ClinVar Miner

Submissions for variant NM_001005242.3(PKP2):c.2065_2070delinsG (p.His689fs) (rs397517021)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000211842 SCV000061871 pathogenic Arrhythmogenic right ventricular cardiomyopathy 2015-05-26 criteria provided, single submitter clinical testing 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chromosomes (Syrris 2006, Dalal 2006, Watkins 2009, Xu 2010, Tan 2010, Fressart 2010, Rajkumar 2012, Baskin 2013, LMM unpublished data - please note that several studies refer to this variant as p.A la733fs).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addition, this variant was observed to segregate with disease in 6 affected relatives from 3 families (Syrris 2006, LMM unpublished data).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,; 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. based upon segregation studies and the pr edicted impact of the variant.
GeneDx RCV000183813 SCV000236295 pathogenic not provided 2017-06-01 criteria provided, single submitter clinical testing The c.2197_2202delCACACCinsG pathogenic variant in the PKP2 gene has been reported multiple individuals in association with ARVC (Syrris et al., 2006; Dalal et al., 2006; den Haan et al., 2009; Fressart et al., 2010; Tan et al., 2010; Xu et al., 2010; Rajkumar et al., 2012; Baskin et al., 2013; Phillips et al., 2014; Groeneweg et al., 2015). Additionally, this variant has been shown to segregate with ARVC in six relatives from two different families (Syrris et al., 2006). It has also been observed in multiple individuals referred for cardiomyopathy genetic testing at GeneDx, and is classified in ClinVar as a pathogenic variant in association with ARVC by three different clinical laboratories (SCV000061871.4; SCV000220023.2; SCV000320553.1; Landrum et al., 2016). This pathogenic variant causes a shift in reading frame starting at codon Histidine 733, changing it to an Alanine, and creating a premature stop codon at position 8 of the new reading frame, denoted p.His733AlafsX8. This variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Other downstream frameshift variants in the PKP2 gene have been reported in the Human Gene Mutation Database in association with ARVC (Stenson et al., 2014). Furthermore, the c.2197_2202delCACACCinsG variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, nor was it observed in the Exome Aggregation Consortium (ExAC), indicating it is not a common benign variant in these populations.In summary, c.2197_2202delCACACCinsG in the PKP2 gene is interpreted as a pathogenic variant.
Ambry Genetics RCV000247451 SCV000320553 pathogenic Cardiovascular phenotype 2018-07-24 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Invitae RCV000539343 SCV000638886 pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 9 2020-01-07 criteria provided, single submitter clinical testing This sequence change deletes 6 nucleotides and inserts 1 nucleotide in exon 11 of the PKP2 mRNA (c.2197_2202delinsG), causing a frameshift at codon 733. This creates a premature translational stop signal (p.His733Alafs*8) and is expected to result in an absent or disrupted protein product. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been reported in the literature in several individuals affected with arrhythmogenic right ventricular cardiomyopathy (ARVD) and has been shown to segregate with disease in several families (PMID: 16415378, 24585727, 23810883, 23307527, 20031617, 20400443, 27532257, 30161220). This variant is also known as A733fsX740 in the literature. ClinVar contains an entry for this variant (Variation ID: 45063). Loss-of-function variants in PKP2 are known to be pathogenic (PMID:23911551, 15489853). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000587629 SCV000698469 pathogenic Arrhythmogenic right ventricular dysplasia/cardiomyopathy 2016-09-14 criteria provided, single submitter clinical testing 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.
Fulgent Genetics,Fulgent Genetics RCV000539343 SCV000893977 pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 9 2018-10-31 criteria provided, single submitter clinical testing
Blueprint Genetics RCV000183813 SCV000927571 pathogenic not provided 2018-03-06 criteria provided, single submitter clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000539343 SCV001190501 pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 9 2019-12-13 criteria provided, single submitter research
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV001171157 SCV001333841 pathogenic Cardiomyopathy 2017-12-11 criteria provided, single submitter clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000183813 SCV000280411 pathogenic not provided 2011-07-01 no assertion criteria provided clinical testing 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.
GenomeConnect, ClinGen RCV000183813 SCV001423450 not provided not provided no assertion provided phenotyping only 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.

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