NM_002667.4(PLN):c.116T>G (p.Leu39Ter) AND Dilated cardiomyopathy 1P

Clinical significance:Pathogenic (Last evaluated: Dec 12, 2017)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
2 submissions [Details]
Record status:

Allele description

NM_002667.4(PLN):c.116T>G (p.Leu39Ter)

CEP85L:centrosomal protein 85 like [Gene - HGNC]
PLN:phospholamban [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
NM_002667.4(PLN):c.116T>G (p.Leu39Ter)
  • NC_000006.12:g.118559037T>G
  • NG_009082.1:g.15759T>G
  • NM_002667.4:c.116T>G
  • NP_002658.1:p.Leu39Ter
  • LRG_390t1:c.116T>G
  • LRG_390:g.15759T>G
  • LRG_390p1:p.Leu39Ter
  • NC_000006.11:g.118880200T>G
  • NM_002667.3:c.116T>G
  • p.Leu39X
Protein change:
L39*; LEU39TER
OMIM: 172405.0002; dbSNP: rs111033560
NCBI 1000 Genomes Browser:
Allele Frequency:
Molecular consequence:
  • NM_002667.4:c.116T>G - nonsense - [Sequence Ontology: SO:0001587]


Dilated cardiomyopathy 1P (CMD1P)
MedGen: C1835928; Orphanet: 154; OMIM: 609909

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
SCV000034862OMIMno assertion criteria providedPathogenic
(Jan 1, 2011)
germlineliterature only

PubMed (3)
[See all records that cite these PMIDs]

SCV000761442Invitaecriteria provided, single submitter
(Dec 12, 2017)
germlineclinical testing

PubMed (7)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing



Human phospholamban null results in lethal dilated cardiomyopathy revealing a critical difference between mouse and human.

Haghighi K, Kolokathis F, Pater L, Lynch RA, Asahi M, Gramolini AO, Fan GC, Tsiapras D, Hahn HS, Adamopoulos S, Liggett SB, Dorn GW 2nd, MacLennan DH, Kremastinos DT, Kranias EG.

J Clin Invest. 2003 Mar;111(6):869-76.

PubMed [citation]

Genetic screening of calcium regulation genes in familial hypertrophic cardiomyopathy.

Chiu C, Tebo M, Ingles J, Yeates L, Arthur JW, Lind JM, Semsarian C.

J Mol Cell Cardiol. 2007 Sep;43(3):337-43. Epub 2007 Jun 30.

PubMed [citation]
See all PubMed Citations (7)

Details of each submission

From OMIM, SCV000034862.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (3)


In 2 unrelated families with idiopathic dilated cardiomyopathy (609909), Haghighi et al. (2003) identified a 116T-G transversion in the PLN gene, resulting in a leu39-to-ter (L39X) substitution that truncated the 52-amino acid protein in the highly conserved transmembrane domain II. The 2 homozygous individuals developed dilated cardiomyopathy and heart failure requiring cardiac transplantation at ages 16 and 27 years, respectively; 11 heterozygous individuals exhibited variable clinical findings indicating incomplete penetrance of the cardiomyopathy phenotype: 2 had dilated cardiomyopathy with ejection fractions of 25% or less, 4 had left ventricular hypertrophy with normal left ventricular systolic function, and 5 had normal echocardiograms.

In a 65-year-old Australian woman who was diagnosed with familial hypertrophic cardiomyopathy (CMH18; 613874) at age 61 years, Chiu et al. (2007) identified heterozygosity for the L39X mutation in the PLN gene. Echocardiography revealed asymmetric septal hypertrophy with a maximum wall thickness of 20 mm, normal systolic contractile function, and no evidence of left ventricular dilation. Her mother had also been diagnosed with CMH and had died at age 80 of noncardiac causes.

In a 58-year-old man with CMH18, Landstrom et al. (2011) identified heterozygosity for the L39X mutation in the PLN gene. The mutation segregated with disease in the family and was not found in 300 controls.

OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV000761442.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (7)


This sequence change creates  a premature translational stop signal in the only exon of the PLN mRNA (p.Leu39*).  While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 14 amino acids of the PLN protein. This variant is present in population databases (rs111033560, ExAC 0.001%). This variant has been shown to segregate with disease in families affected with  dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM) (PMID: 27532257, 12639993, 26535225, 25611685, 17655857, 21167350 ) and has been reported in homozygous relatives with DCM and heart failure, requiring cardiac transplantation (PMID: 12639993).   ClinVar contains an entry for this variant (Variation ID: 13637). Experimental studies have shown that this variant results in the production of a truncated protein affecting protein activity and localization (PMID: 12639993). For these reasons, this variant has been classified as Pathogenic.

OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jul 21, 2018