rs397516784

Positions:

• chr6-118558956-TAAG-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM4_Supporting PP5_Very_Strong

The ENST00000357525.6(PLN):​c.40_42del​(p.Arg14del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,613,470 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: PLN ENST00000357525.6 inframe_deletion
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:20 U:1
• Conservation: PhyloP100: 8.28

Genes affected

PLN (HGNC:9080): (phospholamban) The protein encoded by this gene is found as a pentamer and is a major substrate for the cAMP-dependent protein kinase in cardiac muscle. The encoded protein is an inhibitor of cardiac muscle sarcoplasmic reticulum Ca(2+)-ATPase in the unphosphorylated state, but inhibition is relieved upon phosphorylation of the protein. The subsequent activation of the Ca(2+) pump leads to enhanced muscle relaxation rates, thereby contributing to the inotropic response elicited in heart by beta-agonists. The encoded protein is a key regulator of cardiac diastolic function. Mutations in this gene are a cause of inherited human dilated cardiomyopathy with refractory congestive heart failure, and also familial hypertrophic cardiomyopathy. [provided by RefSeq, Apr 2016]

CEP85L (HGNC:21638): (centrosomal protein 85 like) The protein encoded by this gene was identified as a breast cancer antigen. Nothing more is known of its function at this time. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2010]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in ENST00000357525.6
• PM4: Nonframeshift variant in NON repetitive region in ENST00000357525.6. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 6-118558956-TAAG-T is Pathogenic according to our data. Variant chr6-118558956-TAAG-T is described in ClinVar as [Pathogenic]. Clinvar id is 44580.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-118558956-TAAG-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLN	NM_002667.5	c.40_42del	p.Arg14del	inframe_deletion	2/2	ENST00000357525.6	NP_002658.1
CEP85L	NM_001042475.3	c.1020+6570_1020+6572del		intron_variant		ENST00000368491.8	NP_001035940.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLN	ENST00000357525.6	c.40_42del	p.Arg14del	inframe_deletion	2/2	1	NM_002667.5	ENSP00000350132	P1
CEP85L	ENST00000368491.8	c.1020+6570_1020+6572del		intron_variant		1	NM_001042475.3	ENSP00000357477	P1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251122 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135734

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461292 Hom.: 0 AF XY: 0.00000688 AC XY: 5 AN XY: 727016

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152178 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74344

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000508 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:20 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:7

Pathogenic, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Feb 08, 2013	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). -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 28, 2022	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) -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Jul 27, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 21, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Sep 13, 2022	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. -

Dilated cardiomyopathy 1P Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	North West Genomic Laboratory Hub, Manchester University NHS Foundation Trust	Jul 26, 2024	PM2 PM4_Supp PP1_Str PS3_Str -
Pathogenic, criteria provided, single submitter	clinical testing	Lifecell International Pvt. Ltd	-	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	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 -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	KTest Genetics, KTest	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 31, 2006	- -

Cardiomyopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Nov 27, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Apr 27, 2023	- -

Primary dilated cardiomyopathy Pathogenic:1 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 19, 2013	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. -
Uncertain significance, flagged submission	research	Genetics and Genomics Program, Sidra Medicine	-	- -

Arrhythmogenic right ventricular dysplasia 9 Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Institut für Laboratoriums- und Transfusionsmedizin, Herz- und Diabeteszentrum Nordrhein-Westfalen

May 01, 2016

- -

SUDDEN INFANT DEATH SYNDROME Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Robert's Program, Boston Children's Hospital

Oct 01, 2021

We classify this variant as pathogenic using the following ACMG/AMP criteria: PS3, PM4, PP1, PP5 -

Hypertrophic cardiomyopathy 18 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Oct 31, 2018

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM4. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 06, 2022

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. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs397516784; hg19: chr6-118880119;