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

dbSNP: rs397516784

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham 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.
Blueprint Genetics	RCV000183818	SCV000207162	pathogenic	Cardiomyopathy	2014-11-27	criteria provided, single submitter	clinical testing
GeneDx	RCV000212833	SCV000236300	pathogenic	not provided	2022-03-28	criteria provided, single submitter	clinical testing	Results in an in-frame deletion of 1 amino acid in a non-repeat region; 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).; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24732829, 24909667, 23785128, 25923014, 29750433, 30830208, 31402444, 22427649, 22707725, 25775607, 23270881, 22820313, 16432188, 26970417, 27450564, 25700660, 27532257, 19324307, 22155237, 23568436, 17010801, 29635323, 29447731, 30763825, 30547415, 31152552, 30847666, 32555305, 29544605, 29253866, 33662488, 33673806, 32880476, 34135346, 33998164)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000233546	SCV000287496	pathogenic	Dilated cardiomyopathy 1P	2024-01-19	criteria provided, single submitter	clinical testing	This variant, c.40_42del, results in the deletion of 1 amino acid(s) of the PLN protein (p.Arg14del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs778096369, gnomAD 0.002%). This variant has been observed in individuals with arrythmogenic right ventricular dysplasia or dilated cardiomyopathy (PMID: 16432188, 22820313, 23568436). It is commonly reported in individuals of Dutch ancestry (PMID: 16432188). ClinVar contains an entry for this variant (Variation ID: 44580). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects PLN function (PMID: 16432188, 22155237, 22707725). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000244830	SCV000318486	pathogenic	Cardiovascular phenotype	2022-04-06	criteria provided, single submitter	clinical testing	The c.40_42delAGA pathogenic mutation (also known as p.R14del) is located in coding exon 1 of the PLN gene. This pathogenic mutation results from an in-frame AGA deletion at nucleotide positions 40 to 42. This results in the in-frame deletion of an arginine at codon 14. This mutation has been identified in multiple individuals with arrhythmogenic right ventricular cardiomyopathy (ARVC) or dilated cardiomyopathy (DCM), and it has shown strong segregation with cardiomyopathy in a number of unrelated extended pedigrees (DeWitt M et al. J Am Coll Cardiol. 2006;48(7):1396-8; Haghighi K et al. Proc Natl Acad Sci. U.S.A. 2006;103(5):1388-93; Posch M et al. Heart Rhythm. 2009;6(4):480-6; van der Zwaag PA et al. Eur J Heart Fail. 2012;14(11):1199-207; Groeneweg J et al. Am J Cardiol. 2013;112(8):1197-206). Haploytpe analysis has indicated that this variant is a Dutch founder mutation (van der Zwaag PA et al. 2013. Neth Heart J. 2013;21(6):286-93). Functional assays have demonstrated that this alteration disrupts protein function and leads to dominant negative effects (Haghighi K et al. Proc Natl Acad Sci. U.S.A. 2006;103(5):1388-93; Haghighi K et al. J Mol Cell Cardiol. 2012;52(3):773-82; Ceholski D et al. J Biol Chem. 2012;287(32):26596-605; Ceholski DK et al. J Biol Chem. 2012;287(20):16521-9). In addition, a study has found that PLN gene editing can rescue the abnormalities observed in human cardiomyocytes derived from an affected individual heterozygous for this alteration (Karakikes I et al. Nat Commun. 2015;6:6955). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001197004	SCV001367639	pathogenic	Hypertrophic cardiomyopathy 18	2018-10-31	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM4.
KTest Genetics, KTest	RCV000233546	SCV001499971	pathogenic	Dilated cardiomyopathy 1P		criteria provided, single submitter	clinical testing
Robert's Program, Boston Children's Hospital	RCV001787831	SCV002030067	pathogenic	SUDDEN INFANT DEATH SYNDROME	2021-10-01	criteria provided, single submitter	research	We classify this variant as pathogenic using the following ACMG/AMP criteria: PS3, PM4, PP1, PP5
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000183818	SCV002043208	pathogenic	Cardiomyopathy	2023-04-27	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000233546	SCV002557137	pathogenic	Dilated cardiomyopathy 1P	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as pathogenic. 0104 - Dominant negative is a known mechanism of disease in this gene and is associated with dilated cardiomyopathy (MIM# 609909). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. The p.(Arg14del) variant has been reported to cause DCM and ARVC (PMID: 22820313). (I) 0213 - In-frame deletion in a non-repetitive region that has high conservation. (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (2 heterozygotes, 0 homozygotes). (SP) 0600 - Variant is located in the annotated cytoplasmic domain (UniProt). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as a Dutch founder mutation and has been identified in at least 40 DCM patient and more than 10 ARVC patients (PMID: 22820313, PMID: 16432188, PMID: 17010801, ClinVar). (SP) 0902 - This variant has moderate evidence for segregation with disease. This variant has been shown to segregate with DCM and heart failure in a large family (PMID: 16432188). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional analysis has shown that this variant has a dominant negative effect and results in sarcoplasmic reticulum Ca2+-ATPase inhibition. Additionally, transgenic mice develop DCM, abnormal histopathology and suffer premature death (PMID: 16432188). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Illumina Laboratory Services, Illumina	RCV000212833	SCV003802801	pathogenic	not provided	2022-09-13	criteria provided, single submitter	clinical testing	The PLN c.40_42del (p.Arg14del) variant results in the deletion of three nucleotides starting at position c.40 and ending at position c.42, causing an in-frame deletion of the arginine residue at position 14 in the protein. This variant has been reported as a Dutch founder variant and is observed in 10-15% of Dutch patients with either dilated or arrhythmogenic right ventricular cardiomyopathy (PMID: 22820313; PMID: 23568436). Across a selection of the available literature, the c.40_42del variant has been identified in a heterozygous state in more than one hundred patients with cardiomyopathy, including in families where it segregated with disease (PMID: 16432188; PMID: 17010801; PMID: 22820313; PMID: 23568436; PMID: 25700660). Clinical evaluation of 52 Dutch patients carrying this variant showed that the mean age of onset of symptoms was 44.3 ± 12.6 years, with most patients presenting with ventricular tachycardia/fibrillation, heart failure, or syncope (PMID: 22820313). Additionally, patients specifically diagnosed with dilated cardiomyopathy who carried this variant were found to have a significantly higher family history of sudden cardiac death before the age of 50 years compared to patients who did not carry this variant (PMID: 22820313). In-vitro cell culture-based functional studies have shown that this variant results in the inhibition of SERCA, which is an important ATP-dependent calcium pump in the sarcoplasmic reticulum, and in-vivo studies have shown that transgenic mice that express this variant in the heart recapitulate the human cardiac phenotype (PMID: 16432188; PMID: 22155237; PMID: 22427649). This variant is reported in the Genome Aggregation Database in two alleles at a frequency of 0.000029 in the European (non-Finnish) population (version 3.1.2). Based on the available evidence, the c.40_42del (p.Arg14del) variant is classified as pathogenic for intrinsic cardiomyopathy.
Lifecell International Pvt. Ltd	RCV000233546	SCV003852658	pathogenic	Dilated cardiomyopathy 1P		criteria provided, single submitter	clinical testing	A Homozygote Inframe indel variant c.36_38delAAG in Exon 2 of the PLN gene that results in the amino acid substitution p.Arg13del was identified. The observed variant has a minor allele frequency of 0.00000/0.00003% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic (Variant ID: 44580),.The observed variant has previously been reported in the patient affected with cardiomyopathy (Haghighi K et.al 2006). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines.
Mayo Clinic Laboratories, Mayo Clinic	RCV000212833	SCV004226788	pathogenic	not provided	2022-06-21	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000212833	SCV005196723	pathogenic	not provided	2023-07-27	criteria provided, single submitter	clinical testing
North West Genomic Laboratory Hub, Manchester University NHS Foundation Trust	RCV000233546	SCV005374709	pathogenic	Dilated cardiomyopathy 1P	2024-07-26	criteria provided, single submitter	clinical testing	PM2 PM4_Supp PP1_Str PS3_Str
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).
Institut für Laboratoriums- und Transfusionsmedizin, Herz- und Diabeteszentrum Nordrhein-Westfalen	RCV000491072	SCV000298153	pathogenic	Arrhythmogenic right ventricular dysplasia 9	2016-05-01	no assertion criteria provided	clinical testing
Genetics and Genomics Program, Sidra Medicine	RCV000037582	SCV001434217	uncertain significance	Primary dilated cardiomyopathy		flagged submission	research
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000212833	SCV001742376	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000212833	SCV001926519	pathogenic	not provided		no assertion criteria provided	clinical testing