NM_002667.5(PLN):c.37AGA[1] (p.Arg14del) AND Dilated cardiomyopathy 1P

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Jan 19, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000233546.18

Allele description [Variation Report for NM_002667.5(PLN):c.37AGA[1] (p.Arg14del)]

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

Genes:

CEP85L:centrosomal protein 85 like [Gene - OMIM - HGNC]
PLN:phospholamban [Gene - OMIM - HGNC]

Variant type:

Microsatellite

Cytogenetic location:

6q22.31

Genomic location:

Preferred name:

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

HGVS:

NC_000006.11:g.118880120_118880122del
NC_000006.12:g.118558958AGA[1]
NG_009082.1:g.15680AGA[1]
NG_021248.1:g.156114CTT[1]
NM_001042475.3:c.1020+6570_1020+6572delMANE SELECT
NM_001178035.2:c.1029+6570_1029+6572del
NM_002667.5:c.36_38delAAG
NM_002667.5:c.37AGA[1]MANE SELECT
NM_206921.3:c.1020+6570_1020+6572del
NP_002658.1:p.Arg14del
LRG_390t1:c.40_42del
LRG_390:g.15680AGA[1]
NC_000006.11:g.118880120_118880122del
NC_000006.11:g.118880121AGA[1]
NC_000006.11:g.118880124_118880126delAGA
NM_002667.3:c.40_42del
NM_002667.3:c.40_42delAGA
NM_002667.4:c.36_38del
NM_002667.4:c.40_42del
NM_002667.4:c.40_42delAGA
NM_002667.5:c.36_38delAAGMANE SELECT
NM_002667.5:c.40_42delMANE SELECT
c.40_42delAGA
p.R14del

Protein change:

R14del

Links:

OMIM: 172405.0003; dbSNP: rs397516784

NCBI 1000 Genomes Browser:

rs397516784

Molecular consequence:

NM_002667.5:c.37AGA[1] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001042475.3:c.1020+6570_1020+6572del - intron variant - [Sequence Ontology: SO:0001627]
NM_001178035.2:c.1029+6570_1029+6572del - intron variant - [Sequence Ontology: SO:0001627]
NM_206921.3:c.1020+6570_1020+6572del - intron variant - [Sequence Ontology: SO:0001627]

Observations:

Condition(s)

Name:: Dilated cardiomyopathy 1P (CMD1P)
Identifiers:: MONDO: MONDO:0012362; MedGen: C1835928; Orphanet: 154; OMIM: 609909

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000034863	OMIM	no assertion criteria provided	Pathogenic (Jan 31, 2006)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000287496	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 19, 2024)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 22820313, 23568436, 16432188, 22155237, 22707725, 28492532
SCV001499971	KTest Genetics, KTest	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002557137	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 2, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 16432188, 17010801, 22820313, 25741868
SCV003852658	Lifecell International Pvt. Ltd	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 16432188, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
Asian	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Recurrent and founder mutations in the Netherlands-Phospholamban p.Arg14del mutation causes arrhythmogenic cardiomyopathy.

van der Zwaag PA, van Rijsingen IA, de Ruiter R, Nannenberg EA, Groeneweg JA, Post JG, Hauer RN, van Gelder IC, van den Berg MP, van der Harst P, Wilde AA, van Tintelen JP.

Neth Heart J. 2013 Jun;21(6):286-93. doi: 10.1007/s12471-013-0401-3.

PubMed [citation]

PMID:: 23568436
PMCID:: PMC3661879

The human phospholamban Arg14-deletion mutant localizes to plasma membrane and interacts with the Na/K-ATPase.

Haghighi K, Pritchard T, Bossuyt J, Waggoner JR, Yuan Q, Fan GC, Osinska H, Anjak A, Rubinstein J, Robbins J, Bers DM, Kranias EG.

J Mol Cell Cardiol. 2012 Mar;52(3):773-82. doi: 10.1016/j.yjmcc.2011.11.012. Epub 2011 Dec 1.

PubMed [citation]

PMID:: 22155237
PMCID:: PMC3376549

See all PubMed Citations (8)

Details of each submission

From OMIM, SCV000034863.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV000287496.11

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From KTest Genetics, KTest, SCV001499971.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002557137.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Lifecell International Pvt. Ltd, SCV003852658.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Asian	1	not provided	not provided	clinical testing	PubMed (2)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

Last Updated: May 19, 2024

ClinVar

Relating variation to medicine