ClinVar Genomic variation as it relates to human health
NM_006888.6(CALM1):c.293A>G (p.Asn98Ser)
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_006888.6(CALM1):c.293A>G (p.Asn98Ser)
Variation ID: 39758 Accession: VCV000039758.11
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 14q32.11 14: 90404386 (GRCh38) [ NCBI UCSC ] 14: 90870730 (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 Dec 20, 2014 May 1, 2024 Sep 3, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_006888.6:c.293A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_008819.1:p.Asn98Ser missense NM_001363669.2:c.185A>G NP_001350598.1:p.Asn62Ser missense NM_001363670.2:c.296A>G NP_001350599.1:p.Asn99Ser missense NC_000014.9:g.90404386A>G NC_000014.8:g.90870730A>G NG_013338.1:g.12404A>G P62158:p.Asn98Ser - Protein change
- N98S, N62S, N99S
- Other names
- N97S
- Canonical SPDI
- NC_000014.9:90404385:A:G
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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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- Comment on variant
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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CALM1 | No evidence available | No evidence available |
GRCh38 GRCh37 |
96 | 161 |
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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Likely pathogenic (4) |
criteria provided, single submitter
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Jul 13, 2016 | RCV000032977.41 | |
Likely pathogenic (1) |
no assertion criteria provided
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Nov 26, 2014 | RCV000157134.9 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Aug 10, 2017 | RCV000714909.11 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 3, 2023 | RCV000526484.14 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Oct 20, 2017 | RCV002433484.9 |
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
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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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Likely pathogenic
(Jul 13, 2016)
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criteria provided, single submitter
Method: clinical testing
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Catecholaminergic polymorphic ventricular tachycardia 4
Affected status: yes
Allele origin:
de novo
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Center for Medical Genetics Ghent, University of Ghent
Accession: SCV000299265.1
First in ClinVar: Mar 24, 2015 Last updated: Mar 24, 2015 |
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Likely pathogenic
(Aug 10, 2017)
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criteria provided, single submitter
Method: clinical testing
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Catecholaminergic polymorphic ventricular tachycardia
Affected status: yes
Allele origin:
germline
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Royal Brompton Clinical Genetics And Genomics Laboratory, NHS South East Genomic Laboratory Hub
Accession: SCV000845664.2
First in ClinVar: Nov 03, 2018 Last updated: Dec 11, 2022 |
Comment:
To the best of our knowledge the CALM1 c.293A>G variant has not been reported in any other patients, nor detected in approximately 120,000 individuals in … (more)
To the best of our knowledge the CALM1 c.293A>G variant has not been reported in any other patients, nor detected in approximately 120,000 individuals in control populations. Functional studies have demonstrated the variant has an impact on protein structure/function (Hwang et al. Circ Res. 2014 Mar 28;114(7):1114-24; Søndergaard et al. FEBS J. 2015 Feb;282(4):803-16; Søndergaard et al. J Biol Chem. 2015 Oct 23;290(43):26151-62; Vassilakopoulou et al. Biochim Biophys Acta. 2015 Nov;1850(11):2168-76). Evidence for pathogenicity: - Population Controls alleles / total (frequency): Exome Agregation Consortium (ExAC) - 0/121412 (0.0), RBH healthy cohort - 0/2144 (0.0) - Missense Effect Predictions - 42.86% (3/7) of algorithms have predicted that this variant will adversely affect protein function (less)
Number of individuals with the variant: 1
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Pathogenic
(Sep 03, 2023)
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criteria provided, single submitter
Method: clinical testing
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Long QT syndrome 14
Catecholaminergic polymorphic ventricular tachycardia 4
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000655574.6
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
This missense change has been observed in individual(s) with catecholaminergic polymorphic VT (PMID: 23040497). In at least one individual the variant was observed to be … (more)
This missense change has been observed in individual(s) with catecholaminergic polymorphic VT (PMID: 23040497). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 98 of the CALM1 protein (p.Asn98Ser). This variant is also known as p.Asn97Ser. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CALM1 function (PMID: 23040497, 24563457, 24816216, 25557436, 26309258). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 39758). (less)
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Likely pathogenic
(Oct 20, 2017)
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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: SCV002747815.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.N98S variant (also known as c.293A>G), located in coding exon 5 of the CALM1 gene, results from an A to G substitution at nucleotide … (more)
The p.N98S variant (also known as c.293A>G), located in coding exon 5 of the CALM1 gene, results from an A to G substitution at nucleotide position 293. The asparagine at codon 98 is replaced by serine, an amino acid with highly similar properties. This alteration has been reported to occur de novo in an individual with catecholaminergic polymorphic ventricular tachycardia (Nyegaard M et al. Am. J. Hum. Genet., 2012 Oct;91:703-12). Internal structure analysis revealed that this alteration is indicated to disrupt a calcium binding residue. Consistent with that, functional studies in various experimental systems have shown that this alteration would attenuate calcium binding (Nyegaard M et al. Am. J. Hum. Genet., 2012 Oct;91:703-12; Hwang HS et al. Circ. Res., 2014 Mar;114:1114-24; Limpitikul WB et al. J. Mol. Cell. Cardiol., 2014 Sep;74:115-24; Søndergaard MT et al. FEBS J., 2015 Feb;282:803-16; Søndergaard MT et al. J. Biol. Chem., 2015 Oct;290:26151-62; Yu CC et al. Heart Rhythm, 2016 Aug;13:1716-23; Vassilakopoulou V et al. Biochim. Biophys. Acta, 2015 Nov;1850:2168-76). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
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Pathogenic
(Jul 23, 2012)
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no assertion criteria provided
Method: research
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Ventricular tachycardia, catecholaminergic polymorphic, 4
Affected status: yes
Allele origin:
de novo
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Nyegaard lab; Aarhus University
Accession: SCV000187714.1
First in ClinVar: Dec 20, 2014 Last updated: Dec 20, 2014
Comment:
Identified in a single patient with CPVT
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Number of individuals with the variant: 1
Clinical Features:
CPVT-like phenotype (present)
Family history: no
Geographic origin: Iraq
Method: Re-sequencing
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Likely pathogenic
(Nov 26, 2014)
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no assertion criteria provided
Method: clinical testing
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Catecholaminergic polymorphic ventricular tachycardia
Affected status: yes
Allele origin:
germline
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Blueprint Genetics
Accession: SCV000206857.1
First in ClinVar: Feb 06, 2015 Last updated: Feb 06, 2015 |
Number of individuals with the variant: 1
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Pathogenic
(Oct 05, 2012)
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no assertion criteria provided
Method: literature only
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VENTRICULAR TACHYCARDIA, CATECHOLAMINERGIC POLYMORPHIC, 4
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000056752.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 09, 2016 |
Comment on evidence:
In a 23-year-old Iraqi woman with catecholaminergic polymorphic ventricular tachycardia (CPVT4; 614916), Nyegaard et al. (2012) identified heterozygosity for a de novo 293A-G transition in … (more)
In a 23-year-old Iraqi woman with catecholaminergic polymorphic ventricular tachycardia (CPVT4; 614916), Nyegaard et al. (2012) identified heterozygosity for a de novo 293A-G transition in exon 5 of the CALM1 gene, resulting in an asn97-to-ser (N97S) substitution at a highly conserved Ca(2+)-binding residue within the high-affinity binding-site III in the calmodulin C domain. The mutation was not found in her unaffected parents or in 500 Danish controls, and the patient was negative for mutation in 8 other arrhythmia-associated genes. At age 4 years, the patient underwent cardiac arrest due to ventricular fibrillation while running; she was stabilized by treatment with a beta-1 adrenergic receptor blocker. Electrocardiography (ECG) showed prominent U-waves in anterior leads but no evidence for long QT or Brugada syndromes. At 12 years of age, an off-medication exercise ECG demonstrated ventricular ectopy with couplets and triplets of varying morphology, which appeared to be bidirectional at times. At age 15, she suffered a second cardiac arrest and underwent implantation of an internal cardiac defibrillator (ICD). Functional analysis demonstrated that the mutant had significantly reduced Ca(2+) affinity compared to wildtype calmodulin. In addition, for the N97S mutant, calmodulin-RYR2 (180902) interaction was defective at low intracellular Ca(2+) concentrations and restored at moderate to high Ca(2+) concentrations. (less)
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not provided
(-)
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no classification provided
Method: literature only
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Catecholaminergic polymorphic ventricular tachycardia 4
Affected status: yes
Allele origin:
germline
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GeneReviews
Accession: SCV000147940.3
First in ClinVar: Apr 19, 2014 Last updated: Oct 01, 2022 |
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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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Catecholaminergic Polymorphic Ventricular Tachycardia. | Adam MP | - | 2022 | PMID: 20301466 |
Arrhythmogenic calmodulin mutations impede activation of small-conductance calcium-activated potassium current. | Yu CC | Heart rhythm | 2016 | PMID: 27165696 |
Arrhythmogenic Calmodulin Mutations Affect the Activation and Termination of Cardiac Ryanodine Receptor-mediated Ca2+ Release. | Søndergaard MT | The Journal of biological chemistry | 2015 | PMID: 26309258 |
Distinctive malfunctions of calmodulin mutations associated with heart RyR2-mediated arrhythmic disease. | Vassilakopoulou V | Biochimica et biophysica acta | 2015 | PMID: 26164367 |
Calmodulin mutations causing catecholaminergic polymorphic ventricular tachycardia confer opposing functional and biophysical molecular changes. | Søndergaard MT | The FEBS journal | 2015 | PMID: 25557436 |
Calmodulin mutations associated with long QT syndrome prevent inactivation of cardiac L-type Ca(2+) currents and promote proarrhythmic behavior in ventricular myocytes. | Limpitikul WB | Journal of molecular and cellular cardiology | 2014 | PMID: 24816216 |
Divergent regulation of ryanodine receptor 2 calcium release channels by arrhythmogenic human calmodulin missense mutants. | Hwang HS | Circulation research | 2014 | PMID: 24563457 |
Mutations in calmodulin cause ventricular tachycardia and sudden cardiac death. | Nyegaard M | American journal of human genetics | 2012 | PMID: 23040497 |
Text-mined citations for rs267607277 ...
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.
NCBI staff reviewed the sequence information reported in PubMed 23040497 to determine the location of this allele on the current reference sequence. Their numbering of Asn97Ser, when begun at Met1, will be Asn98Ser.