chr14-90404386-A-G

Position:

• chr14-90404386-A-G

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PP2 PP5_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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8 O:1
• 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]

(HGNC:):

ACMG classification

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, 6 uncertain in NM_006888.6
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CALM1. . Gene score misZ 3.051 (greater than the threshold 3.09). Trascript score misZ 3.5833 (greater than threshold 3.09). GenCC has associacion of gene with long QT syndrome, catecholaminergic polymorphic ventricular tachycardia 4, long QT syndrome 14, catecholaminergic polymorphic ventricular tachycardia.
• 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

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Catecholaminergic polymorphic ventricular tachycardia 4 Pathogenic:4 Other: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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.052	T
BayesDel_noAF	Benign	-0.31
CADD	Pathogenic	27
DANN	Benign	0.92
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;.;D;.;.
M_CAP	Pathogenic	0.53	D
MetaRNN	Uncertain	0.68	D;D;D;D;D
MetaSVM	Benign	-0.53	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-4.4	D;D;D;D;D
REVEL	Uncertain	0.44
Sift4G	Benign	0.20	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		0.83
MPC		1.6
ClinPred		0.98	D
GERP RS		5.5
Varity_R		0.79
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs267607277; hg19: chr14-90870730;