rs397517021
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001005242.3(PKP2):c.2065_2070delinsG(p.His689AlafsTer8) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. HTR689A?) has been classified as Pathogenic. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Consequence
PKP2
NM_001005242.3 frameshift
NM_001005242.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.97
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 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 12-32802500-GGTGTG-C is Pathogenic according to our data. Variant chr12-32802500-GGTGTG-C is described in ClinVar as [Pathogenic]. Clinvar id is 45063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| PKP2 | NM_001005242.3 | c.2065_2070delinsG | p.His689AlafsTer8 | frameshift_variant | 10/13 | ENST00000340811.9 | NP_001005242.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| PKP2 | ENST00000340811.9 | c.2065_2070delinsG | p.His689AlafsTer8 | frameshift_variant | 10/13 | 1 | NM_001005242.3 | ENSP00000342800 | P1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:18Other:1
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 | Genetics and Molecular Pathology, SA Pathology | Jun 01, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Jan 25, 2023 | PVS1, PS4_Supporting, PM2 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Jul 17, 2023 | Based on the classification scheme VCGS_Germline_v1.3.4, 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 ARVC (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, PMID: 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 <0.001 for a dominant condition (v2 & v3: 7 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Other variants predicted to cause NMD have been reported as pathogenic in individuals with arrhythmogenic right ventricular cardiomyopathy (ARVC) (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple (>20) unrelated individuals with ARVC. (ClinVar, VCGS, PMID: 16415378, PMID: 28588093). (SP) 0902 - This variant has moderate evidence for segregation with disease. This variant has been shown to segregate with disease in two unrelated families with ARVC (PMID: 16415378). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Feb 15, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | North West Genomic Laboratory Hub, Manchester University NHS Foundation Trust | Jul 18, 2024 | PM2 PP1_Mod PS4_Str PVS1_Str - |
| Pathogenic, criteria provided, single submitter | research | HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology | Dec 13, 2019 | - - |
not provided Pathogenic:5Other:1
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | Mar 01, 2024 | - - |
| not provided, no classification provided | phenotyping only | GenomeConnect, ClinGen | - | Variant interpretted as Pathogenic and reported on 01-06-2017 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 01, 2024 | Reported in multiple individuals in association with ARVC and in individuals referred for ARVC testing at GeneDx (PMID: 25820315, 16415378, 16549640, 20400443, 20857253, 20152563, 22458570, 23812740, 27532257, 30820396); 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: 24585727, 34120153, 33743362, 19880068, 16415378, 20152563, 21606390, 22458570, 23810883, 23812740, 23810894, 16549640, 20857253, 20031617, 20400443, 26743238, 27532257, 28153106, 23671136, 23307527, 30820396, 30790397, 30731207, 30161220, 32372669, 31386562, 31402444, 34400560, 36396199, 36578016, 25820315) - |
| Pathogenic, no assertion criteria provided | clinical testing | Stanford Center for Inherited Cardiovascular Disease, Stanford University | Jul 01, 2011 | Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.His733AlafsX8 (H733AfsX8; c.2197_2202delCACACCinsG) in the PKP2 gene This variant has been reported multiple times in patients with ARVC (Syrris P et al., 2006; Fressart V et al., 2010; den Haan A et al., 2009; Dalal D et al., 2006). Syrris et al. observed it in 3 families with ARVC. It has also been observed in multiple other unrelated individuals tested for ARVC at GeneDx. This variant is in exon 11. It creates a frameshift beginning with codon Histidine 733, changing this to an Alanine and creating a premature Stop codon at position 8 of the new reading frame. It is expected to result in an abnormal, truncated protein or in the absence of protein from this allele due to mRNA decay. Other frameshift mutations in the PKP2 gene have been reported in HGMD in association with ARVC. The variant has not been seen ~6600 individuals from published controls and publicly available population datasets. Syrris et al. did not detect it in 100 ethnically-matched controls. It is absent from the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~4300 Caucasian and ~2200 African American individuals. The phenotype of those individuals is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Mar 06, 2018 | - - |
Arrhythmogenic right ventricular cardiomyopathy Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | May 26, 2015 | The p.His733fs variant in PKP2 has been identified in >20 individuals with ARVC and was absent from at least 1600 control chromosomes (Syrris 2006, Dalal 2006, Watkins 2009, Xu 2010, Tan 2010, Fressart 2010, Rajkumar 2012, Baskin 2013, LMM unpublished data - please note that several studies refer to this variant as p.A la733fs). In addition, this variant was observed to segregate with disease in 6 affected relatives from 3 families (Syrris 2006, LMM unpublished data). This var iant is predicted to cause a frameshift, which alters the protein's amino acid s equence beginning at codon 733 and leads to a premature stop codon 8 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Frameshift and other truncating variants in PKP2 are well-reported in i ndividuals with ARVC (ARVD/C Genetic Variant Database, http://arvcdatabase.info; Human Gene Mutation Database). In summary, this variant meets our criteria to b e classified as pathogenic for ARVC in an autosomal dominant manner (http://www. partners.org/personalizedmedicine/LMM) based upon segregation studies and the pr edicted impact of the variant. - |
| Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Aug 28, 2023 | This variant deletes 5 nucleotides and inserts one nucleotide in exon 11 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 20 unrelated individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 16415378, 16549640, 19880068, 20400443, 20152563, 20857253, 22458570, 23812740, 27532257, 34469894, 16415378, 34469894). It has been shown that this variant segregates with disease in multiple affected individuals across multiple families (PMID: 16415378, 34469894). 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. - |
Cardiomyopathy Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Nov 17, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 03, 2023 | This variant deletes 5 nucleotides and inserts one nucleotide in exon 11 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 20 unrelated individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 16415378, 16549640, 19880068, 20400443, 20152563, 20857253, 22458570, 23812740, 27532257, 34469894, 16415378, 34469894). It has been shown that this variant segregates with disease in multiple affected individuals across multiple families (PMID: 16415378, 34469894). 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. - |
PKP2-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 05, 2024 | The PKP2 c.2197_2202delinsG variant is predicted to result in a frameshift and premature protein termination (p.His733Alafs*8). This variant has been reported in numerous individuals with arrhythmogenic right ventricular dysplasia (ARVC/D) (see, for example, Syrris et al. 2006. PubMed ID: 16415378; Table S2, Philips et al. 2014. PubMed ID: 24585727; Table S1A, Walsh et al. 2016. PubMed ID: 27532257) and was shown to segregate with ARVC in two families (Syrris et al. 2006. PubMed ID: 16415378). It has also been reported in asymptomatic ARVC carriers, which can be attributed to the known reduced penetrance and variable expressivity in PKP2 pathogenic variants (Perrin et al. 2013. PubMed ID: 23810883). In gnomAD, the c.2197_2202delinsG variant appears as two separate allele calls (12-32955433-GGGTGT-G; 12-32955439-G-C), but review of underlying data shows the variants are present occur in cis (on the same allele) in 5 heterozygous individuals. Frameshift variants in PKP2 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Cardiovascular phenotype Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 25, 2021 | The c.2197_2202delCACACCinsG pathogenic mutation, located in coding exon 11 of the PKP2 gene, results from the deletion of 6 nucleotides and insertion of one nucleotide causing a translational frameshift with a predicted alternate stop codon (p.H733Afs*8). This mutation has been described in many patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) (Dalal D et al. Circulation. 2006;113(13):1641-9; Fressart V et al. Europace. 2010;12(6):861-8; Xu T et al. J Am Coll Cardiol. 2010;55(6):587-97; Rajkumar R et al. BMC Med Genet. 2012;13:21; Svensson A et al. Cardiology. 2021 Sep [Online ahead of print]). This mutation has shown co-segregation with ARVC in multiple relatives in a family (Syrris P et al. Circulation. 2006;113(3):356-64). In another family, this mutation was reportedly detected in trans with a likely pathogenic variant in PKP2 in two siblings with severe early onset ARVC (Watkins DA et al. Heart Rhythm. 2009;6(11 suppl):S10-7). 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 14, 2016 | Variant summary: The PKP2 c.2197_2202delinsG (p.His733Alafs) variant results in a premature termination codon, predicted to cause a truncated or absent PKP2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations located downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Ser837fs). Mutation taster predicts a damaging outcome for this variant. This variant was absent in 121800 control chromosomes while it was reported in several ARVD patients, and segregated with disease in at least one family, indicating causality. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant was classified as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at