rs794729137
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Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_001005242.3(PKP2):c.1511delG(p.Gly504fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,613,750 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )
Consequence
PKP2
NM_001005242.3 frameshift
NM_001005242.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.16
Genes affected
PKP2 (HGNC:9024): (plakophilin 2) This gene encodes a member of the arm-repeat (armadillo) and plakophilin gene families. Plakophilin proteins contain numerous armadillo repeats, localize to cell desmosomes and nuclei, and participate in linking cadherins to intermediate filaments in the cytoskeleton. This gene may regulate the signaling activity of beta-catenin and is required to maintain transcription of genes that control intracellular calcium cycling including ryanodine receptor 2, ankyrin-B, triadin, and calcium channel, voltage-dependent, L type, alpha 1C. Mutations in this gene are associated with different inherited cardiac conditions including Arrythmogenic Cardiomyopathy, Brugada Syndrome, and Idiopathic Ventricular Fibrillation. A processed pseudogene with high similarity to this gene has been mapped to chromosome 12p13. [provided by RefSeq, May 2022]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
Variant 12-32841072-AC-A is Pathogenic according to our data. Variant chr12-32841072-AC-A is described in ClinVar as [Pathogenic]. Clinvar id is 202035.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-32841072-AC-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Ensembl
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GnomAD3 genomes 0.0000263 AC: 4AN: 152074Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461676Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 727148
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GnomAD4 genome 0.0000263 AC: 4AN: 152074Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74284
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:13
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Arrhythmogenic right ventricular dysplasia 9 Pathogenic:6
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 05, 2019 | The PKP2 c.1643delG; p.Gly548fs variant (rs794729137), also published as 1642delG, is reported in the literature in multiple individuals affected with arrhythmogenic right ventricular cardiomyopathy (ARVC) (Alcalde 2014, Dalal 2006, den Haan 2009, Gerull 2004). This variant occurred in all affected members of a kindred with ARVC, though it was also found in several asymptomatic individuals, suggesting incomplete penetrance (Dalal 2006). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Alcalde M et al. Stop-gain mutations in PKP2 are associated with a later age of onset of arrhythmogenic right ventricular cardiomyopathy. PLoS One. 2014 Jun 26;9(6):e100560. Dalal D et al. Penetrance of mutations in plakophilin-2 among families with arrhythmogenic right ventricular dysplasia/cardiomyopathy. J Am Coll Cardiol. 2006 Oct 3;48(7):1416-24. den Haan AD et al. Comprehensive desmosome mutation analysis in north americans with arrhythmogenic right ventricular dysplasia/cardiomyopathy. Circ Cardiovasc Genet. 2009 Oct;2(5):428-35. Gerull B et al. Mutations in the desmosomal protein plakophilin-2 are common in arrhythmogenic right ventricular cardiomyopathy. Nat Genet. 2004 Nov;36(11):1162-4. - |
| Pathogenic, criteria provided, single submitter | clinical testing | North West Genomic Laboratory Hub, Manchester University NHS Foundation Trust | Nov 22, 2023 | PS4_Str PVS1_VStr - |
| Pathogenic, criteria provided, single submitter | clinical testing | Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine | Oct 08, 2018 | The c.1643delG (p.Gly548Valfs*15) frameshift variant in the PKP2 gene is predicted to introduce a premature translation termination codon. It has been reported in multiple unrelated patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) [PMID 15489853, 17010805, 19358943, 20152563, 20400443, 21723241, 23810883, 24967631].Therefore, this c.1643delG (p.Gly548Valfs*15) variant in the PKP2 gene is classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | Oct 06, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Oct 10, 2024 | Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with arrhythmogenic right ventricular dysplasia 9 (ARVD9; MIM#609040). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID: 17010805, 23183494). (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 17010805, 23183494). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v4) <0.001 for a dominant condition (8 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported as pathogenic by many clinical laboratories and identified in individuals with ARVD (ClinVar; PMID: 36008935). (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 11, 2023 | This sequence change creates a premature translational stop signal (p.Gly548Valfs*15) in the PKP2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PKP2 are known to be pathogenic (PMID: 15489853, 23911551). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with arrythmogenic right ventricular cardiomyopathy (PMID: 15489853, 17010805, 20031617, 20400443, 24070718, 24704780, 24967631). This variant is also known as c.1642delG. ClinVar contains an entry for this variant (Variation ID: 202035). For these reasons, this variant has been classified as Pathogenic. - |
Arrhythmogenic right ventricular cardiomyopathy Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jul 05, 2018 | The p.Gly548ValfsX15 variant in PKP2 has been reported in at least 7 individuals with either possible or definitive diagnosis of ARVC and segregated with diseas e in 1 affected relative (Gerull 2004, Dalal 2006, Perrin 2013, Fressart 2010, D alal 2006, LMM data). This variant is absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein?s amino ac id sequence beginning at position 548 and leads to a premature termination codon 15 amino acids downstream. This alteration is then predicted to lead to a trunc ated or absent protein. Heterozygous loss of function of the PKP2 gene is an est ablished disease mechanism in ARVC. In summary, this variant is pathogenic in an autosomal dominant manner. ACMG/AMP Criteria applied: PVS1, PS4_Moderate, PM2. - |
| Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Aug 07, 2024 | The c.1643del (p.Gly548Valfs*15) variant in the PKP2 gene is located on the exon 7 and is predicted to cause reading frame shift that introduces a premature translation termination codon (p.Gly548Valfs*15), resulting in an absent or disrupted protein product. The variant has been reported in multiple individuals with arrhythmogenic right ventricular dysplasia/cardiomyopathy (PMID: 32102357, 34134068, 35712781, 33652588, 20031617, 24967631, 29606362). Loss-of-function variants in PKP2 are known to be pathogenic and frameshift/truncating variants located upstream and downstream to this position have been reported in individuals with arrhythmogenic right ventricular dysplasia/cardiomyopathy (PMID: 15489853, 24704780). The variant is reported in ClinVar as pathogenic (ID: 202035). The variant is absent in the general population database (gnomAD). Therefore, the c.1643del (p.Gly548Valfs*15) variant of PKP2 has been classified as pathogenic. - |
not provided Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 01, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 15489853, 20857253, 28097316, 20400443, 23810883, 21723241, 20031617, 19358943, 20152563, 24070718, 17010805, 26850880, 29606362, 24704780, 24967631, 30790397, 32155531, 30535908, 31702781, 30161220, 32102357, 31447099, 31402444, 32372669, 31386562, 29940860, 35819174, 34120153, 34134068, 23810894, 28588093) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Oct 08, 2020 | This variant is expected to result in the loss of a functional protein. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. (PMID: 17010805, 20031617, 20152563, 20400443, 24967631, 29940860, 30790397).This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study. - |
Cardiomyopathy Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 03, 2023 | This variant deletes 1 nucleotide in exon 7 of the PKP2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in over ten unrelated individuals affected with arrhythmogenic cardiomyopathy (15489853, 20152563, 20400443, 23810883, 24704780, 24967631, 28588093, 29940860, 30790397, 31702781). It has been shown that this variant segregates with disease in at least two of these families (PMID: 17010805, 24704780). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of PKP2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. - |
Cardiovascular phenotype Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 13, 2024 | The c.1643delG pathogenic mutation, located in coding exon 7 of the PKP2 gene, results from a deletion of one nucleotide at nucleotide position 1643, causing a translational frameshift with a predicted alternate stop codon (p.G548Vfs*15). This alteration has been described in multiple patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) (Gerull B et al. Nat Genet. 2004;36(11):1162-4; Xu T et al. J Am Coll Cardiol. 2010;55(6):587-97; Fressart V et al. Europace. 2010;12(6):861-8; te Riele AS et al. J Am Coll Cardiol. 2013;62(19):1761-9; Perrin MJ et al. J Am Coll Cardiol. 2013;62(19):1772-9; Alcalde M et al. PLoS ONE. 2014;9(6):e100560). In one study, this alteration was described to co-segregate with ARVC in two siblings; however, additional relatives with this alteration in the same family exhibited either absent or limited clinical phenotype suggesting reduced penetrance (Dalal D et al. J Am Coll Cardiol. 2006;48(7):1416-24). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
Familial isolated arrhythmogenic right ventricular dysplasia Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 08, 2020 | Variant summary: PKP2 c.1643delG (p.Gly548ValfsX15) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 251310 control chromosomes (gnomAD). c.1643delG has been reported in the literature in multiple individuals affected with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (example: Hermida_2019, Hoorntje_2018, Segura-Rodriguez_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Computational scores
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