ClinVar Miner

Submissions for variant NM_002667.5(PLN):c.37_39AGA[1] (p.Arg14del) (rs397516784)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000244830 SCV000318486 pathogenic Cardiovascular phenotype 2017-08-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Strong segregation with disease (lod >3 = >10 meioses),Deficient protein function in appropriate functional assay(s),Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Rarity in general population databases (dbsnp, esp, 1000 genomes),Other strong data supporting pathogenic classification
Blueprint Genetics RCV000183818 SCV000207162 pathogenic Cardiomyopathy 2014-11-27 criteria provided, single submitter clinical testing
Erich and Hanna Klessmann Institute for Cardiovascular Research and Development,Heart and Diabetes Center North Rhine-Westphalia RCV000491072 SCV000298153 pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 9 2016-05-01 no assertion criteria provided clinical testing
GeneDx RCV000212833 SCV000236300 pathogenic not provided 2018-10-01 criteria provided, single submitter clinical testing The c.40_42delAGA pathogenic variant (reported as R14del) in the PLN gene has been published multiple times in association with both DCM and arrhythmogenic right ventricular cardiomyopathy (ARVC) (Haghighi et al., 2006; Ceholski et al., 2012; Haghighi et al., 2012; van der Zwaag et al, 2012; Groeneweg et al., 2013). This variant was first identified in a large family with multiple relatives diagnosed with DCM and an extensive family history of cardiomyopathy in deceased relatives (Haghighi et al., 2006).The c.40_42delAGA pathogenic variant was not present in 658 control individuals and the Arg14 residue is highly conserved across species (Haghighi et al., 2006). Subsequently, this variant has been reported as a founder mutation in 12% of ARVC patients and 15% of DCM patients in the Dutch population (van der Zwaag et al., 2012). In this study, approximately 50% of all patients who harbored c.40_42delAGA (18/39 individuals) presented with a sustained or non-sustained ventricular tachycardia or ventricular fibrillation at baseline (van der Zwaag et al., 2012). Another study identified this variant in 9 individuals from a large Dutch family, 6 of whom met 2010 Task Force Criteria for ARVC and 7 of whom had left-ventricular involvement (inverted T waves in leads V4-V6, LV wall motion abnormalities and late enhancement, and reduced LV ejection fraction) (Groeneweg et al., 2013).Furthermore, transgenic mice harboring this variant exhibited features similar to the human phenotype with abnormal heart histopathology and premature death (Haghighi et al., 2006; Haghighi et al., 2012). An in vitro functional study reported that R14del is a partial inhibitor of the sarcoplasmic reticulum calcium pump, and that it inhibits the phospholamban-protein kinase A interaction (Ceholski et al., 2012).
Invitae RCV000233546 SCV000287496 pathogenic Dilated cardiomyopathy 1P 2018-12-03 criteria provided, single submitter clinical testing This sequence change deletes 3 nucleotides from exon 2 of the PLN mRNA (c.40_42delAGA). This leads to the deletion of 1 amino acid residue in the PLN protein (p.Arg14del) but otherwise preserves the integrity of the reading frame. This variant is clearly defined as an arrythmogenic right ventricular dysplasia or dilated cardiomyopathy causative allele (PMID: 22820313, 23568436). It is a founder mutation in the Dutch population and has been observed in hundreds of patients with either arrhythmogenic right ventricular dysplasia or dilated cardiomyopathy. ClinVar contains an entry for this variant (Variation ID: 44580). Experimental studies have shown that this change disrupts the protein kinase A recognition motif, which prevents phospholamban phosphorylation (PMID: 22707725) and transgenic mice containing this sequence develop cardiomyopathy (PMID: 16432188, 22155237). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000037582 SCV000061240 pathogenic Primary dilated cardiomyopathy 2013-08-19 criteria provided, single submitter clinical testing The p.Arg14del variant in PLN has been identified in >50 individuals with DCM an d >10 individuals with ARVC, and was found to segregate with disease in at least >10 affected relatives with DCM (DeWitt 2006, Haghighi 2006, Posch 2009, van de r Zwagg 2012). Multiple functional studies, including mouse models, all support that the Arg14del variant impacts protein function (Haghighi 2006, Ceholski 2012 a, Ceholski 2012b, Haghighi 2012). In summary, the p.Arg14del variant meets our criteria for pathogenicity (http://www.partners.org/personalizedmedicine/LMM) ba sed on segregation and functional evidence.
OMIM RCV000233546 SCV000034863 pathogenic Dilated cardiomyopathy 1P 2006-01-31 no assertion criteria provided literature only
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000212833 SCV000280420 pathogenic not provided 2013-02-08 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.R14del (c.40_42delAGA) The p.Arg14del variant in PLN has been identified in >50 individuals with DCM and >10 individuals with ARVC, and was found to segregate with disease in at least >10 affected relatives with DCM (DeWitt 2006, Haghighi 2006, Posch 2009, van der Zwagg 2012). Multiple functional studies, including mouse models, all support that the Arg14del variant impacts protein function (Haghighi 2006, Ceholski 2012a, Ceholski 2012b, Haghighi 2012). This variant is also a founder mutation in the dutch population. Risk stratification for sudden cardiac death is also available (Circ Cardiovasc Genet. 2014;7:455-465). In total the variant has not been seen in laboratory controls, published controls and individuals from publicly available population datasets. There is no variation at codon 14 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on 5600 Caucasian and African American individuals (as of April 15, 2015). There is also no variation at this codon listed in dbSNP or 1000 genomes (as of April 15, 2015). There is one missense variation at codon 14 listed in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of 8/26/2015).

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