ClinVar Genomic variation as it relates to human health

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].

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)

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.

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.

PVS1, PM2, PP5

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.

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.

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.

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0104 - Dominant negative is a known mechanism of disease for missense variants in this gene, and is associated with dilated cardiomyopathy 1P (MIM#609909), and hypertrophic cardiomyopathy 18 (MIM#613874) (PMID: 16432188). The mechanism of truncating variants is unclear. (I) 0107 - This gene is associated with autosomal dominant disease. Rare reports of biallelic individuals has also been reported (OMIM). (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 22820313, PMID: 16432188). (I) 0205 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with less than 1/3 of the protein sequence affected. (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (4 heterozygotes, 0 homozygotes). (SP) 0600 - Variant is located within the annotated phospholamban domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as likely pathogenic and pathogenic, and observed in individuals with hypertrophic cardiomyopathy, dilated cardiomyopathy and cardiac arrest, with incomplete penetrance (ClinVar). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign