rs267607277
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PP2PP5_Very_Strong
The NM_006888.6(CALM1):c.293A>G(p.Asn98Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 33)
Consequence
CALM1
NM_006888.6 missense
NM_006888.6 missense
Scores
4
5
6
Clinical Significance
Conservation
PhyloP100: 9.27
Genes affected
CALM1 (HGNC:1442): (calmodulin 1) This gene encodes one of three calmodulin proteins which are members of the EF-hand calcium-binding protein family. Calcium-induced activation of calmodulin regulates and modulates the function of cardiac ion channels. Two pseudogenes have been identified on chromosome 7 and X. Multiple transcript variants encoding different isoforms have been found for this gene.A missense mutation in the CALM1 gene has been associated with ventricular tachycardia.[provided by RefSeq, May 2020]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 13 ACMG points.
PM1
?
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_006888.6
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, CALM1
PP5
?
Variant 14-90404386-A-G is Pathogenic according to our data. Variant chr14-90404386-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 39758.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-90404386-A-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CALM1 | NM_006888.6 | c.293A>G | p.Asn98Ser | missense_variant | 5/6 | ENST00000356978.9 | |
CALM1 | NM_001363670.2 | c.296A>G | p.Asn99Ser | missense_variant | 5/6 | ||
CALM1 | NM_001363669.2 | c.185A>G | p.Asn62Ser | missense_variant | 5/6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CALM1 | ENST00000356978.9 | c.293A>G | p.Asn98Ser | missense_variant | 5/6 | 1 | NM_006888.6 | P1 | |
ENST00000555853.1 | n.44+806T>C | intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome Cov.: 30
GnomAD4 exome
Cov.:
30
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:8Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Catecholaminergic polymorphic ventricular tachycardia 4 Pathogenic:4Other:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 05, 2012 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, no assertion criteria provided | research | Nyegaard lab; Aarhus University | Jul 23, 2012 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Center for Medical Genetics Ghent, University of Ghent | Jul 13, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Dec 21, 2023 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0104 - Dominant negative is a known mechanism of disease in this gene and is associated with catecholaminergic polymorphic ventricular tachycardia 4 (CPVT; MIM#614916) and Long QT syndrome 14 (LQTS; MIM#616247). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from asparagine to serine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). The variant is located in the EF-hand III domain (PMID: 37380439). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as likely pathogenic/pathogenic by five clinical laboratories in ClinVar and in three de novo individuals with CPVT or a combination of CPVT/LQTS (PMID: 23040497, PMID: 37380439). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Catecholaminergic polymorphic ventricular tachycardia Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Royal Brompton Clinical Genetics And Genomics Laboratory, NHS South East Genomic Laboratory Hub | Aug 10, 2017 | 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 - |
Catecholaminergic polymorphic ventricular tachycardia 4;C4015671:Long QT syndrome 14 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 03, 2023 | 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). - |
Catecholaminergic polymorphic ventricular tachycardia 1 Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | Blueprint Genetics | Nov 26, 2014 | - - |
Cardiovascular phenotype Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 20, 2017 | 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Benign
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;.;D;.;.
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D;D;D;D;D
MetaSVM
Benign
T
MutationTaster
Benign
D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D;D;D;D
REVEL
Uncertain
Sift4G
Benign
T;T;T;T;T
Polyphen
0.032
.;.;B;.;.
Vest4
0.79, 0.90, 0.80, 0.89
MutPred
0.64
.;.;Gain of glycosylation at N99 (P = 0.0445);.;.;
MVP
MPC
1.6
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at