rs111033560
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_StrongPP5_Very_Strong
The NM_002667.5(PLN):โc.116T>Gโ(p.Leu39Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000192 in 1,610,992 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (โ โ ).
Frequency
Genomes: ๐ 0.0000066 ( 0 hom., cov: 32)
Exomes ๐: 0.000021 ( 0 hom. )
Consequence
PLN
NM_002667.5 stop_gained
NM_002667.5 stop_gained
Scores
3
3
1
Clinical Significance
Conservation
PhyloP100: 6.64
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 4 pathogenic variants in the truncated region.
PP5
?
Variant 6-118559037-T-G is Pathogenic according to our data. Variant chr6-118559037-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 13637.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-118559037-T-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PLN | NM_002667.5 | c.116T>G | p.Leu39Ter | stop_gained | 2/2 | ENST00000357525.6 | |
CEP85L | NM_001042475.3 | c.1020+6492A>C | intron_variant | ENST00000368491.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PLN | ENST00000357525.6 | c.116T>G | p.Leu39Ter | stop_gained | 2/2 | 1 | NM_002667.5 | P1 | |
CEP85L | ENST00000368491.8 | c.1020+6492A>C | intron_variant | 1 | NM_001042475.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152226Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251234Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135768
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:19
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:5
Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 18, 2022 | Reported in association with DCM and HCM (Haghighi et al., 2003; Chiu et al., 2007; Landstrom et al., 2011; Medeiros et al., 2011; Sanoudou et al., 2015; Walsh et al., 2017); Not observed at significant frequency in large population cohorts (gnomAD); Functional studies show significantly reduced expression of the p.(L39*) protein (Haghighi et al., 2003; Kelly et al., 2008); Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 14 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 26917049, 17010801, 31402444, 23861362, 26535225, 16829191, 16432188, 22427649, 23139254, 23989713, 21332051, 18287099, 12724757, 25928149, 17655857, 25611685, 28102477, 27532257, 21167350, 12639993, 16235537, 30259183, 28986455, 28600387, 28449774, 28790153, 34426522, 31589614, 22137083) - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Dec 02, 2021 | - - |
Dilated cardiomyopathy 1P Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | This sequence change creates a premature translational stop signal (p.Leu39*) in the PLN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 14 amino acid(s) of the PLN protein. This variant is present in population databases (rs111033560, gnomAD 0.004%). This premature translational stop signal has been observed in individuals with dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM) (PMID: 12639993, 17655857, 21167350, 25611685, 26535225, 27532257). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13637). 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 premature translational stop signal affects PLN function (PMID: 12639993). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2011 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Sep 09, 2022 | PVS1, PM2, PP5 - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 30, 2019 | This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Hypertrophic cardiomyopathy 18 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU Mรผnchen | May 25, 2022 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2011 | - - |
Intrinsic cardiomyopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Sep 06, 2023 | The PLN c.116T>G (p.Leu39Ter) nonsense variant occurs in the only coding exon of the gene and may escape nonsense-mediated decay. Across a selection of available literature, this variant has been identified in a heterozygous state in eight unrelated individuals with cardiac phenotypes (hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), left ventricular hypertrophy (LVH), and cardiac arrest) and in a homozygous state in two individuals with severe DCM, LVH and heart failure requiring cardiac transplantation. This variant has been shown to segregate with disease in multiple families, with reduced penetrance (PMID: 12639993; 17655857; 21167350; 22137083; 25611685; 28600387; 28986455). Functional studies conducted in human cell lines demonstrated that this variant resulted in mislocalization of the protein, and examination of heart tissue from a homozygous patient showed reduced mRNA expression and no detectable protein product (PMID: 12639993). This variant is not observed at a significant frequency in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. This variant has been classified as pathogenic by at least three submitters in ClinVar. Based on the available evidence, the c.116T>G (p.Leu39Ter) variant is classified as pathogenic for intrinsic cardiomyopathy. - |
Cardiac arrest Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | Blueprint Genetics | Oct 14, 2014 | - - |
Cardiomyopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | May 02, 2023 | - - |
Dilated cardiomyopathy 1P;C3151265:Hypertrophic cardiomyopathy 18 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | New York Genome Center | Jun 19, 2020 | The c.116T>G (p.Leu39Ter) variant identified in the PLN gene is a nonsense variant predicted to lead to the premature termination of the protein at amino acid 39/53 (exon 2/2). This variant is absent from gnomAD(v3.0) suggesting it is not a common benign variant in the populations represented in that database. The c.116T>G (p.Leu39Ter) variant is reported as Likely Pathogenic/Pathogenic in ClinVar (VarID:13637), and functional studies suggest the p.Leu39Ter variant leads to significantly reduced or absent protein expression [PMID:12639993]. The p.Leu39Ter variant has been identified in many affected individuals with dilated cardiomyopathy, cardiac hypertrophy, and arrhythmias [PMID:12639993;PMID:17655857;PMID:26535225;PMID:28600387]. Given its deleterious nature, absence in population databases, functional studies suggesting altered protein expression, and observation in many affected individuals in the literature, the c.116T>G (p.Leu39Ter) variant identified in the PLN gene is reported as Pathogenic. - |
Primary dilated cardiomyopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Jun 24, 2013 | - - |
Hypertrophic cardiomyopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 11, 2015 | The p.Leu39X variant in PLN leads to a premature termination codon at position 3 9 which is predicted to lead to a truncated or absent protein. This variant has been identified in 1/66694 European chromosomes by the Exome Aggregation Consort ium (ExAC, http://exac.broadinstitute.org; dbSNP rs111033560). It has been repor ted in 4 families with cardiomyopathy (2 families with HCM and conduction system disease; 2 families with DCM and LVH) (Haghighi 2003, Chiu 2007, Landstrom 2011 ). In one family, 2 individuals with severe DCM were homozygous for the variant (Haghighi 2003), and heterozygous family members presented with a range of featu res including LVH, HCM +/- conduction system disease, or DCM. Across these 4 fam ilies, this variant segregated with disease in 8 affected relatives. The increas ed severity in homozygosity lends additional support for a pathogenic role. In s ummary, the p.Leu39X variant meets our criteria to be classified as pathogenic f or HCM in an autosomal dominant manner (http://www.partners.org/personalizedmedi cine/LMM) based upon segregation studies, virtual absence in the general populat ion and the predicted severe impact on the protein. - |
Sudden cardiac death Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | Blueprint Genetics | Oct 14, 2014 | - - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 09, 2024 | The p.L39* pathogenic mutation (also known as c.116T>G), located in coding exon 1 of the PLN gene, results from a T to G substitution at nucleotide position 116. This changes the amino acid from a leucine to a stop codon within coding exon 1. This alteration has been previously reported in association with dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM) and demonstrated segregation with disease in families with variable expression and reduced penetrance (Haghighi K et al. J Clin Invest. 2003 Mar;111(6):869-76; Chiu C et al. J Mol Cell Cardiol. 2007 Sep;43(3):337-43; Landstrom AP et al. Am Heart J. 2011 Jan;161(1):165-71). Two homozygous siblings with severe DCM requiring transplantation were reported, one of whom had only mild left ventricular hypertrophy that progressed to left ventricular dilation and cardiac failure; their heterozygous family members exhibited a range of clinical features from some with DCM, to those with left ventricular hypertrophy and normal ejection fractions, and others with no reported findings (Haghighi K et al. J Clin Invest. 2003 Mar;111(6):869-76). This alteration was reported in an individual with unexplained sudden cardiac arrest and no detectable cardiac findings; however, she remained under the age of 18 at time of follow-up (Mellor G et al. Circ Cardiovasc Genet, 2017 Jun;10). In addition, one study reported this alteration to result in reduction of detectable mRNA, no detectable protein product, and loss of normal protein-protein interaction in a sample from a homozygous individual with DCM (Haghighi K et al. J Clin Invest. 2003;111(6):869-76). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A;A;A;A;A;A
Vest4
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at