ClinVar Genomic variation as it relates to human health
NM_001035.3(RYR2):c.5170G>A (p.Glu1724Lys)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001035.3(RYR2):c.5170G>A (p.Glu1724Lys)
Variation ID: 201254 Accession: VCV000201254.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q43 1: 237614298 (GRCh38) [ NCBI UCSC ] 1: 237777598 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline May 29, 2016 Feb 14, 2024 Jan 8, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001035.3:c.5170G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001026.2:p.Glu1724Lys missense NC_000001.11:g.237614298G>A NC_000001.10:g.237777598G>A NG_008799.3:g.577115G>A LRG_402:g.577115G>A LRG_402t1:c.5170G>A LRG_402p1:p.Glu1724Lys - Protein change
- E1724K
- Other names
- p.E1724K:GAG>AAG
- Canonical SPDI
- NC_000001.11:237614297:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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RYR2 | No evidence available | No evidence available |
GRCh38 GRCh37 |
7342 | 7978 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (1) |
criteria provided, single submitter
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Apr 27, 2015 | RCV000182731.10 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Mar 29, 2021 | RCV002336457.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 4, 2023 | RCV002515328.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 8, 2024 | RCV003318367.9 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Apr 27, 2015)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000235115.9
First in ClinVar: Jul 05, 2015 Last updated: May 29, 2016 |
Comment:
p.Glu1724Lys (E1724K) GAG>AAG: c.5170 G>A in exon 37 of the RYR2 gene (NM_001035.2). Postma et al (2005) identified the Glu1724Lys mutation in one female patient … (more)
p.Glu1724Lys (E1724K) GAG>AAG: c.5170 G>A in exon 37 of the RYR2 gene (NM_001035.2). Postma et al (2005) identified the Glu1724Lys mutation in one female patient diagnosed with CPVT in childhood and this mutation was also identified in this patient's affected daughter. The Glu1724Lys mutation was absent from 400 control alleles from individuals of Northern European ancestry (Postma et al, 2005). In addition, the Glu1724Lys mutation was not detected in up to 600 alleles from control individuals of Caucasian and African American ancestry tested at GeneDx, indicating it is not a common benign variant in these populations. Glu1724Lys results in a non-conservative amino acid substitution of a negatively charged Glutamic acid with a positively charged Lysine. The closest pathogenic mutation reported in association with CPVT is Glu1837Lys (Medeiros-Domingo et al, 2009). However, other genetic and environmental factors influence disease expression and severity, and some mutation carriers may never become symptomatic. The variant is found in CPVT panel(s). (less)
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Likely pathogenic
(Mar 29, 2021)
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criteria provided, single submitter
Method: clinical testing
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Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002643685.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The p.E1724K variant (also known as c.5170G>A), located in coding exon 37 of the RYR2 gene, results from a G to A substitution at nucleotide … (more)
The p.E1724K variant (also known as c.5170G>A), located in coding exon 37 of the RYR2 gene, results from a G to A substitution at nucleotide position 5170. The glutamic acid at codon 1724 is replaced by lysine, an amino acid with similar properties. This variant has been detected in individuals with catecholaminergic polymorphic ventricular tachycardia (CPVT), and was reported to segregate with symptoms in an additional relative in two unrelated families, one with confirmed CPVT and one with a history of syncope (Postma AV et al. J. Med. Genet., 2005 Nov;42:863-70; van der Werf C et al. J. Am. Coll. Cardiol., 2011 May;57:2244-54; Ohno S et al. PLoS ONE, 2015 Jun;10:e0131517; Kawata H et al. Circ. J., 2016 Aug;80:1907-15). This variant was also reported to be de novo in one CPVT case; however, clinical details were limited (Broendberg AK et al. Heart, 2017 06;103:901-909). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
Number of individuals with the variant: 1
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Pathogenic
(Jan 08, 2024)
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criteria provided, single submitter
Method: research
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Long QT syndrome
Affected status: yes
Allele origin:
de novo
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Dept of Medical Biology, Uskudar University
Accession: SCV004022026.2
First in ClinVar: Jul 29, 2023 Last updated: Jan 26, 2024 |
Comment:
Criteria: PS2_Strong, PM2, PP2, PP3
Number of individuals with the variant: 1
Sex: male
Ethnicity/Population group: Turkish
Geographic origin: Turkey
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Pathogenic
(Dec 04, 2023)
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criteria provided, single submitter
Method: clinical testing
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Catecholaminergic polymorphic ventricular tachycardia 1
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001393038.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1724 of the RYR2 protein … (more)
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1724 of the RYR2 protein (p.Glu1724Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with catecholaminergic polymorphic ventricular tachycardia (CPVT) (PMID: 16272262, 22787013, 26114861, 28237968, 29032884). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 201254). 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) performed at Invitae indicates that this missense variant is expected to disrupt RYR2 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Assessment and Validation of a Phenotype-Enhanced Variant Classification Framework to Promote or Demote RYR2 Missense Variants of Uncertain Significance. | Giudicessi JR | Circulation. Genomic and precision medicine | 2019 | PMID: 31112425 |
Bradycardia Is a Specific Phenotype of Catecholaminergic Polymorphic Ventricular Tachycardia Induced by RYR2 Mutations. | Miyata K | Internal medicine (Tokyo, Japan) | 2018 | PMID: 29434162 |
The genetics underlying idiopathic ventricular fibrillation: A special role for catecholaminergic polymorphic ventricular tachycardia? | Leinonen JT | International journal of cardiology | 2018 | PMID: 29032884 |
Nationwide experience of catecholaminergic polymorphic ventricular tachycardia caused by RyR2 mutations. | Broendberg AK | Heart (British Cardiac Society) | 2017 | PMID: 28237968 |
Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) Associated With Ryanodine Receptor (RyR2) Gene Mutations - Long-Term Prognosis After Initiation of Medical Treatment. | Kawata H | Circulation journal : official journal of the Japanese Circulation Society | 2016 | PMID: 27452199 |
Gender Differences in the Inheritance Mode of RYR2 Mutations in Catecholaminergic Polymorphic Ventricular Tachycardia Patients. | Ohno S | PloS one | 2015 | PMID: 26114861 |
New exome data question the pathogenicity of genetic variants previously associated with catecholaminergic polymorphic ventricular tachycardia. | Jabbari J | Circulation. Cardiovascular genetics | 2013 | PMID: 24025405 |
Familial evaluation in catecholaminergic polymorphic ventricular tachycardia: disease penetrance and expression in cardiac ryanodine receptor mutation-carrying relatives. | van der Werf C | Circulation. Arrhythmia and electrophysiology | 2012 | PMID: 22787013 |
Flecainide therapy reduces exercise-induced ventricular arrhythmias in patients with catecholaminergic polymorphic ventricular tachycardia. | van der Werf C | Journal of the American College of Cardiology | 2011 | PMID: 21616285 |
The RYR2-encoded ryanodine receptor/calcium release channel in patients diagnosed previously with either catecholaminergic polymorphic ventricular tachycardia or genotype negative, exercise-induced long QT syndrome: a comprehensive open reading frame mutational analysis. | Medeiros-Domingo A | Journal of the American College of Cardiology | 2009 | PMID: 19926015 |
Catecholaminergic polymorphic ventricular tachycardia: RYR2 mutations, bradycardia, and follow up of the patients. | Postma AV | Journal of medical genetics | 2005 | PMID: 16272262 |
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Text-mined citations for rs794728740 ...
HelpRecord last updated Apr 20, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.