VCV000044580.44 - ClinVar

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

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(21)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Pathogenic(15); Uncertain significance(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 44580 Accession: VCV000044580.44

Type and length

Microsatellite, 3 bp

Location

Cytogenetic: 6q22.31 6: 118558957-118558959 (GRCh38) [ NCBI UCSC ] 6: 118880120-118880122 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Apr 4, 2013	Oct 20, 2024	Jul 26, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001042475.3:c.1020+6570_1020+6572del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		intron variant
NM_002667.5:c.36_38delAAG MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		inframe deletion
NM_002667.5:c.37AGA[1] MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_002658.1:p.Arg14del	inframe deletion
NM_002667.5:c.40_42del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		inframe deletion
NM_001178035.2:c.1029+6570_1029+6572del		intron variant
NM_002667.3:c.37_39AGA[1]	NP_002658.1:p.Arg14del	inframe indel
NM_002667.3:c.40_42del		inframe indel
NM_002667.3:c.40_42delAGA		inframe indel
NM_002667.4:c.36_38del
NM_002667.4:c.40_42del
NM_206921.3:c.1020+6570_1020+6572del		intron variant
NC_000006.12:g.118558958AGA[1]
NC_000006.11:g.118880121AGA[1]
NG_009082.1:g.15680AGA[1]
NG_021248.1:g.156114CTT[1]
LRG_390:g.15680AGA[1]
LRG_390t1:c.37_39AGA[1]	LRG_390p1:p.Arg14del

... more HGVS ... less HGVS

Protein change

R14del

Other names

Canonical SPDI

NC_000006.12:118558956:AAGAAGA:AAGA

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA261528 OMIM: 172405.0003 dbSNP: rs397516784 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
CEP85L		-	-	GRCh38 GRCh37	97	294
PLN		-	-	GRCh38 GRCh37	2	190

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Primary dilated cardiomyopathy	Conflicting interpretations of pathogenicity (2)	criteria provided, conflicting classifications	Aug 19, 2013	RCV000037582.9
Cardiomyopathy	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Apr 27, 2023	RCV000183818.7
not provided	Pathogenic (7)	criteria provided, multiple submitters, no conflicts	Jul 27, 2023	RCV000212833.15
Dilated cardiomyopathy 1P	Pathogenic (6)	criteria provided, multiple submitters, no conflicts	Jul 26, 2024	RCV000233546.21
Cardiovascular phenotype	Pathogenic (1)	criteria provided, single submitter	Apr 6, 2022	RCV000244830.4
Arrhythmogenic right ventricular dysplasia 9	Pathogenic (1)	no assertion criteria provided	May 1, 2016	RCV000491072.3
Hypertrophic cardiomyopathy 18	Pathogenic (1)	criteria provided, single submitter	Oct 31, 2018	RCV001197004.2
SUDDEN INFANT DEATH SYNDROME	Pathogenic (1)	criteria provided, single submitter	Oct 1, 2021	RCV001787831.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Oct 31, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypertrophic cardiomyopathy 18 Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV001367639.2 First in ClinVar: Jul 04, 2020 Last updated: Jul 04, 2020	Comment: This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM4.
Pathogenic (Mar 28, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000236300.15 First in ClinVar: Jul 05, 2015 Last updated: Mar 04, 2023	Comment: 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 … (more) 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) (less)
Pathogenic (Jun 21, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV004226788.1 First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024	Publications: PubMed (6) PubMed: 16432188‚ 22155237‚ 22707725‚ 22820313‚ 23568436‚ 32555305 Number of individuals with the variant: 6
Pathogenic (Jan 19, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Dilated cardiomyopathy 1P Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000287496.11 First in ClinVar: Jul 01, 2016 Last updated: Feb 20, 2024	Publications: PubMed (6) PubMed: 28492532‚ 16432188‚ 22820313‚ 23568436‚ 22155237‚ 22707725 Comment: 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. … (more) 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. (less)
Pathogenic (Nov 27, 2014)	criteria provided, single submitter (Variant Classification) Method: clinical testing	Cardiomyopathy Variant found in one individual (more...) Affected status: yes Allele origin: germline	Blueprint Genetics Accession: SCV000207162.3 First in ClinVar: Feb 06, 2015 Last updated: May 29, 2016	Publications: PubMed (3) PubMed: 16432188‚ 22820313‚ 23785128 Number of individuals with the variant: 3
Pathogenic (Aug 19, 2013)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	Primary dilated cardiomyopathy (Autosomal dominant inheritance) Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000061240.6 First in ClinVar: May 03, 2013 Last updated: Aug 26, 2019	Publications: PubMed (7) PubMed: 16432188‚ 17010801‚ 19324307‚ 22155237‚ 22427649‚ 22707725‚ 22820313 Comment: 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 … (more) 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. (less) Number of individuals with the variant: 6
Uncertain significance (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Primary dilated cardiomyopathy Affected status: yes Allele origin: unknown	Genetics and Genomics Program, Sidra Medicine Accession: SCV001434217.1 First in ClinVar: Feb 27, 2021 Last updated: Feb 27, 2021	Number of individuals with the variant: 1
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Dilated cardiomyopathy 1P Affected status: yes Allele origin: germline	KTest Genetics, KTest Accession: SCV001499971.1 First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021
Pathogenic (Oct 01, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	SUDDEN INFANT DEATH SYNDROME Affected status: yes Allele origin: germline	Robert's Program, Boston Children's Hospital Accession: SCV002030067.1 First in ClinVar: Dec 12, 2021 Last updated: Dec 12, 2021	Comment: We classify this variant as pathogenic using the following ACMG/AMP criteria: PS3, PM4, PP1, PP5 Clinical Features: Sudden infant death syndrome (present) Sex: male
Pathogenic (Sep 13, 2022)	criteria provided, single submitter (ICSL CNVClassificationCriteria Aug2020) Method: clinical testing	Not provided Affected status: yes Allele origin: unknown	Illumina Laboratory Services, Illumina Accession: SCV003802801.1 First in ClinVar: Feb 18, 2023 Last updated: Feb 18, 2023	Publications: PubMed (7) PubMed: 16432188‚ 22820313‚ 23568436‚ 22427649‚ 22155237‚ 25700660‚ 17010801 Comment: 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 … (more) 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. (less)
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Dilated cardiomyopathy 1P Affected status: yes Allele origin: germline	Lifecell International Pvt. Ltd Accession: SCV003852658.1 First in ClinVar: Apr 09, 2023 Last updated: Apr 09, 2023	Publications: PubMed (1) PubMed: 16432188 Comment: 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 … (more) 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. (less) Ethnicity/Population group: Asian Geographic origin: India
Pathogenic (Apr 27, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cardiomyopathy Affected status: unknown Allele origin: germline	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario Accession: SCV002043208.3 First in ClinVar: Jan 01, 2022 Last updated: Feb 04, 2024
Pathogenic (Apr 06, 2022)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000318486.7 First in ClinVar: Oct 02, 2016 Last updated: May 01, 2024	Publications: PubMed (23) PubMed: 16432188‚ 17010801‚ 19324307‚ 22155237‚ 22427649‚ 22707725‚ 22820313‚ 23349452‚ 23568436‚ 23785128‚ 23871674‚ 24503780‚ 24732829‚ 24909667‚ 25157032‚ 25700660‚ 25775607‚ 25923014‚ 26970417‚ 27450564‚ 27532257‚ 28759816‚ 29447731 Comment: 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 … (more) 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. (less)
Pathogenic (Feb 02, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Dilated cardiomyopathy 1P (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002557137.2 First in ClinVar: Aug 08, 2022 Last updated: Jul 23, 2024	Publications: PubMed (3) PubMed: 16432188‚ 17010801‚ 22820313 Comment: 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 … (more) 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 (less)
Pathogenic (Jul 27, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, Skane University Hospital Lund Accession: SCV005196723.1 First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024
Pathogenic (Jul 26, 2024)	criteria provided, single submitter (ACGS Best Practice Guidelines for Variant Classification in Rare Disease 2020) Method: clinical testing	Dilated cardiomyopathy 1P Affected status: yes Allele origin: germline	North West Genomic Laboratory Hub, Manchester University NHS Foundation Trust Accession: SCV005374709.1 First in ClinVar: Oct 20, 2024 Last updated: Oct 20, 2024	Publications: PubMed (16) PubMed: 17010801‚ 23270881‚ 22155237‚ 25700660‚ 16432188‚ 22427649‚ 22707725‚ 25775607‚ 27450564‚ 22820313‚ 23568436‚ 24732829‚ 23785128‚ 24909667‚ 23349452‚ 27532257 Comment: PM2 PM4_Supp PP1_Str PS3_Str
Pathogenic (May 01, 2016)	no assertion criteria provided Method: clinical testing	Arrhythmogenic right ventricular dysplasia 9 Affected status: yes Allele origin: inherited	Institut für Laboratoriums- und Transfusionsmedizin, Herz- und Diabeteszentrum Nordrhein-Westfalen Accession: SCV000298153.1 First in ClinVar: Jun 25, 2017 Last updated: Jun 25, 2017	Number of individuals with the variant: 2
Pathogenic (Jan 31, 2006)	no assertion criteria provided Method: literature only	CARDIOMYOPATHY, DILATED, 1P Affected status: not provided Allele origin: germline	OMIM Accession: SCV000034863.2 First in ClinVar: Apr 04, 2013 Last updated: Mar 18, 2023	Publications: PubMed (1) PubMed: 16432188 Comment on evidence: In a 7-generation family with idiopathic dilated cardiomyopathy (CMD1P; 609909) and ventricular tachycardia, Haghighi et al. (2006) identified heterozygosity for a 3-bp deletion in the … (more) In a 7-generation family with idiopathic dilated cardiomyopathy (CMD1P; 609909) and ventricular tachycardia, Haghighi et al. (2006) identified heterozygosity for a 3-bp deletion in the PLN gene, resulting in deletion of a highly conserved arg14 residue. By middle age, heterozygous individuals in this family developed left ventricular dilation, contractile dysfunction, and episodic ventricular arrhythmias, with overt heart failure in some cases. No homozygous individuals were identified. (less)
Pathogenic (Feb 08, 2013)	no assertion criteria provided Method: clinical testing	Not provided Affected status: not provided Allele origin: germline	Stanford Center for Inherited Cardiovascular Disease, Stanford University Accession: SCV000280420.1 First in ClinVar: Jun 03, 2016 Last updated: Jun 03, 2016	Comment: 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 … (more) 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). (less) Number of individuals with the variant: 10
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001742376.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001926519.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
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Comment:

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)

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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

Comment:

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).

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
The phospholamban p.(Arg14del) pathogenic variant leads to cardiomyopathy with heart failure and is unreponsive to standard heart failure therapy.	Eijgenraam TR	Scientific reports	2020	PMID: 32555305
Genetics, Clinical Features, and Long-Term Outcome of Noncompaction Cardiomyopathy.	van Waning JI	Journal of the American College of Cardiology	2018	PMID: 29447731
Phospholamban immunostaining is a highly sensitive and specific method for diagnosing phospholamban p.Arg14del cardiomyopathy.	Te Rijdt WP	Cardiovascular pathology : the official journal of the Society for Cardiovascular Pathology	2017	PMID: 28759816
Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples.	Walsh R	Genetics in medicine : official journal of the American College of Medical Genetics	2017	PMID: 27532257
Genomic correction of familial cardiomyopathy in human engineered cardiac tissues.	Stillitano F	European heart journal	2016	PMID: 27450564
Phospholamban p.Arg14del cardiomyopathy is characterized by phospholamban aggregates, aggresomes, and autophagic degradation.	Te Rijdt WP	Histopathology	2016	PMID: 26970417
Correction of human phospholamban R14del mutation associated with cardiomyopathy using targeted nucleases and combination therapy.	Karakikes I	Nature communications	2015	PMID: 25923014
Dysfunctional conformational dynamics of protein kinase A induced by a lethal mutant of phospholamban hinder phosphorylation.	Kim J	Proceedings of the National Academy of Sciences of the United States of America	2015	PMID: 25775607
Phospholamban p.arg14del mutation in a Spanish family with arrhythmogenic cardiomyopathy: evidence for a European founder mutation.	López-Ayala JM	Revista espanola de cardiologia (English ed.)	2015	PMID: 25700660
Titin and desmosomal genes in the natural history of arrhythmogenic right ventricular cardiomyopathy.	Brun F	Journal of medical genetics	2014	PMID: 25157032
Outcome in phospholamban R14del carriers: results of a large multicentre cohort study.	van Rijsingen IA	Circulation. Cardiovascular genetics	2014	PMID: 24909667
High resolution systematic digital histological quantification of cardiac fibrosis and adipose tissue in phospholamban p.Arg14del mutation associated cardiomyopathy.	Gho JM	PloS one	2014	PMID: 24732829
The landscape of genetic variation in dilated cardiomyopathy as surveyed by clinical DNA sequencing.	Pugh TJ	Genetics in medicine : official journal of the American College of Medical Genetics	2014	PMID: 24503780
Arrhythmogenic right ventricular dysplasia/cardiomyopathy according to revised 2010 task force criteria with inclusion of non-desmosomal phospholamban mutation carriers.	Groeneweg JA	The American journal of cardiology	2013	PMID: 23871674
Targeted sequence capture and GS-FLX Titanium sequencing of 23 hypertrophic and dilated cardiomyopathy genes: implementation into diagnostics.	Mook OR	Journal of medical genetics	2013	PMID: 23785128
Recurrent and founder mutations in the Netherlands-Phospholamban p.Arg14del mutation causes arrhythmogenic cardiomyopathy.	van der Zwaag PA	Netherlands heart journal : monthly journal of the Netherlands Society of Cardiology and the Netherlands Heart Foundation	2013	PMID: 23568436
Genetic analysis in 418 index patients with idiopathic dilated cardiomyopathy: overview of 10 years' experience.	van Spaendonck-Zwarts KY	European journal of heart failure	2013	PMID: 23349452
Left-dominant arrhythmogenic cardiomyopathy in a large family: associated desmosomal or nondesmosomal genotype?	Groeneweg JA	Heart rhythm	2013	PMID: 23270881
Phospholamban R14del mutation in patients diagnosed with dilated cardiomyopathy or arrhythmogenic right ventricular cardiomyopathy: evidence supporting the concept of arrhythmogenic cardiomyopathy.	van der Zwaag PA	European journal of heart failure	2012	PMID: 22820313
Lethal, hereditary mutants of phospholamban elude phosphorylation by protein kinase A.	Ceholski DK	The Journal of biological chemistry	2012	PMID: 22707725
Hydrophobic imbalance in the cytoplasmic domain of phospholamban is a determinant for lethal dilated cardiomyopathy.	Ceholski DK	The Journal of biological chemistry	2012	PMID: 22427649
The human phospholamban Arg14-deletion mutant localizes to plasma membrane and interacts with the Na/K-ATPase.	Haghighi K	Journal of molecular and cellular cardiology	2012	PMID: 22155237
Genetic deletion of arginine 14 in phospholamban causes dilated cardiomyopathy with attenuated electrocardiographic R amplitudes.	Posch MG	Heart rhythm	2009	PMID: 19324307
Phospholamban R14 deletion results in late-onset, mild, hereditary dilated cardiomyopathy.	DeWitt MM	Journal of the American College of Cardiology	2006	PMID: 17010801
A mutation in the human phospholamban gene, deleting arginine 14, results in lethal, hereditary cardiomyopathy.	Haghighi K	Proceedings of the National Academy of Sciences of the United States of America	2006	PMID: 16432188
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Record last updated Oct 20, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs397516784 ...