rs111033560

Positions:

• chr6-118559037-T-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Strong PP5_Very_Strong

The NM_002667.5(PLN):​c.116T>G​(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 (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: PLN NM_002667.5 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:19
• 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]

ACMG classification

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: 1 AN: 152226 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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251234 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135768

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: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000206 AC: 30 AN: 1458766 Hom.: 0 Cov.: 28 AF XY: 0.0000262 AC XY: 19 AN XY: 725946

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000252

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152226 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74376

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: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000558 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:19

Revision: criteria provided, multiple submitters, no conflicts

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 München	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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	36
DANN	Uncertain	0.97
Eigen	Pathogenic	0.75
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.93	D
MutationTaster	Benign	1.0	A;A;A;A;A;A
Vest4		0.79
GERP RS		5.6

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: rs111033560; hg19: chr6-118880200;