndrome (PMID: 18752142), sudden unexplained death (PMID: 24631775), and early-onset atrial fibrillation (PMID: 31638414). This variant has also been identified in 54/242862 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although this variant allele frequency is thought to be higher than expected for RYR2-related disorders, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Cardiomyopathy Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | May 09, 2023 | This missense variant replaces glutamic acid with lysine at codon 4431 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 been reported in individuals affected with long QT syndrome (PMID: 18752142), sudden unexplained death (PMID: 24631775), and early-onset atrial fibrillation (PMID: 31638414). This variant has also been identified in 54/242862 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although this variant allele frequency is thought to be higher than expected for RYR2-related disorders, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Left ventricular noncompaction Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Phosphorus, Inc. | Aug 01, 2017 | - - |
Hypertrophic cardiomyopathy Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego | Jul 26, 2017 | - - |
Cardiovascular phenotype Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 07, 2021 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Benign
DEOGEN2
Uncertain
D
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T
M_CAP
Uncertain
D
MetaRNN
Uncertain
T
MetaSVM
Uncertain
T
MutationAssessor
Benign
L
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Benign
N
REVEL
Uncertain
Sift
Benign
T
Polyphen
B
Vest4
MVP
MPC
ClinPred
T
GERP RS
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gMVP
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at