ClinVar Genomic variation as it relates to human health
NM_001035.3(RYR2):c.12667_12669del (p.Lys4223del)
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.
Uncertain significance(8); Likely benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001035.3(RYR2):c.12667_12669del (p.Lys4223del)
Variation ID: 201411 Accession: VCV000201411.21
- Type and length
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Deletion, 3 bp
- Location
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Cytogenetic: 1q43 1: 237784377-237784379 (GRCh38) [ NCBI UCSC ] 1: 237947677-237947679 (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 Jul 5, 2015 May 1, 2024 Jan 2, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001035.3:c.12667_12669del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001026.2:p.Lys4223del inframe deletion NM_001035.3:c.12667_12669delAAG MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_001035.2:c.12667_12669del NC_000001.11:g.237784379_237784381del NC_000001.10:g.237947679_237947681del NG_008799.3:g.747196_747198del LRG_402:g.747196_747198del LRG_402t1:c.12667_12669del LRG_402p1:p.Lys4223del - Protein change
- K4223del
- Other names
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- Canonical SPDI
- NC_000001.11:237784376:AGAAG:AG
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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 |
7381 | 8021 | |
LOC126806068 | - | - | - | GRCh38 | - | 402 |
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
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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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Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Jan 22, 2021 | RCV000182901.13 | |
Likely benign (1) |
criteria provided, single submitter
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Sep 7, 2023 | RCV000781826.10 | |
Uncertain significance (1) |
criteria provided, single submitter
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Dec 9, 2022 | RCV001177598.12 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 20, 2023 | RCV002372118.10 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Jan 2, 2024 | RCV002517809.10 | |
Uncertain significance (1) |
criteria provided, single submitter
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Sep 24, 2021 | RCV002467648.8 | |
Uncertain significance (1) |
criteria provided, single submitter
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Mar 30, 2021 | RCV003227704.8 |
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
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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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Uncertain significance
(Jan 22, 2021)
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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: SCV000235290.11
First in ClinVar: Jul 05, 2015 Last updated: Jul 05, 2015 |
Comment:
Reported in a patient with a history of sudden cardiac arrest and borderline ARVC upon evaluation (Asatryan et al., 2019; reported as c.12665_12667delAGA due to … (more)
Reported in a patient with a history of sudden cardiac arrest and borderline ARVC upon evaluation (Asatryan et al., 2019; reported as c.12665_12667delAGA due to alternate nomenclature); Reported in ClinVar (ClinVar Variant ID# 201411; Landrum et al., 2016); In-frame deletion of one amino acid in a non-repeat region; In silico analysis supports that this variant does not alter protein structure/function; 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); This variant is associated with the following publications: (PMID: 30975432) (less)
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Uncertain significance
(Sep 24, 2021)
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criteria provided, single submitter
Method: clinical testing
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Catecholaminergic polymorphic ventricular tachycardia 1
Ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome Catecholaminergic polymorphic ventricular tachycardia 1
Affected status: unknown
Allele origin:
germline
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New York Genome Center
Accession: SCV002764362.1
First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022 |
Clinical Features:
Hyperlipidemia (present)
Secondary finding: no
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Uncertain significance
(Mar 30, 2021)
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criteria provided, single submitter
Method: clinical testing
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Catecholaminergic polymorphic ventricular tachycardia 1
Ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome
Affected status: unknown
Allele origin:
germline
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Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago
Accession: SCV003924239.1
First in ClinVar: May 20, 2023 Last updated: May 20, 2023 |
Comment:
RYR2 NM_001035.2 exon 90 p.Lys4223del (c.12667_12669del): This variant has not been reported in the literature and is present in 0.02% (6/24184) of African alleles in … (more)
RYR2 NM_001035.2 exon 90 p.Lys4223del (c.12667_12669del): This variant has not been reported in the literature and is present in 0.02% (6/24184) of African alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/1-237947676-GAGA-G). This variant is present in ClinVar (Variation ID:201411). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant represents an in-frame deletion of one amino acid at position 4223 and is not predicted to alter the reading frame. However, the effect of this variant on the protein is unclear. Of note, this variant is located in one of the three "hot spot" domains of the RYR2 gene, where the majority of disease-associated variants have been observed to cluster (Medieros-Domingo 2009 PMID:19926015). In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. (less)
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Likely benign
(Sep 07, 2023)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000920174.2
First in ClinVar: Jun 02, 2019 Last updated: Nov 04, 2023 |
Comment:
Variant summary: RYR2 c.12667_12669delAAG (p.Lys4223del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele … (more)
Variant summary: RYR2 c.12667_12669delAAG (p.Lys4223del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 9.7e-05 in 393308 control chromosomes (i.e., 38 heterozygotes), predominantly at a frequency of 0.00014 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2.33 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 a benign polymorphism. The variant, c.12667_12669delAAG, has been reported in the literature in an individual with suspected-CPVT (Catecholaminergic Polymorphic Ventricular Tachycardia) referred for clinical genetic testing (e.g., Kapplinger_2018) and in an individual who experienced sudden cardiac arrest and had borderline arrhythmogenic right ventricular cardiomyopathy (e.g., Asatryan_2019), however without strong evidence for causality (e.g., lack of co-segregation data) in both instances. These reports therefore 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. The following publications have been ascertained in the context of this evaluation (PMID: 29453246, 30975432, 28404607). Seven submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. (less)
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Uncertain significance
(Dec 09, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV003820593.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Uncertain significance
(Jan 02, 2024)
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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: SCV001392673.4
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
This variant, c.12667_12669del, results in the deletion of 1 amino acid(s) of the RYR2 protein (p.Lys4223del), but otherwise preserves the integrity of the reading frame. … (more)
This variant, c.12667_12669del, results in the deletion of 1 amino acid(s) of the RYR2 protein (p.Lys4223del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs780366391, gnomAD 0.02%). This variant has been observed in individual(s) with clinical features of RYR2 related features (PMID: 29453246, 30975432). ClinVar contains an entry for this variant (Variation ID: 201411). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. (less)
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Uncertain significance
(Dec 09, 2022)
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criteria provided, single submitter
Method: clinical testing
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Cardiomyopathy
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV001341835.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This variant causes a deletion of lysine at codon 4223 of the RYR2 protein. To our knowledge, functional studies have not been reported for this … (more)
This variant causes a deletion of lysine at codon 4223 of the RYR2 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a sudden cardiac arrest survivor who was affected with borderline arrhythmogenic right ventricular cardiomyopathy (PMID: 30975432) and in an individual suspected of having catecholaminergic polymorphic ventricular tachycardia (PMID: 29453246). This variant has also been identified in 22/279956 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. (less)
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Uncertain significance
(Sep 04, 2023)
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criteria provided, single submitter
Method: clinical testing
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Catecholaminergic polymorphic ventricular tachycardia 1
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Molecular Genetics, Royal Melbourne Hospital
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV004812345.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
Comment:
This sequence change is predicted to cause a change in the length of the protein due to an in-frame deletion of one amino acid in … (more)
This sequence change is predicted to cause a change in the length of the protein due to an in-frame deletion of one amino acid in a non-repeat region of the RYR2 protein, p.(Lys4223del). The region deleted is moderately conserved (100 vertebrates, UCSC), and is located in the cytoplasmic region. The highest population minor allele frequency in the population database gnomAD v3.1 is 0.012% (5/41,444 alleles) in the African/African American population. This variant has been reported in at least two probands with cardiac phenotypes (PMID: 30975432, 29453246). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PM4_Supporting. (less)
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Uncertain significance
(Jan 20, 2023)
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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: SCV002687789.3
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The c.12667_12669delAAG variant (also known as p.K4223del) is located in coding exon 90 of the RYR2 gene. This variant results from an in-frame AAG deletion … (more)
The c.12667_12669delAAG variant (also known as p.K4223del) is located in coding exon 90 of the RYR2 gene. This variant results from an in-frame AAG deletion at nucleotide positions 12667 to 12669. This results in the in-frame deletion of a lysine at codon 4223. This variant was detected in an individual with sudden cardiac arrest and borderline arrhythmogenic right ventricular cardiomyopathy (ARVC) findings (Asatryan B et al. Am. J. Cardiol., 2019 06;123:2031-2038). This variant has also been described in catecholaminergic polymorphic ventricular tachycardia (CPVT) and exome cohorts; however, clinical details were limited (Landstrom AP et al. Circ Arrhythm Electrophysiol, 2017 Apr;10:[Epub ahead of print]; Kapplinger JD et al. Circ Genom Precis Med, 2018 02;11:e001424). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be neutral by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (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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Usefulness of Genetic Testing in Sudden Cardiac Arrest Survivors With or Without Previous Clinical Evidence of Heart Disease. | Asatryan B | The American journal of cardiology | 2019 | PMID: 30975432 |
Yield of the RYR2 Genetic Test in Suspected Catecholaminergic Polymorphic Ventricular Tachycardia and Implications for Test Interpretation. | Kapplinger JD | Circulation. Genomic and precision medicine | 2018 | PMID: 29453246 |
Interpreting Incidentally Identified Variants in Genes Associated With Catecholaminergic Polymorphic Ventricular Tachycardia in a Large Cohort of Clinical Whole-Exome Genetic Test Referrals. | Landstrom AP | Circulation. Arrhythmia and electrophysiology | 2017 | PMID: 28404607 |
Text-mined citations for rs794728838 ...
HelpRecord last updated May 01, 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.