NM_006888.6(CALM1):c.293A>G (p.Asn98Ser) AND Cardiovascular phenotype

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Oct 20, 2017
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV002433484.9

Allele description [Variation Report for NM_006888.6(CALM1):c.293A>G (p.Asn98Ser)]

NM_006888.6(CALM1):c.293A>G (p.Asn98Ser)

Gene:

CALM1:calmodulin 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

14q32.11

Genomic location:

Preferred name:

NM_006888.6(CALM1):c.293A>G (p.Asn98Ser)

Other names:

N97S

HGVS:

NC_000014.9:g.90404386A>G
NG_013338.1:g.12404A>G
NM_001363669.2:c.185A>G
NM_001363670.2:c.296A>G
NM_006888.6:c.293A>GMANE SELECT
NP_001350598.1:p.Asn62Ser
NP_001350599.1:p.Asn99Ser
NP_008819.1:p.Asn98Ser
NC_000014.8:g.90870730A>G
NM_006888.4:c.293A>G
NM_006888.5:c.293A>G
NP_008819.1:p.Asn98Ser(Asn97Ser)
P62158:p.Asn98Ser

Note:

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.

Protein change:

N62S; ASN97SER

Links:

UniProtKB: P62158#VAR_069223; OMIM: 114180.0002; dbSNP: rs267607277

NCBI 1000 Genomes Browser:

rs267607277

Molecular consequence:

NM_001363669.2:c.185A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001363670.2:c.296A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_006888.6:c.293A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Cardiovascular phenotype
Identifiers:: MedGen: CN230736

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002747815	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Oct 20, 2017)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 23040497, 24563457, 24816216, 25557436, 26164367, 26309258, 27165696 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002747815

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Oct 20, 2017)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mutations in calmodulin cause ventricular tachycardia and sudden cardiac death.

Nyegaard M, Overgaard MT, Søndergaard MT, Vranas M, Behr ER, Hildebrandt LL, Lund J, Hedley PL, Camm AJ, Wettrell G, Fosdal I, Christiansen M, Børglum AD.

Am J Hum Genet. 2012 Oct 5;91(4):703-12. doi: 10.1016/j.ajhg.2012.08.015.

PubMed [citation]

PMID:: 23040497
PMCID:: PMC3484646

Divergent regulation of ryanodine receptor 2 calcium release channels by arrhythmogenic human calmodulin missense mutants.

Hwang HS, Nitu FR, Yang Y, Walweel K, Pereira L, Johnson CN, Faggioni M, Chazin WJ, Laver D, George AL Jr, Cornea RL, Bers DM, Knollmann BC.

Circ Res. 2014 Mar 28;114(7):1114-24. doi: 10.1161/CIRCRESAHA.114.303391. Epub 2014 Feb 21.

PubMed [citation]

PMID:: 24563457
PMCID:: PMC3990285

See all PubMed Citations (7)

Details of each submission

From Ambry Genetics, SCV002747815.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jun 9, 2024

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