ClinVar Miner

Submissions for variant NM_006888.6(CALM1):c.293A>G (p.Asn98Ser) (rs267607277)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Medical Genetics Ghent,University of Ghent RCV000032977 SCV000299265 likely pathogenic Ventricular tachycardia, catecholaminergic polymorphic, 4 2016-07-13 criteria provided, single submitter clinical testing
Invitae RCV000526484 SCV000655574 pathogenic Ventricular tachycardia, catecholaminergic polymorphic, 4; Long QT syndrome 14 2018-03-27 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 98 of the CALM1 protein (p.Asn98Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been shown to arise de novo (i.e. not present in the parents) in an individual affected with catecholaminergic polymorphic VT (CPVT) (PMID: 23040497). ClinVar contains an entry for this variant (Variation ID: 39758). This variant is also known as p.Asn97Ser in the literature. Experimental studies have shown that this variant and this protein change (p.Asn98Ser) decreases calcium binding affinity in the C-domain of CALM1, which leads to an impaired inhibition of RYR2 channel activity (PMID: 23040497, 24563457, 25557436, 26309258) . In addition, it has been shown to significantly prolong action potentials in guinea pig ventricular myocytes, which relates this variant to long QT syndrome (PMID: 24816216). For these reasons, this variant has been classified as Pathogenic.
RBHT Clinical Genetics and Genomics Laboratory,Royal Brompton and Harefield NHS Foundation Trust RCV000714909 SCV000845664 likely pathogenic Catecholaminergic polymorphic ventricular tachycardia 2017-08-10 criteria provided, single submitter clinical testing 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
OMIM RCV000032977 SCV000056752 pathogenic Ventricular tachycardia, catecholaminergic polymorphic, 4 2012-10-05 no assertion criteria provided literature only
GeneReviews RCV000032977 SCV000147940 pathogenic Ventricular tachycardia, catecholaminergic polymorphic, 4 2014-03-06 no assertion criteria provided literature only
Nyegaard lab; Aarhus University RCV000032977 SCV000187714 pathogenic Ventricular tachycardia, catecholaminergic polymorphic, 4 2012-07-23 no assertion criteria provided research
Blueprint Genetics RCV000157134 SCV000206857 likely pathogenic Catecholaminergic polymorphic ventricular tachycardia type 1 2014-11-26 no assertion criteria provided clinical testing

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